WorldWideScience

Sample records for ancestral susceptible genetic

  1. Ancestral susceptibility to colorectal cancer

    Czech Academy of Sciences Publication Activity Database

    Huhn, S.; Pardini, Barbara; Naccarati, Alessio; Vodička, Pavel (ed.); Hemminki, K.; Försti, A.

    2012-01-01

    Roč. 27, č. 2 (2012), s. 197-204. ISSN 0267-8357 R&D Projects: GA ČR GA310/07/1430; GA ČR GAP304/10/1286 Grant ostatní: EU FP7(XE) HEALTH-F4-2007-200767 Institutional research plan: CEZ:AV0Z50390512 Keywords : cancer susceptibility * molecular epidemiology * genetic susceptibility Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.500, year: 2012

  2. The population structure of Acinetobacter baumannii: expanding multiresistant clones from an ancestral susceptible genetic pool.

    Directory of Open Access Journals (Sweden)

    Laure Diancourt

    Full Text Available Outbreaks of hospital infections caused by multidrug resistant Acinetobacter baumannii strains are of increasing concern worldwide. Although it has been reported that particular outbreak strains are geographically widespread, little is known about the diversity and phylogenetic relatedness of A. baumannii clonal groups. Sequencing of internal portions of seven housekeeping genes (total 2,976 nt was performed in 154 A. baumannii strains covering the breadth of known diversity and including representatives of previously recognized international clones, and in 19 representatives of other Acinetobacter species. Restricted amounts of diversity and a star-like phylogeny reveal that A. baumannii is a genetically compact species that suffered a severe bottleneck in the recent past, possibly linked to a restricted ecological niche. A. baumannii is neatly demarcated from its closest relative (genomic species 13TU and other Acinetobacter species. Multilocus sequence typing analysis demonstrated that the previously recognized international clones I to III correspond to three clonal complexes, each made of a central, predominant genotype and few single locus variants, a hallmark of recent clonal expansion. Whereas antimicrobial resistance was almost universal among isolates of these and a novel international clone (ST15, isolates of the other genotypes were mostly susceptible. This dichotomy indicates that antimicrobial resistance is a major selective advantage that drives the ongoing rapid clonal expansion of these highly problematic agents of nosocomial infections.

  3. The Population Structure of Acinetobacter baumannii: Expanding Multiresistant Clones from an Ancestral Susceptible Genetic Pool

    Science.gov (United States)

    Diancourt, Laure; Passet, Virginie; Nemec, Alexandr; Dijkshoorn, Lenie; Brisse, Sylvain

    2010-01-01

    Outbreaks of hospital infections caused by multidrug resistant Acinetobacter baumannii strains are of increasing concern worldwide. Although it has been reported that particular outbreak strains are geographically widespread, little is known about the diversity and phylogenetic relatedness of A. baumannii clonal groups. Sequencing of internal portions of seven housekeeping genes (total 2,976 nt) was performed in 154 A. baumannii strains covering the breadth of known diversity and including representatives of previously recognized international clones, and in 19 representatives of other Acinetobacter species. Restricted amounts of diversity and a star-like phylogeny reveal that A. baumannii is a genetically compact species that suffered a severe bottleneck in the recent past, possibly linked to a restricted ecological niche. A. baumannii is neatly demarcated from its closest relative (genomic species 13TU) and other Acinetobacter species. Multilocus sequence typing analysis demonstrated that the previously recognized international clones I to III correspond to three clonal complexes, each made of a central, predominant genotype and few single locus variants, a hallmark of recent clonal expansion. Whereas antimicrobial resistance was almost universal among isolates of these and a novel international clone (ST15), isolates of the other genotypes were mostly susceptible. This dichotomy indicates that antimicrobial resistance is a major selective advantage that drives the ongoing rapid clonal expansion of these highly problematic agents of nosocomial infections. PMID:20383326

  4. Ancestral Origins and Genetic History of Tibetan Highlanders.

    Science.gov (United States)

    Lu, Dongsheng; Lou, Haiyi; Yuan, Kai; Wang, Xiaoji; Wang, Yuchen; Zhang, Chao; Lu, Yan; Yang, Xiong; Deng, Lian; Zhou, Ying; Feng, Qidi; Hu, Ya; Ding, Qiliang; Yang, Yajun; Li, Shilin; Jin, Li; Guan, Yaqun; Su, Bing; Kang, Longli; Xu, Shuhua

    2016-09-01

    The origin of Tibetans remains one of the most contentious puzzles in history, anthropology, and genetics. Analyses of deeply sequenced (30×-60×) genomes of 38 Tibetan highlanders and 39 Han Chinese lowlanders, together with available data on archaic and modern humans, allow us to comprehensively characterize the ancestral makeup of Tibetans and uncover their origins. Non-modern human sequences compose ∼6% of the Tibetan gene pool and form unique haplotypes in some genomic regions, where Denisovan-like, Neanderthal-like, ancient-Siberian-like, and unknown ancestries are entangled and elevated. The shared ancestry of Tibetan-enriched sequences dates back to ∼62,000-38,000 years ago, predating the Last Glacial Maximum (LGM) and representing early colonization of the plateau. Nonetheless, most of the Tibetan gene pool is of modern human origin and diverged from that of Han Chinese ∼15,000 to ∼9,000 years ago, which can be largely attributed to post-LGM arrivals. Analysis of ∼200 contemporary populations showed that Tibetans share ancestry with populations from East Asia (∼82%), Central Asia and Siberia (∼11%), South Asia (∼6%), and western Eurasia and Oceania (∼1%). Our results support that Tibetans arose from a mixture of multiple ancestral gene pools but that their origins are much more complicated and ancient than previously suspected. We provide compelling evidence of the co-existence of Paleolithic and Neolithic ancestries in the Tibetan gene pool, indicating a genetic continuity between pre-historical highland-foragers and present-day Tibetans. In particular, highly differentiated sequences harbored in highlanders' genomes were most likely inherited from pre-LGM settlers of multiple ancestral origins (SUNDer) and maintained in high frequency by natural selection. PMID:27569548

  5. Ancestral genome inference using a genetic algorithm approach.

    Science.gov (United States)

    Gao, Nan; Yang, Ning; Tang, Jijun

    2013-01-01

    Recent advancement of technologies has now made it routine to obtain and compare gene orders within genomes. Rearrangements of gene orders by operations such as reversal and transposition are rare events that enable researchers to reconstruct deep evolutionary histories. An important application of genome rearrangement analysis is to infer gene orders of ancestral genomes, which is valuable for identifying patterns of evolution and for modeling the evolutionary processes. Among various available methods, parsimony-based methods (including GRAPPA and MGR) are the most widely used. Since the core algorithms of these methods are solvers for the so called median problem, providing efficient and accurate median solver has attracted lots of attention in this field. The "double-cut-and-join" (DCJ) model uses the single DCJ operation to account for all genome rearrangement events. Because mathematically it is much simpler than handling events directly, parsimony methods using DCJ median solvers has better speed and accuracy. However, the DCJ median problem is NP-hard and although several exact algorithms are available, they all have great difficulties when given genomes are distant. In this paper, we present a new algorithm that combines genetic algorithm (GA) with genomic sorting to produce a new method which can solve the DCJ median problem in limited time and space, especially in large and distant datasets. Our experimental results show that this new GA-based method can find optimal or near optimal results for problems ranging from easy to very difficult. Compared to existing parsimony methods which may severely underestimate the true number of evolutionary events, the sorting-based approach can infer ancestral genomes which are much closer to their true ancestors. The code is available at http://phylo.cse.sc.edu. PMID:23658708

  6. Genetic susceptibility to Candida infections

    NARCIS (Netherlands)

    Smeekens, S.P.; Veerdonk, F.L. van de; Kullberg, B.J.; Netea, M.G.

    2013-01-01

    Candida spp. are medically important fungi causing severe mucosal and life-threatening invasive infections, especially in immunocompromised hosts. However, not all individuals at risk develop Candida infections, and it is believed that genetic variation plays an important role in host susceptibility

  7. Genetic susceptibility to radiation

    Science.gov (United States)

    Hall, E. J.; Brenner, D. J.; Worgul, B.; Smilenov, L.

    In the context of space radiation, it is important to know whether the human population includes genetically predisposed radiosensitive subsets. One possibility is that haploinsufficiency for ATM confers radiosensitivity, and this defect involves 1 3% of the population. Using knock-out mice we chose to study cataractogenesis in the lens and oncogenic transformation in mouse embryo fibroblasts to assay for effects of ATM deficiency. Radiation induced cataracts appeared earlier in the heterozygous versus wild-type animals following exposure to either gamma rays or 1 GeV/nucleon iron ions. In addition, it was found that embryo fibroblasts of Atm heterozygotes showed an increased incidence of oncogenic transformation compared with their normal litter-matched counterparts. From these data we suggest that Ataxia Telangiectasia heterozygotes could indeed represent a societally significant radiosensitive subpopulation. Knock-out mice are now available for other genes including BRCA1 and 2, and Mrad9. An exciting possibility is the creation of double heterozygotes for pairs of mutated genes that function in the same signal transduction pathway, and consequently confer even greater radiosensitivity.

  8. Genetic susceptibility to Candida infections.

    Science.gov (United States)

    Smeekens, Sanne P; van de Veerdonk, Frank L; Kullberg, Bart Jan; Netea, Mihai G

    2013-06-01

    Candida spp. are medically important fungi causing severe mucosal and life-threatening invasive infections, especially in immunocompromised hosts. However, not all individuals at risk develop Candida infections, and it is believed that genetic variation plays an important role in host susceptibility. On the one hand, severe fungal infections are associated with monogenic primary immunodeficiencies such as defects in STAT1, STAT3 or CARD9, recently discovered as novel clinical entities. On the other hand, more common polymorphisms in genes of the immune system have also been associated with fungal infections such as recurrent vulvovaginal candidiasis and candidemia. The discovery of the genetic susceptibility to Candida infections can lead to a better understanding of the pathogenesis of the disease, as well as to the design of novel immunotherapeutic strategies. This review is part of the review series on host-pathogen interactions. See more reviews from this series. PMID:23629947

  9. Genetic susceptibility to Candida infections

    OpenAIRE

    Smeekens, S P; Veerdonk, F.L. van de; Kullberg, B J; Netea, M.G.

    2013-01-01

    Candida spp. are medically important fungi causing severe mucosal and life-threatening invasive infections, especially in immunocompromised hosts. However, not all individuals at risk develop Candida infections, and it is believed that genetic variation plays an important role in host susceptibility. On the one hand, severe fungal infections are associated with monogenic primary immunodeficiencies such as defects in STAT1, STAT3 or CARD9, recently discovered as novel clinical entities. On the...

  10. Neanderthal and Denisova genetic affinities with contemporary humans: introgression versus common ancestral polymorphisms.

    Science.gov (United States)

    Lowery, Robert K; Uribe, Gabriel; Jimenez, Eric B; Weiss, Mark A; Herrera, Kristian J; Regueiro, Maria; Herrera, Rene J

    2013-11-01

    Analyses of the genetic relationships among modern humans, Neanderthals and Denisovans have suggested that 1-4% of the non-Sub-Saharan African gene pool may be Neanderthal derived, while 6-8% of the Melanesian gene pool may be the product of admixture between the Denisovans and the direct ancestors of Melanesians. In the present study, we analyzed single nucleotide polymorphism (SNP) diversity among a worldwide collection of contemporary human populations with respect to the genetic constitution of these two archaic hominins and Pan troglodytes (chimpanzee). We partitioned SNPs into subsets, including those that are derived in both archaic lineages, those that are ancestral in both archaic lineages and those that are only derived in one archaic lineage. By doing this, we have conducted separate examinations of subsets of mutations with higher probabilities of divergent phylogenetic origins. While previous investigations have excluded SNPs from common ancestors in principal component analyses, we included common ancestral SNPs in our analyses to visualize the relative placement of the Neanderthal and Denisova among human populations. To assess the genetic similarities among the various hominin lineages, we performed genetic structure analyses to provide a comparison of genetic patterns found within contemporary human genomes that may have archaic or common ancestral roots. Our results indicate that 3.6% of the Neanderthal genome is shared with roughly 65.4% of the average European gene pool, which clinally diminishes with distance from Europe. Our results suggest that Neanderthal genetic associations with contemporary non-Sub-Saharan African populations, as well as the genetic affinities observed between Denisovans and Melanesians most likely result from the retention of ancient mutations in these populations. PMID:23872234

  11. Contributions of ancestral inter-species recombination to the genetic diversity of extant Streptomyces lineages.

    Science.gov (United States)

    Andam, Cheryl P; Choudoir, Mallory J; Vinh Nguyen, Anh; Sol Park, Han; Buckley, Daniel H

    2016-07-01

    Streptomyces species produce many important antibiotics and have a crucial role in soil nutrient cycling. However, their evolutionary history remains poorly characterized. We have evaluated the impact of homologous recombination on the evolution of Streptomyces using multi-locus sequence analysis of 234 strains that represent at least 11 species clusters. Evidence of inter-species recombination is widespread but not uniform within the genus and levels of mosaicism vary between species clusters. Most phylogenetically incongruent loci are monophyletic at the scale of species clusters and their subclades, suggesting that these recombination events occurred in shared ancestral lineages. Further investigation of two mosaic species clusters suggests that genes acquired by inter-species recombination may have become fixed in these lineages during periods of demographic expansion; implicating a role for phylogeography in determining contemporary patterns of genetic diversity. Only by examining the phylogeny at the scale of the genus is apparent that widespread phylogenetically incongruent loci in Streptomyces are derived from a far smaller number of ancestral inter-species recombination events. PMID:26849310

  12. Localization of Type 1 Diabetes susceptibility in the ancestral haplotype 18.2 by high density SNP mapping.

    Science.gov (United States)

    Santiago, Jose Luis; Li, Wentian; Lee, Annette; Martinez, Alfonso; Chandrasekaran, Alamelu; Fernandez-Arquero, Miguel; Khalili, Houman; de la Concha, Emilio G; Urcelay, Elena; Gregersen, Peter K

    2009-10-01

    Previous studies have suggested that the ancestral haplotype 18.2 (AH18.2) carries additional susceptibility gene to Type 1 Diabetes (T1D) on the Major Histocompatibility Complex (MHC). We analyzed 10 DR3/TNFa1b5 homozygous subjects in order to establish the conservation of the AH18.2 and then compared this conserved region with other DR3 haplotype, the AH8.1. The Illumina's HumanHap550 Bead chip was used to perform an extensive genotyping of the MHC region. The AH18.2 was highly conserved between DDR1 and HLA-DQA1 genes; therefore most probably the second susceptibility gene is located within this region. We can exclude the region centromeric to HLA-DRA gene and telomeric to DDR1 gene. A comparison between the AH18.2 and AH8.1 haplotypes showed that 233 SNPs were different in the aforementioned conserved region. These data suggest that the 1.65 Mb MHC region between DDR1 and HLA-DRA genes is likely to carry additional susceptibility alleles for T1D on the AH18.2 haplotype. PMID:19591919

  13. Genetic susceptibility to breast and endometrial cancer

    OpenAIRE

    Wedrén, Sara

    2004-01-01

    Hormones are central in the carcinogenic process in the breast and in the uterine epithelium. Individual genetically determined variation in the response to hormonal influence may alter susceptibility to breast and endometrial cancers. Many small studies of this hypothesis have generated inconclusive results. Since the effect of any genetic variant is expected to be modest, large studies are needed to draw reliable conclusions. Also, there may be interaction between genetic ...

  14. Update in genetic susceptibility in melanoma.

    Science.gov (United States)

    Potrony, Miriam; Badenas, Celia; Aguilera, Paula; Puig-Butille, Joan Anton; Carrera, Cristina; Malvehy, Josep; Puig, Susana

    2015-09-01

    Melanoma is the most deadly of the common skin cancers and its incidence is rapidly increasing. Approximately 10% of cases occur in a familial context. To date, cyclin-dependent kinase inhibitor 2A (CDKN2A), which was identified as the first melanoma susceptibility gene more than 20 years ago, is the main high-risk gene for melanoma. A few years later cyclin-dependent kinase 4 (CDK4) was also identified as a melanoma susceptibility gene. The technologic advances have allowed the identification of new genes involved in melanoma susceptibility: Breast cancer 1 (BRCA1) associated protein 1 (BAP1), CXC genes, telomerase reverse transcriptase (TERT), protection of telomeres 1 (POT1), ACD and TERF2IP, the latter four being involved in telomere maintenance. Furthermore variants in melanocortin 1 receptor (MC1R) and microphthalmia-associated transcription factor (MITF) give a moderately increased risk to develop melanoma. Melanoma genetic counseling is offered to families in order to better understand the disease and the genetic susceptibility of developing it. Genetic counseling often implies genetic testing, although patients can benefit from genetic counseling even when they do not fulfill the criteria for these tests. Genetic testing for melanoma predisposition mutations can be used in clinical practice under adequate selection criteria and giving a valid test interpretation and genetic counseling to the individual. PMID:26488006

  15. Genetic susceptibility to environmental toxicants

    DEFF Research Database (Denmark)

    2001-01-01

    The toxicological challenges to the chemical industry have in recent years been greatly affected by the rapid innovation and development of analytical, molecular and genetic technologies. ECETOC recognises the importance of developing the technical and intellectual skill bases in academia and ind...

  16. Genetic susceptibility variants in parkinsonism.

    Science.gov (United States)

    Soto-Ortolaza, Alexandra I; Ross, Owen A

    2016-01-01

    Parkinsonism is an umbrella term for a group of disorders characterized by the clinical signs of tremor, bradykinesia, rigidity, and postural instability. On neuropathologic examination parkinsonism can display alternate protein pathologies (e.g. α-synucleinopathy or tauopathy) but the degeneration of nigral neurons is consistent. The main forms of parkinsonism are, Parkinson's disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). Genetic studies from candidate gene, to unbiased genome-wide approaches including association and next-generation sequencing have nominated a number of disease determinants. Within this review we will highlight the genetic loci that are associated with disease and discuss the implications and importance for a better understanding of the genes involved and thus the underlying pathophysiology of these disorders. PMID:26414118

  17. Shared ancestral susceptibility to colorectal cancer and other nutrition related diseases

    Czech Academy of Sciences Publication Activity Database

    Huhn, S.; Bevier, M.; Rudolph, A.; Pardini, Barbara; Naccarati, Alessio; Hein, R.; Hoffmeister, M.; Vodičková, Ludmila; Novotný, J.; Brenner, H.; Chang-Claude, J.; Vodička, Pavel; Hemminki, K.; Försti, A.

    2012-01-01

    Roč. 13, č. 1 (2012), s. 94. ISSN 1471-2350 R&D Projects: GA ČR GAP304/10/1286; GA ČR GAP304/12/1585 Institutional research plan: CEZ:AV0Z50390512 Institutional support: RVO:68378041 Keywords : colorectal cancer * nutrition * complex diseases Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.536, year: 2012

  18. Genetic polymorphisms and susceptibility to lung disease

    Directory of Open Access Journals (Sweden)

    Crain Karen

    2006-04-01

    Full Text Available Abstract Susceptibility to infection by bacterium such as Bacillus anthracis has a genetic basis in mice and may also have a genetic basis in humans. In the limited human cases of inhalation anthrax, studies suggest that not all individuals exposed to anthrax spores were infected, but rather, individuals with underlying lung disease, particularly asthma, sarcoidosis and tuberculosis, might be more susceptible. In this study, we determined if polymorphisms in genes important in innate immunity are associated with increased susceptibility to infectious and non-infectious lung diseases, particularly tuberculosis and sarcoidosis, respectively, and therefore might be a risk factor for inhalation anthrax. Examination of 45 non-synonymous polymorphisms in ten genes: p47phox (NCF1, p67phox (NCF2, p40phox (NCF4, p22phox (CYBA, gp91phox (CYBB, DUOX1, DUOX2, TLR2, TLR9 and alpha 1-antitrypsin (AAT in a cohort of 95 lung disease individuals and 95 control individuals did not show an association of these polymorphisms with increased susceptibility to lung disease.

  19. Population screening for genetic susceptibility to disease.

    OpenAIRE

    Clarke, A.

    1995-01-01

    Genetic screening for susceptibility to common diseases, such as the common cancers, cardiovascular disease, and diabetes, may soon be technically feasible. Commercial interests should not be allowed to introduce such screening before proper evaluation or without adequate counselling and support. The evaluation of such testing should include psychosocial and medical outcomes and outcomes for those given low risks as well as high risks. These tests may distract attention away from environmenta...

  20. Genetic susceptibility in ecosystems: the challenge for ecotoxicology.

    OpenAIRE

    Evenden, A J; Depledge, M H

    1997-01-01

    Environmental management is inevitably complicated by the large variation in susceptibility to chemical toxicity exhibited by the living components of ecosystems, a significant proportion of which is determined by genetic factors. This paper examines the concept of genetic susceptibility in ecosystems and suggests the existence of two distinct forms reflecting genetic changes at the level of the individual and at the level of population and community. The influence of genetic susceptibility o...

  1. A major genetic component of BSE susceptibility

    Directory of Open Access Journals (Sweden)

    Williams John L

    2006-10-01

    Full Text Available Abstract Background Coding variants of the prion protein gene (PRNP have been shown to be major determinants for the susceptibility to transmitted prion diseases in humans, mice and sheep. However, to date, the effects of polymorphisms in the coding and regulatory regions of bovine PRNP on bovine spongiform encephalopathy (BSE susceptibility have been considered marginal or non-existent. Here we analysed two insertion/deletion (indel polymorphisms in the regulatory region of bovine PRNP in BSE affected animals and controls of four independent cattle populations from UK and Germany. Results In the present report, we show that two previously reported 23- and 12-bp insertion/deletion (indel polymorphisms in the regulatory region of bovine PRNP are strongly associated with BSE incidence in cattle. Genotyping of BSE-affected and control animals of UK Holstein, German Holstein, German Brown and German Fleckvieh breeds revealed a significant overrepresentation of the deletion alleles at both polymorphic sites in diseased animals (P = 2.01 × 10-3 and P = 8.66 × 10-5, respectively. The main effect on susceptibility is associated with the 12-bp indel polymorphism. Compared with non-carriers, heterozygous and homozygous carriers of the 12-bp deletion allele possess relatively higher risks of having BSE, ranging from 1.32 to 4.01 and 1.74 to 3.65 in the different breeds. These values correspond to population attributable risks ranging from 35% to 53%. Conclusion Our results demonstrate a substantial genetic PRNP associated component for BSE susceptibility in cattle. Although the BSE risk conferred by the deletion allele of the 12-bp indel in the regulatory region of PRNP is substantial, the main risk factor for BSE in cattle is environmental, i.e. exposure to feedstuffs contaminated with the infectious agent.

  2. Genetic susceptibility, evolution and the kuru epidemic.

    Science.gov (United States)

    Mead, Simon; Whitfield, Jerome; Poulter, Mark; Shah, Paresh; Uphill, James; Beck, Jonathan; Campbell, Tracy; Al-Dujaily, Huda; Hummerich, Holger; Alpers, Michael P; Collinge, John

    2008-11-27

    The acquired prion disease kuru was restricted to the Fore and neighbouring linguistic groups of the Papua New Guinea highlands and largely affected children and adult women. Oral history documents the onset of the epidemic in the early twentieth century, followed by a peak in the mid-twentieth century and subsequently a well-documented decline in frequency. In the context of these strong associations (gender, region and time), we have considered the genetic factors associated with susceptibility and resistance to kuru. Heterozygosity at codon 129 of the human prion protein gene (PRNP) is known to confer relative resistance to both sporadic and acquired prion diseases. In kuru, heterozygosity is associated with older patients and longer incubation times. Elderly survivors of the kuru epidemic, who had multiple exposures at mortuary feasts, are predominantly PRNP codon 129 heterozygotes and this group show marked Hardy-Weinberg disequilibrium. The deviation from Hardy-Weinberg equilibrium is most marked in elderly women, but is also significant in a slightly younger cohort of men, consistent with their exposure to kuru as boys. Young Fore and the elderly from populations with no history of kuru show Hardy-Weinberg equilibrium. An increasing cline in 129V allele frequency centres on the kuru region, consistent with the effect of selection in elevating the frequency of resistant genotypes in the exposed population. The genetic data are thus strikingly correlated with exposure. Considering the strong coding sequence conservation of primate prion protein genes, the number of global coding polymorphisms in man is surprising. By intronic resequencing in a European population, we have shown that haplotype diversity at PRNP comprises two major and divergent clades associated with 129M and 129V. Kuru may have imposed the strongest episode of recent human balancing selection, which may not have been an isolated episode in human history. PMID:18849290

  3. Personalized Genetic Testing and Norovirus Susceptibility

    Directory of Open Access Journals (Sweden)

    Natalie Prystajecky

    2014-01-01

    Full Text Available BACKGROUND: The availability of direct-to-consumer personalized genetic testing has enabled the public to access and interpret their own genetic information. Various genetic traits can be determined including resistance to norovirus through a nonsense mutation (G428A in the FUT2 gene. Although this trait is believed to confer resistance to the most dominant norovirus genotype (GII.4, the spectrum of resistance to other norovirus strains is unknown. The present report describes a cluster of symptomatic norovirus GI.6 infection in a family identified to have norovirus resistance through personalized genetic testing.

  4. Update in genetic susceptibility in melanoma

    OpenAIRE

    Potrony, Miriam; Badenas, Celia; Aguilera, Paula; Puig-Butille, Joan Anton; Carrera, Cristina; Malvehy, Josep; Puig, Susana

    2015-01-01

    Melanoma is the most deadly of the common skin cancers and its incidence is rapidly increasing. Approximately 10% of cases occur in a familial context. To date, cyclin-dependent kinase inhibitor 2A (CDKN2A), which was identified as the first melanoma susceptibility gene more than 20 years ago, is the main high-risk gene for melanoma. A few years later cyclin-dependent kinase 4 (CDK4) was also identified as a melanoma susceptibility gene. The technologic advances have allowed the identificatio...

  5. Update on Genetic Susceptibility and Pathogenesis in Juvenile Idiopathic Arthritis

    Directory of Open Access Journals (Sweden)

    Morten Herlin

    2014-07-01

    Full Text Available Juvenile idiopathic arthritis (JIA is a multifactorial disease with a pathogenesis which remains inexplicable. However, genome-wide association studies brought forward within recent years have discovered several new susceptibility genes, and accumulating evidence supports genetic variability as playing a key role in JIA development. This review summarises the present knowledge of human leukocyte antigen (HLA and non-HLA polymorphisms conferring disease susceptibility, and discusses the areas in JIA genetics, which are still to be investigated in order to apply JIA genetics in a clinical setting.

  6. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci

    OpenAIRE

    Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

    2016-01-01

    Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wid...

  7. Immunogenetics and genetic susceptibility in the pathogenesis of autoimmune hepatitis

    Directory of Open Access Journals (Sweden)

    Das Anup K

    2014-11-01

    Full Text Available vAutoimmune hepatitis is a progressive liver disease. Its pathogenesis is unclear, but needs a ‘trigger’ to initiate the disease in a genetically susceptible person. The susceptibility is partly related to MHCII class genes, and more so with human leukocyte antigen (HLA. Several mechanisms have been proposed which, however, cannot fully explain the immunologic findings in autoimmune hepatitis. The susceptibility to any autoimmune disease is determined by several factors where genetic and immunological alterations, along with, environmental factor are active. MHCII antigens as a marker for AIH, or a predictor of treatment response and prognosis has been investigated. Since MHCII antigens show significant ethnic heterogeneity, mutations in MHCII may merely act as only precursors of the surface markers of immune cells, which can be of significance, because the changes in HLA and MHC are missing in certain populations. One such marker is the CTLA-4 (CD152 gene mutation, reported in the phenotypes representing susceptibility to AIH. Other candidate genes of cytokines, TNF, TGF-beta1 etc, have also been investigated but with unvalidated results. Paediatric AIH show differences in genetic susceptibility. Genetic susceptibility or resistance to AIH may be associated with polypeptides in DRB1 with certain amino-acid sequences. Understanding which genes are implicated in genesis and/or disease progression will obviously help to identify key pathways in AIH and provide better insights into its pathogenesis. But studies to identify responsible genes are complex because of the complex trait of AIH.

  8. Understanding Genetic and Environmental Risk Factors in Susceptible Persons

    OpenAIRE

    Williams, Roger R.

    1984-01-01

    Most major chronic diseases probably result from environmental factors accumulating over time in genetically susceptible persons. A detailed family history assessment can help identify the subset of the general population with a strong predisposition to certain major diseases. An understanding of the environmental factors promoting disease development will facilitate more effective prevention or delay disease in a targeted susceptible population. To effectively use this growing knowledge in g...

  9. Genetic susceptibility, evolution and the kuru epidemic

    OpenAIRE

    Mead, S.; Whitfield, J; Poulter, M.; Shah, P.; Uphill, J; Beck, J.; Campbell, T.; Al-Dujaily, H.; Hummerich, H.; Alpers, M. P.; Collinge, J

    2008-01-01

    The acquired prion disease kuru was restricted to the Fore and neighbouring linguistic groups of the Papua New Guinea highlands and largely affected children and adult women. Oral history documents the onset of the epidemic in the early twentieth century, followed by a peak in the mid-twentieth century and subsequently a well-documented decline in frequency. In the context of these strong associations (gender, region and time), we have considered the genetic factors associated with susceptibi...

  10. Genetic Susceptibility to Head and Neck Squamous Cell Carcinoma

    International Nuclear Information System (INIS)

    Head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and its incidence is growing. Although environmental carcinogens and carcinogenic viruses are the main etiologic factors, genetic predisposition obviously plays a risk-modulating role, given that not all individuals exposed to these carcinogens experience the disease. This review highlights some aspects of genetic susceptibility to HNSCC: among others, genetic polymorphisms in biotransformation enzymes, DNA repair pathway, apoptotic pathway, human papillomavirus-related pathways, mitochondrial polymorphisms, and polymorphism related to the bilirubin-metabolized pathway. Furthermore, epigenetic variations, familial forms of HNSCC, functional assays for HNSCC risk assessment, and the implications and perspectives of research on genetic susceptibility in HNSCC are discussed

  11. Genetic Susceptibility to Head and Neck Squamous Cell Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Lacko, Martin [Department of Otorhinolaryngology—Head and Neck Surgery, Maastricht University Medical Center, Maastricht (Netherlands); Braakhuis, Boudewijn J.M. [Department of Otolaryngology—Head and Neck Surgery, VU University Medical Center, Amsterdam (Netherlands); Sturgis, Erich M. [Department of Head and Neck Surgery and Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Boedeker, Carsten C. [Department of Otorhinolaryngology—Head and Neck Surgery, Albert-Ludwigs-University, Freiburg, Germany and Department of Otorhinolaryngology - Head and Neck Surgery, HELIOS Hanseklinikum Stralsund, Stralsund (Germany); Suárez, Carlos [Department of Otolaryngology, Hospital Universitario Central de Asturias, Oviedo (Spain); Instituto Universitario de Oncología del Principado de Asturias, Oviedo (Spain); Rinaldo, Alessandra; Ferlito, Alfio [ENT Clinic, University of Udine, Udine (Italy); Takes, Robert P., E-mail: robert.takes@radboudumc.nl [Department of Otolaryngology—Head and Neck Surgery, Radboud University Nijmegen Medical Center, Nijmegen (Netherlands)

    2014-05-01

    Head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and its incidence is growing. Although environmental carcinogens and carcinogenic viruses are the main etiologic factors, genetic predisposition obviously plays a risk-modulating role, given that not all individuals exposed to these carcinogens experience the disease. This review highlights some aspects of genetic susceptibility to HNSCC: among others, genetic polymorphisms in biotransformation enzymes, DNA repair pathway, apoptotic pathway, human papillomavirus-related pathways, mitochondrial polymorphisms, and polymorphism related to the bilirubin-metabolized pathway. Furthermore, epigenetic variations, familial forms of HNSCC, functional assays for HNSCC risk assessment, and the implications and perspectives of research on genetic susceptibility in HNSCC are discussed.

  12. Genetic Susceptibility to Feline Infectious Peritonitis in Birman Cats

    OpenAIRE

    Golovko, Lyudmila; Lyons, Leslie A.; Liu, Hongwei; Sorensen, Anne; Wehnert, Suzanne; Pedersen, Niels C.

    2013-01-01

    Genetic factors are presumed to influence the incidence of feline infectious peritonitis (FIP), especially among pedigreed cats. However, proof for the existence of such factors has been limited and mainly anecdotal. Therefore, we sought evidence for genetic susceptibility to FIP using feline high density single nucleotide polymorphism (SNP) arrays in a genome-wide association study (GWAS). Birman cats were chosen for GWAS because they are highly inbred and suffer a high incidence of FIP. DNA...

  13. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci.

    Science.gov (United States)

    Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

    2016-01-01

    Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo. PMID:26870082

  14. Genetic susceptibility factors for multiple chemical sensitivity revisited

    DEFF Research Database (Denmark)

    Rasmussen, Henrik Berg; Linneberg, Allan; Andersen, Charlotte Brasch; Fenger, Mogens; Dirksen, Asger; Vesterhauge, Søren; Werge, Thomas; Elberling, Jesper; Berg, Nikolaj Drimer

    2010-01-01

    study was to investigate genetic susceptibility factors for MCS and self-reported chemical sensitivity in a population sample. Ninety six MCS patients and 1,207 controls from a general population divided into four severity groups of chemical sensitivity were genotyped for variants in the genes encoding...

  15. Human genetic susceptibility and infection with Leishmania peruviana

    Energy Technology Data Exchange (ETDEWEB)

    Shaw, M.A.; Davis, C.R.; Collins, A. [and others

    1995-11-01

    Racial differences, familial clustering, and murine studies are suggestive of host genetic control of Leishmania infections. Complex segregation analysis has been carried out by use of the programs POINTER and COMDS and data from a total population survey, comprising 636 nuclear families, from an L. perurviana endemic area. The data support genetic components controlling susceptibility to clinical leishmaniasis, influencing severity of disease and resistance to disease among healthy individuals. A multifactorial model is favored over a sporadic model. Two-locus models provided the best fit to the data, the optimal model being a recessive gene (frequency .57) plus a modifier locus. Individuals infected at an early age and with recurrent lesions are genetically more susceptible than those infected with a single episode of disease at a later age. Among people with no lesions, those with a positive skin-test response are genetically less susceptible than those with a negative response. The possibility of the involvement of more than one gene together with environmental effects has implications for the design of future linkage studies. 31 refs., 7 tabs.

  16. Epigenomic functional characterization of genetic susceptibility variants in systemic vasculitis.

    Science.gov (United States)

    Sawalha, Amr H; Dozmorov, Mikhail G

    2016-02-01

    Systemic vasculitides are poorly understood inflammatory diseases of the blood vessels that are frequently associated with significant organ damage. Genetic risk variants contribute to the susceptibility of vasculitis, but functional consequences of these genetic variants are largely unknown. Most genetic risk variants in immune-mediated diseases, including systemic vasculitis, are localized to non-coding genetic regions suggesting they might increase disease risk by influencing regulatory elements within the genome. Long range regulatory interactions pose an additional obstacle in localizing functional consequences associated with risk variants to specific genes or cell types. We used cell-type specific enrichment patterns of histone changes that mark poised, primed, and active enhancers, and DNase hypersensitivity to identify specific immune cells mediating genetic risk in vasculitis. Our data suggest that genetic risk variants in ANCA-associated vasculitis are significantly enriched in enhancer elements in Th17 cells, supporting a role for Th17 cells in this disease. Primed and active enhancer elements in B cells can be potentially affected by genetic risk variants associated with Kawasaki disease. Genetic risk in Behçet's disease and Takayasu arteritis might affect enhancer elements in multiple cell types, possibly explained by influencing enhancers in hematopoietic stem cells. Interestingly, our analyses indicate a role for B cells in Kawasaki disease, Behçet's disease, and Takayasu arteritis, and suggest that further work to characterize the involvement of B cells in these diseases is warranted. PMID:26492816

  17. Genetic susceptibility factors for multiple chemical sensitivity revisited

    DEFF Research Database (Denmark)

    Berg, Nikolaj Drimer; Berg Rasmussen, Henrik; Linneberg, Allan; Brasch-Andersen, Charlotte; Fenger, Mogens; Dirksen, Asger; Vesterhauge, Søren; Werge, Thomas; Elberling, Jesper

    2010-01-01

    study was to investigate genetic susceptibility factors for MCS and self-reported chemical sensitivity in a population sample. Ninety six MCS patients and 1,207 controls from a general population divided into four severity groups of chemical sensitivity were genotyped for variants in the genes encoding...... compared in post hoc analyses with all individuals from the population sample (p=0.02). Genetic variants in paraoxonase 1 and methylene tetrahydrofolate reductase were not associated with MSC or with self-reported chemical sensitivity in the population sample. Our results suggest that variants in the genes...

  18. MMP-9 genetic polymorphism may confer susceptibility to COPD.

    Science.gov (United States)

    Jiang, S; Yang, Z H; Chen, Y Y; He, Z; Zhou, Y; Gao, Y; Zhang, Q; Tan, M Q

    2016-01-01

    Correlations between genetic polymorphisms of three matrix metalloproteinase (MMP) genes and susceptibility to chronic obstructive pulmonary disease (COPD) were investigated. Relevant case-control studies were selected using rigorous inclusion and exclusion criteria. The comprehensive Meta-analysis 2.0 software was used to conduct the statistical analysis. An odds ratio with 95% confidence intervals was applied to assess the correlation between genetic polymorphisms of MMPs and susceptibility to COPD. Twelve high-quality studies were selected for inclusion in this meta-analysis. These studies included a combined total of 1533 COPD patients and 1530 healthy controls. The result of the meta-analysis showed that MMP-9 rs3918242 C > T was significantly correlated with increased susceptibility to COPD. However, MMP-1 rs1799750 1G > 2G and MMP-3 rs3025058 5A > 6A were not associated with COPD risk (all P > 0.05). Based on our meta-analysis, MMP-9 rs3918242 C > T is correlated with susceptibility to COPD, but MMP-1 rs1799750 1G > 2G and MMP-3 rs3025058 5A > 6A are not. These results should be further confirmed using a larger sample size. PMID:27173221

  19. Genetic susceptibility to lead poisoning—A case report

    OpenAIRE

    Anita R Bijoor; Venkatesh, T

    2007-01-01

    Lead poisoning is well documented in persons occupationally exposed to lead. What is less known is, that even in persons working in lead based industries, the effect of lead and the appearance of signs and symptoms of lead poisoning is genetically determined. Three genes related to lead metabolism, exhibiting polymorphism have already been demonstrated-δALA-dehydratase, Vitamin D receptor gene and Hemochromatosis gene. These alleles determine the susceptibility of the individuals to lead. We ...

  20. Genetic evidence for the ancestral loss of short-wavelength-sensitive cone pigments in mysticete and odontocete cetaceans.

    OpenAIRE

    Levenson, D H; Dizon, A

    2003-01-01

    All mammals ancestrally possessed two types of cone pigments, an arrangement that persists in nearly all contemporary species. However, the absence of one of these cone types, the short-wavelength-sensitive (SWS) cone, has recently been established in several delphinoid cetacean species, indicating that the loss of this pigment type may be widespread among cetaceans. To evaluate the functional condition of SWS cones in cetaceans, partial SWS cone-opsin gene sequences were obtained from nuclea...

  1. Genetic susceptibility to feline infectious peritonitis in Birman cats.

    Science.gov (United States)

    Golovko, Lyudmila; Lyons, Leslie A; Liu, Hongwei; Sørensen, Anne; Wehnert, Suzanne; Pedersen, Niels C

    2013-07-01

    Genetic factors are presumed to influence the incidence of feline infectious peritonitis (FIP), especially among pedigreed cats. However, proof for the existence of such factors has been limited and mainly anecdotal. Therefore, we sought evidence for genetic susceptibility to FIP using feline high density single nucleotide polymorphism (SNP) arrays in a genome-wide association study (GWAS). Birman cats were chosen for GWAS because they are highly inbred and suffer a high incidence of FIP. DNA from 38 Birman cats that died of FIP and 161 healthy cats from breeders in Denmark and USA were selected for genotyping using 63K SNPs distributed across the feline genome. Danish and American Birman cats were closely related and the populations were therefore combined and analyzed in two manners: (1) all cases (FIP) vs. all controls (healthy) regardless of age, and (2) cases 1½ years of age and younger (most susceptible) vs. controls 2 years of age and older (most resistant). GWAS of the second cohort was most productive in identifying significant genome-wide associations between case and control cats. Four peaks of association with FIP susceptibility were identified, with two being identified on both analyses. Five candidate genes ELMO1, RRAGA, TNFSF10, ERAP1 and ERAP2, all relevant to what is known about FIP virus pathogenesis, were identified but no single association was fully concordant with the disease phenotype. Difficulties in doing GWAS in cats and interrogating complex genetic traits were discussed. PMID:23619280

  2. AN EPIDEMIOLOGY AND MOLECULAR GENETIC STUDY ON BREAST CANCER SUSCEPTIBILITY

    Institute of Scientific and Technical Information of China (English)

    贾卫华; 王继先; 李本孝; 李征

    2000-01-01

    Objectives. To investigate the genetic susceptibility for breast cancer of Chinese, a hospital-based case-control study, pedigree survey and molecular genetic study were conducted. Methods. Logistic regression model and stratification methods were used in the risk factors analysis. Li-Mantel art and Falconer methods were used to analyze the segregation ratio and heritability. Polymerase chain reaction (PCR) and polyacrylamide gel electrophoresis were used to detect AI, G-banding technique was used to detect the chromosome aberration of peripheral blood lymphocyte. Results. Family history of breast cancer is related to enhanced breast cancer risk significartly, OR is 3.905 ( 95 % CI = 1.079 ~ 14.13), and it widely interacts with other risk factors. Accumulative incidence of breast cancer in first degree relatives is 9.99%, which is larger than that in second, third degree and non-blood relatives. Segregation ratio is 0.021, heritability among first degree relatives is 35.6 ± 5.8%. Frequencies of LOH at BRCA1 and BRCA2 loci in sporadic breast cancer are 6.12% and 5.77% respectively. In the sibs, both of them show LOH at D13S173 locus, and high frequencies of chromosome aberrations were observed. Conclusions. Genetic susceptibility contributes to breast cancer occurrence of Chinese, and its racial variation may be one of the important reasons for the large difference of incidence between western and eastern countries.

  3. AN EPIDEMIOLOGY AND MOLECULAR GENETIC STUDY ON BREAST CANCER SUSCEPTIBILITY

    Institute of Scientific and Technical Information of China (English)

    贾卫华; 王继先; 李本孝; 李征

    2000-01-01

    Obieaites. To investigate the genetic susceptibility for breast cancer of Chinese, a hospital-besed case-control study, pedigree survey and molecular genetic study were conducted. Methods. Logistic regression model and stratification methods were used in the risk factors analysis. Li-Mantel-Gart and Falconer methods were used to analyze the segregation ratio and heritability. Polymemse chain reaction (PCR) and polyacrylamide gel electrophoresis were used to detect AI, G-banding technique was used to detect the chromosome aberration of peripheral blood lymphocyte. Results. Family history of breast cancer is related to enhanced breast cancer risk significantly, OR is 3.905(95% CI = 1.079—14.13), and it widely interacts with other risk factors. Accumulative incidence of breast cancer in first degree relatives is 9.99%, which is larger than that in second, third degree and non-blnod relatives. Segregation ratio is 0.021, heritability among first degree relatives is 35.6 ± 5.8%. Frequencies of LDH at BRCA1 and BRCA2 loci in sporadic breast cancer are 6.12% and 5.77% respectively. In the sibs, both of them show LOH at D13S173 locus, and high frequencies of chromosome abermtions were observed.Condusions. Genetic susceptibility contributes to breast cancer occurrence of Chinese, and its racial variation may be one of the important reasons for the large difference of incidence between western and eastern countries.

  4. Additional mechanisms conferring genetic susceptibility to Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Miguel Calero

    2015-04-01

    Full Text Available Familial Alzheimer's disease (AD, mostly associated with early onset, is caused by mutations in three genes (APP, PSEN1 and PSEN2 involved in the production of the amyloid  peptide. In contrast, the molecular mechanisms that trigger the most common late onset sporadic AD remain largely unknown. With the implementation of an increasing number of case-control studies and the upcoming of large-scale genome-wide association studies (GWAS there is a mounting list of genetic risk factors associated to common genetic variants that have been associated to sporadic AD. Besides APOE, that presents a strong association with the disease (OR~4, the rest of these genes have moderate or low degrees of association, with OR ranging from 0.88 to 1.23. Taking together, these genes may account only for a fraction of the attributable AD risk and therefore, rare variants and epistastic gene interactions should be taken into account in order to get the full picture of the genetic risks associated to AD. Here, we review recent whole-exome studies looking for rare variants, somatic brain mutations with a strong association to the disease, and several studies dealing with epistasis as additional mechanisms conferring genetic susceptibility to AD. Altogether, recent evidence underlines the importance of defining molecular and genetic pathways and networks rather than the contribution of specific genes.

  5. Association of susceptible genetic markers and autoantibodies in rheumatoid arthritis

    Indian Academy of Sciences (India)

    Vasanth Konda Mohan; Nalini Ganesan; Rajasekhar Gopalakrishnan

    2014-08-01

    Rheumatoid arthritis (RA) is a chronic autoimmune disorder of unknown aetiology resulting in inflammation of the synovium, cartilage and bone. The disease has a heterogeneous character, consisting of clinical subsets of anti-citrullinated protein antibody (ACPA)-positive and APCA-negative disease. Although, the pathogenesis of RA is incompletely understood, genetic factors play a vital role in susceptibility to RA as the heritability of RA is between 50 and 60%, with the human leukocyte antigen (HLA) locus accounting for at least 30% of overall genetic risk. Non-HLA genes, i.e. tumour necrosis factor- (TNF-) within the MHC (major histocompatibility complex) have also been investigated for association with RA. Although, some contradictory results have originated from several studies on TNF- gene, the data published so far indicate the possible existence of TNF- gene promoter variants that act as markers for disease severity and response to treatment in RA. The correlation of HLA and non-HLA genes within MHC region is apparently interpreted. A considerable number of confirmed associations with RA and other autoimmune disease susceptibility loci including peptidylarginine deiminase type 4 (PADI4), protein tyrosine phosphatase non-receptor type 22 (PTPN22), signal transducer and activator of transcription (STAT4), cluster of differentiation 244 (CD244) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4), located outside the MHC have been reported recently. In this review, we aim to give an update on recent progress in RA genetics, the importance of the combination of HLA-DRB1 alleles, non-HLA gene polymorphism, its detection and autoantibodies as susceptibility markers for early RA disease.

  6. Genetic susceptibility to teratogens: state of the art.

    Science.gov (United States)

    Cassina, Matteo; Salviati, Leonardo; Di Gianantonio, Elena; Clementi, Maurizio

    2012-09-01

    There is evidence that the susceptibility to the teratogenic effect of drugs within human populations varies extremely from one individual to another, even after identical exposures. One of the factors that may explain these interindividual differences is the genetic makeup in the pharmacokinetics and pharmacodynamics of the respective drugs. In fact, both maternal and embryonic/fetal genotypes can affect placental transport, absorption, metabolism, distribution and receptor binding of an agent, influencing its teratogenicity. We have reviewed the literature and commented on the reported correlations between genetic factors and drug-induced birth defects. There is still a clear lack of knowledge regarding this issue and the available data are often conflicting. However, the identification of specific polymorphisms associated with predisposition to teratogenesis may allow in the future the development of personalized non-teratogenic therapies for pregnant women. PMID:22659091

  7. Contribution of environment and genetics to pancreatic cancer susceptibility.

    Directory of Open Access Journals (Sweden)

    Barbara A Hocevar

    Full Text Available Several risk factors have been identified as potential contributors to pancreatic cancer development, including environmental and lifestyle factors, such as smoking, drinking and diet, and medical conditions such as diabetes and pancreatitis, all of which generate oxidative stress and DNA damage. Oxidative stress status can be modified by environmental factors and also by an individual's unique genetic makeup. Here we examined the contribution of environment and genetics to an individual's level of oxidative stress, DNA damage and susceptibility to pancreatic cancer in a pilot study using three groups of subjects: a newly diagnosed pancreatic cancer group, a healthy genetically-unrelated control group living with the case subject, and a healthy genetically-related control group which does not reside with the subject. Oxidative stress and DNA damage was evaluated by measuring total antioxidant capacity, direct and oxidative DNA damage by Comet assay, and malondialdehyde levels. Direct DNA damage was significantly elevated in pancreatic cancer patients (age and sex adjusted mean ± standard error: 1.00 ± 0.05 versus both healthy unrelated and related controls (0.70 ± 0.06, pA and ERCC4 R415Q polymorphisms. These results suggest that measurement of DNA damage, as well as select SNPs, may provide an important screening tool to identify individuals at risk for development of pancreatic cancer.

  8. Genetic susceptibility to radiation: which impact on medical practice?

    International Nuclear Information System (INIS)

    Recent progress especially in the field of gene identification and expression have raised more attention on genetic susceptibility to cancer possibly enhanced by radiations. Radiation therapists are mostly concerned by this question since hypersensitive patients may suffer from adverse effects in normal tissues following a standard radiation therapy and normally sensitive patients could benefit from higher doses of radiations for a better cure of their malignant tumors. Although only a small percentage of individuals are 'hypersensitive' to radiation effects, all medical specialists using ionising radiations should be aware of these new progress in medical knowledge. The present paper reviews the main pathologies (diseases, syndromes...) known or strongly suspected to be associated with a hypersensitivity to ionizing radiations. Then the main tests capable to detect in advance such pathologies are analyzed and compared. Finally guidelines are provided, especially to the radiation therapists to limit the risk of severe complications (or even deaths) for these specific subset of patients suffering from a genetic disorder with a susceptibility to radiations. (author)

  9. Radiation-sensitive genetically susceptible pediatric sub-populations

    Energy Technology Data Exchange (ETDEWEB)

    Kleinerman, Ruth A. [National Cancer Institute, NIH, DHHS, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, Rockville, MD (United States)

    2009-02-15

    Major advances in pediatric cancer treatment have resulted in substantial improvements in survival. However, concern has emerged about the late effects of cancer therapy, especially radiation-related second cancers. Studies of childhood cancer patients with inherited cancer syndromes can provide insights into the interaction between radiation and genetic susceptibility to multiple cancers. Children with retinoblastoma (Rb), neurofibromatosis type 1 (NF1), Li-Fraumeni syndrome (LFS), and nevoid basal cell carcinoma syndrome (NBCCS) are at substantial risk of developing radiation-related second and third cancers. A radiation dose-response for bone and soft-tissue sarcomas has been observed in hereditary Rb patients, with many of these cancers occurring in the radiation field. Studies of NF1 patients irradiated for optic pathway gliomas have reported increased risks of developing another cancer associated with radiotherapy. High relative risks for second and third cancers were observed for a cohort of 200 LFS family members, especially children, possibly related to radiotherapy. Children with NBCCS are very sensitive to radiation and develop multiple basal cell cancers in irradiated areas. Clinicians following these patients should be aware of their increased genetic susceptibility to multiple primary malignancies enhanced by sensitivity to ionizing radiation. (orig.)

  10. Genetic susceptibility loci, pesticide exposure and prostate cancer risk.

    Directory of Open Access Journals (Sweden)

    Stella Koutros

    Full Text Available Uncovering SNP (single nucleotide polymorphisms-environment interactions can generate new hypotheses about the function of poorly characterized genetic variants and environmental factors, like pesticides. We evaluated SNP-environment interactions between 30 confirmed prostate cancer susceptibility loci and 45 pesticides and prostate cancer risk in 776 cases and 1,444 controls in the Agricultural Health Study. We used unconditional logistic regression to estimate odds ratios (ORs and 95% confidence intervals (CIs. Multiplicative SNP-pesticide interactions were calculated using a likelihood ratio test. After correction for multiple tests using the False Discovery Rate method, two interactions remained noteworthy. Among men carrying two T alleles at rs2710647 in EH domain binding protein 1 (EHBP1 SNP, the risk of prostate cancer in those with high malathion use was 3.43 times those with no use (95% CI: 1.44-8.15 (P-interaction= 0.003. Among men carrying two A alleles at rs7679673 in TET2, the risk of prostate cancer associated with high aldrin use was 3.67 times those with no use (95% CI: 1.43, 9.41 (P-interaction= 0.006. In contrast, associations were null for other genotypes. Although additional studies are needed and the exact mechanisms are unknown, this study suggests known genetic susceptibility loci may modify the risk between pesticide use and prostate cancer.

  11. Genetic susceptibility to radiation: which impact on medical practice?

    Energy Technology Data Exchange (ETDEWEB)

    Alapetite, C.; Cosset, J.M. [Institut Curie, Dept. de Radiotherapie, 75 - Paris (France); Bourguignon, M.H.; Masse, R. [Office de Protection contre les Rayonnements Ionisants, 78 - le Vesinet (France)

    2001-07-01

    Recent progress especially in the field of gene identification and expression have raised more attention on genetic susceptibility to cancer possibly enhanced by radiations. Radiation therapists are mostly concerned by this question since hypersensitive patients may suffer from adverse effects in normal tissues following a standard radiation therapy and normally sensitive patients could benefit from higher doses of radiations for a better cure of their malignant tumors. Although only a small percentage of individuals are 'hypersensitive' to radiation effects, all medical specialists using ionising radiations should be aware of these new progress in medical knowledge. The present paper reviews the main pathologies (diseases, syndromes...) known or strongly suspected to be associated with a hypersensitivity to ionizing radiations. Then the main tests capable to detect in advance such pathologies are analyzed and compared. Finally guidelines are provided, especially to the radiation therapists to limit the risk of severe complications (or even deaths) for these specific subset of patients suffering from a genetic disorder with a susceptibility to radiations. (author)

  12. Mating animals by minimising the covariance between ancestral contributions generates less inbreeding without compromising genetic gain in breeding schemes with truncation selection

    DEFF Research Database (Denmark)

    Henryon, M; Berg, P; Sørensen, A C

    2009-01-01

    they can be achieved without extra costs or practical constraints. MCAC mating merely uses pedigree information to pair the animals more appropriately and is clearly a worthy alternative to minimum-coancestry mating and probably any other mating criterion. We believe, therefore, that MCAC mating should......We reasoned that mating animals by minimising the covariance between ancestral contributions (MCAC mating) will generate less inbreeding and at least as much genetic gain as minimum-coancestry mating in breeding schemes where the animals are truncation-selected. We tested this hypothesis...... by stochastic simulation and compared the mating criteria in hierarchical and factorial breeding schemes, where the animals were selected based on breeding values predicted by animal-model BLUP. Random mating was included as a reference-mating criterion. We found that MCAC mating generated 4% to 8% less...

  13. Genetic control of immune response in carriers of ancestral haplotype 8.1: the study of chemotaxis.

    Science.gov (United States)

    Candore, Giuseppina; Balistreri, Carmela R; Campagna, Anna Maria; Colombo, Alfredo; Cuppari, Irene; Di-Carlo, Daniele; Grimaldi, Maria P; Orlando, Valentina; Piazza, Giuseppina; Vasto, Sonya; Lio, Domenico; Caruso, Calogero

    2006-11-01

    In all caucasian populations the association of an impressive number of autoimmune diseases with genes from the HLA-B8, DR3 haplotype that is part of the ancestral haplotype (AH) 8.1 HLA-A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*0301, DRB3*0101, DQA1*0501, DQB1*0201 has been reported by different research groups. This haplotype, which is more common in northern Europe, is also associated with a number of immune system dysfunctions in healthy subjects. Analyzing the data according to gender, some dysfunctions are observed in women but not in men, in agreement with the role of X-linked genes and/or estrogens in the development and progression of autoimmune diseases. It has been proposed that a small number of genes within the 8.1 AH modify immune responsiveness and hence affect multiple immunopathological diseases. In this article, we demonstrate that neutrophil chemotaxis is significantly decreased in carriers of this AH, suggesting that this impairment may also be related to the increased occurrence of autoimmune diseases in these individuals. PMID:17261794

  14. Genetic susceptibility to pancreatic cancer and its functional characterisation: The PANcreatic Disease ReseArch (PANDoRA) consortium

    Czech Academy of Sciences Publication Activity Database

    Campa, D.; Rizzato, C.; Capurso, G.; Giese, N.; Funel, N.; Greenhalf, W.; Souček, P.; Gazouli, M.; Pezzilli, R.; Pasquali, C.; Talar-Wojnarowska, R.; Cantore, M.; Andriulli, A.; Scarpa, A.; Jamroziak, K.; Delle Fave, G.; Costello, E.; Khaw, K. T.; Heller, A.; Key, T. K.; Theodoropoulos, G.; Malecka-Panas, E.; Mambrini, A.; Bambi, F.; Landi, S.; Pedrazzoli, S.; Bassi, C.; Pacetti, P.; Piepoli, A.; Tavano, F.; di Sebastiano, P.; Vodičková, Ludmila; Basso, D.; Plebani, M.; Fogar, P.; Buechler, M. W.; Bugert, P.; Vodička, Pavel; Boggi, U.; Neoptolemos, J. P.; Werner, J.; Canzian, F.

    2013-01-01

    Roč. 45, č. 2 (2013), s. 95-99. ISSN 1590-8658 Institutional support: RVO:68378041 Keywords : cancer susceptibility * genetic polymorphisms * genetic susceptibility Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.889, year: 2013

  15. Genetic susceptibility to HPV infection and cervical cancer

    Directory of Open Access Journals (Sweden)

    P.C. Maciag

    1999-07-01

    Full Text Available Squamous cell carcinoma of the cervix (SCCC is one of the leading causes of death in developing countries. Infection with high-risk human papillomavirus (HPV is the major risk factor to develop malignant lesions in the cervix. Polymorphisms of the MHC and p53 genes seem to influence the outcome of HPV infection and progression to SCCC, although controversial data have been reported. MHC are highly polymorphic genes that encode molecules involved in antigen presentation, playing a key role in immune regulation, while p53 is a tumor suppressor gene that regulates cell proliferation. The HPV E6 protein from high-risk types binds p53 and mediates its degradation by the ubiquitin pathway. The role of these polymorphisms in genetic susceptibility to HPV infection and to SCCC remains under investigation.

  16. Heterogeneity of HLA genetic factors in IDDM susceptibility.

    Science.gov (United States)

    Martell, M; Marcadet, A; Moine, A; Boitard, C; Deschamps, I; Dausset, J; Bach, J F; Cohen, D

    1990-01-01

    The association of certain HLA-D alleles with insulin-dependent diabetes mellitus (IDDM) is well known. One hundred and sixty-one non-related diabetic individuals and 142 non-related healthy controls were typed for the HLA DR-DQw-Dw association, using a restriction fragment length polymorphism (RFLP) typing method that combines three probe/enzyme systems: DRB/Taq I, DQB/Taq I, and DQB/Bam HI. Comparison of frequencies in both diabetics and controls confirms previous results in terms of HLA class II and IDDM association. Moreover, we have found that DR3/3 heterozygous individuals are more susceptible to IDDM when they are also Dw25 (associated with B18) than when they are Dw24 (associated with B8). Using oligonucleotide dot-blot hybridizations we analyzed the HLA-DQB1 sequence of DR3,Dw24 and DR3,Dw25 homozygous individuals, and we found no difference at position 57 between these two DR3-carrying haplotypes. This observation points to the heterogeneity of HLA genetic factors in IDDM susceptibility. PMID:1970333

  17. New Genetic Susceptibility Factors for Sjögren's Syndrome Revealed

    Science.gov (United States)

    ... Spotlight on Research 2014 March 2014 (historical) New Genetic Susceptibility Factors for Sjögren’s Syndrome Revealed By analyzing ... syndrome. The findings, published in the journal Nature Genetics, could help researchers develop new strategies to diagnose ...

  18. Genetic susceptibility factors for alcohol-induced chronic pancreatitis.

    Science.gov (United States)

    Aghdassi, Ali A; Weiss, F Ulrich; Mayerle, Julia; Lerch, Markus M; Simon, Peter

    2015-07-01

    Chronic pancreatitis is a progressive inflammatory disease of the pancreas and frequently associated with immoderate alcohol consumption. Since only a small proportion of alcoholics eventually develop chronic pancreatitis genetic susceptibility factors have long been suspected to contribute to the pathogenesis of the disease. Smaller studies in ethnically defined populations have found that not only polymorphism in proteins involved in the metabolism of ethanol, such as Alcohol Dehydrogenase and Aldehyde Dehydrogenase, can confer a risk for developing chronic pancreatitis but also mutations that had previously been reported in association with idiopathic pancreatitis, such as SPINK1 mutations. In a much broader approach employing genome wide search strategies the NAPS study found that polymorphisms in the Trypsin locus (PRSS1 rs10273639), and the Claudin 2 locus (CLDN2-RIPPLY1-MORC4 locus rs7057398 and rs12688220) confer an increased risk of developing alcohol-induced pancreatitis. These results from North America have now been confirmed by a European consortium. In another genome wide approach polymorphisms in the genes encoding Fucosyltransferase 2 (FUT2) non-secretor status and blood group B were not only found in association with higher serum lipase levels in healthy volunteers but also to more than double the risk for developing alcohol-associated chronic pancreatitis. These novel genetic associations will allow to investigate the pathophysiological and biochemical basis of alcohol-induced chronic pancreatitis on a cellular level and in much more detail than previously possible. PMID:26149858

  19. Genetic Relatedness, Antimicrobial and Biocide Susceptibility Comparative Analysis of Methicillin-Resistant and -Susceptible Staphylococcus pseudintermedius from Portugal

    OpenAIRE

    Couto, Natacha; Belas, Adriana; Couto, Isabel; Perreten, Vincent; Pomba, Constança

    2014-01-01

    Forty methicillin-resistant and -susceptible Staphylococcus pseudintermedius (MRSP and MSSP, respectively) from colonization and infection in dogs and cats were characterized for clonality, antimicrobial, and biocide susceptibility. MSSP were genetically more diverse than MRSP by multi-locus sequence typing and pulsed-field gel electrophoresis. Three different spa types (t06, t02, t05) and two SCCmec types (II-III and V) were detected in the MRSP isolates. All MRSP and two MSSP strains were m...

  20. HLA and Celiac Disease Susceptibility: New Genetic Factors Bring Open Questions about the HLA Influence and Gene-Dosage Effects

    Science.gov (United States)

    Medrano, Luz María; Dema, Bárbara; López-Larios, Arturo; Maluenda, Carlos; Bodas, Andrés; López-Palacios, Natalia; Figueredo, M. Ángeles; Fernández-Arquero, Miguel; Núñez, Concepción

    2012-01-01

    Celiac disease (CD) is a chronic inflammatory disorder triggered after gluten ingestion in genetically susceptible individuals. The major genetic determinants are HLA-DQA1*05 and HLA-DQB1*02, which encode the DQ2 heterodimer. These alleles are commonly inherited in cis with DRB1*03∶01, which is associated with numerous immune-related disorders, in some cases contributing with a different amount of risk depending on the haplotype context. We aimed at investigating those possible differences involving DRB1*03∶01-carrying haplotypes in CD susceptibility. A family (274 trios) and a case-control sample (369 CD cases/461 controls) were analyzed. DRB1*03∶01-carrying individuals were classified according to the haplotype present (ancestral haplotype (AH) 8.1, AH 18.2 or non-conserved haplotype) after genotyping of HLA-DRB1, -DQA1, -DQB1, -B8, TNF -308, TNF -376 and the TNFa and TNFb microsatellites. We observe that the AH 8.1 confers higher risk than the remaining DRB1*03∶01-carrying haplotypes, and this effect only involves individuals possessing a single copy of DQB1*02. CD risk for these individuals is similar to the one conferred by inherit DQA1*05 and DQB1*02 in trans. It seems that an additional CD susceptibility factor is present in the AH 8.1 but not in other DRB1*03∶01-carrying haplotypes. This factor could be shared with individuals possessing DQ2.5 trans, according to the similar risk observed in those two groups of individuals. PMID:23119005

  1. HLA and celiac disease susceptibility: new genetic factors bring open questions about the HLA influence and gene-dosage effects.

    Directory of Open Access Journals (Sweden)

    Luz María Medrano

    Full Text Available Celiac disease (CD is a chronic inflammatory disorder triggered after gluten ingestion in genetically susceptible individuals. The major genetic determinants are HLA-DQA1*05 and HLA-DQB1*02, which encode the DQ2 heterodimer. These alleles are commonly inherited in cis with DRB1*03∶01, which is associated with numerous immune-related disorders, in some cases contributing with a different amount of risk depending on the haplotype context. We aimed at investigating those possible differences involving DRB1*03∶01-carrying haplotypes in CD susceptibility. A family (274 trios and a case-control sample (369 CD cases/461 controls were analyzed. DRB1*03∶01-carrying individuals were classified according to the haplotype present (ancestral haplotype (AH 8.1, AH 18.2 or non-conserved haplotype after genotyping of HLA-DRB1, -DQA1, -DQB1, -B8, TNF -308, TNF -376 and the TNFa and TNFb microsatellites. We observe that the AH 8.1 confers higher risk than the remaining DRB1*03∶01-carrying haplotypes, and this effect only involves individuals possessing a single copy of DQB1*02. CD risk for these individuals is similar to the one conferred by inherit DQA1*05 and DQB1*02 in trans. It seems that an additional CD susceptibility factor is present in the AH 8.1 but not in other DRB1*03∶01-carrying haplotypes. This factor could be shared with individuals possessing DQ2.5 trans, according to the similar risk observed in those two groups of individuals.

  2. Genetic Factors Affecting Late-Onset Alzheimer's Disease Susceptibility.

    Science.gov (United States)

    Rezazadeh, Maryam; Khorrami, Aziz; Yeghaneh, Tarlan; Talebi, Mahnaz; Kiani, Seyed Jalal; Heshmati, Yaser; Gharesouran, Jalal

    2016-03-01

    Alzheimer's disease is considered a progressive brain disease in the older population. Late-onset Alzheimer's disease (LOAD) as a multifactorial dementia has a polygenic inheritance. Age, environment, and lifestyle along with a growing number of genetic factors have been reported as risk factors for LOAD. Our aim was to present results of LOAD association studies that have been done in northwestern Iran, and we also explored possible interactions with apolipoprotein E (APOE) status. We re-evaluated the association of these markers in dominant, recessive, and additive models. In all, 160 LOAD and 163 healthy control subjects of Azeri Turkish ethnicity were studied. The Chi-square test with Yates' correction and Fisher's exact test were used for statistical analysis. A Bonferroni-corrected p value, based on the number of statistical tests, was considered significant. Our results confirmed that chemokine receptor type 2 (CCR2), estrogen receptor 1 (ESR1), toll-like receptor 2 (TLR2), tumor necrosis factor alpha (TNF α), APOE, bridging integrator 1 (BIN1), and phosphatidylinositol-binding clathrin assembly protein (PICALM) are LOAD susceptibility loci in Azeri Turk ancestry populations. Among them, variants of CCR2, ESR1, TNF α, and APOE revealed associations in three different genetic models. After adjusting for APOE, the association (both allelic and genotypic) with CCR2, BIN1, and ESRα (PvuII) was evident only among subjects without the APOE ε4, whereas the association with CCR5, without Bonferroni correction, was significant only among subjects carrying the APOE ε4 allele. This result is an evidence of a synergistic and antagonistic effect of APOE on variant associations with LOAD. PMID:26553058

  3. Genetic susceptibility to progressive massive fibrosis in coal miners

    Energy Technology Data Exchange (ETDEWEB)

    Yucesoy, B.; Johnson, V.J.; Kissling, G.E.; Fluharty, K.; Kashon, M.L.; Slaven, J.; Germolec, D.; Vallyathan, V.; Luster, M.I. [NIOSH, Morgantown, WV (United States)

    2008-06-15

    Progressive massive fibrosis (PMF) is a chronic interstitial lung disease with a complex aetiology that can occur after cumulative dust exposure. A case-control study was conducted to test the hypothesis that single nucleotide polymorphisms (SNPs) within genes involved in inflammatory and fibrotic processes modulate the risk of PMF development. The study population consisted of 648 underground coal miners participating in the National Coal Workers Autopsy Study, of which 304 were diagnosed with PMF SNPs that influence the regulation of interleukin (IL)-1, IL-6, tumour necrosis factor-alpha, transforming growth factor-beta 1, vascular endothelial growth factor (VEGF), epidermal growth factor intercellular cell adhesion molecule (ICAM)-1 and matrix metalloproteinase-2 genes were determined using a 5'-nuclease real-time PCR assay. There were no significant differences in the distribution of any individual SNP or haplotype between the PMF and control groups. However, the polygenotype of VEGF +405/ICAM-1 +241/IL-6 -174 (C-A-G) conferred an increased risk for PMF (odds ratio 3.4, 95% confidence interval 1.3-8.8). The present study suggests that the examined genetic variations that help regulate inflammatory and fibrotic processes are unlikely to strongly influence susceptibility to this interstitial lung disease, although the role of vascular endothelial growth factor, intercellular cell adhesion molecule-1 and interleukin-6 polymorphisms in the development of progressive massive fibrosis may require further investigation.

  4. [Studies on the genetic susceptibility to dilated cardiomyopathy].

    Science.gov (United States)

    Li, Y Y; Zhang, J N; Ma, W Z

    1993-01-01

    HLA-DQB1,-DRB1 genes of 27 Chinese patients with dilated cardiomyopathy (DCM), 7 high risk individuals in a DCM kindred and 17 normal control subjects were analysed with the use of restriction fragment length polymorphisms (RFLP) with full length DQB1 and DRB1 cDNA probes according to the standard and nomenclature of the Xth International Histocompatibility Workshop. The resulting restriction patterns allowed genotyping of HLA-DR and HLA-DQw. D-DQw8 frequency increased significantly in patients with DCM as compared with that of the controls (P DQw4 also increased in patients although no statistical significance was shown when Chi-square value was corrected with Yate's correction, whereas D-DQw5 overrepresented in controls (P DQw8 and D-DQw4. These results support the hypothesis that HLA class II genes were associated with an increased risk for DCM, HLA-DQB rather than -DRB may confer genetic susceptibility to DCM. PMID:8104770

  5. Admixture mapping of end stage kidney disease genetic susceptibility using estimated mutual information ancestry informative markers

    Directory of Open Access Journals (Sweden)

    Geiger Dan

    2010-10-01

    Full Text Available Abstract Background The question of a genetic contribution to the higher prevalence and incidence of end stage kidney disease (ESKD among African Americans (AA remained unresolved, until recent findings using admixture mapping pointed to the association of a genomic locus on chromosome 22 with this disease phenotype. In the current study we utilize this example to demonstrate the utility of applying a multi-step admixture mapping approach. Methods A multi-step case only admixture mapping study, consisted of the following steps was designed: 1 Assembly of the sample dataset (ESKD AA; 2 Design of the estimated mutual information ancestry informative markers (n = 2016 screening panel 3; Genotyping the sample set whose size was determined by a power analysis (n = 576 appropriate for the initial screening panel; 4 Inference of local ancestry for each individual and identification of regions with increased AA ancestry using two different ancestry inference statistical approaches; 5 Enrichment of the initial screening panel; 6 Power analysis of the enriched panel 7 Genotyping of additional samples. 8 Re-analysis of the genotyping results to identify a genetic risk locus. Results The initial screening phase yielded a significant peak using the ADMIXMAP ancestry inference program applying case only statistics. Subgroup analysis of 299 ESKD patients with no history of diabetes yielded peaks using both the ANCESTRYMAP and ADMIXMAP ancestry inference programs. The significant peak was found on chromosome 22. Genotyping of additional ancestry informative markers on chromosome 22 that took into account linkage disequilibrium in the ancestral populations, and the addition of samples increased the statistical significance of the finding. Conclusions A multi-step admixture mapping analysis of AA ESKD patients replicated the finding of a candidate risk locus on chromosome 22, contributing to the heightened susceptibility of African Americans to develop non

  6. Ancestral genetic diversity associated with the rapid spread of stress-tolerant coral symbionts in response to Holocene climate change.

    Science.gov (United States)

    Hume, Benjamin C C; Voolstra, Christian R; Arif, Chatchanit; D'Angelo, Cecilia; Burt, John A; Eyal, Gal; Loya, Yossi; Wiedenmann, Jörg

    2016-04-19

    Coral communities in the Persian/Arabian Gulf (PAG) withstand unusually high salinity levels and regular summer temperature maxima of up to ∼35 °C that kill conspecifics elsewhere. Due to the recent formation of the PAG and its subsequent shift to a hot climate, these corals have had only coral reefs may respond to global warming. One key to coral survival in the world's warmest reefs are symbioses with a newly discovered alga,Symbiodinium thermophilum Currently, it is unknown whether this symbiont originated elsewhere or emerged from unexpectedly fast evolution catalyzed by the extreme environment. Analyzing genetic diversity of symbiotic algae across >5,000 km of the PAG, the Gulf of Oman, and the Red Sea coastline, we show thatS. thermophilumis a member of a highly diverse, ancient group of symbionts cryptically distributed outside the PAG. We argue that the adjustment to temperature extremes by PAG corals was facilitated by the positive selection of preadapted symbionts. Our findings suggest that maintaining the largest possible pool of potentially stress-tolerant genotypes by protecting existing biodiversity is crucial to promote rapid adaptation to present-day climate change, not only for coral reefs, but for ecosystems in general. PMID:27044109

  7. Family system characteristics and psychological adjustment to cancer susceptibility genetic testing : a prospective study

    NARCIS (Netherlands)

    van Oostrom, I.; Meijers-Heijboer, H.; Duivenvoorden, H. J.; Brocker-Vriends, A. H. J. T.; van Asperen, C. J.; Sijmons, R. H.; Seynaeve, C.; Van Gool, A. R.; Klijn, J. G. M.; Tibben, A.

    2007-01-01

    This study examined prospectively the contribution of family functioning, differentiation to parents, family communication and support from relatives to psychological distress in individuals undergoing genetic susceptibility testing for a known familial pathogenic BRCA1/2 or Hereditary nonpolyposis

  8. Birth Weight, Genetic Susceptibility, and Adulthood Risk of Type 2 Diabetes

    OpenAIRE

    Li, Yanping; Qi, Qibin; Workalemahu, Tsegaselassie; Hu, Frank B.; Qi, Lu

    2012-01-01

    OBJECTIVE Both stressful intrauterine milieus and genetic susceptibility have been linked to later-life diabetes risk. The current study aims to examine the interaction between low birth weight, a surrogate measure of stressful intrauterine milieus, and genetic susceptibility in relation to risk of type 2 diabetes in adulthood. RESEARCH DESIGN AND METHODS The analysis included two independent, nested case-control studies of 2,591 type 2 diabetic case subjects and 3,052 healthy control subject...

  9. Estimating Ancestral Population Parameters

    OpenAIRE

    Wakeley, J.; Hey, J.

    1997-01-01

    The expected numbers of different categories of polymorphic sites are derived for two related models of population history: the isolation model, in which an ancestral population splits into two descendents, and the size-change model, in which a single population undergoes an instantaneous change in size. For the isolation model, the observed numbers of shared, fixed, and exclusive polymorphic sites are used to estimate the relative sizes of the three populations, ancestral plus two descendent...

  10. Identifying variation in resistance to the take-all fungus, Gaeumannomyces graminis var. tritici, between different ancestral and modern wheat species

    OpenAIRE

    McMillan, Vanessa E; Gutteridge, Richard J; Hammond-Kosack, Kim E.

    2014-01-01

    Background Ancestral wheat relatives are important sources of genetic diversity for the introduction of novel traits for the improvement of modern bread wheat. In this study the aim was to assess the susceptibility of 34 accessions of the diploid wheat Triticum monococcum (A genome) to Gaeumannomyces graminis var. tritici (Ggt), the causal agent of take-all disease. The second aim was to explore the susceptibility of tetraploid wheat (T. durum) and the B genome progenitor species Aegilops spe...

  11. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.

    NARCIS (Netherlands)

    Plon, S.E.; Eccles, D.M.; Easton, D.; Foulkes, W.D.; Genuardi, M.; Greenblatt, M.S.; Hogervorst, F.B.; Hoogerbrugge, N.; Spurdle, A.B.; Tavtigian, S.V.

    2008-01-01

    Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genet

  12. A Counselling Model for BRCA1/2 Genetic Susceptibility Testing

    Directory of Open Access Journals (Sweden)

    van Oostrom Iris

    2004-02-01

    Full Text Available Abstract When BRCA1/2 genetic susceptibility testing was introduced in the clinic in the mid-nineties, the "Huntington protocol" was used in the counselling of individuals applying for genetic testing. This protocol includes at least three sessions with a certain reflection period before blood sampling. Evidence on the psychological impact of BRCA1/2 genetic susceptibility testing has been accumulating in the last years. We will give a short overview of these psychological studies in order to reflect the need of using the extensive Huntington protocol in the counselling of individuals applying for BRCA1/2 genetic susceptibility testing. A shortened and more flexible BRCA1/2 counselling protocol is delineated, in which the attention is focused on the needs and strengths of the individual.

  13. Ancestral Relationships Using Metafounders

    DEFF Research Database (Denmark)

    Legarra, Andres; Christensen, Ole Fredslund; Vitezica, Zulma G;

    2015-01-01

    Recent use of genomic (marker-based) relationships shows that relationships exist within and across base population (breeds or lines). However, current treatment of pedigree relationships is unable to consider relationships within or across base populations, although such relationships must exist...... due to finite size of the ancestral population and connections between populations. This complicates the conciliation of both approaches and, in particular, combining pedigree with genomic relationships. We present a coherent theoretical framework to consider base population in pedigree relationships....... We suggest a conceptual framework that considers each ancestral population as a finite-sized pool of gametes. This generates across-individual relationships and contrasts with the classical view where each population is considered as an infinite, unrelated pool. Several ancestral populations may be...

  14. Genetic susceptibility to type 2 diabetes and obesity

    DEFF Research Database (Denmark)

    Grarup, Niels; Sandholt, Camilla H; Hansen, Torben; Pedersen, Oluf

    2014-01-01

    During the past 7 years, genome-wide association studies have shed light on the contribution of common genomic variants to the genetic architecture of type 2 diabetes, obesity and related intermediate phenotypes. The discoveries have firmly established more than 175 genomic loci associated with...... these phenotypes. Despite the tight correlation between type 2 diabetes and obesity, these conditions do not appear to share a common genetic background, since they have few genetic risk loci in common. The recent genetic discoveries do however highlight specific details of the interplay between the...... pathogenesis of type 2 diabetes, insulin resistance and obesity. The focus is currently shifting towards investigations of data from targeted array-based genotyping and exome and genome sequencing to study the individual and combined effect of low-frequency and rare variants in metabolic disease. Here we...

  15. Meta-analysis and genome-wide interpretation of genetic susceptibility to drug addiction

    OpenAIRE

    Johnson Catherine; Zhang Ping-Wu; Zhou Wei-Zhen; Li Chuan-Yun; Wei Liping; Uhl George R

    2011-01-01

    Abstract Background Classical genetic studies provide strong evidence for heritable contributions to susceptibility to developing dependence on addictive substances. Candidate gene and genome-wide association studies (GWAS) have sought genes, chromosomal regions and allelic variants likely to contribute to susceptibility to drug addiction. Results Here, we performed a meta-analysis of addiction candidate gene association studies and GWAS to investigate possible functional mechanisms associate...

  16. Genetic susceptibility of newborn daughters to oxidative stress

    DEFF Research Database (Denmark)

    Decordier, Ilse; De Bont, Kelly; De Bock, Kirsten;

    2007-01-01

    challenge with H2O2 the repair capacity was assessed by the Comet assay and chromosome/genome mutations by the cytokinesis-block MN assay. No statistically significant differences were found between mothers and their newborn daughters either for initial DNA damage or for residual DNA damage. Mothers showed......A central question in risk assessment is whether newborns' susceptibility to mutagens is different from that of adults. Therefore we investigated whether genotype and/or the DNA strand break repair phenotype in combination with the MN assay would allow estimation of the relative sensitivity of a...

  17. Genetic polyrnorphisms in susceptibility to Type 1 Diabetes

    NARCIS (Netherlands)

    Alizadeh, Behrooz Z.; Koeleman, Bobby P. C.

    2008-01-01

    Type 1 Diabetes is a serious complex disease caused by several environmental and genetic factors. It is one of most common childhood diseases, requires life-long treatment, and is associated with increased mortality, mainly due to complications that occur later in life. More than three decades of ge

  18. Genetic selection for coping style predicts stressor susceptibility

    NARCIS (Netherlands)

    Veenema, AH; Meijer, OC; de Kloet, ER; Koolhaas, JM

    2003-01-01

    Genetically selected aggressive (SAL) and nonaggressive (LAL) male wild house-mice which show distinctly different coping styles, also display a differential regulation of the hypothalamic-pituitary-adrenal axis after exposure to an acute stressor. To test the hypothesis that coping style predicts s

  19. Cancer survivorship--genetic susceptibility and second primary cancers: research strategies and recommendations.

    OpenAIRE

    Travis, Lois B.; Rabkin, Charles S.; Brown, Linda Morris; Allan, James M.; Alter, Blanche P.; Ambrosone, Christine B.; Begg, Colin B.; Caporaso, Neil; Chanock, Stephen; DeMichele, Angela; Figg, William Douglas; Mary K Gospodarowicz; Hall, Eric J.; Hisada, Michie; Inskip, Peter

    2006-01-01

    KEYWORDS - CLASSIFICATION: adverse effects;Antineoplastic Agents;biomarkers of individual susceptibility: validation;Biotechnology;cancer epidemiology;chemically induced;Carcinogens;Case-Control Studies;Clinical Trials;Cohort Studies;Congresses;drug therapy;epidemiology;etiology;genetics;Genetic Predisposition to Disease;Humans;methods;mortality;Medical Informatics;Multicenter Studies;Neoplasms;Neoplasms,Radiation-Induced;Neoplasms,Second Primary;radiotherapy;Radiotherapy;Registries;Research;...

  20. Genetic polymorphisms of paraoxonase 1 and susceptibility to atherogenesis

    Directory of Open Access Journals (Sweden)

    Grubiša Ivana

    2013-01-01

    Full Text Available Introduction. Paraoxonase 1 (PON1 is a multifunctional enzyme associated with high-density lipoprotein particles (HDL. It is a cellular antioxidant that hydrolyses oxidized macromolecules, especially low-density lipoproteins (ox-LDL. Because increased oxidative stress is believed to play a crucial role in the initiation and propagation of atherosclerosis, coding (Q192R and L55M and promoter (C(-107T region polymorphisms of pon1 gene, that are responsible for catalytic efficiency, activity and the level of the enzyme, have been of great interest as a potential markers of susceptibility for atherogenesis. Objective. The aim of the study was to assess possible association between these pon1 gene variants and clinical manifestations of the atherosclerosis and oxidative stress. Methods. A total of 60 angiographically documented patients with manifested atherosclerotic disease and 100 control individuals were analyzed. Genomic DNA was isolated from the peripheral blood cells and genotyping was performed using polymerase chain reaction followed by the restriction fragment length polymorphism (PCR-RFLP analysis. Results No significant difference in allele and genotype frequencies of all three examined polymorphisms was found between the atherosclerotic patients and healthy controls. The obtained results could not support an association of pon1 gene variants with the oxidative stress and atherogenesis. Conclusion. These polymorphisms cannot be considered risk factors of atherosclerosis in Serbian population. A larger study is required in order to establish possible contribution of pon1 variants to atherosclerosis-related cardiovascular diseases. [Projekat Ministarstva nauke Republike Srbije, br. 175075

  1. Genetic markers between Biomphalaria glabrata snails susceptible and resistant to Schistosoma mansoni infection

    Directory of Open Access Journals (Sweden)

    RGM Spada

    2002-10-01

    Full Text Available The analysis of the genetic variability related to susceptibility to Schistosoma mansoni infection in the vector of the genus Biomphalaria is important in terms of a better understanding of the epidemiology of schistosomiasis itself, the possible pathological implications of this interaction in vertebrate hosts, and the formulation of new strategies and approaches for disease control. In the present study, the genetic variability of B. glabrata strains found to be resistant or susceptible to S. mansoni infection was investigated using DNA amplification by random amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR. The amplification products were analyzed on 8% polyacrylamide gel and stained with silver. We selected 10 primers, since they have previously been useful to detect polymorphism among B. glabrata and/or B. tenagophila. The results showed polymorphisms with 5 primers. Polymorphic bands observed only in the susceptible strain. The RAPD-PCR methodology represents an adequate approach for the analysis of genetic polymorphisms. The understanding of the genetic polymorphisms associated to resistance may contribute to the future identification of genomic sequences related to the resistance/susceptibility of Biomphalaria to the larval forms of S. mansoni and to the development of new strategies for the control of schistosomiasis.

  2. Genetic Based Plant Resistance and Susceptibility Traits to Herbivory Influence Needle and Root Litter Nutrient Dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Classen, Aimee T [ORNL; Chapman, Samantha K. [Smithsonian Environmental Research Center, Edgewater, MD; Whitham, Thomas G [Northern Arizona University; Hart, Stephen C [Northern Arizona University; Koch, George W [Northern Arizona University

    2007-01-01

    It is generally assumed that leaf and root litter decomposition have similar drivers and that nutrient release from these substrates is synchronized. Few studies have examined these assumptions, and none has examined how plant genetics (i.e., plant susceptibility to herbivory) could affect these relationships. Here we examine the effects of herbivore susceptibility and resistance on needle and fine root litter decomposition of pi on pine, Pinus edulis. The study population consists of individual trees that are either susceptible or resistant to herbivory by the pi on needle scale, Matsucoccus acalyptus, or the stem-boring moth, Dioryctria albovittella. Genetic analyses and experimental removals and additions of these insects have identified trees that are naturally resistant and susceptible to these insects. These herbivores increase the chemical quality of litter inputs and alter soil microclimate, both of which are important decomposition drivers. Our research leads to four major conclusions: Herbivore susceptibility and resistance effects on 1) needle litter mass loss and phosphorus (P) retention in moth susceptible and resistant litter are governed by microclimate, 2) root litter nitrogen (N) and P retention, and needle litter N retention are governed by litter chemical quality, 3) net nutrient release from litter can reverse over time, 4) root and needle litter mass loss and nutrient release are determined by location (above- vs. belowground), suggesting that the regulators of needle and root decomposition differ at the local scale. Understanding of decomposition and nutrient retention in ecosystems requires consideration of herbivore effects on above- and belowground processes and how these effects may be governed by plant genotype. Because an underlying genetic component to herbivory is common to most ecosystems of the world and herbivory may increase in climatic change scenarios, it is important to evaluate the role of plant genetics in affecting carbon and

  3. Susceptibility

    Czech Academy of Sciences Publication Activity Database

    Petrovský, Eduard

    Dordrecht: Springer, 2007 - (Gubbins, D.; Herrero-Bervera, E.), s. 931-933. (Encyclopedia of Earth sciences series). ISBN 978-1-4020-3992-8 Institutional research plan: CEZ:AV0Z30120515 Keywords : magnetic susceptibility * magnetic field * magnetization curve Subject RIV: DE - Earth Magnetism, Geodesy, Geography

  4. Fetal radiation exposure induces testicular cancer in genetically susceptible mice.

    Directory of Open Access Journals (Sweden)

    Gunapala Shetty

    Full Text Available The prevalence of testicular germ cell tumors (TGCT, a common solid tissue malignancy in young men, has been annually increasing at an alarming rate of 3%. Since the majority of testicular cancers are derived from germ cells at the stage of transformation of primordial germ cell (PGC into gonocytes, the increase has been attributed to maternal/fetal exposures to environmental factors. We examined the effects of an estrogen (diethylstilbestrol, DES, an antiandrogen (flutamide, or radiation on the incidence of testicular germ cell tumors in genetically predisposed 129.MOLF-L1 (L1 congenic mice by exposing them to these agents on days 10.5 and 11.5 of pregnancy. Neither flutamide nor DES produced noticeable increases in testis cancer incidence at 4 weeks of age. In contrast, two doses of 0.8-Gy radiation increased the incidence of TGCT from 45% to 100% in the offspring. The percentage of mice with bilateral tumors, weights of testes with TGCT, and the percentage of tumors that were clearly teratomas were higher in the irradiated mice than in controls, indicating that irradiation induced more aggressive tumors and/or more foci of initiation sites in each testis. This radiation dose did not disrupt spermatogenesis, which was qualitatively normal in tumor-free testes although they were reduced in size. This is the first proof of induction of testicular cancer by an environmental agent and suggests that the male fetus of women exposed to radiation at about 5-6 weeks of pregnancy might have an increased risk of developing testicular cancer. Furthermore, it provides a novel tool for studying the molecular and cellular events of testicular cancer pathogenesis.

  5. Red Cell Genetic Markers in Malarial Susceptibility and Selective Advantage Hypothesis

    Directory of Open Access Journals (Sweden)

    RS Balgir

    2014-02-01

    Full Text Available Malaria is still a serious public health challenge in many parts of the world including India. Human genetic susceptibility to malaria varies from individual to individual depending upon the genetic constitution and from region to region based on geo-ecological and climatic conditions. In the present study, intravenous 334 random blood samples of unrelated adult individuals belonging to Mongoloid ethnic stock were taken after informed consent from the endemic localities of Arunachal Pradesh, Assam and Nagaland to find out the relationship between the abnormal hemoglobin and G6PD enzyme deficiency, and susceptibility to malaria. Abnormal hemoglobin E and G6PD enzyme deficiency seem to interact with malarial parasite in such a way that they probably provide decreased susceptibility or inhibitory effect or increased resistance. Genetic alterations in human genome are maintained in the specific population by natural selection to protect the host against the malarial infection. These findings are consistent with those studies which support the notion of selective genetic advantage hypothesis against the malaria infection.

  6. American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.

    Science.gov (United States)

    Robson, Mark E; Bradbury, Angela R; Arun, Banu; Domchek, Susan M; Ford, James M; Hampel, Heather L; Lipkin, Stephen M; Syngal, Sapna; Wollins, Dana S; Lindor, Noralane M

    2015-11-01

    The American Society of Clinical Oncology (ASCO) has long affirmed that the recognition and management of individuals with an inherited susceptibility to cancer are core elements of oncology care. ASCO released its first statement on genetic testing in 1996 and updated that statement in 2003 and 2010 in response to developments in the field. In 2014, the Cancer Prevention and Ethics Committees of ASCO commissioned another update to reflect the impact of advances in this area on oncology practice. In particular, there was an interest in addressing the opportunities and challenges arising from the application of massively parallel sequencing-also known as next-generation sequencing-to cancer susceptibility testing. This technology introduces a new level of complexity into the practice of cancer risk assessment and management, requiring renewed effort on the part of ASCO to ensure that those providing care to patients with cancer receive the necessary education to use this new technology in the most effective, beneficial manner. The purpose of this statement is to explore the challenges of new and emerging technologies in cancer genetics and provide recommendations to ensure their optimal deployment in oncology practice. Specifically, the statement makes recommendations in the following areas: germline implications of somatic mutation profiling, multigene panel testing for cancer susceptibility, quality assurance in genetic testing, education of oncology professionals, and access to cancer genetic services. PMID:26324357

  7. Patients' understanding of genetic susceptibility testing in mainstream medicine: qualitative study on thrombophilia

    Directory of Open Access Journals (Sweden)

    Shepherd Maggie H

    2007-06-01

    Full Text Available Abstract Background UK and US policy initiatives have suggested that, in the future, patients and clinicians in mainstream medicine could use genetic information to prevent common illnesses. There are no studies on patients' experience and understanding of the process of testing for common genetic susceptibilities in mainstream medicine. Methods Qualitative interviews with 42 individuals who had undergone testing for a genetic susceptibility for deep vein thrombosis in primary and secondary care in the UK. Results Some participants, often from higher social classes, had a good understanding of the test and its implications. They had often sought additional information on thrombophilia from relatives and from the Internet. Others, often from less privileged backgrounds, had a poorer understanding of the test – seven individuals were unaware of having had the genetic test. Features of genetic information led to misunderstandings: (i at referral, (ii when communicating results, and (iii when making sense of the implications of testing. Participants' accounts indicated that non-specialist doctors may feel obliged to refer a patient for a genetic test they know little about, because a patient requests it after a relative had tested positive. Sometimes a referral for a genetic test was lost under information overload when multiple tests and issues were considered. The inconsistent and informal ways of communicating test results – for example by phone – in mainstream medicine also led to confusion. Participants did not generally overestimate their risk, but some were uncertain about whether they were taking the right preventive actions and/or whether their children were at risk. Information about genetic susceptibilities was difficult to make sense of, as it related to ambiguous risks for participants and family members, complicated and unfamiliar terminology and multiple genes and preventive strategies. Conclusion Policy visions of clinicians

  8. Lung cancer susceptibility model based on age, family history and genetic variants.

    Directory of Open Access Journals (Sweden)

    Robert P Young

    Full Text Available BACKGROUND: Epidemiological and pedigree studies suggest that lung cancer results from the combined effects of age, smoking, impaired lung function and genetic factors. In a case control association study of healthy smokers and lung cancer cases, we identified genetic markers associated with either susceptibility or protection to lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: We screened 157 candidate single nucleotide polymorphisms (SNP in a discovery cohort of 439 subjects (200 controls and 239 lung cancer cases and identified 30 SNPs associated with either the healthy smokers (protective or lung cancer (susceptibility phenotype. After genotyping this 30 SNP panel in a validation cohort of 491 subjects (248 controls and 207 lung cancers and, using the same protective and susceptibility genotypes from our discovery cohort, a 20 SNP panel was selected based on replication of SNP associations in the validation cohort. Following multivariate logistic regression analyses, including the selected SNPs from runs 1 and 2, we found age and family history of lung cancer to be significantly and independently associated with lung cancer. Numeric scores were assigned to both the SNP and demographic data, and combined to form a simple algorithm of risk. CONCLUSIONS/SIGNIFICANCE: Significant differences in the distribution of the lung cancer susceptibility score was found between normal controls and lung cancer cases, which remained after accounting for differences in lung function. Validation in other case-control and prospective cohorts are underway to further define the potential clinical utility of this model.

  9. Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility

    DEFF Research Database (Denmark)

    Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B;

    2016-01-01

    Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and.......5 × 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry....

  10. Genetic susceptibility to systemic lupus erythematosus protects against cerebral malaria in mice

    OpenAIRE

    Waisberg, Michael; Tarasenko, Tatyana; Brandi K Vickers; Scott, Bethany L.; Willcocks, Lisa C.; Molina-Cruz, Alvaro; Pierce, Matthew A.; Huang, Chiung-Yu; Torres-Velez, Fernando J.; Smith, Kenneth G.C.; Barillas-Mury, Carolina; Miller, Louis H.; Pierce, Susan K.; Bolland, Silvia

    2010-01-01

    Plasmodium falciparum has exerted tremendous selective pressure on genes that improve survival in severe malarial infections. Systemic lupus erythematosus (SLE) is an autoimmune disease that is six to eight times more prevalent in women of African descent than in women of European descent. Here we provide evidence that a genetic susceptibility to SLE protects against cerebral malaria. Mice that are prone to SLE because of a deficiency in FcγRIIB or overexpression of Toll-like receptor 7 are p...

  11. The Impact of Genetic Susceptibility to Systemic Lupus Erythematosus on Placental Malaria in Mice

    OpenAIRE

    Waisberg, Michael; Lin, Christina K.; Huang, Chiung-Yu; Pena, Mirna; Orandle, Marlene; Bolland, Silvia; Pierce, Susan K.

    2013-01-01

    Severe malaria, including cerebral malaria (CM) and placental malaria (PM), have been recognized to have many of the features of uncontrolled inflammation. We recently showed that in mice genetic susceptibility to the lethal inflammatory autoimmune disease, systemic lupus erythematosus (SLE), conferred resistance to CM. Protection appeared to be mediated by immune mechanisms that allowed SLE-prone mice, prior to the onset of overt SLE symptoms, to better control their inflammatory response to...

  12. Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans

    OpenAIRE

    Chen, Fang; Chen, Gary K.; Millikan, Robert C.; John, Esther M; Ambrosone, Christine B.; Bernstein, Leslie; Zheng, Wei; Jennifer J Hu; Ziegler, Regina G.; Deming, Sandra L.; Bandera, Elisa V.; Nyante, Sarah; Palmer, Julie R.; Rebbeck, Timothy R.; Sue A Ingles

    2011-01-01

    Genome-wide association studies (GWAS) have revealed 19 common genetic variants that are associated with breast cancer risk. Testing of the index signals found through GWAS and fine-mapping of each locus in diverse populations will be necessary for characterizing the role of these risk regions in contributing to inherited susceptibility. In this large study of breast cancer in African-American women (3016 cases and 2745 controls), we tested the 19 known risk variants identified by GWAS and re...

  13. Genetic Variation in the Dectin-1/CARD9 Recognition Pathway and Susceptibility to Candidemia

    OpenAIRE

    Rosentul, Diana C.; Plantinga, Theo S.; Oosting, Marije; Scott, William K.; Digna R. Velez Edwards; Smith, P. Brian; Alexander, Barbara D.; Yang, John C.; Laird, Gregory M.; Joosten, Leo A. B.; van der Meer, Jos W.M.; Perfect, John R.; Kullberg, Bart-Jan; Mihai G Netea; Johnson, Melissa D.

    2011-01-01

    Background. Candidemia is an important cause of morbidity and mortality in critically ill patients or patients undergoing invasive treatments. Dectin-1 is the main β-glucan receptor, and patients with a complete deficiency of either dectin-1 or its adaptor molecule CARD9 display persistent mucosal infections with Candida albicans. The role of genetic variation of DECTIN-1 and CARD9 genes on the susceptibility to candidemia is unknown.

  14. The impact of genetic susceptibility to systemic lupus erythematosus on placental malaria in mice.

    Directory of Open Access Journals (Sweden)

    Michael Waisberg

    Full Text Available Severe malaria, including cerebral malaria (CM and placental malaria (PM, have been recognized to have many of the features of uncontrolled inflammation. We recently showed that in mice genetic susceptibility to the lethal inflammatory autoimmune disease, systemic lupus erythematosus (SLE, conferred resistance to CM. Protection appeared to be mediated by immune mechanisms that allowed SLE-prone mice, prior to the onset of overt SLE symptoms, to better control their inflammatory response to Plasmodium infection. Here we extend these findings to ask does SLE susceptibility have 1 a cost to reproductive fitness and/or 2 an effect on PM in mice? The rates of conception for WT and SLE susceptible (SLE(s mice were similar as were the number and viability of fetuses in pregnant WT and SLE(s mice indicating that SLE susceptibility does not have a reproductive cost. We found that Plasmodium chabaudi AS (Pc infection disrupted early stages of pregnancy before the placenta was completely formed resulting in massive decidual necrosis 8 days after conception. Pc-infected pregnant SLE(s mice had significantly more fetuses (∼1.8 fold but SLE did not significantly affect fetal viability in infected animals. This was despite the fact that Pc-infected pregnant SLE(s mice had more severe symptoms of malaria as compared to Pc-infected pregnant WT mice. Thus, although SLE susceptibility was not protective in PM in mice it also did not have a negative impact on reproductive fitness.

  15. Mitochondrial DNA Haplogroup A may confer a genetic susceptibility to AIDS group from Southwest China.

    Science.gov (United States)

    Wang, Hua-Wei; Xu, Yu; Miao, Ying-Lei; Luo, Hua-You; Wang, Kun-Hua

    2016-05-01

    The acquired immunodeficiency syndrome (AIDS) in humans was one of the chronic infections caused by human immunodeficiency virus (HIV), and the interactions between viral infection and mitochondrial energetic implicated that mitochondrial DNA (mtDNA) variation(s) may effect genetic susceptibility to AIDS. Thus, to illustrate the maternal genetic structure and further identify whether mtDNA variation(s) can effect HIV infection among southwest Chinese AIDS group, the whole mtDNA control region sequences of 70 AIDS patients and 480 health individuals from southwest China were analyzed here. Our results indicated the plausible recent genetic admixture results of AIDS group; comparison of matrilineal components between AIDS and matched Han groups showed that mtDNA haplogroup A (p = 0.048, OR = 3.006, 95% CI = 1.109-8.145) has a significant higher difference between the two groups; further comparison illustrated that mtDNA mutations 16,209 (p = 0.046, OR = 2.607, 95% CI = 0.988-6.876) and 16,319 (p = 0.009, OR = 2.965, 95% CI = 1.278-6.876) have significant differences between AIDS and matched control groups, and both of which were the defining variations of mtDNA haplogroup A, they further confirmed that mtDNA haplogroup A may confer genetic susceptibility to AIDS. Our results suggested that haplogroup A may confer a genetic susceptibility to AIDS group from Southwest China. PMID:25431816

  16. Cellular basis of the genetic susceptibility of murine experimental allergic encephalomyelitis

    International Nuclear Information System (INIS)

    Murine experimental allergic encephalomyelitis (EAE) is an induced autoimmune disease that resembles human multiple sclerosis. The authors have investigated the cellular basis of the genetic predisposition and resistance of inbred strains of mice to EAE using an adoptive transfer system between two H-2 compatible, Thy 1 antigen disparate strains of mice. Genetically EAE susceptible SJL/J strain mice (H-2/sup s/, Thy 1.2) and resistant B10.S Thy 1.1 (H-2/sub s/, Thy 1.1) strain mice were lethally irradiated (700R) and reconstituted with 5-10 x 106 bone marrow cells from either SJL/J or congenic B10.S (Thy 1.1 or Thy 1.2) donors. After 30-45 days, more than 95% of the thymocytes and 75% of the peripheral T cells in the chimeras were of donor origin. These lymphohemopoietic chimeras were then sensitized in their hind footpads with porcine myelin basic protein in complete Freund's adjuvant containing M. tuberculosis H37RA, followed at 24 and 72 hours by i.v. injection of B. pertussis. Clinical signs of EAE developed in unirradiated SJL/J, but not B10.S, controls, and in irradiated B10.S and SJL/J recipients of SJL/J, but not B10.S, bone marrow. These results indicate that bone marrow cells can transfer the predisposition to EAE from genetically susceptible to genetically resistant mouse strains. The cellular component in the bone marrow that is responsible for the transfer of the genetic susceptibility to EAE is under investigation

  17. Risk of colorectal adenomas in relation to meat consumption, meat preparation, and genetic susceptibility in a Dutch population

    NARCIS (Netherlands)

    Tiemersma, E.W.; Voskuil, D.W.; Bunschoten, A.; Kok, F.J.; Kampman, E.

    2004-01-01

    Objective: We studied the association between meat consumption and colorectal adenomas, and potential influence of genetic susceptibility to heterocyclic aromatic amines (HCAs) formed during meat cooking at high temperatures. Methods: We studied HCA concentration in relation to preparation habits am

  18. Risk of colorectal adenomas in relation to meat consumption, meat preparation, and genetic susceptibility in a Dutch population.

    NARCIS (Netherlands)

    Tiemersma, E.W.; Voskuil, D.W.; Bunschoten, A.; Hogendoorn, E.A.; Witteman, B.J.M.; Nagengast, F.M.; Glatt, H.; Kok, F.J.; Kampman, E.

    2004-01-01

    OBJECTIVE: We studied the association between meat consumption and colorectal adenomas, and potential influence of genetic susceptibility to heterocyclic aromatic amines (HCAs) formed during meat cooking at high temperatures. METHODS: We studied HCA concentration in relation to preparation habits am

  19. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.

    Science.gov (United States)

    2003-06-15

    As the leading organization representing cancer specialists involved in patient care and clinical research, the American Society of Clinical Oncology (ASCO) reaffirms its commitment to integrating cancer risk assessment and management, including molecular analysis of cancer predisposition genes, into the practice of oncology and preventive medicine. The primary goal of this effort is to foster expanded access to, and continued advances in, medical care provided to patients and families affected by hereditary cancer syndromes. The 1996 ASCO Statement on Genetic Testing for Cancer Susceptibility set forth specific recommendations relating to clinical practice, research needs, educational opportunities, requirement for informed consent, indications for genetic testing, regulation of laboratories, and protection from discrimination, as well as access to and reimbursement for cancer genetics services. In updating this Statement, ASCO endorses the following principles: Indications for Genetic Testing: ASCO recommends that genetic testing be offered when 1) the individual has personal or family history features suggestive of a genetic cancer susceptibility condition, 2) the test can be adequately interpreted, and 3) the results will aid in diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer. ASCO recommends that genetic testing only be done in the setting of pre- and post-test counseling, which should include discussion of possible risks and benefits of cancer early detection and prevention modalities. Special Issues in Testing Children for Cancer Susceptibility: ASCO recommends that the decision to offer testing to potentially affected children should take into account the availability of evidence-based risk-reduction strategies and the probability of developing a malignancy during childhood. Where risk-reduction strategies are available or cancer predominantly develops in childhood, ASCO believes that

  20. Genetically determined inflammatory-response related cytokine and chemokine transcript profiles between mammary carcinoma resistant and susceptible rat strains

    OpenAIRE

    Devapatla, Bharat; Sanders, Jennifer; Samuelson, David J.

    2012-01-01

    Multiple human breast and rat mammary carcinoma susceptibility (Mcs) alleles have been identified. Wistar Kyoto (WKY) rats are resistant to developing mammary carcinomas, while Wistar Furth (WF) females are susceptible. Gene transcripts at Mcs5a1, Mcs5a2, and Mcs5c are differentially expressed between resistant WKY and susceptible WF alleles in immune-system tissues. We hypothesized that immune-related gene transcript profiles are genetically determined in mammary carcinoma resistant and susc...

  1. Genome-wide Association Study Identifies HLA 8.1 Ancestral Haplotype Alleles as Major Genetic Risk Factors for Myositis Phenotypes

    OpenAIRE

    Miller, Frederick W.; Chen, Wei; O’Hanlon, Terrance P.; Cooper, Robert G.; Vencovsky, Jiri; Rider, Lisa G; Danko, Katalin; Wedderburn, Lucy R; Lundberg, Ingrid E; Pachman, Lauren M.; Reed, Ann M.; Ytterberg, Steven R.; Padyukov, Leonid; Selva-O’Callaghan, Albert; Radstake, Timothy R.

    2015-01-01

    Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis; 473 juvenile dermatomyositis; 532 polymyositis; and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl tRN...

  2. Interleukin-16 Gene Polymorphisms Are Considerable Host Genetic Factors for Patients’ Susceptibility to Chronic Hepatitis B Infection

    OpenAIRE

    Sara Romani; Seyed Masoud Hosseini; Seyed Reza Mohebbi; Shabnam Kazemian; Shaghayegh Derakhshani; Mahsa Khanyaghma; Pedram Azimzadeh; Afsaneh Sharifian; Mohammad Reza Zali

    2014-01-01

    Host genetic background is known as an important factor in patients’ susceptibility to infectious diseases such as viral hepatitis. The aim of this study was to determine the effect of genetic polymorphisms of interleukin-16 (IL-16) cytokine on susceptibility of hepatitis B virus (HBV) infected patients to develop chronic HBV infection. Genotyping was conducted using PCR followed by enzymatic digestion and RFLP (restriction fragment length polymorphism) analysis. We genotyped three single nuc...

  3. Relative susceptibilities of male germ cells to genetic defects induced by cancer chemotherapies

    Energy Technology Data Exchange (ETDEWEB)

    Wyrobek, A J; Schmid, T E; Marchetti, F

    2004-06-15

    Some chemotherapy regimens include agents that are mutagenic or clastogenic in model systems. This raises concerns that cancer survivors, who were treated before or during their reproductive years, may be at increased risks for abnormal reproductive outcomes. However, the available data from offspring of cancer survivors are limited, representing diverse cancers, therapies, time-to-pregnancies, and reproductive outcomes. Rodent breeding data after paternal exposures to individual chemotherapeutic agents illustrate the complexity of factors that influence the risk for transmitted genetic damage including agent, dose, endpoint, and the germ-cell susceptibility profiles that vary across agents. Direct measurements of chromosomal abnormalities in sperm of mice and humans by sperm FISH have corroborated the differences in germ-cell susceptibilities. The available evidence suggests that the risk of producing chromosomally defective sperm is highest during the first few weeks after the end of chemotherapy, and decays with time. Thus, sperm samples provided immediately after the initiation of cancer therapies may contain treatment-induced genetic defects that will jeopardize the genetic health of offspring.

  4. No association between genetic ancestry and susceptibility to asthma or atopy in Canary Islanders.

    Science.gov (United States)

    Pino-Yanes, María; Corrales, Almudena; Cumplido, José; González, Ruperto; Torres-Galván, María José; Fernández, Orlando Acosta; Sánchez-Machín, Inmaculada; Figueroa, Javier; Sánchez-Palacios, Anselmo; Villar, Jesús; Hernández, Mariano; Carrillo, Teresa; Flores, Carlos

    2012-09-01

    Asthma is a complex respiratory disease characterized by chronic inflammation of airways and frequently associated with atopic symptoms. The population from the Canary Islands, which has resulted from a recent admixture of North African and Iberian populations, shows the highest prevalence of asthma and atopic symptoms among the Spanish populations. Although environmental particularities would account for the majority of such disparity, genetic ancestry might play a role in increasing the susceptibility of asthma or atopy, as have been demonstrated in other recently African-admixed populations. Here, we aimed to explore whether genetic ancestry was associated with asthma or related traits in the Canary Islanders. For that, a total of 734 DNA samples from unrelated individuals of the GOA study, self-reporting at least two generations of ancestors from the Canary Islands (391 asthmatics and 343 controls), were successfully genotyped for 83 ancestry informative markers (AIMs), which allowed to precisely distinguishing between North African and Iberian ancestries. No association was found between genetic ancestry and asthma or related traits after adjusting by demographic variables differing among compared groups. Similarly, none of the individual AIMs was associated with asthma when results were considered in the context of the multiple comparisons performed (0.005 ≤ p value ≤ 0.042; 0.221 ≤ q value ≤ 0.443). Our results suggest that if genetic ancestry were involved in the susceptibility to asthma or related traits among Canary Islanders, its effects would be modest. Larger studies, examining more genetic variants, would be needed to explore such possibility. PMID:22710824

  5. Genetic control of immune response in carriers of the 8.1 ancestral haplotype: correlation with levels of IgG subclasses: its relevance in the pathogenesis of autoimmune diseases.

    Science.gov (United States)

    Candore, Giuseppina; Campagna, Anna Maria; Cuppari, Irene; Di Carlo, Daniele; Mineo, Claudia; Caruso, Calogero

    2007-09-01

    Ancestral haplotype (AH) 8.1(HLA-A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*0301, DRB3*0101, DQA1*0501, DQB1*0201) seems to be associated with susceptibility to autoimmune diseases. Different mechanisms are probably involved in increasing autoimmunity, such as unbalanced cytokine production and the lack of C4A protein. So AH 8.1 modifies immune response in many ways. In this study we demonstrate that IgG2 serum levels were significantly lower in 8.1 AH carriers than in 8.1 AH non-carriers. On the contrary, as regards IgG1, IgG3, IgG4 serum levels, no significant differences were observed between the two groups. In AH 8.1 carriers low IgG2 levels might take to slower clearance of the infectious agent and hence to a lasting presence of it. The persistence of infectious antigens could determine an increased production of autoantibodies with a higher risk of cross-reactions. PMID:17911430

  6. Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes.

    Science.gov (United States)

    Miller, F W; Chen, W; O'Hanlon, T P; Cooper, R G; Vencovsky, J; Rider, L G; Danko, K; Wedderburn, L R; Lundberg, I E; Pachman, L M; Reed, A M; Ytterberg, S R; Padyukov, L; Selva-O'Callaghan, A; Radstake, T R; Isenberg, D A; Chinoy, H; Ollier, W E R; Scheet, P; Peng, B; Lee, A; Byun, J; Lamb, J A; Gregersen, P K; Amos, C I

    2015-10-01

    Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (PAH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations. PMID:26291516

  7. Genetic susceptibility to family environment: BDNF Val66met and 5-HTTLPR influence depressive symptoms.

    Science.gov (United States)

    Dalton, Elizabeth D; Hammen, Constance L; Najman, Jake M; Brennan, Patricia A

    2014-12-01

    Functional genetic polymorphisms associated with Brain-Derived Neurotrophic Factor (BDNF) and serotonin (5-HTTLPR) have demonstrated associations with depression in interaction with environmental stressors. In light of evidence for biological connections between BDNF and serotonin, it is prudent to consider genetic epistasis between variants in these genes in the development of depressive symptoms. The current study examined the effects of val66met, 5-HTTLPR, and family environment quality on youth depressive symptoms in adolescence and young adulthood in a longitudinal sample oversampled for maternal depression history. A differential susceptibility model was tested, comparing the effects of family environment on depression scores across different levels of a cumulative plasticity genotype, defined as presence of both, either, or neither plasticity alleles (defined here as val66met Met and 5-HTTLPR 'S'). Cumulative plasticity genotype interacted with family environment quality to predict depression among males and females at age 15. After age 15, however, the interaction of cumulative plasticity genotype and early family environment quality was only predictive of depression among females. Results supported a differential susceptibility model at age 15, such that plasticity allele presence was associated with more or less depressive symptoms depending on valence of the family environment, and a diathesis-stress model of gene-environment interaction after age 15. These findings, although preliminary because of the small sample size, support prior results indicating interactive effects of 5-HTTLPR, val66met, and environmental stress, and suggest that family environment may have a stronger influence on genetically susceptible women than men. PMID:25347540

  8. The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy.

    Science.gov (United States)

    Jodele, Sonata; Zhang, Kejian; Zou, Fanggeng; Laskin, Benjamin; Dandoy, Christopher E; Myers, Kasiani C; Lane, Adam; Meller, Jaroslav; Medvedovic, Mario; Chen, Jenny; Davies, Stella M

    2016-02-25

    Transplant-associated thrombotic microangiopathy (TA-TMA) occurs frequently after hematopoietic stem cell transplantation (HSCT) and can lead to significant morbidity and mortality. There are no data addressing individual susceptibility to TA-TMA. We performed a hypothesis-driven analysis of 17 candidate genes known to play a role in complement activation as part of a prospective study of TMA in HSCT recipients. We examined the functional significance of gene variants by using gene expression profiling. Among 77 patients undergoing genetic testing, 34 had TMA. Sixty-five percent of patients with TMA had genetic variants in at least one gene compared with 9% of patients without TMA (P < .0001). Gene variants were increased in patients of all races with TMA, but nonwhites had more variants than whites (2.5 [range, 0-7] vs 0 [range, 0-2]; P < .0001). Variants in ≥3 genes were identified only in nonwhites with TMA and were associated with high mortality (71%). RNA sequencing analysis of pretransplantation samples showed upregulation of multiple complement pathways in patients with TMA who had gene variants, including variants predicted as possibly benign by computer algorithm, compared with those without TMA and without gene variants. Our data reveal important differences in genetic susceptibility to HSCT-associated TMA based on recipient genotype. These data will allow prospective risk assessment and intervention to prevent TMA in highly susceptible transplant recipients. Our findings may explain, at least in part, racial disparities previously reported in transplant recipients and may guide treatment strategies to improve outcomes. PMID:26603840

  9. Association of cancer stem cell markers genetic variants with gallbladder cancer susceptibility, prognosis, and survival.

    Science.gov (United States)

    Yadav, Anu; Gupta, Annapurna; Rastogi, Neeraj; Agrawal, Sushma; Kumar, Ashok; Kumar, Vijay; Mittal, Balraj

    2016-02-01

    Genes important to stem cell progression have been involved in the genetics and clinical outcome of cancers. We investigated germ line variants in cancer stem cell (CSC) genes to predict susceptibility and efficacy of chemoradiotherapy treatment in gallbladder cancer (GBC) patients. In this study, we assessed the effect of SNPs in CSC genes (surface markers CD44, ALCAM, EpCAM, CD133) and (molecular markers NANOG, SOX-2, LIN-28A, ALDH1A1, OCT-4) with GBC susceptibility and prognosis. Total 610 GBC patients and 250 controls were genotyped by using PCR-RFLP, ARMS-PCR, and TaqMan allelic discrimination assays. Chemotoxicity graded 2-4 in 200 patients and tumor response was recorded in 140 patients undergoing neoadjuvant chemotherapy (NACT). Differences in genotype and haplotype frequency distributions were calculated by binary logistic regression. Gene-gene interaction model was analyzed by generalized multifactor dimensionality reduction (GMDR). Overall survival was assessed by Kaplan-Meier survival curve and multivariate Cox-proportional methods. ALCAM Ars1157Crs10511244 (P = 0.0035) haplotype was significantly associated with GBC susceptibility. In GMDR analysis, ALCAM rs1157G>A, EpCAM rs1126497T>C emerged as best significant interaction model with GBC susceptibility and ALDH1A1 rs13959T>G with increased risk of grade 3-4 hematological toxicity. SOX-2 rs11915160A>C, OCT-4 rs3130932T>G, and NANOG rs11055786T>C were found best gene-gene interaction model for predicting response to NACT. In both Cox-proportional and recursive partitioning ALCAM rs1157GA+AA genotype showed higher mortality and hazard ratio. ALCAM gene polymorphisms associated with GBC susceptibility and survival while OCT-4, SOX-2, and NANOG variants showed an interactive role with treatment response. PMID:26318430

  10. Genetic mutation susceptibility of hearing loss in child with severe neonatal jaundice

    International Nuclear Information System (INIS)

    This case report demonstrates a case of 5-year-old non-syndromic Malay boy who passed the hearing screening test however he was confirmed has bilateral profound sensorineural hearing loss diagnosed at 3 months of age by brain stem evoked response (BSER). He has background history of severe neonatal jaundice and male siblings of hearing impairment. The antenatal and birth history was uneventful apart from maternal hypothyroidism. His other two elder brothers have bilateral sensorineural hearing loss and history of severe neonatal jaundice as well. The ear examinations, computed tomography scan and magnetic resonance imaging revealed normal findings. Right sided cochlear implantation was done at the age of 3 years old and he is still under audiology follow-up. Conclusion: Genetic studies are important to determine the cause of genetic mutation in susceptibility to hearing impairment that run in his family after severe neonatal jaundice. Those baby with risk of developing hearing loss required diagnostic hearing assessment. (author)

  11. Future management of human obesity: understanding the meaning of genetic susceptibility

    Directory of Open Access Journals (Sweden)

    Jenkins AB

    2014-12-01

    Full Text Available Arthur B Jenkins,1,2 Lesley V Campbell2,3 1School of Medicine, University of Wollongong, Wollongong, NSW, Australia; 2Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia; 3Diabetes Centre and Department of Endocrinology, St Vincent's Hospital, Sydney, NSW, Australia Abstract: Gene–environment interactions are central to the expression of obesity. The condition is strongly heritable (ie, genetic, and most of the variation in obesity levels between countries and between individuals can be explained by the effects of obesogenic environments on individual genetic susceptibilities. The nature of the obesogenic environmental influences is not clear in detail, but they correlate closely with measures of affluence. The causes of variation in genetic susceptibility are also not clearly defined, but their general nature has become clearer. The failure of genome-wide association studies or large linkage studies to identify or replicate causative genetic variants, together with the segregation of obesity-related traits in families, implicates a heterogenetic mechanism in which rare, dominantly or additively expressed genetic variants are responsible for most of common obesity. The search for rare causative variants continues with some successes, but those identified contribute very little to the overall burden and, assuming heterogenetics, there are many more to find. The time when genomic risk factors provide more information than do currently available markers, such as family history, is a long way off. Genomic studies to date have contributed little, if anything, to the prevention and treatment of common obesity and its associated disorders. This contrasts with the obvious and immediate potential implications of the well-established overall genetic basis of obesity, which have not yet been exploited in the clinical or public health arenas. Genomic studies, which have helped to define the genetic basis of

  12. Genetic testing of newborns for type 1 diabetes susceptibility: a prospective cohort study on effects on maternal mental health

    OpenAIRE

    Magnus Per; Kise Marit S; Tambs Kristian; Aas Kaja K; Rønningen Kjersti S

    2010-01-01

    Abstract Background Concerns about the general psychological impact of genetic testing have been raised. In the Environmental Triggers of Type 1 Diabetes (MIDIA) study, genetic testing was performed for HLA-conferred type 1 diabetes susceptibility among Norwegian newborns. The present study assessed whether mothers of children who test positively suffer from poorer mental health and well-being after receiving genetic risk information about their children. Methods The study was based on questi...

  13. Identifying predictors of activity based anorexia susceptibility in diverse genetic rodent populations.

    Directory of Open Access Journals (Sweden)

    Eneda Pjetri

    Full Text Available Animal studies are very useful in detection of early disease indicators and in unravelling the pathophysiological processes underlying core psychiatric disorder phenotypes. Early indicators are critical for preventive and efficient treatment of progressive psychiatric disorders like anorexia nervosa. Comparable to physical hyperactivity observed in anorexia nervosa patients, in the activity-based anorexia rodent model, mice and rats express paradoxical high voluntary wheel running activity levels when food restricted. Eleven inbred mouse strains and outbred Wistar WU rats were exposed to the activity-based anorexia model in search of identifying susceptibility predictors. Body weight, food intake and wheel running activity levels of each individual mouse and rat were measured. Mouse strains and rats with high wheel running activity levels during food restriction exhibited accelerated body weight loss. Linear mixed models for repeated measures analysis showed that baseline wheel running activity levels preceding the scheduled food restriction phase strongly predicted activity-based anorexia susceptibility (mice: Beta  =  -0.0158 (±0.003 SE, P<0.0001; rats: Beta  =  -0.0242 (±0.004 SE, P<0.0001 compared to other baseline parameters. These results suggest that physical activity levels play an important role in activity-based anorexia susceptibility in different rodent species with genetically diverse background. These findings support previous retrospective studies on physical activity levels in anorexia nervosa patients and indicate that pre-morbid physical activity levels could reflect an early indicator for disease severity.

  14. Identifying predictors of activity based anorexia susceptibility in diverse genetic rodent populations.

    Science.gov (United States)

    Pjetri, Eneda; de Haas, Ria; de Jong, Simone; Gelegen, Cigdem; Oppelaar, Hugo; Verhagen, Linda A W; Eijkemans, Marinus J C; Adan, Roger A; Olivier, Berend; Kas, Martien J

    2012-01-01

    Animal studies are very useful in detection of early disease indicators and in unravelling the pathophysiological processes underlying core psychiatric disorder phenotypes. Early indicators are critical for preventive and efficient treatment of progressive psychiatric disorders like anorexia nervosa. Comparable to physical hyperactivity observed in anorexia nervosa patients, in the activity-based anorexia rodent model, mice and rats express paradoxical high voluntary wheel running activity levels when food restricted. Eleven inbred mouse strains and outbred Wistar WU rats were exposed to the activity-based anorexia model in search of identifying susceptibility predictors. Body weight, food intake and wheel running activity levels of each individual mouse and rat were measured. Mouse strains and rats with high wheel running activity levels during food restriction exhibited accelerated body weight loss. Linear mixed models for repeated measures analysis showed that baseline wheel running activity levels preceding the scheduled food restriction phase strongly predicted activity-based anorexia susceptibility (mice: Beta  =  -0.0158 (±0.003 SE), Pphysical activity levels play an important role in activity-based anorexia susceptibility in different rodent species with genetically diverse background. These findings support previous retrospective studies on physical activity levels in anorexia nervosa patients and indicate that pre-morbid physical activity levels could reflect an early indicator for disease severity. PMID:23226287

  15. Host genetics determine susceptibility to avian influenza infection and transmission dynamics.

    Science.gov (United States)

    Ruiz-Hernandez, Raul; Mwangi, William; Peroval, Marylene; Sadeyen, Jean-Remy; Ascough, Stephanie; Balkissoon, Devanand; Staines, Karen; Boyd, Amy; McCauley, John; Smith, Adrian; Butter, Colin

    2016-01-01

    Host-genetic control of influenza virus infection has been the object of little attention. In this study we determined that two inbred lines of chicken differing in their genetic background , Lines 0 and C-B12, were respectively relatively resistant and susceptible to infection with the low pathogenicity influenza virus A/Turkey/England/647/77 as defined by substantial differences in viral shedding trajectories. Resistant birds, although infected, were unable to transmit virus to contact birds, as ultimately only the presence of a sustained cloacal shedding (and not oropharyngeal shedding) was critical for transmission. Restriction of within-bird transmission of virus occurred in the resistant line, with intra-nares or cloacal infection resulting in only local shedding and failing to transmit fully through the gastro-intestinal-pulmonary tract. Resistance to infection was independent of adaptive immune responses, including the expansion of specific IFNγ secreting cells or production of influenza-specific antibody. Genetic resistance to a novel H9N2 virus was less robust, though significant differences between host genotypes were still clearly evident. The existence of host-genetic determination of the outcome of influenza infection offers tools for the further dissection of this regulation and also for understanding the mechanisms of influenza transmission within and between birds. PMID:27279280

  16. Host genetics determine susceptibility to avian influenza infection and transmission dynamics

    Science.gov (United States)

    Ruiz-Hernandez, Raul; Mwangi, William; Peroval, Marylene; Sadeyen, Jean-Remy; Ascough, Stephanie; Balkissoon, Devanand; Staines, Karen; Boyd, Amy; McCauley, John; Smith, Adrian; Butter, Colin

    2016-01-01

    Host-genetic control of influenza virus infection has been the object of little attention. In this study we determined that two inbred lines of chicken differing in their genetic background , Lines 0 and C-B12, were respectively relatively resistant and susceptible to infection with the low pathogenicity influenza virus A/Turkey/England/647/77 as defined by substantial differences in viral shedding trajectories. Resistant birds, although infected, were unable to transmit virus to contact birds, as ultimately only the presence of a sustained cloacal shedding (and not oropharyngeal shedding) was critical for transmission. Restriction of within-bird transmission of virus occurred in the resistant line, with intra-nares or cloacal infection resulting in only local shedding and failing to transmit fully through the gastro-intestinal-pulmonary tract. Resistance to infection was independent of adaptive immune responses, including the expansion of specific IFNγ secreting cells or production of influenza-specific antibody. Genetic resistance to a novel H9N2 virus was less robust, though significant differences between host genotypes were still clearly evident. The existence of host-genetic determination of the outcome of influenza infection offers tools for the further dissection of this regulation and also for understanding the mechanisms of influenza transmission within and between birds. PMID:27279280

  17. Differential genetic susceptibility to child risk at birth in predicting observed maternal behavior.

    Directory of Open Access Journals (Sweden)

    Keren Fortuna

    Full Text Available This study examined parenting as a function of child medical risks at birth and parental genotype (dopamine D4 receptor; DRD4. Our hypothesis was that the relation between child risks and later maternal sensitivity would depend on the presence/absence of a genetic variant in the mothers, thus revealing a gene by environment interaction (GXE. Risk at birth was defined by combining risk indices of children's gestational age at birth, birth weight, and admission to the neonatal intensive care unit. The DRD4-III 7-repeat allele was chosen as a relevant genotype as it was recently shown to moderate the effect of environmental stress on parental sensitivity. Mothers of 104 twin pairs provided DNA samples and were observed with their children in a laboratory play session when the children were 3.5 years old. Results indicate that higher levels of risk at birth were associated with less sensitive parenting only among mothers carrying the 7-repeat allele, but not among mothers carrying shorter alleles. Moreover, mothers who are carriers of the 7-repeat allele and whose children scored low on the risk index were observed to have the highest levels of sensitivity. These findings provide evidence for the interactive effects of genes and environment (in this study, children born at higher risk on parenting, and are consistent with a genetic differential susceptibility model of parenting by demonstrating that some parents are inherently more susceptible to environmental influences, both good and bad, than are others.

  18. Overlapping dopaminergic pathway genetic susceptibility to heroin and cocaine addictions in African Americans.

    Science.gov (United States)

    Levran, Orna; Randesi, Matthew; da Rosa, Joel Correa; Ott, Jurg; Rotrosen, John; Adelson, Miriam; Kreek, Mary Jeanne

    2015-05-01

    Drugs of abuse activate the mesolimbic dopaminergic pathway. Genetic variations in the dopaminergic system may contribute to drug addiction. Several processes are shared between cocaine and heroin addictions but some neurobiological mechanisms may be specific. This study examined the association of 98 single nucleotide polymorphisms in 13 dopamine-related genes with heroin addiction (OD) and/or cocaine addiction (CD) in a sample of 801 African Americans (315 subjects with OD ± CD, 279 subjects with CD, and 207 controls). Single-marker analyses provided nominally significant evidence for associations of 24 SNPs) in DRD1, ANKK1/DRD2, DRD3, DRD5, DBH, DDC, COMT and CSNK1E. A DRD2 7-SNPs haplotype that includes SNPs rs1075650 and rs2283265, which were shown to alter D2S/D2L splicing, was indicated in both addictions. The Met allele of the functional COMT Val158Met was associated with protection from OD. None of the signals remained significant after correction for multiple testing. The study results are in accordance with the results of previous studies, including our report of association of DRD1 SNP rs5326 with OD. The findings suggest the presence of an overlap in genetic susceptibility for OD and CD, as well as shared and distinct susceptibility for OD in subjects of African and European descent. PMID:25875614

  19. Hypobaric hypoxia in ascites resistant and susceptible broiler genetic lines influences gut morphology.

    Science.gov (United States)

    de los, Santos F Solis; Tellez, G; Farnell, M B; Balog, J M; Anthony, N B; Pavlidis, H O; Donoghue, A M

    2005-09-01

    Genetic selection based on rapid growth rates, improved feed conversion, and increased body weights has led to a predisposition to ascites in broiler populations. Sire-family selection was applied to a commercial elite line to produce divergent lines of ascites-resistant (RES) and ascites-susceptible (SUS) broilers by the 8th generation. One objective of this research was to determine the effects of hypobaric hypoxia on gut morphology in these genetic lines. In two separate trials, pedigree broiler chickens were randomly assigned to cages in a hypobaric chamber (simulated 2,900 m above sea level) or a matching local altitude chamber (390 m above sea level). Ascites incidence was characterized by heart enlargement and fluid accumulation in the abdominal cavity. At the end of the study on d 42, all surviving birds were killed and evaluated for the presence of ascites and 2-cm sections from the duodenum and lower ileum were collected from 5 chickens per line, per altitude for each trial for morphometric analysis. At a high altitude, ascites incidence was lower in the RES line (20.9 and 3.7%) than in the SUS line (86.4 and 66.9%, Trials 1 and 2, respectively). No ascites was observed at a local altitude. Under hypoxic conditions, duodenum villus surface area was higher (P ascites susceptibility suggests reduced enteric function and may provide clues as to why these birds have increased incidence of ascites. PMID:16206574

  20. Rationale for an international consortium to study inherited genetic susceptibility to childhood acute lymphoblastic leukemia

    Science.gov (United States)

    Sherborne, Amy L.; Hemminki, Kari; Kumar, Rajiv; Bartram, Claus R.; Stanulla, Martin; Schrappe, Martin; Petridou, Eleni; Semsei, Ágnes F.; Szalai, Csaba; Sinnett, Daniel; Krajinovic, Maja; Healy, Jasmine; Lanciotti, Marina; Dufour, Carlo; Indaco, Stefania; El-Ghouroury, Eman A; Sawangpanich, Ruchchadol; Hongeng, Suradej; Pakakasama, Samart; Gonzalez-Neira, Anna; Ugarte, Evelia L.; Leal, Valeria P.; Espinoza, Juan P.M.; Kamel, Azza M.; Ebid, Gamal T.A.; Radwan, Eman R.; Yalin, Serap; Yalin, Erdinc; Berkoz, Mehmet; Simpson, Jill; Roman, Eve; Lightfoot, Tracy; Hosking, Fay J.; Vijayakrishnan, Jayaram; Greaves, Mel; Houlston, Richard S.

    2011-01-01

    Acute lymphoblastic leukemia is the major pediatric cancer in developed countries. To date most association studies of acute lymphoblastic leukemia have been based on the candidate gene approach and have evaluated a restricted number of polymorphisms. Such studies have served to highlight difficulties in conducting statistically and methodologically rigorous investigations into acute lymphoblastic leukemia risk. Recent genome-wide association studies of childhood acute lymphoblastic leukemia have provided robust evidence that common variation at four genetic loci confers a modest increase in risk. The accumulated experience to date and relative lack of success of initial efforts to identify novel acute lymphoblastic leukemia predisposition loci emphasize the need for alternative study designs and methods. The International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium includes 12 research groups in Europe, Asia, the Middle East and the Americas engaged in studying the genetics of acute lymphoblastic leukemia. The initial goal of this consortium is to identify and characterize low-penetrance susceptibility variants for acute lymphoblastic leukemia through association-based analyses. Efforts to develop genome-wide association studies of acute lymphoblastic leukemia, in terms of both sample size and single nucleotide polymorphism coverage, and to increase the number of single nucleotide polymorphisms taken forward to large-scale replication should lead to the identification of additional novel risk variants for acute lymphoblastic leukemia. Ethnic differences in the risk of acute lymphoblastic leukemia are well recognized and thus in assessing the interplay between inherited and non-genetic risk factors, analyses using different population cohorts with different incidence rates are likely to be highly informative. Given that the frequency of many acute lymphoblastic leukemia subgroups is small, identifying differential effects will realistically only be

  1. Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis.

    Directory of Open Access Journals (Sweden)

    Arne S Schaefer

    2009-02-01

    Full Text Available Recent studies indicate a mutual epidemiological relationship between coronary heart disease (CHD and periodontitis. Both diseases are associated with similar risk factors and are characterized by a chronic inflammatory process. In a candidate-gene association study, we identify an association of a genetic susceptibility locus shared by both diseases. We confirm the known association of two neighboring linkage disequilibrium regions on human chromosome 9p21.3 with CHD and show the additional strong association of these loci with the risk of aggressive periodontitis. For the lead SNP of the main associated linkage disequilibrium region, rs1333048, the odds ratio of the autosomal-recessive mode of inheritance is 1.99 (95% confidence interval 1.33-2.94; P = 6.9 x 10(-4 for generalized aggressive periodontitis, and 1.72 (1.06-2.76; P = 2.6 x 10(-2 for localized aggressive periodontitis. The two associated linkage disequilibrium regions map to the sequence of the large antisense noncoding RNA ANRIL, which partly overlaps regulatory and coding sequences of CDKN2A/CDKN2B. A closely located diabetes-associated variant was independent of the CHD and periodontitis risk haplotypes. Our study demonstrates that CHD and periodontitis are genetically related by at least one susceptibility locus, which is possibly involved in ANRIL activity and independent of diabetes associated risk variants within this region. Elucidation of the interplay of ANRIL transcript variants and their involvement in increased susceptibility to the interactive diseases CHD and periodontitis promises new insight into the underlying shared pathogenic mechanisms of these complex common diseases.

  2. Lack of association between genetic variation in G-protein-coupled receptor for asthma susceptibility and childhood asthma and atopy

    OpenAIRE

    Wu, H; Romieu, I; Sienra-Monge, J-J; del Rio-Navarro, BE; Burdett, L; Yuenger, J; Li, H; Chanock, SJ; London, SJ

    2008-01-01

    G-protein-coupled receptor for asthma susceptibility (GPRA or GPR154) was identified as an asthma and atopy candidate gene by positional cloning. Some subsequent studies suggest associations of GPRA single nucleotide polymorphisms (SNPs) and haplotypes with asthma or atopy susceptibility. However, the associated SNPs or haplotypes vary among studies. The role of GPRA genetic variation in asthma and atopy remains unsolved. Published data on GRPA variants and asthma come exclusively from Caucas...

  3. Genetic antimicrobial susceptibility testing in Gram-negative sepsis - impact on time to results in a routine laboratory.

    Science.gov (United States)

    Kommedal, Øyvind; Aasen, Johanne Lind; Lindemann, Paul Christoffer

    2016-07-01

    Diagnostic testing of positive blood cultures is among the most critical tasks performed by clinical microbiology laboratories, and the total analysis time from sampling to results should be kept as short as possible. By providing identification of pelleted bacteria directly from positive blood-cultures, MALDI-TOF MS opens for relatively low-complex species-adjusted genetic susceptibility testing from the same bacterial pellet. In our lab routine, we prospectively evaluated a rapid in-house real-time PCR targeting the most common aminoglycoside and cephalosporin resistance genes in Escherichia coli and Klebsiella pneumoniae and measured time to preliminary susceptibility reporting for 138 samples. The results were compared to direct phenotypic susceptibility testing with interpretation after 6 h and overnight incubation respectively. Results from the genetic susceptibility testing were available for 69.5% (96/138) of the positive blood cultures within 24 h after sample collection. No phenotypic susceptibility results were available at this time. Compared to overnight direct susceptibility testing, the average time from sample collection to preliminary susceptibility reporting was reduced with 43%, from 45 h and 5 min to 25 h and 44 min, providing an earlier adjustment of antimicrobial therapy for 12 patients. Minor logistic adjustments have the potential to save yet another 4 h. PMID:27197792

  4. Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity.

    Science.gov (United States)

    Acuña, Gonzalo; Foernzler, Dorothee; Leong, Diane; Rabbia, Michael; Smit, Ralf; Dorflinger, Ernest; Gasser, Rodolfo; Hoh, Josephine; Ott, Jürg; Borroni, Edilio; To, Zung; Thompson, Annick; Li, Jia; Hashimoto, Lara; Lindpaintner, Klaus

    2002-01-01

    A retrospective pharmacogenetic study was conducted to identify possible genetic susceptibility factors in patients in whom the administration of the anti-Parkinson drug, tolcapone (TASMAR), was associated with hepatic toxicity. We studied 135 cases of patients with elevated liver transaminase levels (ELT) of >/=1.5 times above the upper limit of normal, in comparison with matched controls that had also received the drug but had not experienced ELT. DNA samples were genotyped for 30 previously described or newly characterized bi-allelic single nucleotide polymorphisms (SNPs), representing 12 candidate genes selected based on the known metabolic pathways involved in the tolcapone elimination. SNPs located within the UDP-glucuronosyl transferase 1A gene complex, which codes for the enzymes involved in the main elimination pathway of the drug, were found to be significantly associated with the occurrence of tolcapone-associated ELTs. PMID:12439739

  5. Arsenic-Induced Genotoxicity and Genetic Susceptibility to Arsenic-Related Pathologies

    Directory of Open Access Journals (Sweden)

    Fabrizio Bianchi

    2013-04-01

    Full Text Available The arsenic (As exposure represents an important problem in many parts of the World. Indeed, it is estimated that over 100 million individuals are exposed to arsenic, mainly through a contamination of groundwaters. Chronic exposure to As is associated with adverse effects on human health such as cancers, cardiovascular diseases, neurological diseases and the rate of morbidity and mortality in populations exposed is alarming. The purpose of this review is to summarize the genotoxic effects of As in the cells as well as to discuss the importance of signaling and repair of arsenic-induced DNA damage. The current knowledge of specific polymorphisms in candidate genes that confer susceptibility to arsenic exposure is also reviewed. We also discuss the perspectives offered by the determination of biological markers of early effect on health, incorporating genetic polymorphisms, with biomarkers for exposure to better evaluate exposure-response clinical relationships as well as to develop novel preventative strategies for arsenic- health effects.

  6. A genome scan for type 2 diabetes susceptibility loci in a genetically isolated population.

    Science.gov (United States)

    Permutt, M A; Wasson, J C; Suarez, B K; Lin, J; Thomas, J; Meyer, J; Lewitzky, S; Rennich, J S; Parker, A; DuPrat, L; Maruti, S; Chayen, S; Glaser, B

    2001-03-01

    A total of 896 individuals of Ashkenazi Jewish descent were ascertained in Israel from 267 multiplex families, including 472 sib-pairs affected with type 2 diabetes. A genome-wide scan with average marker spacing of 9.5 cM revealed five regions on four chromosomes (4q, 8q, 14q, and 20q) that exhibited nominal evidence for linkage (P families were ranked by BMI (in increasing order) did a subset attain nominal significance, and only for chromosome 4. The findings reported here lend credence to the hypothesis, now supported by four studies of Caucasian populations and most recently by a combined analysis of 1,852 pedigrees, that a type 2 diabetes susceptibility locus resides on chromosome 20q. This population, because of its unique genetic attributes, may facilitate identification of this and other genes contributing to type 2 diabetes. PMID:11246891

  7. Genetic susceptibility to systemic lupus erythematosus protects against cerebral malaria in mice.

    Science.gov (United States)

    Waisberg, Michael; Tarasenko, Tatyana; Vickers, Brandi K; Scott, Bethany L; Willcocks, Lisa C; Molina-Cruz, Alvaro; Pierce, Matthew A; Huang, Chiung-yu; Torres-Velez, Fernando J; Smith, Kenneth G C; Barillas-Mury, Carolina; Miller, Louis H; Pierce, Susan K; Bolland, Silvia

    2011-01-18

    Plasmodium falciparum has exerted tremendous selective pressure on genes that improve survival in severe malarial infections. Systemic lupus erythematosus (SLE) is an autoimmune disease that is six to eight times more prevalent in women of African descent than in women of European descent. Here we provide evidence that a genetic susceptibility to SLE protects against cerebral malaria. Mice that are prone to SLE because of a deficiency in FcγRIIB or overexpression of Toll-like receptor 7 are protected from death caused by cerebral malaria. Protection appears to be by immune mechanisms that allow SLE-prone mice better to control their overall inflammatory responses to parasite infections. These findings suggest that the high prevalence of SLE in women of African descent living outside of Africa may result from the inheritance of genes that are beneficial in the immune control of cerebral malaria but that, in the absence of malaria, contribute to autoimmune disease. PMID:21187399

  8. Genetic susceptibility to systemic lupus erythematosus protects against cerebral malaria in mice

    Science.gov (United States)

    Waisberg, Michael; Tarasenko, Tatyana; Vickers, Brandi K.; Scott, Bethany L.; Willcocks, Lisa C.; Molina-Cruz, Alvaro; Pierce, Matthew A.; Huang, Chiung-yu; Torres-Velez, Fernando J.; Smith, Kenneth G. C.; Barillas-Mury, Carolina; Miller, Louis H.; Pierce, Susan K.; Bolland, Silvia

    2011-01-01

    Plasmodium falciparum has exerted tremendous selective pressure on genes that improve survival in severe malarial infections. Systemic lupus erythematosus (SLE) is an autoimmune disease that is six to eight times more prevalent in women of African descent than in women of European descent. Here we provide evidence that a genetic susceptibility to SLE protects against cerebral malaria. Mice that are prone to SLE because of a deficiency in FcγRIIB or overexpression of Toll-like receptor 7 are protected from death caused by cerebral malaria. Protection appears to be by immune mechanisms that allow SLE-prone mice better to control their overall inflammatory responses to parasite infections. These findings suggest that the high prevalence of SLE in women of African descent living outside of Africa may result from the inheritance of genes that are beneficial in the immune control of cerebral malaria but that, in the absence of malaria, contribute to autoimmune disease. PMID:21187399

  9. Differential Susceptibility: The Genetic Moderation of Peer Pressure on Alcohol Use.

    Science.gov (United States)

    Griffin, Amanda M; Cleveland, H Harrington; Schlomer, Gabriel L; Vandenbergh, David J; Feinberg, Mark E

    2015-10-01

    Although peer pressure can influence adolescents' alcohol use, individual susceptibility to these pressures varies across individuals. The dopamine receptor D4 gene (DRD4) is a potential candidate gene that may influence adolescents' susceptibility to their peer environment due to the role dopamine plays in reward sensation during social interaction. We hypothesized that DRD4 genotype status would moderate the impact of 7th-grade antisocial peer pressure on 12th-grade lifetime alcohol use (n = 414; 58.7% female; 92.8% White). The results revealed significant main effects for antisocial peer pressure, but no main effects for DRD4 genotype on lifetime alcohol use. Adolescent DRD4 genotype moderated the association between peer pressure and lifetime alcohol use. For individuals who carried at least one copy of the DRD4 7-repeat allele (7+), antisocial peer pressure was associated with increased lifetime alcohol use. These findings indicate that genetic sensitivity to peer pressure confers increased alcohol use in late adolescence. PMID:26307243

  10. HLA-DRB1 allele polymorphisms in genetic susceptibility to esophageal carcinoma

    Institute of Scientific and Technical Information of China (English)

    Jun Lin; Chang-Sheng Deng; Jie Sun; Xian-Gong Zheng; Xing Huang; Yan Zhou; Ping Xiong; Ya-Ping Wang

    2003-01-01

    AIM: To probe into the genetic susceptibility of HLA-DRB1 alleles to esophageal carcinoma in Han Chinese in Hubei Province.METHODS: HLA-DRB1 allele polymorphisms were typed by polymerase chain reaction with sequence-specific primers (PCR-SSP) in 42 unrelated patients with esophageal cancer and 136 unrelated normal control subjects and the associated HLA-DRB1 allele was measured by nucleotide sequence analysis with PCR.SAS software was used in statistics.RESULTS: Allele frequency (AF) of HLA-DRB1·0901 was significantly higher in esophageal carcinoma patients than that in the normal controls (0.2500 vs0.1397, P=0.028, the odds ratio 2.053, etiologic fraction 0.1282). After analyzed the allele nucleotide sequence of HLA-DRB1·0901 which approachs to the corresponded exon 2 sequence of the allele in genebank. There was no association between patients and controls in the rested HLA-DRB1 alleles.CONCLUSION: HLA-DRB1·0901 allele is more common in the patients with esophageal carcinoma than in the healthy controls, which is positively associated with the patients of Hubei Han Chinese. Individuals carrying HLA-DRB1·0901may be susceptible to esophageal carcinoma.

  11. Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility

    Directory of Open Access Journals (Sweden)

    Nunes Virginia

    2008-01-01

    Full Text Available Abstract Background Germline genetic variation is associated with the differential expression of many human genes. The phenotypic effects of this type of variation may be important when considering susceptibility to common genetic diseases. Three regions at 8q24 have recently been identified to independently confer risk of prostate cancer. Variation at 8q24 has also recently been associated with risk of breast and colorectal cancer. However, none of the risk variants map at or relatively close to known genes, with c-MYC mapping a few hundred kilobases distally. Results This study identifies cis-regulators of germline c-MYC expression in immortalized lymphocytes of HapMap individuals. Quantitative analysis of c-MYC expression in normal prostate tissues suggests an association between overexpression and variants in Region 1 of prostate cancer risk. Somatic c-MYC overexpression correlates with prostate cancer progression and more aggressive tumor forms, which was also a pathological variable associated with Region 1. Expression profiling analysis and modeling of transcriptional regulatory networks predicts a functional association between MYC and the prostate tumor suppressor KLF6. Analysis of MYC/Myc-driven cell transformation and tumorigenesis substantiates a model in which MYC overexpression promotes transformation by down-regulating KLF6. In this model, a feedback loop through E-cadherin down-regulation causes further transactivation of c-MYC. Conclusion This study proposes that variation at putative 8q24 cis-regulator(s of transcription can significantly alter germline c-MYC expression levels and, thus, contribute to prostate cancer susceptibility by down-regulating the prostate tumor suppressor KLF6 gene.

  12. Comparison of Genetic Backgrounds of Methicillin-Resistant and -Susceptible Staphylococcus aureus Isolates from Portuguese Hospitals and the Community

    OpenAIRE

    de Sousa, M. Aires; Conceição, T.; Simas, C.; de Lencastre, H.

    2005-01-01

    In order to understand the origins of the dominant methicillin-resistant Staphylococcus aureus (MRSA) clones in Portuguese hospitals, we compared the genetic backgrounds of nosocomial MRSA with methicillin-susceptible S. aureus (MSSA) isolates from the same hospitals (n = 155) and from the community (n = 157) where they were located. Pulsed-field gel electrophoresis, spa typing, multilocus sequence typing, and agr type analysis revealed that the genetic backgrounds correspondent to the domina...

  13. Influenza virus surveillance in Argentina during the 2012 season: antigenic characterization, genetic analysis and antiviral susceptibility.

    Science.gov (United States)

    Benedetti, E; Daniels, R S; Pontoriero, A; Russo, M; Avaro, M; Czech, A; Campos, A; Periolo, N; Gregory, V; McCauley, J W; Baumeister, E G

    2016-03-01

    The activity and circulation of influenza viruses in Argentina was studied during 2012 as part of the Argentinean Surveillance for Influenza and other Respiratory Viruses, in the context of Global Influenza Surveillance. The antigenicity and molecular characteristics of haemagglutinins (HA) of circulating influenza A and B viruses were analysed to assess the emergence of virus variants. Susceptibility to oseltamivir and zanamivir was evaluated by enzymatic assay and results were backed-up by sequencing of the neuraminidase (NA) genes. During the 2012 season, influenza virus circulation in Argentina was detected from weeks 24 to 51. The HA sequences of the studied A(H1N1)pdm09 subtype viruses segregated in a different genetic group compared to those identified during the 2009 pandemic, although they were still closely related antigenically to the vaccine virus A/California/07/2009. The HA sequences of the A(H3N2) viruses analysed fell into the A/Victoria/208/2009 clade, genetic group 3C. A mixed circulation of virus variants belonging to B/Victoria and B/Yamagata lineages was detected, with B/Victoria being dominant. All viruses tested were sensitive to oseltamivir and zanamivir except one. This isolate, an A(H1N1)pdm09 virus possessing the substitution NA-N295S, showed highly reduced inhibition by oseltamivir and reduced inhibition by zanamivir. Virological and epidemiological surveillance remains critical for detection of evolving influenza viruses. PMID:26345289

  14. Relationships of OPG Genetic Polymorphisms with Susceptibility to Cardiovascular Disease: A Meta-Analysis.

    Science.gov (United States)

    Song, De-Hua; Zhou, Peng-Zhen; Xiu, Xiao-Lin; Zhou, Guang-Hui; Sun, Yu-Xia; Song, Chun

    2016-01-01

    BACKGROUND The aim of this meta-analysis was to determine whether genetic polymorphisms in the osteoprotegerin (OPG) gene contribute to increased risk of cardiovascular disease (CVD). MATERIAL AND METHODS Electronic databases were searched carefully without any language restriction. Analyses of data were conducted using STATA software. Odds ratios (OR) and 95% confidence intervals (95%CI) were also calculated. RESULTS Seven clinical case-control studies that enrolled 1170 CVD patients and 1194 healthy subjects were included. The results indicated that OPG gene polymorphism might be closely associated with susceptibility to CVD, especially for rs2073617 T>C and rs2073618 G>C polymorphisms. Ethnicity-stratified analysis indicated that genetic polymorphism in the OPG were closely related with the pathogenesis of CVD among Asians (all P0.05). CONCLUSIONS Our meta-analysis provided quantitative evidence that OPG gene polymorphism may be closely related to an increased risk of CVD, especially for rs2073617 T>C and rs2073618 G>C polymorphisms. PMID:27068490

  15. Integrating mechanistic and polymorphism data to characterize human genetic susceptibility for environmental chemical risk assessment in the 21st century

    International Nuclear Information System (INIS)

    Response to environmental chemicals can vary widely among individuals and between population groups. In human health risk assessment, data on susceptibility can be utilized by deriving risk levels based on a study of a susceptible population and/or an uncertainty factor may be applied to account for the lack of information about susceptibility. Defining genetic susceptibility in response to environmental chemicals across human populations is an area of interest in the NAS' new paradigm of toxicity pathway-based risk assessment. Data from high-throughput/high content (HT/HC), including -omics (e.g., genomics, transcriptomics, proteomics, metabolomics) technologies, have been integral to the identification and characterization of drug target and disease loci, and have been successfully utilized to inform the mechanism of action for numerous environmental chemicals. Large-scale population genotyping studies may help to characterize levels of variability across human populations at identified target loci implicated in response to environmental chemicals. By combining mechanistic data for a given environmental chemical with next generation sequencing data that provides human population variation information, one can begin to characterize differential susceptibility due to genetic variability to environmental chemicals within and across genetically heterogeneous human populations. The integration of such data sources will be informative to human health risk assessment

  16. Integrating mechanistic and polymorphism data to characterize human genetic susceptibility for environmental chemical risk assessment in the 21st century

    Energy Technology Data Exchange (ETDEWEB)

    Mortensen, Holly M., E-mail: mortensen.holly@epa.gov [Office of Research and Development, US Environmental Protection Agency, National Center for Computational Toxicology, US EPA, 109 TW Alexander Dr., Mailcode B205-01, Research Triangle Park, NC 27711 (United States); Euling, Susan Y. [Office of Research and Development, US Environmental Protection Agency, National Center for Environmental Assessment, US EPA, 1200 Pennsylvania Ave., NW, Mail Code 8623P, Washington, DC 20460 (United States)

    2013-09-15

    Response to environmental chemicals can vary widely among individuals and between population groups. In human health risk assessment, data on susceptibility can be utilized by deriving risk levels based on a study of a susceptible population and/or an uncertainty factor may be applied to account for the lack of information about susceptibility. Defining genetic susceptibility in response to environmental chemicals across human populations is an area of interest in the NAS' new paradigm of toxicity pathway-based risk assessment. Data from high-throughput/high content (HT/HC), including -omics (e.g., genomics, transcriptomics, proteomics, metabolomics) technologies, have been integral to the identification and characterization of drug target and disease loci, and have been successfully utilized to inform the mechanism of action for numerous environmental chemicals. Large-scale population genotyping studies may help to characterize levels of variability across human populations at identified target loci implicated in response to environmental chemicals. By combining mechanistic data for a given environmental chemical with next generation sequencing data that provides human population variation information, one can begin to characterize differential susceptibility due to genetic variability to environmental chemicals within and across genetically heterogeneous human populations. The integration of such data sources will be informative to human health risk assessment.

  17. Melanoma susceptibility as a complex trait: genetic variation controls all stages of tumor progression.

    Science.gov (United States)

    Ferguson, B; Ram, R; Handoko, H Y; Mukhopadhyay, P; Muller, H K; Soyer, H P; Morahan, G; Walker, G J

    2015-05-28

    Susceptibility to most common cancers is likely to involve interaction between multiple low risk genetic variants. Although there has been great progress in identifying such variants, their effect on phenotype and the mechanisms by which they contribute to disease remain largely unknown. We have developed a mouse melanoma model harboring two mutant oncogenes implicated in human melanoma, CDK4(R24C) and NRAS(Q61K). In these mice, tumors arise from benign precursor lesions that are a recognized strong risk factor for this neoplasm in humans. To define molecular events involved in the pathway to melanoma, we have for the first time applied the Collaborative Cross (CC) to cancer research. The CC is a powerful resource designed to expedite discovery of genes for complex traits. We characterized melanoma genesis in more than 50 CC strains and observed tremendous variation in all traits, including nevus and melanoma age of onset and multiplicity, anatomical site predilection, time for conversion of nevi to melanoma and metastases. Intriguingly, neonatal ultraviolet radiation exposure exacerbated nevus and melanoma formation in most, but not all CC strain backgrounds, suggesting that genetic variation within the CC will help explain individual sensitivity to sun exposure, the major environmental skin carcinogen. As genetic variation brings about dramatic phenotypic diversity in a single mouse model, melanoma-related endophenotype comparisons provide us with information about mechanisms of carcinogenesis, such as whether melanoma incidence is dependent upon the density of pre-existing nevus cells. Mouse models have been used to examine the functional role of gene mutations in tumorigenesis. This work represents their next phase of development to study how biological variation greatly influences lesion onset and aggressiveness even in the setting of known somatic driver mutations. PMID:25088201

  18. Sporadic colorectal cancer and individual susceptibility: A review of the association studies investigating the role of DNA repair genetic polymorphisms

    Czech Academy of Sciences Publication Activity Database

    Naccarati, Alessio; Pardini, B.; Hemminki, K.; Vodička, Pavel

    2007-01-01

    Roč. 635, 2-3(2007), s.118-145. ISSN 1383-5742 R&D Projects: GA MZd NR8563; GA ČR GA310/05/2626 Institutional research plan: CEZ:AV0Z50390512 Keywords : Sporadic colorectal cancer * Individual susceptibility * DNA repair Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.353, year: 2007

  19. Experimental transmission of U.S. scrapie agent by nasal, peritoneal and conjunctival routes to genetically susceptible sheep

    Science.gov (United States)

    Scrapie is a naturally occurring fatal neurodegenerative disease of sheep and goats. This study documents incubation periods, pathological findings and distribution of abnormal prion proteins (PrP**Sc) by immunohistochemistry in tissues of genetically susceptible sheep inoculated with U.S. sheep scr...

  20. Experience of parental cancer in childhood is a risk factor for psychological distress during genetic cancer susceptibility testing

    NARCIS (Netherlands)

    van Oostrom, I.; Meijers-Heijboer, H.; Duivenvoorden, H. J.; Brocker-Vriends, A. H. J. T.; van Asperen, C. J.; Sijmons, R. H.; Seynaeve, C.; Van Gool, A. R.; Klijn, J. G. M.; Tibben, A.

    2006-01-01

    Background: This study explores the effect of age at the time of parental cancer diagnosis or death on psychological distress and cancer risk perception in individuals undergoing genetic testing for a specific cancer susceptibility. Patients and methods: Cancer-related distress, worry and risk perce

  1. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

    DEFF Research Database (Denmark)

    Mahajan, Anubha; Go, Min Jin; Zhang, Weihua;

    2014-01-01

    To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We obs...

  2. Genetic Polymorphism of Folate and Methionine Metabolizing Enzymes and their Susceptibility to Malignant Lymphoma

    International Nuclear Information System (INIS)

    Folate and methionine metabolism is involved in DNA synthesis and methylation. Polymorphisms in the genes of folate metabolism enzymes have been associated with some forms of cancer. In the present study, 2 polymorphisms were evaluated for a folate metabolic enzyme, methylene-tetrahydrofolate reductase (MTHFR), and one was evaluated for methionine synthase (MS). The 2 polymorphisms MTHFR 677 C-7T and MTHFR 1298 A-7C, are reported to reduce the enzyme activity, which causes intracellular accumulation of 5, 10 vm ethylene-tetrahydrofolate and results in a reduced incidence of DNA double strand breakage. The MS 2756 A-7G polymorphism also reduces the enzyme activity and results in the hypo methylation of DNA. Patients and Methods: To test this hypothesis, genetic polymorphisms in the folate metabolic pathway were investigated using the DNA from a case-control study on 31 patients having malignant lymphoma from the Oncology Outpatient Clinic of the New Children's Hospital, Cairo University and 30 controls who were actually normal children attending for vaccination to the same hospital. We found that there is a higher susceptibility with the MTHFR 677CC and MTHFR 1298 AA genotypes (OR=4.3, 95% CI 1.12-16). When those harbor at least one variant allele in either polymorphism of MTHFR they were defined as reference. For the MS 2756 AG genotype polymorphism there was also a higher susceptibility to developing malignant lymphoma (OR=2.6; 95% CI 1.16.4). Results suggest that folate and methionine metabolism may play an important role in the pathogenesis of malignant lymphoma. Further studies to confirm this association and detailed biologic mechanisms are now required

  3. Genetic context determines susceptibility to intraocular pressure elevation in a mouse pigmentary glaucoma

    Directory of Open Access Journals (Sweden)

    Cosma Ioan M

    2006-07-01

    Full Text Available Abstract Background DBA/2J (D2 mice develop an age-related form of glaucoma. Their eyes progressively develop iris pigment dispersion and iris atrophy followed by increased intraocular pressure (IOP and glaucomatous optic nerve damage. Mutant alleles of the Gpnmb and Tyrp1 genes are necessary for the iris disease, but it is unknown whether alleles of other D2 gene(s are necessary for the distinct later stages of disease. We initiated a study of congenic strains to further define the genetic requirements and disease mechanisms of the D2 glaucoma. Results To further understand D2 glaucoma, we created congenic strains of mice on the C57BL/6J (B6 genetic background. B6 double-congenic mice carrying D2-derived Gpnmb and Tyrp1 mutations develop a D2-like iris disease. B6 single-congenics with only the Gpnmb and Tyrp1 mutations develop milder forms of iris disease. Genetic epistasis experiments introducing a B6 tyrosinase mutation into the congenic strains demonstrated that both the single and double-congenic iris diseases are rescued by interruption of melanin synthesis. Importantly, our experiments analyzing mice at ages up to 27 months indicate that the B6 double-congenic mice are much less prone to IOP elevation and glaucoma than are D2 mice. Conclusion As demonstrated here, the Gpnmb and Tyrp1 iris phenotypes are both individually dependent on tyrosinase function. These results support involvement of abnormal melanosomal events in the diseases caused by each gene. In the context of the inbred D2 mouse strain, the glaucoma phenotype is clearly influenced by more genes than just Gpnmb and Tyrp1. Despite the outward similarity of pigment-dispersing iris disease between D2 and the B6 double-congenic mice, the congenic mice are much less susceptible to developing high IOP and glaucoma. These new congenic strains provide a valuable new resource for further studying the genetic and mechanistic complexity of this form of glaucoma.

  4. Sporadic inclusion body myositis in Japanese is associated with the MHC ancestral haplotype 52.1.

    Science.gov (United States)

    Scott, Adrian Phillip; Allcock, Richard James Nigel; Mastaglia, Frank; Nishino, Ichizo; Nonaka, Ikuya; Laing, Nigel

    2006-05-01

    In Caucasians, sporadic inclusion body myositis has been associated with the MHC ancestral haplotypes; HLA-A1, B8, DR3 (8.1AH) and HLA-B35, DR1 (35.2AH). It is not known whether these haplotypes carry susceptibility for the disease in other ethnic groups. We report here the results of HLA-B and -DRB1 typing using a high-resolution sequence-based technique in a cohort of 31 Japanese patients with definite sIBM. Patient allele frequencies were 40.3% for HLA-B*5201 (10.7% in controls: pHLA-DRB1*1502 (10% in controls: p<0.001). Both alleles were found together as part of a conserved haplotype (52.1AH) at a frequency of 37.1% in patients (8.4% in controls: p<0.001). This is the first description of a haplotypic MHC association with sporadic inclusion body myositis in Japanese patients. These findings indicate that different MHC ancestral haplotypes are associated with sIBM in different ethnic groups and further emphasize the importance of genetic factors in this condition. PMID:16564169

  5. Ancestral reconstruction of tick lineages.

    Science.gov (United States)

    Mans, Ben J; de Castro, Minique H; Pienaar, Ronel; de Klerk, Daniel; Gaven, Philasande; Genu, Siyamcela; Latif, Abdalla A

    2016-06-01

    Ancestral reconstruction in its fullest sense aims to describe the complete evolutionary history of a lineage. This depends on accurate phylogenies and an understanding of the key characters of each parental lineage. An attempt is made to delineate our current knowledge with regard to the ancestral reconstruction of the tick (Ixodida) lineage. Tick characters may be assigned to Core of Life, Lineages of Life or Edges of Life phenomena depending on how far back these characters may be assigned in the evolutionary Tree of Life. These include housekeeping genes, sub-cellular systems, heme processing (Core of Life), development, moulting, appendages, nervous and organ systems, homeostasis, respiration (Lineages of Life), specific adaptations to a blood-feeding lifestyle, including the complexities of salivary gland secretions and tick-host interactions (Edges of Life). The phylogenetic relationships of lineages, their origins and importance in ancestral reconstruction are discussed. Uncertainties with respect to systematic relationships, ancestral reconstruction and the challenges faced in comparative transcriptomics (next-generation sequencing approaches) are highlighted. While almost 150 years of information regarding tick biology have been assembled, progress in recent years indicates that we are in the infancy of understanding tick evolution. Even so, broad reconstructions can be made with relation to biological features associated with various lineages. Conservation of characters shared with sister and parent lineages are evident, but appreciable differences are present in the tick lineage indicating modification with descent, as expected for Darwinian evolutionary theory. Many of these differences can be related to the hematophagous lifestyle of ticks. PMID:26868413

  6. Identification of New Genetic Susceptibility Loci for Breast Cancer Through Consideration of Gene-Environment Interactions

    Science.gov (United States)

    Schoeps, Anja; Rudolph, Anja; Seibold, Petra; Dunning, Alison M.; Milne, Roger L.; Bojesen, Stig E.; Swerdlow, Anthony; Andrulis, Irene; Brenner, Hermann; Behrens, Sabine; Orr, Nicholas; Jones, Michael; Ashworth, Alan; Li, Jingmei; Cramp, Helen; Connley, Dan; Czene, Kamila; Darabi, Hatef; Chanock, Stephen J.; Lissowska, Jolanta; Figueroa, Jonine D.; Knight, Julia; Glendon, Gord; Mulligan, Anna M.; Dumont, Martine; Severi, Gianluca; Baglietto, Laura; Olson, Janet; Vachon, Celine; Purrington, Kristen; Moisse, Matthieu; Neven, Patrick; Wildiers, Hans; Spurdle, Amanda; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana M.; Hamann, Ute; Ko, Yon-Dschun; Dieffenbach, Aida K.; Arndt, Volker; Stegmaier, Christa; Malats, Núria; Arias Perez, JoséI.; Benítez, Javier; Flyger, Henrik; Nordestgaard, Børge G.; Truong, Théresè; Cordina-Duverger, Emilie; Menegaux, Florence; Silva, Isabel dos Santos; Fletcher, Olivia; Johnson, Nichola; Häberle, Lothar; Beckmann, Matthias W.; Ekici, Arif B.; Braaf, Linde; Atsma, Femke; van den Broek, Alexandra J.; Makalic, Enes; Schmidt, Daniel F.; Southey, Melissa C.; Cox, Angela; Simard, Jacques; Giles, Graham G.; Lambrechts, Diether; Mannermaa, Arto; Brauch, Hiltrud; Guénel, Pascal; Peto, Julian; Fasching, Peter A.; Hopper, John; Flesch-Janys, Dieter; Couch, Fergus; Chenevix-Trench, Georgia; Pharoah, Paul D. P.; Garcia-Closas, Montserrat; Schmidt, Marjanka K.; Hall, Per; Easton, Douglas F.; Chang-Claude, Jenny

    2014-01-01

    Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10−07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15–1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72–1.11, P for interaction = 3.2 × 10−05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci. PMID:24248812

  7. Contribution of LPHN3 to the genetic susceptibility to ADHD in adulthood: a replication study.

    Science.gov (United States)

    Ribasés, M; Ramos-Quiroga, J A; Sánchez-Mora, C; Bosch, R; Richarte, V; Palomar, G; Gastaminza, X; Bielsa, A; Arcos-Burgos, M; Muenke, M; Castellanos, F X; Cormand, B; Bayés, M; Casas, M

    2011-03-01

    Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable developmental disorder characterized by a persistent impairing pattern of inattention and/or hyperactivity-impulsivity. Using families from a genetic isolate, the Paisa population from Colombia, and five independent datasets from four different populations (United States, Germany, Norway and Spain), a highly consistent association was recently reported between ADHD and the latrophilin 3 (LPHN3) gene, a brain-specific member of the LPHN subfamily of G-protein-coupled receptors that is expressed in ADHD-related regions, such as amygdala, caudate nucleus, cerebellum and cerebral cortex. To replicate the association between LPHN3 and ADHD in adults, we undertook a case-control association study in 334 adult patients with ADHD and 334 controls with 43 single nucleotide polymorphisms (SNPs) covering the LPNH3 gene. Single- and multiple-marker analyses showed additional evidence of association between LPHN3 and combined type ADHD in adulthood [P = 0.0019; df = 1; odds ratio (OR) = 1.82 (1.25-2.70) and P = 5.1e-05; df = 1; OR = 2.25 (1.52-3.34), respectively]. These results further support the LPHN3 contribution to combined type ADHD, and specifically to the persistent form of the disorder, and point at this new neuronal pathway as a common susceptibility factor for ADHD throughout the lifespan. PMID:21040458

  8. Evaluation of genetic damage in Brazilian footwear-workers: biomarkers of exposure, effect, and susceptibility.

    Science.gov (United States)

    Heuser, Vanina Dahlström; Erdtmann, Bernardo; Kvitko, Kátia; Rohr, Paula; da Silva, Juliana

    2007-04-11

    Employees in the footwear manufacturing industry are routinely exposed to complex mixtures of solvents used in cleaning and as diluents in glues, primers, and degreasers. The objective of this study was to determine the genotoxic effects in a group of footwear-workers occupationally exposed to solvent-based adhesive and solutions containing organic solvents, mainly toluene. Peripheral blood and buccal cells samples were collected from 39 footwear-workers (31 males and 8 females) and 55 controls (44 males and 11 females). As biomarker of exposure, we obtained data on hippuric acid (HA), the main metabolite of toluene in urine, and DNA damage detected by the Comet assay in blood cells. Micronucleus frequencies in binucleated lymphocytes (BNMN) and in epithelial buccal cells (EBCMN) were analyzed as biomarkers of effect, while polymorphisms in genes GSTT1, GSTM1, GSTP1, CYP1A1, and CYP2E1 were used as susceptibility biomarkers. Results of HA and Comet assay showed statistical increased values amongst footwear-workers relative to controls (P footwear-worker can be associated with genetic polymorphisms in GSTP1 and CYP2E1 (P=0.006, F=5.876). PMID:17292523

  9. The RadGenomics project. Prediction for radio-susceptibility of individuals with genetic predisposition

    International Nuclear Information System (INIS)

    The ultimate goal of our project, named RadGenomics, is to elucidate the heterogeneity of the response to ionizing radiation arising from genetic variation among individuals, for the purpose of developing personalized radiation therapy regimens for cancer patients. Cancer patients exhibit patient-to-patient variability in normal tissue reactions after radiotherapy. Several observations support the hypothesis that the radiosensitivity of normal tissue is influenced by genetic factors. The rapid progression of human genome sequencing and the recent development of new technologies in molecular biology are providing new opportunities for elucidating the genetic basis of individual differences in susceptibility to radiation exposure. The development of a sufficiently robust, predictive assay enabling individual dose adjustment would improve the outcome of radiation therapy in patients. Our strategy for identification of DNA polymorphisms that contribute to the individual radiosensitivity is as follows. First, we have been categorizing DNA samples obtained from cancer patients, who have been kindly introduced to us through many collaborators, according to their clinical characteristics including the method and effect of treatment and side effects as scored by toxicity criteria, and also the result of an in vitro radiosensitivity assay, e.g., the micronuclei assay of their lymphocytes. Second, we have identified candidate genes for genotyping mainly by using our custom-designed oligonucleotide array with RNA samples, in which the probes were obtained from more than 40 cancer and 3 fibroblast cell lines whose radiosensitivity level was quite heterogeneous. We have also been studying the modification of proteins after irradiation of cells which may be caused by mainly phosphorylation or dephosphorylation, using mass spectrometry. Genes encoding the modified proteins and/or other proteins with which they interact such as specific protein kinases and phosphatases are also

  10. A multidirectional non-cell autonomous control and a genetic interaction restricting tobacco etch virus susceptibility in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Suresh Gopalan

    Full Text Available BACKGROUND: Viruses constitute a major class of pathogens that infect a variety of hosts. Understanding the intricacies of signaling during host-virus interactions should aid in designing disease prevention strategies and in understanding mechanistic aspects of host and pathogen signaling machinery. METHODOLOGY/PRINCIPAL FINDINGS: An Arabidopsis mutant, B149, impaired in susceptibility to Tobacco etch virus (TEV, a positive strand RNA virus of picoRNA family, was identified using a high-throughput genetic screen and a counterselection scheme. The defects include initiation of infection foci, rate of cell-to-cell movement and long distance movement. CONCLUSIONS/SIGNIFICANCE: The defect in infectivity is conferred by a recessive locus. Molecular genetic analysis and complementation analysis with three alleles of a previously published mutant lsp1 (loss of susceptibility to potyviruses indicate a genetic interaction conferring haploinsufficiency between the B149 locus and certain alleles of lsp1 resulting in impaired host susceptibility. The pattern of restriction of TEV foci on leaves at or near the boundaries of certain cell types and leaf boundaries suggest dysregulation of a multidirectional non-cell autonomous regulatory mechanism. Understanding the nature of this multidirectional signal and the molecular genetic mechanism conferring it should potentially reveal a novel arsenal in the cellular machinery.

  11. Relationship between HLA-DQA1 polymorphism and genetic susceptibility to idiopathic dilated cardiomyopathy

    Institute of Scientific and Technical Information of China (English)

    刘巍; 李为民; 孙宁玲

    2004-01-01

    Background Autoimmune mechanisms are likely to participate in the pathogenesis of subgroup of idiopathic dilated cardiomyopathy (IDC), and components of the major histocompatibility complex may serve as markers for the propensity to develop immune-mediated myocardial damage. Human leukocyte antigen (HLA) class Ⅱ genes, especially highly polymorphic HLA-DQ genes, play an important role in the activation of immune responses, and thus control the predisposition for or protect from IDC. This study was conducted to investigate the HLA-DQA1 allele polymorphisms in IDC patients and to explore the underlying immunological mechanism and the hereditary susceptibility to IDC.Methods The polymerase chain reaction sequence-specific primers (PCR-SSP) technique was used to analyze the polymorphisms in the second exon of DQA1 in three groups: 72 IDC patients diagnosed according to the criteria of World Health Organization (IDC group); 100 end-stage heart failure patients suffering from a disease of known etiology (HF group); and 100 healthy subjects enrolled for the study during a routine health survey (control group). Patients in the IDC group were stratified according to ejection fraction (EF). Those with EF values were higher than 35% were placed into subgroup 1; subgroup 2 included patients with an EF value of 15%-35%; and subgroup 3 consisted of those whose EF values less than 15%. Results The frequency of HLA-DQA1*0501 alleles was significantly higher in the IDC group (0.39) than that in the HF group (0.12) and the control group (0.09) (both P<0.05). Further analysis of the three IDC subgroups showed a higher frequency of DQA1*0501 among patients with lower EF values (both P<0.05, compared with subgroups 1 and 2). The frequency of DQA1*0201 was higher in the control group than that in the IDC group (P<0.05).Conclusions The HLA-DQA1*0501 allele confers susceptibility to IDC, while the DQA1*0201 allele confers protection against it, which indicates that genetic background

  12. Association of Wnt signaling pathway genetic variants in gallbladder cancer susceptibility and survival.

    Science.gov (United States)

    Yadav, Anu; Gupta, Annapurna; Yadav, Saurabh; Rastogi, Neeraj; Agrawal, Sushma; Kumar, Ashok; Kumar, Vijay; Misra, Sanjeev; Mittal, Balraj

    2016-06-01

    Gallbladder cancer (GBC) is the most common malignancy of the biliary tract with adverse prognosis and poor survival. Wnt signaling plays an important role in embryonic development and regeneration of tissues in all the species. Deregulation of expression and mutations in this pathway may lead to disease state such as cancer. In this study, we assessed the association of common germline variants of Wnt pathway genes (SFRP2, SFRP4, DKK2, DKK3, WISP3, APC, β-catenin, AXIN-2, GLI-1) to evaluate their contribution in predisposition to GBC and treatment outcomes. The study included 564 GBC patients and 250 controls. Out of 564, 200 patients were followed up for treatment response and survival. Tumor response (RECIST 1.1) was recorded in 116 patients undergoing non-adjuvant chemotherapy (NACT). Survival was assessed by Kaplan-Meier curve and Cox-proportional hazard regression. Single locus analysis showed significant association of SFRP4 rs1802073G > T [p value = 0.0001], DKK2 rs17037102C > T [p value = 0.0001], DKK3 rs3206824C > T [p value = 0.012], APC rs4595552 A/T [p value = 0.021], APC rs11954856G > T [p value = 0.047], AXIN-2 rs4791171C > T [p value = 0.001], β-catenin rs4135385A > G [p value = 0.031], and GLI-1 rs222826C > G [p value = 0.001] with increased risk of GBC. Gene-gene interaction using GMDR analysis predicted APC rs11954856 and AXIN2 rs4791171 as significant in conferring GBC susceptibility. Cox-proportional hazard model showed GLI-1 rs2228226 CG/GG and AXIN-2 rs4791171 TT genotype higher hazard ratio. In recursive partitioning, AXIN-2 rs4791171 TT genotype showed higher mortality and hazard. Most of studied genetic variants influence GBC susceptibility. APC rs11954856, GLI-1 rs2228226, and AXIN-2 rs4791171 were found to be associated with poor survival in advanced GBC patients. PMID:26715268

  13. A Systems Genetic Approach to Identify Low Dose Radiation-Induced Lymphoma Susceptibility/DOE2013FinalReport

    Energy Technology Data Exchange (ETDEWEB)

    Balmain, Allan [University of California, San Francisco; Song, Ihn Young [University of California, San Francisco

    2013-05-15

    The ultimate goal of this project is to identify the combinations of genetic variants that confer an individual's susceptibility to the effects of low dose (0.1 Gy) gamma-radiation, in particular with regard to tumor development. In contrast to the known effects of high dose radiation in cancer induction, the responses to low dose radiation (defined as 0.1 Gy or less) are much less well understood, and have been proposed to involve a protective anti-tumor effect in some in vivo scientific models. These conflicting results confound attempts to develop predictive models of the risk of exposure to low dose radiation, particularly when combined with the strong effects of inherited genetic variants on both radiation effects and cancer susceptibility. We have used a Systems Genetics approach in mice that combines genetic background analysis with responses to low and high dose radiation, in order to develop insights that will allow us to reconcile these disparate observations. Using this comprehensive approach we have analyzed normal tissue gene expression (in this case the skin and thymus), together with the changes that take place in this gene expression architecture a) in response to low or high- dose radiation and b) during tumor development. Additionally, we have demonstrated that using our expression analysis approach in our genetically heterogeneous/defined radiation-induced tumor mouse models can uniquely identify genes and pathways relevant to human T-ALL, and uncover interactions between common genetic variants of genes which may lead to tumor susceptibility.

  14. Abnormalities in the handling of intracellular bacteria in Crohn's disease: a link between infectious etiology and host genetic susceptibility.

    Science.gov (United States)

    Glasser, Anne-Lise; Darfeuille-Michaud, Arlette

    2008-01-01

    The etiology of Crohn's disease (CD) is still poorly understood, but recent advances have highlighted the importance of the innate immune system and the critical relationship between the gut flora and the intestinal mucosa. Several combinations of genetic factors predisposing to CD have been described, with the most significant replicable associations including genes for intracellular receptors of bacterial cell walls (NOD2/CARD15) and for bacterial clearance and antigen processing via autophagy (ATG16L1 and IRGM). One theoretical link between susceptibility genes NOD2/CARD15, ATG16L1, and IRGM is that CD is primarily induced by the presence of a dysfunctional immunological response to persistent infection by intracellular bacterial pathogens such as Mycobacterium avium subspecies paratuberculosis or adherent-invasive Escherichia coli, both first-rank candidates on the basis of host genetic susceptibility, which concerns impaired functions in the defense against intracellular bacteria. PMID:18726145

  15. HLA and Celiac Disease Susceptibility: New Genetic Factors Bring Open Questions about the HLA Influence and Gene-Dosage Effects

    OpenAIRE

    Medrano, Luz María; Dema, Bárbara; López-Larios, Arturo; Maluenda, Carlos; Bodas, Andrés; López-Palacios, Natalia; Figueredo, M. Ángeles; Fernández-Arquero, Miguel; Núñez, Concepción

    2012-01-01

    Celiac disease (CD) is a chronic inflammatory disorder triggered after gluten ingestion in genetically susceptible individuals. The major genetic determinants are HLA-DQA1*05 and HLA-DQB1*02, which encode the DQ2 heterodimer. These alleles are commonly inherited in cis with DRB1*03∶01, which is associated with numerous immune-related disorders, in some cases contributing with a different amount of risk depending on the haplotype context. We aimed at investigating those possible differences in...

  16. Case-control study for colorectal cancer genetic susceptibility in EPICOLON: previously identified variants and mucins

    International Nuclear Information System (INIS)

    Colorectal cancer (CRC) is the second leading cause of cancer death in developed countries. Familial aggregation in CRC is also important outside syndromic forms and, in this case, a polygenic model with several common low-penetrance alleles contributing to CRC genetic predisposition could be hypothesized. Mucins and GALNTs (N-acetylgalactosaminyltransferase) are interesting candidates for CRC genetic susceptibility and have not been previously evaluated. We present results for ten genetic variants linked to CRC risk in previous studies (previously identified category) and 18 selected variants from the mucin gene family in a case-control association study from the Spanish EPICOLON consortium. CRC cases and matched controls were from EPICOLON, a prospective, multicenter, nationwide Spanish initiative, comprised of two independent stages. Stage 1 corresponded to 515 CRC cases and 515 controls, whereas stage 2 consisted of 901 CRC cases and 909 controls. Also, an independent cohort of 549 CRC cases and 599 controls outside EPICOLON was available for additional replication. Genotyping was performed for ten previously identified SNPs in ADH1C, APC, CCDN1, IL6, IL8, IRS1, MTHFR, PPARG, VDR and ARL11, and 18 selected variants in the mucin gene family. None of the 28 SNPs analyzed in our study was found to be associated with CRC risk. Although four SNPs were significant with a P-value < 0.05 in EPICOLON stage 1 [rs698 in ADH1C (OR = 1.63, 95% CI = 1.06-2.50, P-value = 0.02, recessive), rs1800795 in IL6 (OR = 1.62, 95% CI = 1.10-2.37, P-value = 0.01, recessive), rs3803185 in ARL11 (OR = 1.58, 95% CI = 1.17-2.15, P-value = 0.007, codominant), and rs2102302 in GALNTL2 (OR = 1.20, 95% CI = 1.00-1.44, P-value = 0.04, log-additive 0, 1, 2 alleles], only rs3803185 achieved statistical significance in EPICOLON stage 2 (OR = 1.34, 95% CI = 1.06-1.69, P-value = 0.01, recessive). In the joint analysis for both stages, results were only significant for rs3803185 (OR = 1.12, 95% CI = 1

  17. Case-control study for colorectal cancer genetic susceptibility in EPICOLON: previously identified variants and mucins

    Directory of Open Access Journals (Sweden)

    Moreno Victor

    2011-08-01

    Full Text Available Abstract Background Colorectal cancer (CRC is the second leading cause of cancer death in developed countries. Familial aggregation in CRC is also important outside syndromic forms and, in this case, a polygenic model with several common low-penetrance alleles contributing to CRC genetic predisposition could be hypothesized. Mucins and GALNTs (N-acetylgalactosaminyltransferase are interesting candidates for CRC genetic susceptibility and have not been previously evaluated. We present results for ten genetic variants linked to CRC risk in previous studies (previously identified category and 18 selected variants from the mucin gene family in a case-control association study from the Spanish EPICOLON consortium. Methods CRC cases and matched controls were from EPICOLON, a prospective, multicenter, nationwide Spanish initiative, comprised of two independent stages. Stage 1 corresponded to 515 CRC cases and 515 controls, whereas stage 2 consisted of 901 CRC cases and 909 controls. Also, an independent cohort of 549 CRC cases and 599 controls outside EPICOLON was available for additional replication. Genotyping was performed for ten previously identified SNPs in ADH1C, APC, CCDN1, IL6, IL8, IRS1, MTHFR, PPARG, VDR and ARL11, and 18 selected variants in the mucin gene family. Results None of the 28 SNPs analyzed in our study was found to be associated with CRC risk. Although four SNPs were significant with a P-value ADH1C (OR = 1.63, 95% CI = 1.06-2.50, P-value = 0.02, recessive, rs1800795 in IL6 (OR = 1.62, 95% CI = 1.10-2.37, P-value = 0.01, recessive, rs3803185 in ARL11 (OR = 1.58, 95% CI = 1.17-2.15, P-value = 0.007, codominant, and rs2102302 in GALNTL2 (OR = 1.20, 95% CI = 1.00-1.44, P-value = 0.04, log-additive 0, 1, 2 alleles], only rs3803185 achieved statistical significance in EPICOLON stage 2 (OR = 1.34, 95% CI = 1.06-1.69, P-value = 0.01, recessive. In the joint analysis for both stages, results were only significant for rs3803185 (OR = 1

  18. Common genetic variation associated with increased susceptibility to prostate cancer does not increase risk of radiotherapy toxicity.

    OpenAIRE

    Ahmed, M.; Dorling, L.; Kerns, S.; Fachal, L; Elliott, R.; Partliament, M.; Rosenstein, B S; Vega, A; Gómez-Caamaño, A.; Barnett, G.; Dearnaley, D. P.; Hall, E.; Sydes, M; Burnet, N.; Pharoah, P. D.

    2016-01-01

    BACKGROUND: Numerous germline single-nucleotide polymorphisms increase susceptibility to prostate cancer, some lying near genes involved in cellular radiation response. This study investigated whether prostate cancer patients with a high genetic risk have increased toxicity following radiotherapy. METHODS: The study included 1560 prostate cancer patients from four radiotherapy cohorts: RAPPER (n=533), RADIOGEN (n=597), GenePARE (n=290) and CCI (n=150). Data from genome-wide association studie...

  19. Review: Genetic diversity of HLA-DR and varion of asthma susceptibility; an overview of Asthma in Pregnancy

    OpenAIRE

    ACHMAD ARMAN SUBIJANTO

    2008-01-01

    Asthma is the most common potentially serious medical condition to complicate pregnancy. To date, many attempts have been done to detect genetic loci contributing to asthma susceptibility. HLA-DR loci may play an important role in the pathophysiology of allergic inflammation by influencing specific IgE responses. Asthma affects almost 7 percent of women in their childbearing years. When women with asthma become pregnant, a third of the patients improve, one third worsen, and the last third re...

  20. Genetic evaluation of BRCA1-A complex genes with triple-negative breast cancer susceptibility in Chinese women

    Science.gov (United States)

    Zheng, Yi-Zi; Qiao, Feng; Yao, Ling; Cao, Zhi-Gang; Ye, Fu-Gui; Wu, Jiong; Hu, Xin; Wang, Bin; Shao, Zhi-Ming

    2016-01-01

    Background The tumor suppressor BRCA1 plays a pivotal role in maintaining genomic stability and tumor suppression. The BRCA1-A complex is required for recruitment of BRCA1 to DNA damage sites, DNA repair and cell cycle checkpoint control. Since germline mutations of BRCA1 often lead to breast tumors that are triple-negative breast cancer (TNBC) type, we aimed to investigate whether genetic deficiency in genes of the BRCA1-A complex is associated with risk to TNBC development. Results We found that rs7250266 in the promoter region of NBA1 confers a decreased risk to TNBC development, but not to non-TNBC susceptibility. In addition, the haplotypes containing two polymorphisms rs7250266 and rs2278256 are associated with a lower chance of TNBC development specifically. Our studies also showed that the protective alleles of rs7250266 (C > G) and rs2278256 (T > C) down-regulate promoter activity of NBA1 in mammary epithelial cells. Methods We investigated associations between the BRCA1-A complex genes and TNBC developing risk in first case-control study of Chinese Han Women population including 414 patients with TNBC and 354 cancer-free controls. We detected 37 common variants in ABRAXAS, RAP80, BRE, BRCC36 and NBA1/MERIT40 genes encoding the BRCA1-A complex and evaluated their genetic susceptibility to the risk of TNBC. An additional cohort with 652 other types of breast cancer (non-TNBC) cases and 890 controls was used to investigate the associations between TNBC-specific SNPs genotype and non-TNBCs susceptibility. Conclusions Genetic variants in NBA1 may be an important genetic determinant of TNBC susceptibility. Further investigation and validation of these SNPs in larger cohorts may facilitate in predication and prevention of TNBC and in counseling individuals for risk of TNBC development. PMID:26848770

  1. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

    OpenAIRE

    Mahajan, Anubha; Go, Min Jin; Zhang, Weihua; Below, Jennifer E.; Gaulton, Kyle J.; Ferreira, Teresa; Horikoshi, Momoko; Johnson, Andrew D.; Ng, Maggie C. Y.; Prokopenko, Inga; Saleheen, Danish; Wang, Xu; Zeggini, Eleftheria; Goncalo R. Abecasis; Adair, Linda S

    2014-01-01

    To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signal...

  2. Application of a hybrid model of neural networks and genetic algorithms to evaluate landslide susceptibility

    OpenAIRE

    Wang, H. B.; Li, J. W.; Zhou, B.; YUAN, Z. Q.; Chen, Y P

    2013-01-01

    In the last few decades, the development of Geographical Information Systems (GIS) technology has provided a method for the evaluation of landslide susceptibility and hazard. Slope units were found to be appropriate for the fundamental morphological elements in landslide susceptibility evaluation. Following the DEM construction in a loess area susceptible to landslides, the direct-reverse DEM technology was employed to generate 216 slope units in the studied area. After a de...

  3. Recent advances in the characterization of genetic factors involved in human susceptibility to infection by schistosomiasis.

    Science.gov (United States)

    Isnard, Amandine; Chevillard, Christophe

    2008-01-01

    Human resistance to infection by schistosomes is associated to a strong Th2 immune. However a persistent Th2 response can cause severe kidney and liver disease in human. In this review, we mainly focused on the control of infection levels caused by schistosomes. Several experimental models allowed us to better understand the immunological mechanisms of the host against schistosome infection. High IgE and eosinophil levels are associated with resistance to infection by schistosomes and this effect is counterbalanced by IgG4. IgE and eosinophils are highly dependent on IL-4, IL-13, and Il-5, which are three main Th2 cytokines. We also examined the genetic factors involved in human susceptibility to infection by schistosomiasis. Infection levels are mainly regulated by a major locus SM1, in 5q31-q33 region, which contains the genes encoding for the IL-4, IL-13, and Il-5 cytokines. An association between an IL13 polymorphism, rs1800925, and infection levels has been shown. This polymorphism synergistically acts with another polymorphism (rs324013) in the STAT6 gene, encoding for the signal transducer of the IL13 pathway. This pathway has also been involved in atopic disorders. As helminthiasis, atopy is the result of aberrant Th2 cytokine response to allergens, with an increased production of IL-4, IL-13, Il-9 and Il-5, with high amounts of allergen-specific and total IgE and eosinophilia. However, the Th2 immune response is protective in helminthiasis but aggravating in atopic disorders. Several studies reported interplay between helminthic infections and allergic reactions. The different results are discussed here. PMID:19471606

  4. The relationship between genetic variability and the susceptibility of Biomphalaria alexandrina snails to Schistosoma mansoni infection

    Directory of Open Access Journals (Sweden)

    Azza H Mohamed

    2012-05-01

    Full Text Available In the present study, Biomphalaria snails collected from five Egyptian governorates (Giza, Fayoum, Kafr El-Sheikh, Ismailia and Damietta, as well as reference control Biomphalaria alexandrina snails from the Schistosome Biological Supply Center (SBSC (Theodor Bilharz Research Institute, Egypt, were subjected to species-specific polymerase chain reaction (PCR assays to identify the collected species. All of the collected snails were found to be B. alexandrina and there was no evidence of the presence of Biomphalaria glabrata. Randomly amplified polymorphic DNA (RAPD-PCR assays showed different fingerprints with varying numbers of bands for the first generation (F1 of B. alexandrina snail populations (SBSC, Giza, Fayoum, Kafr El-Sheikh, Ismailia and Damietta. The primer OPA-1 produced the highest level of polymorphism and amplified the greatest number of specific bands. The estimated similarity coefficients among the B. alexandrina populations based on the RAPD-PCR profiles ranged from 0.56 (between SBSC and Ismailia snails to 0.72 (between Ismailia and Kafr El-Sheikh snails. Experimental infection of the F1 of progeny from the collected snails with Schistosoma mansoni (SBSC strain showed variable susceptibility rates ranging from 15% in the Fayoum snail group to 50.3% in SBSC snails. A negative correlation was observed between the infection rates in the different snail groups and the distances separating their corresponding governorates from the parasite source. The infection rates of the snail groups and their similarity coefficients with SBSC B. alexandrina snails were positively correlated. The variations in the rates of infection of different B. alexandrina groups with S. mansoni, as well as the differences in the similarity coefficients among these snails, are dependent not only on the geographical distribution of the snails and the parasite, but also on the genetic variability of the snails. Introduction of this variability into endemic

  5. Genetic polymorphisms of DNA double-strand break repair pathway genes and glioma susceptibility

    International Nuclear Information System (INIS)

    Genetic variations in DNA double-strand break repair genes can influence the ability of a cell to repair damaged DNA and alter an individual’s susceptibility to cancer. We studied whether polymorphisms in DNA double-strand break repair genes are associated with an increased risk of glioma development. We genotyped 10 potentially functional single nucleotide polymorphisms (SNPs) in 7 DNA double-strand break repair pathway genes (XRCC3, BRCA2, RAG1, XRCC5, LIG4, XRCC4 and ATM) in a case–control study including 384 glioma patients and 384 cancer-free controls in a Chinese Han population. Genotypes were determined using the OpenArray platform. In the single-locus analysis there was a significant association between gliomas and the LIG4 rs1805388 (Ex2 +54C>T, Thr9Ile) TT genotype (adjusted OR, 3.27; 95% CI, 1.87-5.71), as well as the TC genotype (adjusted OR, 1.62; 95% CI, 1.20-2.18). We also found that the homozygous variant genotype (GG) of XRCC4 rs1805377 (IVS7-1A>G, splice-site) was associated with a significantly increased risk of gliomas (OR, 1.77; 95% CI, 1.12-2.80). Interestingly, we detected a significant additive and multiplicative interaction effect between the LIG4 rs1805388 and XRCC4 rs1805377 polymorphisms with an increasing risk of gliomas. When we stratified our analysis by smoking status, LIG4 rs1805388 was associated with an increased glioma risk among smokers. These results indicate for the first time that LIG4 rs1805388 and XRCC4 rs1805377, alone or in combination, are associated with a risk of gliomas

  6. Interleukin-16 Gene Polymorphisms Are Considerable Host Genetic Factors for Patients’ Susceptibility to Chronic Hepatitis B Infection

    Directory of Open Access Journals (Sweden)

    Sara Romani

    2014-01-01

    Full Text Available Host genetic background is known as an important factor in patients’ susceptibility to infectious diseases such as viral hepatitis. The aim of this study was to determine the effect of genetic polymorphisms of interleukin-16 (IL-16 cytokine on susceptibility of hepatitis B virus (HBV infected patients to develop chronic HBV infection. Genotyping was conducted using PCR followed by enzymatic digestion and RFLP (restriction fragment length polymorphism analysis. We genotyped three single nucleotide polymorphisms (SNPs in the Il-16 gene (rs11556218 T>G, rs4778889 T>C, and rs4072111 C>T to test for relationship between variation at these loci and patients’ susceptibility to chronic HBV infection. Allele frequency of Il-16 gene rs4072111 and rs11556218 was significantly different between chronic HBV patients and healthy blood donors. Genotype frequency of rs4778889 polymorphism of Il-16 gene was significantly different when chronic HBV patients and HBV clearance subjects were compared. Our results showed that Il-16 gene polymorphisms are considerable host genetic factors when we chase biomarkers for prognosis of HBV infected patients.

  7. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

    Science.gov (United States)

    Mahajan, Anubha; Go, Min Jin; Zhang, Weihua; Below, Jennifer E; Gaulton, Kyle J; Ferreira, Teresa; Horikoshi, Momoko; Johnson, Andrew D; Ng, Maggie C Y; Prokopenko, Inga; Saleheen, Danish; Wang, Xu; Zeggini, Eleftheria; Abecasis, Goncalo R; Adair, Linda S; Almgren, Peter; Atalay, Mustafa; Aung, Tin; Baldassarre, Damiano; Balkau, Beverley; Bao, Yuqian; Barnett, Anthony H; Barroso, Ines; Basit, Abdul; Been, Latonya F; Beilby, John; Bell, Graeme I; Benediktsson, Rafn; Bergman, Richard N; Boehm, Bernhard O; Boerwinkle, Eric; Bonnycastle, Lori L; Burtt, Noël; Cai, Qiuyin; Campbell, Harry; Carey, Jason; Cauchi, Stephane; Caulfield, Mark; Chan, Juliana C N; Chang, Li-Ching; Chang, Tien-Jyun; Chang, Yi-Cheng; Charpentier, Guillaume; Chen, Chien-Hsiun; Chen, Han; Chen, Yuan-Tsong; Chia, Kee-Seng; Chidambaram, Manickam; Chines, Peter S; Cho, Nam H; Cho, Young Min; Chuang, Lee-Ming; Collins, Francis S; Cornelis, Marylin C; Couper, David J; Crenshaw, Andrew T; van Dam, Rob M; Danesh, John; Das, Debashish; de Faire, Ulf; Dedoussis, George; Deloukas, Panos; Dimas, Antigone S; Dina, Christian; Doney, Alex S; Donnelly, Peter J; Dorkhan, Mozhgan; van Duijn, Cornelia; Dupuis, Josée; Edkins, Sarah; Elliott, Paul; Emilsson, Valur; Erbel, Raimund; Eriksson, Johan G; Escobedo, Jorge; Esko, Tonu; Eury, Elodie; Florez, Jose C; Fontanillas, Pierre; Forouhi, Nita G; Forsen, Tom; Fox, Caroline; Fraser, Ross M; Frayling, Timothy M; Froguel, Philippe; Frossard, Philippe; Gao, Yutang; Gertow, Karl; Gieger, Christian; Gigante, Bruna; Grallert, Harald; Grant, George B; Grrop, Leif C; Groves, Chrisropher J; Grundberg, Elin; Guiducci, Candace; Hamsten, Anders; Han, Bok-Ghee; Hara, Kazuo; Hassanali, Neelam; Hattersley, Andrew T; Hayward, Caroline; Hedman, Asa K; Herder, Christian; Hofman, Albert; Holmen, Oddgeir L; Hovingh, Kees; Hreidarsson, Astradur B; Hu, Cheng; Hu, Frank B; Hui, Jennie; Humphries, Steve E; Hunt, Sarah E; Hunter, David J; Hveem, Kristian; Hydrie, Zafar I; Ikegami, Hiroshi; Illig, Thomas; Ingelsson, Erik; Islam, Muhammed; Isomaa, Bo; Jackson, Anne U; Jafar, Tazeen; James, Alan; Jia, Weiping; Jöckel, Karl-Heinz; Jonsson, Anna; Jowett, Jeremy B M; Kadowaki, Takashi; Kang, Hyun Min; Kanoni, Stavroula; Kao, Wen Hong L; Kathiresan, Sekar; Kato, Norihiro; Katulanda, Prasad; Keinanen-Kiukaanniemi, Kirkka M; Kelly, Ann M; Khan, Hassan; Khaw, Kay-Tee; Khor, Chiea-Chuen; Kim, Hyung-Lae; Kim, Sangsoo; Kim, Young Jin; Kinnunen, Leena; Klopp, Norman; Kong, Augustine; Korpi-Hyövälti, Eeva; Kowlessur, Sudhir; Kraft, Peter; Kravic, Jasmina; Kristensen, Malene M; Krithika, S; Kumar, Ashish; Kumate, Jesus; Kuusisto, Johanna; Kwak, Soo Heon; Laakso, Markku; Lagou, Vasiliki; Lakka, Timo A; Langenberg, Claudia; Langford, Cordelia; Lawrence, Robert; Leander, Karin; Lee, Jen-Mai; Lee, Nanette R; Li, Man; Li, Xinzhong; Li, Yun; Liang, Junbin; Liju, Samuel; Lim, Wei-Yen; Lind, Lars; Lindgren, Cecilia M; Lindholm, Eero; Liu, Ching-Ti; Liu, Jian Jun; Lobbens, Stéphane; Long, Jirong; Loos, Ruth J F; Lu, Wei; Luan, Jian'an; Lyssenko, Valeriya; Ma, Ronald C W; Maeda, Shiro; Mägi, Reedik; Männisto, Satu; Matthews, David R; Meigs, James B; Melander, Olle; Metspalu, Andres; Meyer, Julia; Mirza, Ghazala; Mihailov, Evelin; Moebus, Susanne; Mohan, Viswanathan; Mohlke, Karen L; Morris, Andrew D; Mühleisen, Thomas W; Müller-Nurasyid, Martina; Musk, Bill; Nakamura, Jiro; Nakashima, Eitaro; Navarro, Pau; Ng, Peng-Keat; Nica, Alexandra C; Nilsson, Peter M; Njølstad, Inger; Nöthen, Markus M; Ohnaka, Keizo; Ong, Twee Hee; Owen, Katharine R; Palmer, Colin N A; Pankow, James S; Park, Kyong Soo; Parkin, Melissa; Pechlivanis, Sonali; Pedersen, Nancy L; Peltonen, Leena; Perry, John R B; Peters, Annette; Pinidiyapathirage, Janini M; Platou, Carl G; Potter, Simon; Price, Jackie F; Qi, Lu; Radha, Venkatesan; Rallidis, Loukianos; Rasheed, Asif; Rathman, Wolfgang; Rauramaa, Rainer; Raychaudhuri, Soumya; Rayner, N William; Rees, Simon D; Rehnberg, Emil; Ripatti, Samuli; Robertson, Neil; Roden, Michael; Rossin, Elizabeth J; Rudan, Igor; Rybin, Denis; Saaristo, Timo E; Salomaa, Veikko; Saltevo, Juha; Samuel, Maria; Sanghera, Dharambir K; Saramies, Jouko; Scott, James; Scott, Laura J; Scott, Robert A; Segrè, Ayellet V; Sehmi, Joban; Sennblad, Bengt; Shah, Nabi; Shah, Sonia; Shera, A Samad; Shu, Xiao Ou; Shuldiner, Alan R; Sigurđsson, Gunnar; Sijbrands, Eric; Silveira, Angela; Sim, Xueling; Sivapalaratnam, Suthesh; Small, Kerrin S; So, Wing Yee; Stančáková, Alena; Stefansson, Kari; Steinbach, Gerald; Steinthorsdottir, Valgerdur; Stirrups, Kathleen; Strawbridge, Rona J; Stringham, Heather M; Sun, Qi; Suo, Chen; Syvänen, Ann-Christine; Takayanagi, Ryoichi; Takeuchi, Fumihiko; Tay, Wan Ting; Teslovich, Tanya M; Thorand, Barbara; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tikkanen, Emmi; Trakalo, Joseph; Tremoli, Elena; Trip, Mieke D; Tsai, Fuu Jen; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Uitterlinden, Andre G; Valladares-Salgado, Adan; Vedantam, Sailaja; Veglia, Fabrizio; Voight, Benjamin F; Wang, Congrong; Wareham, Nicholas J; Wennauer, Roman; Wickremasinghe, Ananda R; Wilsgaard, Tom; Wilson, James F; Wiltshire, Steven; Winckler, Wendy; Wong, Tien Yin; Wood, Andrew R; Wu, Jer-Yuarn; Wu, Ying; Yamamoto, Ken; Yamauchi, Toshimasa; Yang, Mingyu; Yengo, Loic; Yokota, Mitsuhiro; Young, Robin; Zabaneh, Delilah; Zhang, Fan; Zhang, Rong; Zheng, Wei; Zimmet, Paul Z; Altshuler, David; Bowden, Donald W; Cho, Yoon Shin; Cox, Nancy J; Cruz, Miguel; Hanis, Craig L; Kooner, Jaspal; Lee, Jong-Young; Seielstad, Mark; Teo, Yik Ying; Boehnke, Michael; Parra, Esteban J; Chambers, Jonh C; Tai, E Shyong; McCarthy, Mark I; Morris, Andrew P

    2014-03-01

    To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. PMID:24509480

  8. Genetic Determinants Involved in the Susceptibility of Pseudomonas aeruginosa to  -Lactam Antibiotics

    OpenAIRE

    Alvarez-Ortega, C.; Wiegand, I.; Olivares, J.; Hancock, R. E. W.; Martinez, J.L.

    2010-01-01

    The resistome of P. aeruginosa for three β-lactam antibiotics, namely, ceftazidime, imipenem, and meropenem, was deciphered by screening a comprehensive PA14 mutant library for mutants with increased or reduced susceptibility to these antimicrobials. Confirmation of the phenotypes of all selected mutants was performed by Etest. Of the total of 78 confirmed mutants, 41 demonstrated a reduced susceptibility phenotype and 37 a supersusceptibility (i.e., altered intrinsic resistance) phenotype, w...

  9. Differential Susceptibility: The Genetic Moderation of Peer Pressure on Alcohol Use

    OpenAIRE

    Griffin, Amanda M.; Cleveland, H. Harrington.; Schlomer, Gabriel L.; Vandenbergh, David J.; Feinberg, Mark E

    2015-01-01

    Although peer pressure can influence adolescents’ alcohol use, individual susceptibility to these pressures varies across individuals. The dopamine receptor D4 gene (DRD4) is a potential candidate gene that may influence adolescents’ susceptibility to their peer environment due to the role dopamine plays in reward sensation during social interaction. We hypothesized that DRD4 genotype status would moderate the impact of 7th-grade antisocial peer pressure on 12th-grade lifetime alcohol use (n ...

  10. Functional evaluation of TERT-CLPTM1L genetic variants associated with susceptibility of papillary thyroid carcinoma.

    Science.gov (United States)

    Ge, Minghua; Shi, Meng; An, Changming; Yang, Wenjun; Nie, Xilin; Zhang, Jian; Lv, Zheng; Li, Jinliang; Zhou, Liqing; Du, Zhongli; Yang, Ming

    2016-01-01

    TERT is the catalytic subunit of telomerase which plays an essential part in cellular immortality by maintaining telomere integrity. TERT is commonly over-expressed in human malignancies, indicating its key role in cell transformation. The chromosome 5p15.33 TERT-CLPTM1L region has been associated with susceptibility of multiple cancers via a genome-wide association approach. However, the involvement of this locus in papillary thyroid carcinoma (PTC) etiology is still largely unknown. We analyzed 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) of the TERT-CLPTM1L region in a two stage case-control design. After genotyping 2300 PTC patients and frequency-matched 2300 unaffected controls, we found that TERT rs2736100 genetic variant is significantly associated with elevated PTC risk. Ex vivo reporter gene assays indicated that the PTC susceptibility rs2736100 polymorphism locating in a potential TERT intronic enhancer has a genotype-specific effect on TERT expression. Correlations between rs2736100 genotypes and tissue-specific TERT expression supported the regulatory function of this genetic variant in vivo. Our data demonstrated that the functional TERT rs2736100 SNP as a novel genetic component of PTC etiology. This study, together with recent studies in other cancers, unequivocally establishes an essential role of TERT in cancers. PMID:27185198

  11. Genetic variation in the NBS1, MRE11, RAD50 and BLM genes and susceptibility to non-Hodgkin lymphoma

    Directory of Open Access Journals (Sweden)

    Gascoyne Randy D

    2009-11-01

    Full Text Available Abstract Background Translocations are hallmarks of non-Hodgkin lymphoma (NHL genomes. Because lymphoid cell development processes require the creation and repair of double stranded breaks, it is not surprising that disruption of this type of DNA repair can cause cancer. The members of the MRE11-RAD50-NBS1 (MRN complex and BLM have central roles in maintenance of DNA integrity. Severe mutations in any of these genes cause genetic disorders, some of which are characterized by increased risk of lymphoma. Methods We surveyed the genetic variation in these genes in constitutional DNA of NHL patients by means of gene re-sequencing, then conducted genetic association tests for susceptibility to NHL in a population-based collection of 797 NHL cases and 793 controls. Results 114 SNPs were discovered in our sequenced samples, 61% of which were novel and not previously reported in dbSNP. Although four variants, two in RAD50 and two in NBS1, showed association results suggestive of an effect on NHL, they were not significant after correction for multiple tests. Conclusion These results suggest an influence of RAD50 and NBS1 on susceptibility to diffuse large B-cell lymphoma and marginal zone lymphoma. Larger association and functional studies could confirm such a role.

  12. The effects of selective breeding against scrapie susceptibility on the genetic variability of the Latxa Black-Faced sheep breed

    Directory of Open Access Journals (Sweden)

    Legarra Andrés

    2006-09-01

    Full Text Available Abstract Breeding sheep populations for scrapie resistance could result in a loss of genetic variability. In this study, the effect on genetic variability of selection for increasing the ARR allele frequency was estimated in the Latxa breed. Two sources of information were used, pedigree and genetic polymorphisms (fifteen microsatellites. The results based on the genealogical information were conditioned by a low pedigree completeness level that revealed the interest of also using the information provided by the molecular markers. The overall results suggest that no great negative effect on genetic variability can be expected in the short time in the population analysed by selection of only ARR/ARR males. The estimated average relationship of ARR/ARR males with reproductive females was similar to that of all available males whatever its genotype: 0.010 vs. 0.012 for a genealogical relationship and 0.257 vs. 0.296 for molecular coancestry, respectively. However, selection of only ARR/ARR males implied important losses in founder animals (87 percent and low frequency alleles (30 percent in the ram population. The evaluation of mild selection strategies against scrapie susceptibility based on the use of some ARR heterozygous males was difficult because the genetic relationships estimated among animals differed when pedigree or molecular information was used, and the use of more molecular markers should be evaluated.

  13. RAPD analysis of genetic variability among Stylosanthes guianenesis accessions of resistant and susceptible to the stylo anthracnose

    Institute of Scientific and Technical Information of China (English)

    Jiang Changshun; Zou Dongmei; Zhang Yizheng

    2005-01-01

    Stylosanthes guianenesis Sw. is an important tropical forage legume grown and utilized in the tropics and the subtropics of South China. Anthracnose, caused by Colletotrichum gloeosporioides (Penz.) Sacc., is a major constraint to the extensive use of Stylosanthes. Forty-five accessions of S. guianensis were assessed with RAPD for genetic diversity and for resistance to anthracnose. RAPD analysis was performed using twenty primers screened from 200 arbitrary oligonucleotides, and a 71.5% level of polymorphism was found. The dendrogram obtained with unweighted pair group method of averages (UPGMA) based on the RAPD data showed genetic similarity from 50% to 94% among all stylo accessions, and fourteen clusters were defined at 66.5% genetic similarity. Two strains of C. gloeosporioides from stylo in China were used for anthracnose resistance screening. All plant accessions showed variation in the reaction to two strains and the correlation of resistance had a value of 0.904. Multiple correspondence analysis displayed a random distribution of the resistance or susceptibility response with respect to the genetic diversity measured by RAPD analysis except one group. Mean distance was also calculated to determine the diversity within clusters. From our results, the RAPD analysis is an effective and efficient technique of providing quantitative estimates of genetic similarity among stylo accessions.

  14. Genetic testing of newborns for type 1 diabetes susceptibility: a prospective cohort study on effects on maternal mental health

    Directory of Open Access Journals (Sweden)

    Magnus Per

    2010-07-01

    Full Text Available Abstract Background Concerns about the general psychological impact of genetic testing have been raised. In the Environmental Triggers of Type 1 Diabetes (MIDIA study, genetic testing was performed for HLA-conferred type 1 diabetes susceptibility among Norwegian newborns. The present study assessed whether mothers of children who test positively suffer from poorer mental health and well-being after receiving genetic risk information about their children. Methods The study was based on questionnaire data from the Norwegian Mother and Child Cohort (MoBa study conducted by the Norwegian Institute of Public Health. Many of the mothers in the MoBa study also took part in the MIDIA study, in which their newborn children were tested for HLA-conferred genetic susceptibility for type 1 diabetes. We used MoBa questionnaire data from the 30th week of pregnancy (baseline and 6 months post-partum (3-3.5 months after disclosure of test results. We measured maternal symptoms of anxiety and depression (SCL-8, maternal self-esteem (RSES, and satisfaction with life (SWLS. The mothers also reported whether they were seriously worried about their child 6 months post-partum. We compared questionnaire data from mothers who had received information about having a newborn with high genetic risk for type 1 diabetes (N = 166 with data from mothers who were informed that their baby did not have a high-risk genotype (N = 7224. The association between genetic risk information and maternal mental health was analysed using multiple linear regression analysis, controlling for baseline mental health scores. Results Information on genetic risk in newborns was found to have no significant impact on maternal symptoms of anxiety and depression (p = 0.9, self-esteem (p = 0.2, satisfaction with life (p = 0.2, or serious worry about their child (OR = 0.98, 95% CI 0.64-1.48. Mental health before birth was strongly associated with mental health after birth. In addition, an increased

  15. Atopic Dermatitis: Clinical Connotations, Especially a Focus on Concomitant Atopic Undertones in Immunocompromised/Susceptible Genetic and Metabolic Disorders.

    Science.gov (United States)

    Sehgal, Virendra N; Khurana, Ananta; Mendiratta, Vibhu; Saxena, Deepti; Srivastava, Govind; Aggarwal, Ashok K; Chatterjee, Kingshuk

    2016-01-01

    Atopic dermatitis (AD) is an intriguing clinical entity. Its clinical connotations are varied, the updates of which are required to be done periodically. An attempt to bring its various facets have been made highlighting its clinical features keeping in view the major and the minor criteria to facilitate the diagnosis, differential diagnosis, complications, and associated dermatoses. The benefit of the current dissertation may percolate to the trainees in dermatology, in addition to revelations that atopic undertones in genetic susceptibility and metabolic disorder may provide substantive insight for the future in the understanding of thus far enigmatic etiopathogenesis of AD. PMID:27293243

  16. The genetic and regulatory architecture of ERBB3-type 1 diabetes susceptibility locus

    DEFF Research Database (Denmark)

    Kaur, Simranjeet; Mirza, Aashiq H; Brorsson, Caroline Anna;

    2016-01-01

    -producing INS-1E cells and the genetic and regulatory architecture of the ERBB3 locus to provide insights to how rs2292239 may confer disease susceptibility. rs2292239 strongly correlated with residual β-cell function and metabolic control in children with T1D. ERBB3 locus associated lncRNA (NONHSAG011351) was......The study aimed to explore the role of ERBB3 in type 1 diabetes (T1D). We examined whether genetic variation of ERBB3 (rs2292239) affects residual β-cell function in T1D cases. Furthermore, we examined the expression of ERBB3 in human islets, the effect of ERBB3 knockdown on apoptosis in insulin...

  17. Media violence and children’s ADHD-related behaviors: a genetic susceptibility perspective

    NARCIS (Netherlands)

    S.W.C. Nikkelen; H.G.M. Vossen; P.M. Valkenburg; F.P. Velders; D.A. Windhorst; V.W.V. Jaddoe; A. Hofman; F.C. Verhulst; H. Tiemeier

    2014-01-01

    This study examined the relationship between media violence exposure and Attention-deficit/hyperactivity disorder (ADHD)-related behaviors. Using survey (parent-reported) and genetic data of 1,612 Dutch children (aged 5 to 9 years), we examined genetic disposition as a possible cause of individual d

  18. Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions

    DEFF Research Database (Denmark)

    Schoeps, Anja; Rudolph, Anja; Seibold, Petra;

    2014-01-01

    Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,47...

  19. Analysis of a p53 Mutation Associated with Cancer Susceptibility for Biochemistry and Genetic Laboratory Courses

    Science.gov (United States)

    Soto-Cruz, Isabel; Legorreta-Herrera, Martha

    2009-01-01

    We have devised and implemented a module for an upper division undergraduate laboratory based on the amplification and analysis of a p53 polymorphism associated with cancer susceptibility. First, students collected a drop of peripheral blood cells using a sterile sting and then used FTA cards to extract the genomic DNA. The p53 region is then PCR…

  20. The Correlation between the CLEC16A Gene and Genetic Susceptibility to Type 1 Diabetes in Chinese Children

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    Yanmei Sang

    2012-01-01

    Full Text Available Objective. The CLEC16A gene is related to the genetic susceptibility to T1DM with racial variability. This study investigated the association between CLEC16A gene polymorphisms and T1DM in Chinese children. Methods. 131 Chinese children with T1DM were selected for study, and 121 healthy adult blood donors were selected as normal controls. PCR and mass spectrometry was used to study the distributions of 17 CLEC16A alleles in patients and controls. The relationship between CLEC16A gene polymorphisms and T1DM was studied. Results. The distributions of two polymorphisms (rs12921922, rs12931878 of CLEC16A in T1DM and healthy controls were significantly different, while the distributions of other CLEC16A polymorphisms show no significant differences. The alleles of rs12921922 are C and T. The frequency of the T allele was significantly increased in patients versus healthy controls. The alleles of rs12931878 are A and C. The frequencies of the A allele are significantly increased in T1DM patients versus healthy controls. Conclusion. Two polymorphisms in the CLEC16A gene correlate with increased susceptibility to T1DM in Chinese children, revealing that it was another new gene that correlates with susceptibility to T1DM in multiple populations.

  1. Vitamin D level and vitamin D receptor genetic variations contribute to HCV infection susceptibility and chronicity in a Chinese population.

    Science.gov (United States)

    Wu, Mengping; Yue, Ming; Huang, Peng; Zhang, Yun; Xie, Chaonan; Yu, Rongbin; Li, Jun; Wang, Jie

    2016-07-01

    Vitamin D and vitamin D receptor (VDR) are involved in multiple immune-mediated disorders including chronic hepatitis C virus (HCV) infection. The aim of this study was to determine the association between plasma vitamin D level, VDR genetic polymorphisms and risk of HCV infection susceptibility and chronicity. Seven single nucleotide polymorphisms (SNPs) in VDR gene were genotyped and plasma 25-hydroxyvitamin D [25(OH)D] levels were measured in a Han Chinese population of 898 HCV persistent infection cases, 558 spontaneous clearance subjects and 1136 uninfected controls with high risk of HCV infection. In this case-control study, the average plasma 25(OH)D level in persistent infection patients was significantly lower than that in spontaneous clearance cases (P=0.039) and controls (P=0.005). Logistic analyses indicated that rs7975232-C, rs2239185-T and rs11574129-T alleles were significantly associated with a decreased risk of HCV infection susceptibility (all PBonferroniVDR variants (rs7975232-C, rs2239185-T and rs11574129-T) might contribute to a decreased susceptibility to HCV infection in a high-risk Chinese population. PMID:27063396

  2. Obstructive Sleep Apnea Susceptibility Genes in Chinese Population: A Field Synopsis and Meta-Analysis of Genetic Association Studies.

    Directory of Open Access Journals (Sweden)

    Jinxian Sun

    Full Text Available Epidemiological studies to date have evaluated the association between genetic variants and the susceptibility to obstructive sleep apnea (OSA. However, the results of these studies have been inconclusive. In this current study we performed meta-analysis of genetic association studies (GAS to pool OSA-susceptible genes in Chinese population, to perform a more precise evaluation of the association.Various databases (i.e., PubMed, EMBASE, HuGE Navigator, Wanfang and CNKI were searched to identify all eligible GAS-related variants associated with susceptibility to OSA. The generalized odds ratio metric (ORG and the odds ratio (OR of the allele contrast were used to quantify the impact of genetic variants on the risk of OSA. Cumulative and recursive cumulative meta-analyses (CMA were also performed to investigate the trend and stability of effect sizes as evidence was accumulated.Thirty-two GAS evaluating 13 polymorphisms in 10 genes were included in our meta-analysis. Significant associations were derived for four polymorphisms either for the allele contrast or for the ORG. The variants TNF-α-308G/A, 5-HTTLPR, 5-HTTVNTR, and APOE showed marginal significance for ORG (95% confidence interval [CI]: 2.01(1.31-3.07; 1.31(1.09-1.58; 1.85(1.16-2.95; 1.79(1.10-2.92; and 1.79(1.10-2.92 respectively. In addition, the TNF-α-308G/A, 5-HTTLPR, and 5-HTTVNTR variants showed significance for the allele contrast: 2.15(1.39-3.31; 2.26(1.58-3.24; 1.32(1.12-1.55; and 1.86(1.12-3.08 respectively. CMA showed a trend towards an association, and recursive CMA indicated that more evidence was needed to determine whether this was significant.TNF-α, 5-HTT, and APOE genes can all be proposed as OSA-susceptibility genes in Chinese population. Genome-wide association studies (GWAS are therefore urgently needed to confirm our findings within a larger sample of OSA patients in China.

  3. Obesity and Increased Susceptibility : Role of FTO and MGAT1 Genetic Variants

    OpenAIRE

    Jacobsson, Josefin A.

    2011-01-01

    Obesity is a complex and a highly individualized disease and the molecular mechanisms behind this disorder need to be better elucidated. Identification of genes and genetic variants that are involved provide opportunities to establish a genetic understanding of the disease. These findings may also provide more rational approaches to therapy, either by identifying underlying causes or point out the need for different treatments. In addition, the timing and severity of obesity may provide insig...

  4. Genetic Susceptibility to Peripheral Arterial Disease: A Dark Corner in Vascular Biology

    OpenAIRE

    Knowles, Joshua W.; Assimes, Themistocles L.; Li, Jun; Quertermous, Thomas; Cooke, John P.

    2007-01-01

    Peripheral arterial disease (PAD) is characterized by reduced blood flow to the limbs, usually as a consequence of atherosclerosis, and affects ≈12 million Americans. It is a common cause of cardiovascular morbidity and an independent predictor of cardiovascular mortality. Similar to other atherosclerotic diseases, such as coronary artery disease, PAD is the result of the complex interplay between injurious environmental stimuli and genetic predisposing factors of the host. Genetic susceptibi...

  5. Correlation between XRCC1 Arg399Gln genetic polymorphisms and susceptibility to bladder cancer: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Liu N

    2016-01-01

    Full Text Available Nannan Liu,1 Xiawei Fei,2 Yi Shen,1 Weifeng Shi,1 Jinhong Ma1 1Department of Clinical Laboratory, The Third Affiliated Hospital of Suzhou University, Changzhou, Jiangsu, People’s Republic of China; 2Department of Urology Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China Abstract: The relationship between XRCC1 polymorphisms and bladder cancer has been widely studied. Here, our meta-analysis was conducted to evaluate the correlations between common genetic polymorphisms in XRCC1 and susceptibility to bladder cancer. In order to derive a more precise estimation of the association, 27 clinical case-control studies (which met all the inclusion criteria were included in this meta-analysis. A total of 8,539 cancer cases and 10,750 controls were involved in this meta-analysis. Overall, no significant association was detected in allelic model (A allele vs T allele odds ratio [OR] =0.87, 95% confidence interval [CI], 0.71–1.06, homozygote comparison (AA vs GG OR =1.12, 95% CI, 0.68–1.85, heterozygote comparison (AT vs TT OR =1.01, 95% CI, 0.81–1.26, dominant model (AA + AG vs GG OR =0.93, 95% CI, 0.85–1.02, and recessive model (AA vs AG + GG OR =1.01, 95% CI, 0.88–1.15, but a moderately significant association was found for AG vs GG (OR =0.241, 95% CI =0.17–0.35. Subgroup analysis based on ethnicity. Ethnicity analysis suggested that genetic polymorphisms in XRCC1 were not correlated with increased bladder cancer risk among Asians (all P>0.05. Therefore, we concluded that XRCC1 genetic polymorphism may not contribute to bladder cancer susceptibility in the present meta-analysis, and further well-designed studies with a large sample size are warranted to validate our conclusion. Keywords: XRCC1, genetic polymorphism, susceptibility, bladder cancer, meta-analysis

  6. Phlebotomus orientalis sand flies from two geographically distant Ethiopian localities: biology, genetic analyses and susceptibility to Leishmania donovani.

    Directory of Open Access Journals (Sweden)

    Veronika Seblova

    Full Text Available BACKGROUND: Phlebotomus orientalis Parrot (Diptera: Psychodidae is the main vector of visceral leishmaniasis (VL caused by Leishmania donovani in East Africa. Here we report on life cycle parameters and susceptibility to L. donovani of two P. orientalis colonies originating from different sites in Ethiopia: a non-endemic site in the lowlands - Melka Werer (MW, and an endemic focus of human VL in the highlands - Addis Zemen (AZ. METHODOLOGY/PRINCIPAL FINDINGS: Marked differences in life-cycle parameters between the two colonies included distinct requirements for larval food and humidity during pupation. However, analyses using Random Amplified Polymorphic DNA (RAPD PCR and DNA sequencing of cytB and COI mitochondrial genes did not reveal any genetic differences. F1 hybrids developed successfully with higher fecundity than the parental colonies. Susceptibility of P. orientalis to L. donovani was studied by experimental infections. Even the lowest infective dose tested (2×10(3 per ml was sufficient for successful establishment of L. donovani infections in about 50% of the P. orientalis females. Using higher infective doses, the infection rates were around 90% for both colonies. Leishmania development in P. orientalis was fast, the presence of metacyclic promastigotes in the thoracic midgut and the colonization of the stomodeal valve by haptomonads were recorded in most P. orientalis females by day five post-blood feeding. CONCLUSIONS: Both MW and AZ colonies of P. orientalis were highly susceptible to Ethiopian L. donovani strains. As the average volume of blood-meals taken by P. orientalis females are about 0.7 µl, the infective dose at the lowest concentration was one or two L. donovani promastigotes per sand fly blood-meal. The development of L. donovani was similar in both P. orientalis colonies; hence, the absence of visceral leishmaniasis in non-endemic area Melka Werer cannot be attributed to different susceptibility of local P. orientalis

  7. Antimicrobial susceptibility patterns, emm type distribution and genetic diversity of Streptococcus pyogenes recovered in Brazil

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    Glauber P Arêas

    2014-11-01

    Full Text Available Streptococcus pyogenes is responsible for a variety of infectious diseases and immunological complications. In this study, 91 isolates of S. pyogenes recovered from oropharynx secretions were submitted to antimicrobial susceptibility testing, emm typing and pulsed-field gel electrophoresis (PFGE analysis. All isolates were susceptible to ceftriaxone, levofloxacin, penicillin G and vancomycin. Resistance to erythromycin and clindamycin was 15.4%, which is higher than previous reports from this area, while 20.9% of the isolates were not susceptible to tetracycline. The macrolide resistance phenotypes were cMLSB (10 and iMLSB (4. The ermB gene was predominant, followed by the ermA gene. Thirty-two emm types and subtypes were found, but five (emm1, emm4, emm12, emm22, emm81 were detected in 48% of the isolates. Three new emm subtypes were identified (emm1.74, emm58.14, emm76.7. There was a strong association between emm type and PFGE clustering. A variety of PFGE profiles as well as emm types were found among tetracycline and erythromycin-resistant isolates, demonstrating that antimicrobial resistant strains do not result from the expansion of one or a few clones. This study provides epidemiological data that contribute to the development of suitable strategies for the prevention and treatment of such infections in a poorly studied area.

  8. Antimicrobial Susceptibility and Genetic Characterisation of Burkholderia pseudomallei Isolated from Malaysian Patients

    Directory of Open Access Journals (Sweden)

    Yalda Khosravi

    2014-01-01

    Full Text Available Burkholderia pseudomallei, the causative agent of melioidosis, is intrinsically resistant to many antibiotics. Ceftazidime (CAZ, the synthetic β-lactam, is normally used as the first-line antibiotic therapy for treatment of melioidosis. However, acquired CAZ resistance can develop in vivo during treatment with CAZ, leading to mortality if therapy is not switched to a different antibiotic(s in a timely manner. In this study, susceptibilities of 81 B. pseudomallei isolates to nine different antimicrobial agents were determined using the disk diffusion method, broth microdilution test and Etest. Highest percentage of susceptibility was demonstrated to CAZ, amoxicillin/clavulanic acid, meropenem, imipenem, and trimethoprim/sulfamethoxazole. Although these drugs demonstrated the highest percentage of susceptibility in B. pseudomallei, the overall results underline the importance of the emergence of resistance in this organism. PCR results showed that, of the 81 B. pseudomallei, six multidrug resistant (MDR isolates carried bpeB, amrB, and BPSS1119 and penA genes. Genotyping of the isolates using random amplified polymorphic DNA analysis showed six different PCR fingerprinting patterns generated from the six MDR isolates clusters (A and eight PCR fingerprinting patterns generated for the remaining 75 non-MDR isolates clusters (B.

  9. Shrinkage Effect in Ancestral Maximum Likelihood

    CERN Document Server

    Mossel, Elchanan; Steel, Mike

    2008-01-01

    Ancestral maximum likelihood (AML) is a method that simultaneously reconstructs a phylogenetic tree and ancestral sequences from extant data (sequences at the leaves). The tree and ancestral sequences maximize the probability of observing the given data under a Markov model of sequence evolution, in which branch lengths are also optimized but constrained to take the same value on any edge across all sequence sites. AML differs from the more usual form of maximum likelihood (ML) in phylogenetics because ML averages over all possible ancestral sequences. ML has long been known to be statistically consistent -- that is, it converges on the correct tree with probability approaching 1 as the sequence length grows. However, the statistical consistency of AML has not been formally determined, despite informal remarks in a literature that dates back 20 years. In this short note we prove a general result that implies that AML is statistically inconsistent. In particular we show that AML can `shrink' short edges in a t...

  10. Correlation between XRCC1 Arg399Gln genetic polymorphisms and susceptibility to bladder cancer: a meta-analysis

    Science.gov (United States)

    Liu, Nannan; Fei, Xiawei; Shen, Yi; Shi, Weifeng; Ma, Jinhong

    2016-01-01

    The relationship between XRCC1 polymorphisms and bladder cancer has been widely studied. Here, our meta-analysis was conducted to evaluate the correlations between common genetic polymorphisms in XRCC1 and susceptibility to bladder cancer. In order to derive a more precise estimation of the association, 27 clinical case-control studies (which met all the inclusion criteria) were included in this meta-analysis. A total of 8,539 cancer cases and 10,750 controls were involved in this meta-analysis. Overall, no significant association was detected in allelic model (A allele vs T allele odds ratio [OR] =0.87, 95% confidence interval [CI], 0.71–1.06), homozygote comparison (AA vs GG OR =1.12, 95% CI, 0.68–1.85), heterozygote comparison (AT vs TT OR =1.01, 95% CI, 0.81–1.26), dominant model (AA + AG vs GG OR =0.93, 95% CI, 0.85–1.02), and recessive model (AA vs AG + GG OR =1.01, 95% CI, 0.88–1.15), but a moderately significant association was found for AG vs GG (OR =0.241, 95% CI =0.17–0.35). Subgroup analysis based on ethnicity. Ethnicity analysis suggested that genetic polymorphisms in XRCC1 were not correlated with increased bladder cancer risk among Asians (all P>0.05). Therefore, we concluded that XRCC1 genetic polymorphism may not contribute to bladder cancer susceptibility in the present meta-analysis, and further well-designed studies with a large sample size are warranted to validate our conclusion. PMID:26869802

  11. Variants of SCARB1 and VDR Involved in Complex Genetic Interactions May Be Implicated in the Genetic Susceptibility to Clear Cell Renal Cell Carcinoma.

    Science.gov (United States)

    Pośpiech, Ewelina; Ligęza, Janusz; Wilk, Wacław; Gołas, Aniela; Jaszczyński, Janusz; Stelmach, Andrzej; Ryś, Janusz; Blecharczyk, Aleksandra; Wojas-Pelc, Anna; Jura, Jolanta; Branicki, Wojciech

    2015-01-01

    The current data are still inconclusive in terms of a genetic component involved in the susceptibility to renal cell carcinoma. Our aim was to evaluate 40 selected candidate polymorphisms for potential association with clear cell renal cell carcinoma (ccRCC) based on independent group of 167 patients and 200 healthy controls. The obtained data were searched for independent effects of particular polymorphisms as well as haplotypes and genetic interactions. Association testing implied position rs4765623 in the SCARB1 gene (OR = 1.688, 95% CI: 1.104-2.582, P = 0.016) and a haplotype in VDR comprising positions rs739837, rs731236, rs7975232, and rs1544410 (P = 0.012) to be the risk factors in the studied population. The study detected several epistatic effects contributing to the genetic susceptibility to ccRCC. Variation in GNAS1 was implicated in a strong synergistic interaction with BIRC5. This effect was part of a model suggested by multifactor dimensionality reduction method including also a synergy between GNAS1 and SCARB1 (P = 0.036). Significance of GNAS1-SCARB1 interaction was further confirmed by logistic regression (P = 0.041), which also indicated involvement of SCARB1 in additional interaction with EPAS1 (P = 0.008) as well as revealing interactions between GNAS1 and EPAS1 (P = 0.016), GNAS1 and MC1R (P = 0.031), GNAS1 and VDR (P = 0.032), and MC1R and VDR (P = 0.035). PMID:25945350

  12. Do nuclear-encoded core subunits of mitochondrial complex I confer genetic susceptibility to schizophrenia in Han Chinese populations?

    Science.gov (United States)

    Li, Xiao; Zhang, Wen; Tang, Jinsong; Tan, Liwen; Luo, Xiong-jian; Chen, Xiaogang; Yao, Yong-Gang

    2015-01-01

    Schizophrenia is one of the most prevalent psychiatric disorders with complex genetic etiology. Accumulating evidence suggests that energy metabolism and oxidative stress play important roles in the pathophysiology of schizophrenia. Dysfunction of mitochondrial respiratory chain and altered expression of complex I subunits were frequently reported in schizophrenia. To investigate whether nuclear-encoded core subunit genes of mitochondrial complex I are associated with schizophrenia, we performed a genetic association study in Han Chinese. In total, 46 tag single nucleotide polymorphisms (SNPs) from 7 nuclear-encoded core genes of mitochondrial complex I were genotyped in 918 schizophrenia patients and 1042 healthy controls. We also analyzed these SNPs in a large sample mainly composed of Europeans through using the available GWAS datasets from the Psychiatric Genomics Consortium (PGC). No significant associations were detected between these SNPs and schizophrenia in Han Chinese and the PGC data set. However, we observed nominal significant associations of 2 SNPs in the NDUFS1 gene and 4 SNPs in the NDUFS2 gene with early onset schizophrenia (EOS), but none of these associations survived the Bonferroni correction. Taken together, our results suggested that common SNPs in the nuclear-encoded core subunit genes of mitochondrial complex I may not confer genetic susceptibility to schizophrenia. PMID:26053550

  13. Molecular Assay for Detection of Genetic Markers Associated with Decreased Susceptibility to Cephalosporins in Neisseria gonorrhoeae.

    Science.gov (United States)

    Peterson, S W; Martin, I; Demczuk, W; Bharat, A; Hoang, L; Wylie, J; Allen, V; Lefebvre, B; Tyrrell, G; Horsman, G; Haldane, D; Garceau, R; Wong, T; Mulvey, M R

    2015-07-01

    The incidence of antimicrobial-resistant Neisseria gonorrhoeae continues to rise in Canada; however, antimicrobial resistance data are lacking for approximately 70% of gonorrhea infections that are diagnosed directly from clinical specimens by nucleic acid amplification tests (NAATs). We developed a molecular assay for surveillance use to detect mutations in genes associated with decreased susceptibility to cephalosporins that can be applied to both culture isolates and clinical samples. Real-time PCR assays were developed to detect single nucleotide polymorphisms (SNPs) in ponA, mtrR, penA, porB, and one N. gonorrhoeae-specific marker (porA). We tested the real-time PCR assay with 252 gonococcal isolates, 50 nongonococcal isolates, 24 N. gonorrhoeae-negative NAAT specimens, and 34 N. gonorrhoeae-positive NAAT specimens. Twenty-four of the N. gonorrhoeae-positive NAAT specimens had matched culture isolates. Assay results were confirmed by comparison with whole-genome sequencing data. For 252 N. gonorrhoeae strains, the agreement between the DNA sequence and real-time PCR was 100% for porA, ponA, and penA, 99.6% for mtrR, and 95.2% for porB. The presence of ≥2 SNPs correlated with decreased susceptibility to ceftriaxone (sensitivities of >98%) and cefixime (sensitivities of >96%). Of 24 NAAT specimens with matched cultures, the agreement between the DNA sequence and real-time PCR was 100% for porB, 95.8% for ponA and mtrR, and 91.7% for penA. We demonstrated the utility of a real-time PCR assay for sensitive detection of known markers for the decreased susceptibility to cephalosporins in N. gonorrhoeae. Preliminary results with clinical NAAT specimens were also promising, as they correlated well with bacterial culture results. PMID:25878350

  14. The ancestral process of long term seed bank models

    CERN Document Server

    Blath, Jochen; Kurt, Noemi; Spanò, Dario

    2012-01-01

    We present a new model for the evolution of genetic types in the presence of so-called seed banks, i.e., where individuals may obtain their genetic type from ancestors which have lived in the near as well as the very far past. The classical Wright-Fisher model, as well as a seed bank model with bounded age distribution considered by Kaj, Krone and Lascoux (2001) are special cases of our model. We discern three parameter regimes of the seed bank age distribution, which lead to substantially different behaviour in terms of genetic variability, in particular with respect to fixation of types and time to the most recent common ancestor. We prove that for age distributions with finite mean, the rescaled ancestral process converges to a time-changed Kingman coalescent, while in the case of infinite mean, ancestral lineages might not merge at all with positive probability. Further, we present a construction of the forward in time process in equilibrium. The mathematical methods are based on renewal theory, the urn p...

  15. Human Leptospirosis: Seroreactivity and Genetic Susceptibility in the Population of São Miguel Island (Azores, Portugal)

    Science.gov (United States)

    Esteves, Lisa M.; Bulhões, Sara M.; Branco, Claudia C.; Mota, Francisco M.; Paiva, Clara; Cabral, Rita; Vieira, Maria Luisa; Mota-Vieira, Luisa

    2014-01-01

    Background Leptospirosis is a worldwide zoonotic and recognized neglected infectious disease. It has been observed that only a proportion of individuals exposed to pathogenic species of Leptospira become infected and develop clinically evident disease. Moreover, little information is available in subsequent reinfections. In the present study, we determine if a first infection with leptospirosis protects against subsequent reinfection, and investigate which of the host genetic factors are involved in the susceptibility and resistance to leptospirosis. Methodology and Findings We conducted, in 2011, a retrospective hospital-based case-control study in the São Miguel Island population (Azores archipelago). In order to determine the seropositivity against pathogenic Leptospira after the first episode of leptospirosis, we performed a serological evaluation in 97 unrelated participants diagnosed with leptospirosis between 1992 and 2011. The results revealed that 46.4% of the 97 participants have circulating anti-Leptospira antibodies, and from these participants 35.6% maintained the seroprevalence for the same serogroup. Moreover, three of them were reinfected with unrelated Leptospira serovars. The genetic study was carried out by adding a control group composed of 470 unrelated healthy blood donors, also from São Miguel Island. Twenty five SNPs among twelve innate immune genes – IL1α, IL1β, IL6, IL10, IL12RB1, TLR2, TLR4, TLR9, CD14, CISH, LTA and TNF – were genotyped, as well as HLA class I (–A and –B) genes. Association analysis indicates that genotypes -511GG (OR = 1.6, 95%CI 1.01-2.56, p = 0.04) in IL1β, +1196CG (OR = 2.0, 95%CI 1.26-3.27, p = 0.003) in IL12RB1, -292TA (OR = 1.8, 95% CI 1.06–2.1, p = 0.03) and +3415CG (OR = 1.8, 95% CI 1.08–3.08, p = 0.02), both in CISH confer susceptibility to pathogenic Leptospira. Conclusion The present study suggests some degree of long-term protection against leptospires with an

  16. WNT2 Locus Is Involved in Genetic Susceptibility of Peyronie's Disease

    NARCIS (Netherlands)

    Dolmans, Guido H.; Werker, Paul M.; de Jong, Igle J.; Nijman, Rien J.; Wijmenga, Cisca; Ophoff, Roel A.

    2012-01-01

    Introduction. Peyronie's disease (PD) is a fibromatosis of the penis, with a pathology very similar to what is seen in the hand (palmar fascia) in Dupuytren's disease (DD). Recently, we performed a genome-wide association study and identified nine genetic loci containing common variants associated w

  17. Twins as a tool for evaluating the influence of genetic susceptibility in thyroid autoimmunity

    DEFF Research Database (Denmark)

    Brix, T H; Hegedüs, L

    2011-01-01

    By means of large twin cohorts, it has been possible to provide relatively valid and unbiased data regarding the influence of genetic and to some extent epigenetic factors in the aetiology of thyroid autoimmunity. The comparison of concordance rates between monozygotic and dizygotic twins provide...

  18. Genetic Variant rs10757278 on Chromosome 9p21 Contributes to Myocardial Infarction Susceptibility

    Directory of Open Access Journals (Sweden)

    Guangyuan Chen

    2015-05-01

    Full Text Available Large-scale genome-wide association studies (GWAS have revealed that rs10757278 polymorphism (or its proxy rs1333049 on chromosome 9p21 is associated with myocardial infarction (MI susceptibility in individuals of Caucasian ancestry. Following studies in other populations investigated this association. However, some of these studies reported weak or no significant association. Here, we reevaluated this association using large-scale samples by searching PubMed and Google Scholar databases. Our results showed significant association between rs10757278 polymorphism and MI with p = 6.09 × 10−22, odds ratio (OR = 1.29, 95% confidence interval (CI 1.22–1.36 in pooled population. We further performed a subgroup analysis, and found significant association between rs10757278 polymorphism and MI in Asian and Caucasian populations. We identified that the association between rs10757278 polymorphism and MI did not vary substantially by excluding any one study. However, the heterogeneity among the selected studies varies substantially by excluding the study from the Pakistan population. We found even more significant association between rs10757278 polymorphism and MI in pooled population, p = 3.55 × 10−53, after excluding the study from the Pakistan population. In summary, previous studies reported weak or no significant association between rs10757278 polymorphism and MI. Interestingly, our analysis suggests that rs10757278 polymorphism is significantly associated with MI susceptibility by analyzing large-scale samples.

  19. Functional variant in complement C3 gene promoter and genetic susceptibility to temporal lobe epilepsy and febrile seizures.

    Directory of Open Access Journals (Sweden)

    Sarah Jamali

    Full Text Available BACKGROUND: Human mesial temporal lobe epilepsies (MTLE represent the most frequent form of partial epilepsies and are frequently preceded by febrile seizures (FS in infancy and early childhood. Genetic associations of several complement genes including its central component C3 with disorders of the central nervous system, and the existence of C3 dysregulation in the epilepsies and in the MTLE particularly, make it the C3 gene a good candidate for human MTLE. METHODOLOGY/PRINCIPAL FINDINGS: A case-control association study of the C3 gene was performed in a first series of 122 patients with MTLE and 196 controls. Four haplotypes (HAP1 to 4 comprising GF100472, a newly discovered dinucleotide repeat polymorphism [(CA8 to (CA15] in the C3 promoter region showed significant association after Bonferroni correction, in the subgroup of MTLE patients having a personal history of FS (MTLE-FS+. Replication analysis in independent patients and controls confirmed that the rare HAP4 haplotype comprising the minimal length allele of GF100472 [(CA8], protected against MTLE-FS+. A fifth haplotype (HAP5 with medium-size (CA11 allele of GF100472 displayed four times higher frequency in controls than in the first cohort of MTLE-FS+ and showed a protective effect against FS through a high statistical significance in an independent population of 97 pure FS. Consistently, (CA11 allele by its own protected against pure FS in a second group of 148 FS patients. Reporter gene assays showed that GF100472 significantly influenced C3 promoter activity (the higher the number of repeats, the lower the transcriptional activity. Taken together, the consistent genetic data and the functional analysis presented here indicate that a newly-identified and functional polymorphism in the promoter of the complement C3 gene might participate in the genetic susceptibility to human MTLE with a history of FS, and to pure FS. CONCLUSIONS/SIGNIFICANCE: The present study provides important

  20. Alcohol-related cancers and genetic susceptibility in Europe: the ARCAGE project: study samples and data collection.

    LENUS (Irish Health Repository)

    Lagiou, Pagona

    2009-02-01

    Cancers of the upper aerodigestive tract (UADT) include those of the oral cavity, pharynx (other than nasopharynx), larynx, and esophagus. Tobacco smoking and consumption of alcoholic beverages are established causes of UADT cancers, whereas reduced intake of vegetables and fruits are likely causes. The role of genetic predisposition and possible interactions of genetic with exogenous factors, however, have not been adequately studied. Moreover, the role of pattern of smoking and drinking, as well as the exact nature of the implicated dietary variables, has not been clarified. To address these issues, the International Agency for Research on Cancer initiated in 2002 the alcohol-related cancers and genetic susceptibility (ARCAGE) in Europe project, with the participation of 15 centers in 11 European countries. Information and biological data from a total of 2304 cases and 2227 controls have been collected and will be used in a series of analyses. A total of 166 single nucleotide polymorphisms of 76 genes are being studied for genetic associations with UADT cancers. We report here the methodology of the ARCAGE project, main demographic and lifestyle characteristics of the cases and controls, as well as the distribution of cases by histology and subsite. About 80% of cases were males and fewer than 20% of all cases occurred before the age of 50 years. Overall, the most common subsite was larynx, followed by oral cavity, oropharynx, esophagus and hypopharynx. Close to 90% of UADT cancers were squamous cell carcinomas. A clear preponderance of smokers and alcohol drinkers among UADT cases compared with controls was observed.

  1. The relation between HLA-DQA1 genes and genetic susceptibility to duodenal ulcer in Wuhan Hans

    Institute of Scientific and Technical Information of China (English)

    Yi Ping Du; Chang Sheng Deng; De Yin Lu; Mei Fang Huang; Shu Fang Guo; Wei Hou

    2000-01-01

    AIM To study the genetic susceptibility of HLA-DQA1 alleles to duodenal ulcer in Wuhan Hans.METHODS Seventy patients with duodenal ulcer and fifty healthy controls were examined for HLA-DQA1 genotypes. HLA-DQA1 typing was carried out by digesting the locus specific polymerase chain reaction amplified products with alleles specific restriction enzymes (PCR-RFLP), i.e., Apal Ⅰ, Bsaj Ⅰ, Hph Ⅰ, Fok Ⅰ,Mbo Ⅱ and Mnl Ⅰ.RESULTS The allele frequencies of DQA1 * 0301 and DQA1* 0102 in patients with duodenal ulcer were significantly higher and lower respectively than those in healthy controls (0.40 vs 0.20,P=0.003, Pcorret = 0.024) and (0.05 vs 0.14,P= 0.012, but Pcorret >0.05), respectively.CONCLUSION DQA1* 0301 is a susceptible gene for duodenal ulcer in Wuhan Hans, and there are immunogenetic differences in HLA-DQA1 locus between duodenal ulcer patients and healthy controls.

  2. Prevalence, genetic diversity, and antimicrobial susceptibility profiles of Staphylococcus aureus isolated from bovine mastitis in Zhejiang Province, China

    Institute of Scientific and Technical Information of China (English)

    Jian-ping LI; Hai-jian ZHOU; Lin YUAN; Ting HE; Song-hua HU

    2009-01-01

    This study was conducted to determine genetic diversity and antimicrobial susceptibility profiles of Staphylococcusaureus recovered from bovine mastitis in Zhejiang Province, China. Out of 3178 quarter milk samples from 846 lactating cows, among which 459 cows (54.3%) were found HMT positive, 890 quarters (28%) were found having subclinical mastitis. From 75 representative S. aureus isolates, 16 distinct types were identified by pulsed-field gel electrophoresis (PFGE). Four major PFGE types (A, B, C, and D) accounted for 82.7% of all isolates, and type A (41.3%) was observed in multiple herds across the studied areas. Each region was found to have a predominant type: Hangzhou type A (64.1%), Ningbo type C (34.5%) and type B (23.1%), Jinhua type D (53.3%), and Taizhou type C (62.5%). Results of antimicrobial susceptibility tests showed that 90.7% of the isolates were resistant to at least one antimicrobial. Resistance to penicillin and ampicillin (77.3%), tetracycline (60.0%), or erythromycin (48.0%) was observed. The bacteria resistant to multiple antibiotics such as penicillin, ampicillin, tetracycline, and erythromycin were commonly found. The information obtained from this study is useful for designing specific control programs for bovine S. aureus mastiffs in this region.

  3. Antimicrobial susceptibility and genetic characteristics of Neisseria gonorrhoeae isolates from India, Pakistan and Bhutan in 2007–2011

    Directory of Open Access Journals (Sweden)

    Sethi Sunil

    2013-01-01

    Full Text Available Abstract Background Knowledge on antimicrobial drug resistance and genetic characteristics of Neisseria gonorrhoeae isolates circulating in India, Pakistan, and Bhutan is sorely lacking. In this paper, we describe the prevalence of antimicrobial resistance and molecular characteristics of N. gonorrhoeae isolates from India, Pakistan, and Bhutan in 2007–2011. Methods Antimicrobial susceptibility and β-lactamase production were tested for 65 N. gonorrhoeae isolates from India (n=40, Pakistan (n=18 and Bhutan (n=7 using Etest methodology (eight antimicrobials and nitrocefin solution, respectively. Resistance determinants, i.e. penA, mtrR, porB1b, gyrA, and parC, were sequenced. N. gonorrhoeae multiantigen sequence typing (NG-MAST was performed for molecular epidemiology. Results The highest resistance level was observed for ciprofloxacin (94%, followed by penicillin G (68%, erythromycin (62%, tetracycline (55%, and azithromycin (7.7%. All the isolates were susceptible to ceftriaxone, cefixime, and spectinomycin. Thirty-four (52% of the isolates were producing β-lactamase. No penA mosaic alleles or A501-altered alleles of penicillin-binding protein 2 were identified. Forty-nine NG-MAST STs were identified, of which 42 STs have not been previously described worldwide. Conclusions Based on this study, ceftriaxone, cefixime, and spectinomycin can be used as an empirical first-line therapy for gonorrhoea in India, Pakistan, and Bhutan, whereas ciprofloxacin, penicillin G, tetracycline, erythromycin, and azithromycin should not be. It is imperative to strengthen the laboratory infrastructure in this region, as well as to expand the phenotypic and genetic surveillance of antimicrobial resistance, emergence of new resistance, particularly, to extended-spectrum cephalosporins, and molecular epidemiology.

  4. Interactions Within Susceptible Hosts Drive Establishment of Genetically Distinct Variants of an Insect-Borne Pathogen

    OpenAIRE

    Blaisdell, GK; Zhang, S; Bratburd, JR; Daane, KM; Cooper, ML; Almeida, RPP

    2015-01-01

    © The Authors 2015. Published by Oxford University Press on behalf of Entomological Society of America. Coinfections are common, leading to pathogen interactions during transmission and establishment in a host. However, few studies have tested the relative strengths of pathogen interactions in vectors and hosts that determine the outcome of infection. We tested interactions between two genetically distinct variants of the mealybug-transmitted Grapevine leafroll-associated virus 3. The transmi...

  5. Genetics of susceptibility to leishmaniasis in mice: four novel loci and functional heterogeneity of gene effects

    Czech Academy of Sciences Publication Activity Database

    Havelková, Helena; Badalová, Jana; Svobodová, M.; Vojtíšková, Jarmila; Kurey, Irina; Vladimirov, Vladimir; Demant, P.; Lipoldová, Marie

    2006-01-01

    Roč. 7, č. 3 (2006), s. 220-233. ISSN 1466-4879 R&D Projects: GA ČR(CZ) GA310/03/1381; GA ČR(CZ) GD310/03/H147 Grant ostatní: HHMI(US) 55000323 Institutional research plan: CEZ:AV0Z50520514 Keywords : leishmaniasis * host response * gene effect Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.533, year: 2006

  6. Role of Genetic Susceptibility in Development of Treatment-related Adverse Outcomes in Cancer Survivors

    OpenAIRE

    Bhatia, Smita

    2011-01-01

    Clear and unambiguous associations have been established between therapeutic exposures and specific complications. However, considerable inter-individual variability is observed in the risk of developing an outcome for a given therapeutic exposure. Genetic predisposition and especially its interaction with therapeutic exposures can potentially exacerbate the toxic effect of treatment on normal tissues and organ systems, and can possibly explain the inter-individual variability. This article p...

  7. Pathway analysis of GWAS provides new insights into genetic susceptibility to 3 inflammatory diseases.

    Directory of Open Access Journals (Sweden)

    Hariklia Eleftherohorinou

    Full Text Available Although the introduction of genome-wide association studies (GWAS have greatly increased the number of genes associated with common diseases, only a small proportion of the predicted genetic contribution has so far been elucidated. Studying the cumulative variation of polymorphisms in multiple genes acting in functional pathways may provide a complementary approach to the more common single SNP association approach in understanding genetic determinants of common disease. We developed a novel pathway-based method to assess the combined contribution of multiple genetic variants acting within canonical biological pathways and applied it to data from 14,000 UK individuals with 7 common diseases. We tested inflammatory pathways for association with Crohn's disease (CD, rheumatoid arthritis (RA and type 1 diabetes (T1D with 4 non-inflammatory diseases as controls. Using a variable selection algorithm, we identified variants responsible for the pathway association and evaluated their use for disease prediction using a 10 fold cross-validation framework in order to calculate out-of-sample area under the Receiver Operating Curve (AUC. The generalisability of these predictive models was tested on an independent birth cohort from Northern Finland. Multiple canonical inflammatory pathways showed highly significant associations (p 10(-3-10(-20 with CD, T1D and RA. Variable selection identified on average a set of 205 SNPs (149 genes for T1D, 350 SNPs (189 genes for RA and 493 SNPs (277 genes for CD. The pattern of polymorphisms at these SNPS were found to be highly predictive of T1D (91% AUC and RA (85% AUC, and weakly predictive of CD (60% AUC. The predictive ability of the T1D model (without any parameter refitting had good predictive ability (79% AUC in the Finnish cohort. Our analysis suggests that genetic contribution to common inflammatory diseases operates through multiple genes interacting in functional pathways.

  8. Genetic Susceptibility to Dental Caries on Pit and Fissure and Smooth Surfaces

    OpenAIRE

    Shaffer, J.R.; X. Wang; DeSensi, R.S.; Wendell, S.; Weyant, R. J.; Cuenco, K.T.; Crout, R.; McNeil, D.W.; Marazita, M.L.

    2012-01-01

    Carious lesions are distributed nonuniformly across tooth surfaces of the complete dentition, suggesting that the effects of risk factors may be surface-specific. Whether genes differentially affect caries risk across tooth surfaces is unknown. We investigated the role of genetics on two classes of tooth surfaces, pit and fissure surfaces (PFS) and smooth surfaces (SMS), in more than 2,600 subjects from 740 families. Participants were examined for surface-level evidence of dental caries, and ...

  9. Study on relationship of apolipoprotein E gene polymorphism and genetic susceptibility of stress urinary incontinence

    Institute of Scientific and Technical Information of China (English)

    Tong Jia-li; Lang Jing-he; Zhu lan

    2010-01-01

    Objective: To explore the relationship between apolipoprotein E (ApoE) gene polymorphism and susceptibility of stress urinary incontinence (SUI).Methods: ApoE genotypes were examined by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) technique in 99 patients with SUI and 101 asymptomatic controls. Results: The frequency of allele e3 of ApoE was slightly lower in patients with anatomic SUI than that in controls (79.44% vs. 81.68%), while the frequency of allele e4 of ApoE was slightly higher in patients with anatomic SUI than that in controls (10.00% vs. 9.90%). No significant difference was found in frequency of allele e3 or e4 between SUI patients and controls (χ2=0.523, P=0.770).Conclusion: The gene polymorphism of ApoE is not independently involved in the development of SUI.

  10. An Integrated Genome-Wide Systems Genetics Screen for Breast Cancer Metastasis Susceptibility Genes.

    Science.gov (United States)

    Bai, Ling; Yang, Howard H; Hu, Ying; Shukla, Anjali; Ha, Ngoc-Han; Doran, Anthony; Faraji, Farhoud; Goldberger, Natalie; Lee, Maxwell P; Keane, Thomas; Hunter, Kent W

    2016-04-01

    Metastasis remains the primary cause of patient morbidity and mortality in solid tumors and is due to the action of a large number of tumor-autonomous and non-autonomous factors. Here we report the results of a genome-wide integrated strategy to identify novel metastasis susceptibility candidate genes and molecular pathways in breast cancer metastasis. This analysis implicates a number of transcriptional regulators and suggests cell-mediated immunity is an important determinant. Moreover, the analysis identified novel or FDA-approved drugs as potentially useful for anti-metastatic therapy. Further explorations implementing this strategy may therefore provide a variety of information for clinical applications in the control and treatment of advanced neoplastic disease. PMID:27074153

  11. The role of genetic breast cancer susceptibility variants as prognostic factors.

    Science.gov (United States)

    Fasching, Peter A; Pharoah, Paul D P; Cox, Angela; Nevanlinna, Heli; Bojesen, Stig E; Karn, Thomas; Broeks, Annegien; van Leeuwen, Flora E; van't Veer, Laura J; Udo, Renate; Dunning, Alison M; Greco, Dario; Aittomäki, Kristiina; Blomqvist, Carl; Shah, Mitul; Nordestgaard, Børge G; Flyger, Henrik; Hopper, John L; Southey, Melissa C; Apicella, Carmel; Garcia-Closas, Montserrat; Sherman, Mark; Lissowska, Jolanta; Seynaeve, Caroline; Huijts, Petra E A; Tollenaar, Rob A E M; Ziogas, Argyrios; Ekici, Arif B; Rauh, Claudia; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Andrulis, Irene L; Ozcelik, Hilmi; Mulligan, Anna-Marie; Glendon, Gord; Hall, Per; Czene, Kamila; Liu, Jianjun; Chang-Claude, Jenny; Wang-Gohrke, Shan; Eilber, Ursula; Nickels, Stefan; Dörk, Thilo; Schiekel, Maria; Bremer, Michael; Park-Simon, Tjoung-Won; Giles, Graham G; Severi, Gianluca; Baglietto, Laura; Hooning, Maartje J; Martens, John W M; Jager, Agnes; Kriege, Mieke; Lindblom, Annika; Margolin, Sara; Couch, Fergus J; Stevens, Kristen N; Olson, Janet E; Kosel, Matthew; Cross, Simon S; Balasubramanian, Sabapathy P; Reed, Malcolm W R; Miron, Alexander; John, Esther M; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Chenevix-Trench, Georgia; Lambrechts, Diether; Dieudonne, Anne-Sophie; Hatse, Sigrid; van Limbergen, Erik; Benitez, Javier; Milne, Roger L; Zamora, M Pilar; Pérez, José Ignacio Arias; Bonanni, Bernardo; Peissel, Bernard; Loris, Bernard; Peterlongo, Paolo; Rajaraman, Preetha; Schonfeld, Sara J; Anton-Culver, Hoda; Devilee, Peter; Beckmann, Matthias W; Slamon, Dennis J; Phillips, Kelly-Anne; Figueroa, Jonine D; Humphreys, Manjeet K; Easton, Douglas F; Schmidt, Marjanka K

    2012-09-01

    Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at PBreast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility. PMID:22532573

  12. Autoimmune Type 1 Diabetes Genetic Susceptibility Encoded by Human Leukocyte Antigen DRB1 and DQB1 Genes in Tunisia▿

    Science.gov (United States)

    Stayoussef, Mouna; Benmansour, Jihen; Al-Irhayim, Abdul-Qader; Said, Hichem B.; Rayana, Chiheb B.; Mahjoub, Touhami; Almawi, Wassim Y.

    2009-01-01

    Human leukocyte antigen (HLA) class II genes contribute to the genetic susceptibility to type 1 diabetes (T1D), and susceptible alleles and haplotypes were implicated in the pathogenesis of T1D. This study investigated the heterogeneity in HLA class II haplotype distribution among Tunisian patients with T1D. This was a retrospective case control study done in Monastir in central Tunisia. The subjects comprised 88 T1D patients and 112 healthy controls. HLA-DRB1 and -DQB1 genotyping was done by PCR-sequence-specific priming. Significant DRB1 and DQB1 allelic differences were seen between T1D patients and controls; these differences comprised DRB1*030101 and DQB1*0302, which were higher in T1D patients than in control subjects, and DRB1*070101, DRB1*110101, DQB1*030101, and DQB1*060101, which were lower in T1D patients than in control subjects. In addition, the frequencies of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 were higher in T1D patients than in control subjects, and the frequencies of DRB1*070101-DQB1*0201 and DRB1*110101-DQB1*030101 haplotypes were lower in T1D patients than in control subjects. Multiple logistic regression analysis revealed the positive association of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 and the negative association of only DRB1*070101-DQB1*0201 haplotypes with T1D. Furthermore, a significantly increased prevalence of DRB1*030101-DQB1*0201 homozygotes was seen for T1D subjects than for control subjects. Our results confirm the association of specific HLA-DR and -DQ alleles and haplotypes with T1D in Tunisians. The identification of similar and unique haplotypes in Tunisians compared to other Caucasians highlights the need for evaluating the contribution of HLA class II to the genetic susceptibility to T1D with regard to haplotype usage and also to ethnic origin and racial background. PMID:19553558

  13. Autoimmune type 1 diabetes genetic susceptibility encoded by human leukocyte antigen DRB1 and DQB1 genes in Tunisia.

    Science.gov (United States)

    Stayoussef, Mouna; Benmansour, Jihen; Al-Irhayim, Abdul-Qader; Said, Hichem B; Rayana, Chiheb B; Mahjoub, Touhami; Almawi, Wassim Y

    2009-08-01

    Human leukocyte antigen (HLA) class II genes contribute to the genetic susceptibility to type 1 diabetes (T1D), and susceptible alleles and haplotypes were implicated in the pathogenesis of T1D. This study investigated the heterogeneity in HLA class II haplotype distribution among Tunisian patients with T1D. This was a retrospective case control study done in Monastir in central Tunisia. The subjects comprised 88 T1D patients and 112 healthy controls. HLA-DRB1 and -DQB1 genotyping was done by PCR-sequence-specific priming. Significant DRB1 and DQB1 allelic differences were seen between T1D patients and controls; these differences comprised DRB1*030101 and DQB1*0302, which were higher in T1D patients than in control subjects, and DRB1*070101, DRB1*110101, DQB1*030101, and DQB1*060101, which were lower in T1D patients than in control subjects. In addition, the frequencies of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 were higher in T1D patients than in control subjects, and the frequencies of DRB1*070101-DQB1*0201 and DRB1*110101-DQB1*030101 haplotypes were lower in T1D patients than in control subjects. Multiple logistic regression analysis revealed the positive association of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 and the negative association of only DRB1*070101-DQB1*0201 haplotypes with T1D. Furthermore, a significantly increased prevalence of DRB1*030101-DQB1*0201 homozygotes was seen for T1D subjects than for control subjects. Our results confirm the association of specific HLA-DR and -DQ alleles and haplotypes with T1D in Tunisians. The identification of similar and unique haplotypes in Tunisians compared to other Caucasians highlights the need for evaluating the contribution of HLA class II to the genetic susceptibility to T1D with regard to haplotype usage and also to ethnic origin and racial background. PMID:19553558

  14. Ancestral gene and "complementary" antibody dominate early ontogeny.

    Science.gov (United States)

    Arend, Peter

    2013-05-01

    According to N.K. Jerne the somatic generation of immune recognition occurs in conjunction with germ cell evolution and precedes the formation of the zygote, i.e. operates before clonal selection. We propose that it is based on interspecies inherent, ancestral forces maintaining the lineage. Murine oogenesis may be offered as a model. So in C57BL/10BL sera an anti-A reactive, mercapto-ethanol sensitive glycoprotein of up to now unknown cellular origin, but exhibiting immunoglobulin M character, presents itself "complementary" to a syngeneic epitope, which encoded by histocompatibility gene A or meanwhile accepted ancestor of the ABO gene family, arises predominantly in ovarian tissue and was detected statistically significant exclusively in polar glycolipids. Reports either on loss, pronounced expressions or de novo appearances of A-type structures in various conditions of accelerated growth like germ cell evolution, wound healing, inflammation and tumor proliferation in man and ABO related animals might show the dynamics of ancestral functions guarantying stem cell fidelity in maturation and tissue renewal processes. Procedures vice versa generating pluripotent stem cells for therapeutical reasons may indicate, that any artificially started growth should somehow pass through the germ line from the beginning, where according to growing knowledge exclusively the oocyte's genome provides a completely channeling ancestral information. In predatory animals such as the modern-day sea anemone, ancestral proteins, particularly those of the p53 gene family govern the reproduction processes, and are active up to the current mammalian female germ line. Lectins, providing the dual function of growth promotion and defense in higher plants, are suggested to represent the evolutionary precursors of the mammalian immunoglobulin M molecules, or protein moiety implying the greatest functional diversity in nature. And apart from any established mammalian genetic tree, a common vetch

  15. Association Study of Mannose-Binding Lectin Levels and Genetic Variants in Lectin Pathway Proteins with Susceptibility to Age-Related Macular Degeneration: A Case-Control Study

    OpenAIRE

    Osthoff, Michael; Dean, Melinda M.; Baird, Paul N.; Richardson, Andrea J.; Daniell, Mark; Guymer, Robyn H.; Eisen, Damon P

    2015-01-01

    Background In age-related macular degeneration (AMD) the complement system is thought to be activated by chronic oxidative damage with genetic variants identified in the alternative pathway as susceptibility factors. However, the involvement of the lectin pathway of complement, a key mediator of oxidative damage, is controversial. This study investigated whether mannose-binding lectin (MBL) levels and genetic variants in lectin pathway proteins, are associated with the predisposition to and s...

  16. A systems genetics approach identifies CXCL14, ITGAX, and LPCAT2 as novel aggressive prostate cancer susceptibility genes.

    Directory of Open Access Journals (Sweden)

    Kendra A Williams

    2014-11-01

    Full Text Available Although prostate cancer typically runs an indolent course, a subset of men develop aggressive, fatal forms of this disease. We hypothesize that germline variation modulates susceptibility to aggressive prostate cancer. The goal of this work is to identify susceptibility genes using the C57BL/6-Tg(TRAMP8247Ng/J (TRAMP mouse model of neuroendocrine prostate cancer. Quantitative trait locus (QTL mapping was performed in transgene-positive (TRAMPxNOD/ShiLtJ F2 intercross males (n = 228, which facilitated identification of 11 loci associated with aggressive disease development. Microarray data derived from 126 (TRAMPxNOD/ShiLtJ F2 primary tumors were used to prioritize candidate genes within QTLs, with candidate genes deemed as being high priority when possessing both high levels of expression-trait correlation and a proximal expression QTL. This process enabled the identification of 35 aggressive prostate tumorigenesis candidate genes. The role of these genes in aggressive forms of human prostate cancer was investigated using two concurrent approaches. First, logistic regression analysis in two human prostate gene expression datasets revealed that expression levels of five genes (CXCL14, ITGAX, LPCAT2, RNASEH2A, and ZNF322 were positively correlated with aggressive prostate cancer and two genes (CCL19 and HIST1H1A were protective for aggressive prostate cancer. Higher than average levels of expression of the five genes that were positively correlated with aggressive disease were consistently associated with patient outcome in both human prostate cancer tumor gene expression datasets. Second, three of these five genes (CXCL14, ITGAX, and LPCAT2 harbored polymorphisms associated with aggressive disease development in a human GWAS cohort consisting of 1,172 prostate cancer patients. This study is the first example of using a systems genetics approach to successfully identify novel susceptibility genes for aggressive prostate cancer. Such

  17. Host genetic factors in susceptibility to HIV-1 infection and progression to AIDS

    Indian Academy of Sciences (India)

    Koushik Chatterjee

    2010-04-01

    HIV-1 infection has rapidly spread worldwide and has become the leading cause of mortality in infectious diseases. The duration for development of AIDS (AIDS progression) is highly variable among HIV–1 infected individuals, ranging from 2–3 years to no signs of AIDS development in the entire lifetime. Several factors regulate the rate at which HIV-1 infection progresses to AIDS. Host genetic factors play an important role in the outcome of such complex or multifactor diseases as AIDS and are also known to regulate the rate of disease progression. This review focuses on the major host genes reported to affect the progression to AIDS in HIV-1 infected individuals.

  18. Genetics of Transfusion Recipient Alloimmunization: Can Clues from Susceptibility to Autoimmunity Pave the Way?

    OpenAIRE

    Tatari-Calderone, Zohreh; Luban, Naomi L.C.; Vukmanovic, Stanislav

    2014-01-01

    The search for genetic determinants of alloimmunization in sickle cell disease transfusion recipients was based on two premises: i) that polymorphisms responsible for stronger immune and/or inflammatory responses and hemoglobin βS mutation were co-selected by malaria; and ii) that stronger responder status contributes to development of lupus. We found a marker of alloimmunization in the gene encoding for Ro52 protein, also known as Sjögren syndrome antigen 1 (SSA1) and TRIM21. Surprisingly, t...

  19. Impact of Gene Patents and Licensing Practices on Access to Genetic Testing for Inherited Susceptibility to Cancer: Comparing Breast and Ovarian Cancers to Colon Cancers: Patents and Licensing for Breast, Ovarian and Colon Cancer Testing

    OpenAIRE

    Cook-Deegan, Robert; DeRienzo, Christopher; Carbone, Julia; Chandrasekharan, Subhashini; Heaney, Christopher; Conover, Christopher

    2010-01-01

    Genetic testing for inherited susceptibility to breast and ovarian cancer can be compared to similar testing for colorectal cancer as a “natural experiment.” Inherited susceptibility accounts for a similar fraction of both cancers and genetic testing results guide decisions about options for prophylactic surgery in both sets of conditions. One major difference is that in the United States, Myriad Genetics is the sole provider of genetic testing, because it has sole control of relevant patents...

  20. A comprehensive review on host genetic susceptibility to human papillomavirus infection and progression to cervical cancer

    Directory of Open Access Journals (Sweden)

    Koushik Chattopadhyay

    2011-01-01

    Full Text Available Cervical cancer is the second most common cancer in women worldwide. This is caused by oncogenic types of human papillomavirus (HPV infection. Although large numbers of young sexually active women get HPV-infected, only a small fraction develop cervical cancer. This points to different co-factors for regression of HPV infection or progression to cervical cancer. Host genetic factors play an important role in the outcome of such complex or multifactor diseases such as cervical cancer and are also known to regulate the rate of disease progression. The aim of this review is to compile the advances in the field of host genetics of cervical cancer. MEDLINE database was searched using the terms, ′HPV′, ′cervical′, ′CIN′, ′polymorphism(s′, ′cervical′ + FNx01the name of the geneFNx01 and ′HPV′ + FNx01the name of the geneFNx01. This review focuses on the major host genes reported to affect the progression to cervical cancer in HPV infected individuals.

  1. Common variation in ISL1 confers genetic susceptibility for human congenital heart disease.

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    Kristen N Stevens

    Full Text Available Congenital heart disease (CHD is the most common birth abnormality and the etiology is unknown in the overwhelming majority of cases. ISLET1 (ISL1 is a transcription factor that marks cardiac progenitor cells and generates diverse multipotent cardiovascular cell lineages. The fundamental role of ISL1 in cardiac morphogenesis makes this an exceptional candidate gene to consider as a cause of complex congenital heart disease. We evaluated whether genetic variation in ISL1 fits the common variant-common disease hypothesis. A 2-stage case-control study examined 27 polymorphisms mapping to the ISL1 locus in 300 patients with complex congenital heart disease and 2,201 healthy pediatric controls. Eight genic and flanking ISL1 SNPs were significantly associated with complex congenital heart disease. A replication study analyzed these candidate SNPs in 1,044 new cases and 3,934 independent controls and confirmed that genetic variation in ISL1 is associated with risk of non-syndromic congenital heart disease. Our results demonstrate that two different ISL1 haplotypes contribute to risk of CHD in white and black/African American populations.

  2. Detection of PrPres in genetically susceptible fetuses from sheep with natural scrapie.

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    María Carmen Garza

    Full Text Available Scrapie is a transmissible spongiform encephalopathy with a wide PrPres dissemination in many non-neural tissues and with high levels of transmissibility within susceptible populations. Mechanisms of transmission are incompletely understood. It is generally assumed that it is horizontally transmitted by direct contact between animals or indirectly through the environment, where scrapie can remain infectious for years. In contrast, in utero vertical transmission has never been demonstrated and has rarely been studied. Recently, the use of the protein misfolding cyclic amplification technique (PMCA has allowed prion detection in various tissues and excretions in which PrPres levels have been undetectable by traditional assays. The main goal of this study was to detect PrPres in fetal tissues and the amniotic fluid from natural scrapie infected ewes using the PMCA technique. Six fetuses from three infected pregnant ewes in an advanced clinical stage of the disease were included in the study. From each fetus, amniotic fluid, brain, spleen, ileo-cecal valve and retropharyngeal lymph node samples were collected and analyzed using Western blotting and PMCA. Although all samples were negative using Western blotting, PrPres was detected after in vitro amplification. Our results represent the first time the biochemical detection of prions in fetal tissues, suggesting that the in utero transmission of scrapie in natural infected sheep might be possible.

  3. T300A GENETIC POLYMORPHISM: a susceptibility factor for Crohn?s disease?

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    Bruno Lorenzo SCOLARO

    2014-04-01

    Full Text Available Context Crohn’s disease is characterized by a chronic and debilitating inflammatory disorder of the gastrointestinal tract. Several factors may contribute to its development. From extensive studies of the human genome, the polymorphism T300A of the gene ATG16L1 (autophagy-related 16-like 1 has been related to increased risk of developing this disease. Objectives Analyze the role of polymorphism T300A (rs2241880 in patients with Crohn’s disease. Methods 238 samples from (control group and 106 samples from patients with Crohn’s disease recruited at five Southern Brazilian reference centers were evaluated. The genotyping consisted of the amplification via Polymerase Chain Reaction of the genomic segment encompassing T300A, followed by Restriction Fragment Length Polymorphism analysis. The amplicons and fragments were separated by agarose gel electrophoresis and confirmed under ultraviolet light. Results The genotype AG was more prevalent among patients and controls (50% vs 44.8%, followed by genotypes AA (26.4% vs 35.1% and GG (23.6% vs 20.1%. The frequency of the allele G of the polymorphism T300A was higher in the group of patients with Crohn’s disease (48.6% than in controls (42.4%, although not reaching statistical significance. Conclusions It was not possible to confirm the increased susceptibility on development of Crohn’s disease conferred by polymorphism T300A.

  4. Comparison of Enterococcus faecium and Enterococcus faecalis Strains isolated from water and clinical samples: antimicrobial susceptibility and genetic relationships.

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    Gonzalo Castillo-Rojas

    Full Text Available Enterococci are part of the normal intestinal flora in a large number of mammals, and these microbes are currently used as indicators of fecal contamination in water and food for human consumption. These organisms are considered one of the primary causes of nosocomial and environmental infections due to their ability to survive in the environment and to their intrinsic resistance to antimicrobials. The aims of this study were to determine the biochemical patterns and antimicrobial susceptibilities of Enterococcus faecalis and E. faecium isolates from clinical samples and from water (groundwater, water from the Xochimilco wetland, and treated water from the Mexico City Metropolitan Area and to determine the genetic relationships among these isolates. A total of 121 enterococcus strains were studied; 31 and 90 strains were isolated from clinical samples and water (groundwater, water from the Xochimilco wetland, and water for agricultural irrigation, respectively. Identification to the species level was performed using a multiplex PCR assay, and antimicrobial profiles were obtained using a commercial kit. Twenty-eight strains were analyzed by pulsed-field gel electrophoresis (PFGE. E. faecium strains isolated from water showed an atypical biochemical pattern. The clinical isolates showed higher resistance to antibiotics than those from water. Both the enterococci isolated from humans, and those isolated from water showed high genetic diversity according to the PFGE analysis, although some strains seemed to be closely related. In conclusion, enterococci isolated from humans and water are genetically different. However, water represents a potential route of transmission to the community and a source of antimicrobial resistance genes that may be readily transmitted to other, different bacterial species.

  5. Algorithms of Ancestral Gene Length Reconstruction

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    Alexander Bolshoy

    2013-01-01

    Full Text Available Ancestral sequence reconstruction is a well-known problem in molecular evolution. The problem presented in this study is inspired by sequence reconstruction, but instead of leaf-associated sequences we consider only their lengths. We call this problem ancestral gene length reconstruction. It is a problem of finding an optimal labeling which minimizes the total length’s sum of the edges, where both a tree and nonnegative integers associated with corresponding leaves of the tree are the input. In this paper we give a linear algorithm to solve the problem on binary trees for the Manhattan cost function .

  6. Education reduces the effects of genetic susceptibilities to poor physical health

    DEFF Research Database (Denmark)

    Johnson, Wendy; Kyvik, Kirsten Ohm; Mortensen, Erik L;

    2009-01-01

    . Greater education was also associated with smaller variance in health status. In both sexes, 2 standard deviations (SDs) above mean educational level, variance in physical health was only about half that among those 2 SDs below. This was because fewer highly educated people reported poor health. There was......BACKGROUND: Greater education is associated with better physical health. This has been of great concern to public health officials. Most demonstrations show that education influences mean levels of health. Little is known about the influence of education on variance in health status, or about how...... this influence may impact the underlying genetic and environmental sources of health problems. This study explored these influences. METHODS: In a 2002 postal questionnaire, 21 522 members of same-sex pairs in the Danish Twin Registry born between 1931 and 1982 reported physical health in the 12-item...

  7. Evaluation of genetic susceptibility to childhood allergy and asthma in an African American urban population

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    Hudgens Edward E

    2011-02-01

    Full Text Available Abstract Background Asthma and allergy represent complex phenotypes, which disproportionately burden ethnic minorities in the United States. Strong evidence for genomic factors predisposing subjects to asthma/allergy is available. However, methods to utilize this information to identify high risk groups are variable and replication of genetic associations in African Americans is warranted. Methods We evaluated 41 single nucleotide polymorphisms (SNP and a deletion corresponding to 11 genes demonstrating association with asthma in the literature, for association with asthma, atopy, testing positive for food allergens, eosinophilia, and total serum IgE among 141 African American children living in Detroit, Michigan. Independent SNP and haplotype associations were investigated for association with each trait, and subsequently assessed in concert using a genetic risk score (GRS. Results Statistically significant associations with asthma were observed for SNPs in GSTM1, MS4A2, and GSTP1 genes, after correction for multiple testing. Chromosome 11 haplotype CTACGAGGCC (corresponding to MS4A2 rs574700, rs1441586, rs556917, rs502581, rs502419 and GSTP1 rs6591256, rs17593068, rs1695, rs1871042, rs947895 was associated with a nearly five-fold increase in the odds of asthma (Odds Ratio (OR = 4.8, p = 0.007. The GRS was significantly associated with a higher odds of asthma (OR = 1.61, 95% Confidence Interval = 1.21, 2.13; p = 0.001. Conclusions Variation in genes associated with asthma in predominantly non-African ethnic groups contributed to increased odds of asthma in this African American study population. Evaluating all significant variants in concert helped to identify the highest risk subset of this group.

  8. Incorporating epistasis interaction of genetic susceptibility single nucleotide polymorphisms in a lung cancer risk prediction model.

    Science.gov (United States)

    Marcus, Michael W; Raji, Olaide Y; Duffy, Stephen W; Young, Robert P; Hopkins, Raewyn J; Field, John K

    2016-07-01

    Incorporation of genetic variants such as single nucleotide polymorphisms (SNPs) into risk prediction models may account for a substantial fraction of attributable disease risk. Genetic data, from 2385 subjects recruited into the Liverpool Lung Project (LLP) between 2000 and 2008, consisting of 20 SNPs independently validated in a candidate-gene discovery study was used. Multifactor dimensionality reduction (MDR) and random forest (RF) were used to explore evidence of epistasis among 20 replicated SNPs. Multivariable logistic regression was used to identify similar risk predictors for lung cancer in the LLP risk model for the epidemiological model and extended model with SNPs. Both models were internally validated using the bootstrap method and model performance was assessed using area under the curve (AUC) and net reclassification improvement (NRI). Using MDR and RF, the overall best classifier of lung cancer status were SNPs rs1799732 (DRD2), rs5744256 (IL-18), rs2306022 (ITGA11) with training accuracy of 0.6592 and a testing accuracy of 0.6572 and a cross-validation consistency of 10/10 with permutation testing Pmodel was 0.75 (95% CI 0.73-0.77). When epistatic data were incorporated in the extended model, the AUC increased to 0.81 (95% CI 0.79-0.83) which corresponds to 8% increase in AUC (DeLong's test P=2.2e-16); 17.5% by NRI. After correction for optimism, the AUC was 0.73 for the epidemiological model and 0.79 for the extended model. Our results showed modest improvement in lung cancer risk prediction when the SNP epistasis factor was added. PMID:27121382

  9. Antimicrobial susceptibility and genetic characteristics of Neisseria gonorrhoeae isolates from Vietnam, 2011

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    Olsen Birgitta

    2013-01-01

    Full Text Available Abstract Background Antimicrobial resistance (AMR in Neisseria gonorrhoeae is a major public health concern worldwide. In Vietnam, knowledge regarding N. gonorrhoeae prevalence and AMR is limited, and data concerning genetic characteristics of N. gonorrhoeae is totally lacking. Herein, we investigated the phenotypic AMR (previous, current and possible future treatment options, genetic resistance determinants for extended-spectrum cephalosporins (ESCs, and genotypic distribution of N. gonorrhoeae isolated in 2011 in Hanoi, Vietnam. Methods N. gonorrhoeae isolates from Hanoi, Vietnam isolated in 2011 (n = 108 were examined using antibiograms (Etest for 10 antimicrobials, Neisseria gonorrhoeae multi-antigen sequence typing (NG-MAST, and sequencing of ESC resistance determinants (penA, mtrR and penB. Results The levels of in vitro resistance were as follows: ciprofloxacin 98%, tetracycline 82%, penicillin G 48%, azithromycin 11%, ceftriaxone 5%, cefixime 1%, and spectinomycin 0%. The MICs of gentamicin (0.023-6 mg/L, ertapenem (0.002-0.125 mg/L and solithromycin (penA mosaic alleles were found, however, 78% of the isolates contained an alteration of amino acid A501 (A501V (44% and A501T (34% in the encoded penicillin-binding protein 2. A single nucleotide (A deletion in the inverted repeat of the promoter region of the mtrR gene and amino acid alterations in MtrR was observed in 91% and 94% of the isolates, respectively. penB resistance determinants were detected in 87% of the isolates. Seventy-five different NG-MAST STs were identified, of which 59 STs have not been previously described. Conclusions In Vietnam, the highly diversified gonococcal population displayed high in vitro resistance to antimicrobials previously recommended for gonorrhoea treatment (with exception of spectinomycin, but resistance also to the currently recommended ESCs were found. Nevertheless, the MICs of three potential future treatment options were low. It is

  10. Obesity-related abnormalities couple environmental triggers with genetic susceptibility in adult-onset T1D.

    Science.gov (United States)

    Nguyen, K Hoa; Ande, Sudharsana R; Mishra, Suresh

    2016-01-29

    The incidence of adult-onset T1D in low-risk non-HLA type has increased several folds, whereas the contemporaneous incidence in high-risk HLA-type remains stable. Various factors behind this selective increase in T1D in young adults remain unclear. Obesity and its associated abnormalities appear to be an important determinant; however, the underlying mechanism involved is not understood. Recently, we have developed two novel transgenic obese mice models, Mito-Ob and m-Mito-Ob, by expressing a pleiotropic protein prohibitin (PHB) and a phospho mutant form of PHB (Y114F-PHB or m-PHB) from the aP2 gene promoter, respectively. Both mice models develop obesity in a sex-neutral manner, independent of diet; but obesity associated chronic low-grade inflammation and insulin resistance in a male sex-specific manner. Interestingly, on a high fat diet (HFD) only male m-Mito-Ob mice displayed marked mononuclear cell infiltration in pancreas and developed insulitis that mimic adult-onset T1D. Male Mito-Ob mice that share the metabolic phenotype of male m-Mito-Ob mice, and female m-Mito-Ob that harbor m-PHB similar to male m-Mito-Ob mice, did not develop insulitis. Thus, insulitis development in male m-Mito-Ob in response to HFD requires both, obesity-related abnormalities and m-PHB. Collectively, this data provides a proof-of-concept that obesity-associated abnormalities couple environmental triggers with genetic susceptibility in adult-onset T1D and reveals PHB as a potential susceptibility gene for T1D. PMID:26766792

  11. HSD3B and gene-gene interactions in a pathway-based analysis of genetic susceptibility to bladder cancer.

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    Angeline S Andrew

    Full Text Available Bladder cancer is the 4(th most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case-control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene-gene interactions using Multifactor Dimensionality Reduction (MDR and Statistical Epistasis Network analysis. The 3'UTR flanking variant form of the hormone regulation gene HSD3B2 was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31-2.62. This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06-12.63. The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40-3.25 than females (OR 1.56 95%CI 0.83-2.95, (SNP-gender interaction P = 0.048. We also identified a SNP-SNP interaction between T-cell activation related genes GATA3 and CD81 (interaction P = 0.0003. The fact that bladder cancer incidence is 3-4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis.

  12. Genome-wide association study to identify the genetic determinants of otitis media susceptibility in childhood.

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    Marie S Rye

    Full Text Available BACKGROUND: Otitis media (OM is a common childhood disease characterised by middle ear inflammation and effusion. Susceptibility to recurrent acute OM (rAOM; ≥ 3 episodes of AOM in 6 months and chronic OM with effusion (COME; MEE ≥ 3 months is 40-70% heritable. Few underlying genes have been identified to date, and no genome-wide association study (GWAS of OM has been reported. METHODS AND FINDINGS: Data for 2,524,817 single nucleotide polymorphisms (SNPs; 535,544 quality-controlled SNPs genotyped by Illumina 660W-Quad; 1,989,273 by imputation were analysed for association with OM in 416 cases and 1,075 controls from the Western Australian Pregnancy Cohort (Raine Study. Logistic regression analyses under an additive model undertaken in GenABEL/ProbABEL adjusting for population substructure using principal components identified SNPs at CAPN14 (rs6755194: OR = 1.90; 95%CI 1.47-2.45; P(adj-PCA = 8.3 × 10(-7 on chromosome 2p23.1 as the top hit, with independent effects (rs1862981: OR = 1.60; 95%CI 1.29-1.99; P(adj-PCA = 2.2 × 10(-5 observed at the adjacent GALNT14 gene. In a gene-based analysis in VEGAS, BPIFA3 (P(Gene = 2 × 10(-5 and BPIFA1 (P(Gene = 1.07 × 10(-4 in the BPIFA gene cluster on chromosome 20q11.21 were the top hits. In all, 32 genomic regions show evidence of association (P(adj-PCA<10(-5 in this GWAS, with pathway analysis showing a connection between top candidates and the TGFβ pathway. However, top and tag-SNP analysis for seven selected candidate genes in this pathway did not replicate in 645 families (793 affected individuals from the Western Australian Family Study of Otitis Media (WAFSOM. Lack of replication may be explained by sample size, difference in OM disease severity between primary and replication cohorts or due to type I error in the primary GWAS. CONCLUSIONS: This first discovery GWAS for an OM phenotype has identified CAPN14 and GALNT14 on chromosome 2p23.1 and the BPIFA gene cluster on chromosome 20q11.21 as

  13. Paraoxonase-1 genetic polymorphisms and susceptibility to DNA damage in workers occupationally exposed to organophosphate pesticides

    International Nuclear Information System (INIS)

    Human paraoxonase 1 (PON1) is a lipoprotein-associated enzyme involved in the detoxification of organophosphate pesticides (OPs) by hydrolyzing the bioactive oxons. Polymorphisms of the PON1 gene are responsible for variation in the expression and catalytic activity of PON1 enzyme. In the present study, we have determined (a) the prevalence of two common PON1 polymorphisms, (b) the activity of PON1 and acetylcholinesterase enzymes, and (c) the influence of PON1 genotypes and phenotypes variation on DNA damage in workers exposed to OPs. We examined 230 subjects including 115 workers exposed to OPs and an equal number of normal healthy controls. The results revealed that PON1 activity toward paraoxon (179.19 ± 39.36 vs. 241.52 ± 42.32 nmol/min/ml in controls) and phenylacetate (112.74 ± 17.37 vs. 134.28 ± 25.49 μmol/min/ml in controls) was significantly lower in workers than in control subjects (p 192QR (Gln/Arg) and PON155LM (Leu/Met) in workers and control subjects (p > 0.05). The PON1 activity toward paraoxonase was found to be significantly higher in the R/R (Arg/Arg) genotypes than Q/R (Gln/Arg) and lowest in Q/Q (Gln/Gln) genotypes in both workers and control subjects (p 55LM (Leu/Met), PON1 activity toward paraoxonase was observed to be higher in individuals with L/L (Leu/Leu) genotypes and lowest in individuals with M/M (Met/Met) genotypes in both groups (p < 0.001). No influence of PON1 genotypes and phenotypes was seen on the activity of acetylcholinesterase and arylesterase. The DNA damage was observed to be significantly higher in workers than in control subjects (p < 0.05). Further, the individuals who showed least paraoxonase activity i.e., those with (Q/Q [Gln/Gln] and M/M [Met/Met]) genotypes showed significantly higher DNA damage compared to other isoforms in workers exposed to OPs (p < 0.05). The results indicate that the individuals with PON1 Q/Q and M/M genotypes are more susceptible toward genotoxicity. In conclusion, the study suggests wide

  14. Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

    Science.gov (United States)

    Crosslin, D R; Carrell, D S; Burt, A; Kim, D S; Underwood, J G; Hanna, D S; Comstock, B A; Baldwin, E; de Andrade, M; Kullo, I J; Tromp, G; Kuivaniemi, H; Borthwick, K M; McCarty, C A; Peissig, P L; Doheny, K F; Pugh, E; Kho, A; Pacheco, J; Hayes, M G; Ritchie, M D; Verma, S S; Armstrong, G; Stallings, S; Denny, J C; Carroll, R J; Crawford, D C; Crane, P K; Mukherjee, S; Bottinger, E; Li, R; Keating, B; Mirel, D B; Carlson, C S; Harley, J B; Larson, E B; Jarvik, G P

    2015-01-01

    Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine. PMID:25297839

  15. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

    Science.gov (United States)

    Gaulton, Kyle J; Ferreira, Teresa; Lee, Yeji; Raimondo, Anne; Mägi, Reedik; Reschen, Michael E; Mahajan, Anubha; Locke, Adam; Rayner, N William; Robertson, Neil; Scott, Robert A; Prokopenko, Inga; Scott, Laura J; Green, Todd; Sparso, Thomas; Thuillier, Dorothee; Yengo, Loic; Grallert, Harald; Wahl, Simone; Frånberg, Mattias; Strawbridge, Rona J; Kestler, Hans; Chheda, Himanshu; Eisele, Lewin; Gustafsson, Stefan; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Qi, Lu; Karssen, Lennart C; van Leeuwen, Elisabeth M; Willems, Sara M; Li, Man; Chen, Han; Fuchsberger, Christian; Kwan, Phoenix; Ma, Clement; Linderman, Michael; Lu, Yingchang; Thomsen, Soren K; Rundle, Jana K; Beer, Nicola L; van de Bunt, Martijn; Chalisey, Anil; Kang, Hyun Min; Voight, Benjamin F; Abecasis, Gonçalo R; Almgren, Peter; Baldassarre, Damiano; Balkau, Beverley; Benediktsson, Rafn; Blüher, Matthias; Boeing, Heiner; Bonnycastle, Lori L; Bottinger, Erwin P; Burtt, Noël P; Carey, Jason; Charpentier, Guillaume; Chines, Peter S; Cornelis, Marilyn C; Couper, David J; Crenshaw, Andrew T; van Dam, Rob M; Doney, Alex S F; Dorkhan, Mozhgan; Edkins, Sarah; Eriksson, Johan G; Esko, Tonu; Eury, Elodie; Fadista, João; Flannick, Jason; Fontanillas, Pierre; Fox, Caroline; Franks, Paul W; Gertow, Karl; Gieger, Christian; Gigante, Bruna; Gottesman, Omri; Grant, George B; Grarup, Niels; Groves, Christopher J; Hassinen, Maija; Have, Christian T; Herder, Christian; Holmen, Oddgeir L; Hreidarsson, Astradur B; Humphries, Steve E; Hunter, David J; Jackson, Anne U; Jonsson, Anna; Jørgensen, Marit E; Jørgensen, Torben; Kao, Wen-Hong L; Kerrison, Nicola D; Kinnunen, Leena; Klopp, Norman; Kong, Augustine; Kovacs, Peter; Kraft, Peter; Kravic, Jasmina; Langford, Cordelia; Leander, Karin; Liang, Liming; Lichtner, Peter; Lindgren, Cecilia M; Lindholm, Eero; Linneberg, Allan; Liu, Ching-Ti; Lobbens, Stéphane; Luan, Jian'an; Lyssenko, Valeriya; Männistö, Satu; McLeod, Olga; Meyer, Julia; Mihailov, Evelin; Mirza, Ghazala; Mühleisen, Thomas W; Müller-Nurasyid, Martina; Navarro, Carmen; Nöthen, Markus M; Oskolkov, Nikolay N; Owen, Katharine R; Palli, Domenico; Pechlivanis, Sonali; Peltonen, Leena; Perry, John R B; Platou, Carl G P; Roden, Michael; Ruderfer, Douglas; Rybin, Denis; van der Schouw, Yvonne T; Sennblad, Bengt; Sigurðsson, Gunnar; Stančáková, Alena; Steinbach, Gerald; Storm, Petter; Strauch, Konstantin; Stringham, Heather M; Sun, Qi; Thorand, Barbara; Tikkanen, Emmi; Tonjes, Anke; Trakalo, Joseph; Tremoli, Elena; Tuomi, Tiinamaija; Wennauer, Roman; Wiltshire, Steven; Wood, Andrew R; Zeggini, Eleftheria; Dunham, Ian; Birney, Ewan; Pasquali, Lorenzo; Ferrer, Jorge; Loos, Ruth J F; Dupuis, Josée; Florez, Jose C; Boerwinkle, Eric; Pankow, James S; van Duijn, Cornelia; Sijbrands, Eric; Meigs, James B; Hu, Frank B; Thorsteinsdottir, Unnur; Stefansson, Kari; Lakka, Timo A; Rauramaa, Rainer; Stumvoll, Michael; Pedersen, Nancy L; Lind, Lars; Keinanen-Kiukaanniemi, Sirkka M; Korpi-Hyövälti, Eeva; Saaristo, Timo E; Saltevo, Juha; Kuusisto, Johanna; Laakso, Markku; Metspalu, Andres; Erbel, Raimund; Jöcke, Karl-Heinz; Moebus, Susanne; Ripatti, Samuli; Salomaa, Veikko; Ingelsson, Erik; Boehm, Bernhard O; Bergman, Richard N; Collins, Francis S; Mohlke, Karen L; Koistinen, Heikki; Tuomilehto, Jaakko; Hveem, Kristian; Njølstad, Inger; Deloukas, Panagiotis; Donnelly, Peter J; Frayling, Timothy M; Hattersley, Andrew T; de Faire, Ulf; Hamsten, Anders; Illig, Thomas; Peters, Annette; Cauchi, Stephane; Sladek, Rob; Froguel, Philippe; Hansen, Torben; Pedersen, Oluf; Morris, Andrew D; Palmer, Collin N A; Kathiresan, Sekar; Melander, Olle; Nilsson, Peter M; Groop, Leif C; Barroso, Inês; Langenberg, Claudia; Wareham, Nicholas J; O'Callaghan, Christopher A; Gloyn, Anna L; Altshuler, David; Boehnke, Michael; Teslovich, Tanya M; McCarthy, Mark I; Morris, Andrew P

    2015-12-01

    We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. PMID:26551672

  16. Role of genetic susceptibility in development of treatment-related adverse outcomes in cancer survivors.

    Science.gov (United States)

    Bhatia, Smita

    2011-10-01

    Clear and unambiguous associations have been established between therapeutic exposures and specific complications. However, considerable interindividual variability is observed in the risk of developing an outcome for a given therapeutic exposure. Genetic predisposition and especially its interaction with therapeutic exposures can potentially exacerbate the toxic effect of treatment on normal tissues and organ systems, and can possibly explain the interindividual variability. This article provides a brief overview of the current knowledge about the role of genomic variation in the development of therapy-related complications. Relatively common outcomes with strong associations with therapeutic exposures, including cardiomyopathy, obesity, osteonecrosis, ototoxicity, and subsequent malignancies are discussed here. To develop a deeper understanding of the molecular underpinnings of therapy-related complications, comprehensive and near-complete collection of clinically annotated samples is critical. Methodologic issues such as study design, definition of the endpoints or phenotypes, identification of appropriate and adequately sized study population together with a reliable plan for collecting and maintaining high-quality DNA, and selection of an appropriate approach or platform for genotyping are also discussed. Understanding the etiopathogenetic pathways that lead to the morbidity is critical to developing targeted prevention and intervention strategies, optimizing risk-based health care of cancer survivors, thus minimizing chronic morbidities and improving quality of life. PMID:21980013

  17. Genetic mapping of quantitative trait loci affecting susceptibility in chicken to develop pulmonary hypertension syndrome.

    Science.gov (United States)

    Rabie, T S K M; Crooijmans, R P M A; Bovenhuis, H; Vereijken, A L J; Veenendaal, T; van der Poel, J J; Van Arendonk, J A M; Pakdel, A; Groenen, M A M

    2005-12-01

    Pulmonary hypertension syndrome (PHS), also referred to as ascites syndrome, is a growth-related disorder of chickens frequently observed in fast-growing broilers with insufficient pulmonary vascular capacity at low temperature and/or at high altitude. A cross between two genetically different broiler dam lines that originated from the White Plymouth Rock breed was used to produce a three-generation population. This population was used for the detection and localization of quantitative trait loci (QTL) affecting PHS-related traits. Ten full-sib families consisting of 456 G2 birds were typed with 420 microsatellite markers covering 24 autosomal chromosomes. Phenotypic observations were collected on 4202 G3 birds and a full-sib across family regression interval mapping approach was used to identify QTL. There was statistical evidence for QTL on chicken chromosome 2 (GGA2), GGA4 and GGA6. Suggestive QTL were found on chromosomes 5, 8, 10, 27 and 28. The most significant QTL were located on GGA2 for right and total ventricular weight as percentage of body weight (%RV and %TV respectively). A related trait, the ratio of right ventricular weight as percentage to total ventricular weight (RATIO), reached the suggestive threshold on this chromosome. All three QTL effects identified on GGA2 had their maximum test statistic in the region flanked by markers MCW0185 and MCW0245 (335-421 cM). PMID:16293119

  18. Genetic fine-mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

    Science.gov (United States)

    Mahajan, Anubha; Locke, Adam; Rayner, N William; Robertson, Neil; Scott, Robert A; Prokopenko, Inga; Scott, Laura J; Green, Todd; Sparso, Thomas; Thuillier, Dorothee; Yengo, Loic; Grallert, Harald; Wahl, Simone; Frånberg, Mattias; Strawbridge, Rona J; Kestler, Hans; Chheda, Himanshu; Eisele, Lewin; Gustafsson, Stefan; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Qi, Lu; Karssen, Lennart C; van Leeuwen, Elisabeth M; Willems, Sara M; Li, Man; Chen, Han; Fuchsberger, Christian; Kwan, Phoenix; Ma, Clement; Linderman, Michael; Lu, Yingchang; Thomsen, Soren K; Rundle, Jana K; Beer, Nicola L; van de Bunt, Martijn; Chalisey, Anil; Kang, Hyun Min; Voight, Benjamin F; Abecasis, Goncalo R; Almgren, Peter; Baldassarre, Damiano; Balkau, Beverley; Benediktsson, Rafn; Blüher, Matthias; Boeing, Heiner; Bonnycastle, Lori L; Borringer, Erwin P; Burtt, Noël P; Carey, Jason; Charpentier, Guillaume; Chines, Peter S; Cornelis, Marilyn C; Couper, David J; Crenshaw, Andrew T; van Dam, Rob M; Doney, Alex SF; Dorkhan, Mozhgan; Edkins, Sarah; Eriksson, Johan G; Esko, Tonu; Eury, Elodie; Fadista, João; Flannick, Jason; Fontanillas, Pierre; Fox, Caroline; Franks, Paul W; Gertow, Karl; Gieger, Christian; Gigante, Bruna; Gottesman, Omri; Grant, George B; Grarup, Niels; Groves, Christopher J; Hassinen, Maija; Have, Christian T; Herder, Christian; Holmen, Oddgeir L; Hreidarsson, Astradur B; Humphries, Steve E; Hunter, David J; Jackson, Anne U; Jonsson, Anna; Jørgensen, Marit E; Jørgensen, Torben; Kerrison, Nicola D; Kinnunen, Leena; Klopp, Norman; Kong, Augustine; Kovacs, Peter; Kraft, Peter; Kravic, Jasmina; Langford, Cordelia; Leander, Karin; Liang, Liming; Lichtner, Peter; Lindgren, Cecilia M; Lindholm, Eero; Linneberg, Allan; Liu, Ching-Ti; Lobbens, Stéphane; Luan, Jian’an; Lyssenko, Valeriya; Männistö, Satu; McLeod, Olga; Meyer, Julia; Mihailov, Evelin; Mirza, Ghazala; Mühleisen, Thomas W; Müller-Nurasyid, Martina; Navarro, Carmen; Nöthen, Markus M; Oskolkov, Nikolay N; Owen, Katharine R; Palli, Domenico; Pechlivanis, Sonali; Perry, John RB; Platou, Carl GP; Roden, Michael; Ruderfer, Douglas; Rybin, Denis; van der Schouw, Yvonne T; Sennblad, Bengt; Sigurðsson, Gunnar; Stančáková, Alena; Steinbach, Gerald; Storm, Petter; Strauch, Konstantin; Stringham, Heather M; Sun, Qi; Thorand, Barbara; Tikkanen, Emmi; Tonjes, Anke; Trakalo, Joseph; Tremoli, Elena; Tuomi, Tiinamaija; Wennauer, Roman; Wood, Andrew R; Zeggini, Eleftheria; Dunham, Ian; Birney, Ewan; Pasquali, Lorenzo; Ferrer, Jorge; Loos, Ruth JF; Dupuis, Josée; Florez, Jose C; Boerwinkle, Eric; Pankow, James S; van Duijn, Cornelia; Sijbrands, Eric; Meigs, James B; Hu, Frank B; Thorsteinsdottir, Unnur; Stefansson, Kari; Lakka, Timo A; Rauramaa, Rainer; Stumvoll, Michael; Pedersen, Nancy L; Lind, Lars; Keinanen-Kiukaanniemi, Sirkka M; Korpi-Hyövälti, Eeva; Saaristo, Timo E; Saltevo, Juha; Kuusisto, Johanna; Laakso, Markku; Metspalu, Andres; Erbel, Raimund; Jöckel, Karl-Heinz; Moebus, Susanne; Ripatti, Samuli; Salomaa, Veikko; Ingelsson, Erik; Boehm, Bernhard O; Bergman, Richard N; Collins, Francis S; Mohlke, Karen L; Koistinen, Heikki; Tuomilehto, Jaakko; Hveem, Kristian; Njølstad, Inger; Deloukas, Panagiotis; Donnelly, Peter J; Frayling, Timothy M; Hattersley, Andrew T; de Faire, Ulf; Hamsten, Anders; Illig, Thomas; Peters, Annette; Cauchi, Stephane; Sladek, Rob; Froguel, Philippe; Hansen, Torben; Pedersen, Oluf; Morris, Andrew D; Palmer, Collin NA; Kathiresan, Sekar; Melander, Olle; Nilsson, Peter M; Groop, Leif C; Barroso, Inês; Langenberg, Claudia; Wareham, Nicholas J; O’Callaghan, Christopher A; Gloyn, Anna L; Altshuler, David; Boehnke, Michael; Teslovich, Tanya M; McCarthy, Mark I; Morris, Andrew P

    2015-01-01

    We performed fine-mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine-mapping implicated rs10830963 as driving T2D association. We confirmed that this T2D-risk allele increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D-risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. PMID:26551672

  19. [Correlation between the genetic polymorphisms of apolipoprotein M with the susceptibility to rheumatic diseases of Chinese Han populastion in Lanzhou].

    Science.gov (United States)

    Li, Meiyong; Guo, Xinling; Li, Qiannan; You, Chongge

    2016-08-01

    Objective To investigate the relationship between the genetic polymorphisms of apolipoprotein M (ApoM) and the susceptibility to rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and ankylosing spondylitis (AS) among Chinese Han population in Lanzhou. Methods Primers for the two single nucleotide polymorphism (SNP) sites (rs805296 and rs805297) in ApoM gene were designed and their genotyping methods of polymerase chain reaction-high resolution melting (PCR-HRM) assay were established. Case-control studies were performed among the 599 cases of RA, 194 cases of SLE, 179 cases of AS and 273 matched healthy controls to analyze the correlations between the two SNPs and the susceptibility to rheumatic diseases. Results The genotype frequencies of rs805296 were AA 87.0%, AG 12.7%, GG 0.3% in RA cases, AA 84.5%, AG 15.0%, GG 0.5% in SLE cases, AA 91.6%, AG 7.3%, GG 1.1% in AS cases, AA 85.0%, AG 15.0%, GG 0% in healthy controls. The ones of rs805297 were GG 38.2%, GT 51.8%, TT 10.0% in RA cases, GG 44.3%, GT 45.4%, TT 10.3% in SLE cases, GG 37.4%, GT 47.5%, TT 15.1% in AS cases, GG 40.7%, GT 46.1%, TT 13.2% in healthy controls. Statistical analyses showed that only the genotype distribution of rs805296 was significantly different between the AS cases and the healthy controls. Under the dominant model, the G allele carriers of rs805296 (AG heterozygote and GG homozygote) were found to significantly decrease the risk for AS development. Conclusion The established PCR-HRM genotyping assays in the present study can successfully achieve the molecular diagnosis of the two SNPs sites (rs805296 and rs805297) from clinical samples, and the study found a significant association between the SNP of rs805296 and the susceptibility to AS among Chinese Han population in Lanzhou. PMID:27412944

  20. Cerebral blood volume calculated by dynamic susceptibility contrast-enhanced perfusion MR imaging: preliminary correlation study with glioblastoma genetic profiles.

    Directory of Open Access Journals (Sweden)

    Inseon Ryoo

    Full Text Available PURPOSE: To evaluate the usefulness of dynamic susceptibility contrast (DSC enhanced perfusion MR imaging in predicting major genetic alterations in glioblastomas. MATERIALS AND METHODS: Twenty-five patients (M:F = 13∶12, mean age: 52.1±15.2 years with pathologically proven glioblastoma who underwent DSC MR imaging before surgery were included. On DSC MR imaging, the normalized relative tumor blood volume (nTBV of the enhancing solid portion of each tumor was calculated by using dedicated software (Nordic TumorEX, NordicNeuroLab, Bergen, Norway that enabled semi-automatic segmentation for each tumor. Five major glioblastoma genetic alterations (epidermal growth factor receptor (EGFR, phosphatase and tensin homologue (PTEN, Ki-67, O6-methylguanine-DNA methyltransferase (MGMT and p53 were confirmed by immunohistochemistry and analyzed for correlation with the nTBV of each tumor. Statistical analysis was performed using the unpaired Student t test, ROC (receiver operating characteristic curve analysis and Pearson correlation analysis. RESULTS: The nTBVs of the MGMT methylation-negative group (mean 9.5±7.5 were significantly higher than those of the MGMT methylation-positive group (mean 5.4±1.8 (p = .046. In the analysis of EGFR expression-positive group, the nTBVs of the subgroup with loss of PTEN gene expression (mean: 10.3±8.1 were also significantly higher than those of the subgroup without loss of PTEN gene expression (mean: 5.6±2.3 (p = .046. Ki-67 labeling index indicated significant positive correlation with the nTBV of the tumor (p = .01. CONCLUSION: We found that glioblastomas with aggressive genetic alterations tended to have a high nTBV in the present study. Thus, we believe that DSC-enhanced perfusion MR imaging could be helpful in predicting genetic alterations that are crucial in predicting the prognosis of and selecting tailored treatment for glioblastoma patients.

  1. Interactions Within Susceptible Hosts Drive Establishment of Genetically Distinct Variants of an Insect-Borne Pathogen.

    Science.gov (United States)

    Blaisdell, G K; Zhang, S; Bratburd, J R; Daane, K M; Cooper, M L; Almeida, R P P

    2015-08-01

    Coinfections are common, leading to pathogen interactions during transmission and establishment in a host. However, few studies have tested the relative strengths of pathogen interactions in vectors and hosts that determine the outcome of infection. We tested interactions between two genetically distinct variants of the mealybug-transmitted Grapevine leafroll-associated virus 3. The transmission efficiency of each variant in single variant inoculations by two vector species was determined. The effects of vector species, a coinfected source, and simultaneous inoculation from multiple hosts to one host on variant establishment were examined. Within-vector interactions could have a role in transmission from hosts containing mixed infections, but not when vectors were moved from separate singly infected source plants to a single recipient plant. The invasive Planococcus ficus (Signoret) was a more efficient vector than Pseudococcus viburni (Signoret). Transmission efficiency of the two variants did not differ in single variant inoculations. Overall infections were the same whether from singly or coinfected source plants. In mixed inoculations, establishment of one variant was reduced. Mixed inoculations from two singly infected source plants resulted in fewer mixed infections than expected by chance. Therefore, the observed outcome was determined subsequent to host inoculation rather than in the vector. The outcome may be due to resource competition between pathogens. Alternatively apparent competition may be responsible; the pathogens' differential ability to overcome host defenses and colonize the host may determine the final outcome of new infections. Detailed knowledge of interactions between pathogens during transmission and establishment could improve understanding and management of disease spread. PMID:26470292

  2. Role of common sarcomeric gene polymorphisms in genetic susceptibility to left ventricular dysfunction

    Indian Academy of Sciences (India)

    SURENDRA KUMAR; AVSHESH MISHRA; ANSHIKA SRIVASTAVA; MANSI BHATT; N. GARG; S. K. AGARWAL; SHANTANU PANDE; BALRAJ MITTAL

    2016-06-01

    Mutations in sarcomeric genes are common genetic cause of cardiomyopathies. An intronic 25-bp deletion in cardiac myosin binding protein C (MYBPC3) at 3' region is associated with dilated and hypertrophic cardiomyopathies in Southeast Asia. However, the frequency of sarcomeric gene polymorphisms and associated clinical presentation have not been established with left ventricular dysfunction (LVD). Therefore, the aim of the present study was to explore the association of MYBPC3 25-bp deletion, titin (TTN) 18 bp I/D, troponin T type 2 (TNNT2) 5 bp I/D and myospryn K2906N polymorphisms with LVD. This study includes 988 consecutive patients with angiographically confirmed coronary artery disease (CAD) and 300 healthy controls. Among the 988 CAD patients, 253 with reduced left ventricle ejection fraction (LVEF≤45%) were categorized as LVD. MYBPC3 25-bp deletion,TTN 18 bp I/D and TNNT25 bp I/D polymorphisms were determined by direct polymerase chain reaction method, while myospryn K2906N polymorphism by TaqMan assay. Our results showed that MYBPC3 25-bpdeletion polymorphism was significantly associated with elevated risk of LVD (LVEF <45) (healthy controls versus LVD: OR= 3.85,P<0.001; and nonLVD versus LVD: OR=1.65,P=0.035), while TTN 18 bp I/D, TNNT25bpI/Dand myospryn K2906N polymorphisms did not show any significant association with LVD. The results also showed that MYBPC3 25-bp deletion polymorphism was significantly associated with other parameters of LV remodelling, i.e. LV dimensions (LV end diastole dimension, LVEDD: P= 0.037 and LV end systolic dimension, LVESD: P= 0.032).Our data suggests that MYBPC3 25-bp deletion may play significant role in conferring LVD as well as CAD risk in north Indian population

  3. Susceptibility of carnivore hosts to strains of canine distemper virus from distinct genetic lineages.

    Science.gov (United States)

    Nikolin, Veljko M; Wibbelt, Gudrun; Michler, Frank-Uwe F; Wolf, Peter; East, Marion L

    2012-04-23

    Using the complete haemagglutinin (HA) gene and partial phosphoprotein (P) gene we investigated the genotype of canine distemper virus (CDV) strains recovered from two wildlife species in Mecklenburg-Vorpommern, Germany. Phylogenetic analyses demonstrated significant differences between the strains from raccoons Procyon lotor (family Procyonidae) obtained in 2007 and strains from red foxes Vulpes vulpes (family Canidae) obtained in 2008. The raccoon strains belonged to the CDV European wildlife lineage whereas the red fox strains belonged to the CDV Europe lineage. We combined our genetic sequence data with published data from 138 CDV stains worldwide to investigate the proposed importance of amino acid substitutions in the SLAM binding region of the CDV HA protein at position 530 (G/E to R/D/N) and 549 (Y to H) to the spread of domestic dog-adapted CDV strains to other carnivores. We found no evidence that amino acid 530 was strongly affected by host species. Rather, site 530 was conserved within CDV lineages, regardless of host species. Contrary to expectation, strains from non-dog hosts did not exhibit a bias towards the predicted substitution Y549H. Wild canid hosts were more frequently infected by strains with 549Y, a pattern similar to domestic dogs. Non-canid strains showed no significant bias towards either H or Y at site 549, although there was a trend towards 549H. Significant differences between the prevalence of 549Y and 549H in wild canid strains and non-canid strains suggests a degree of virus adaptation to these categories of host. PMID:22024346

  4. Genetic basis of interindividual susceptibility to cancer cachexia: selection of potential candidate gene polymorphisms for association studies

    Indian Academy of Sciences (India)

    N. Johns; B. H. Tan; M. Macmillan; T. S. Solheim; J. A. Ross; V. E. Baracos; S. Damaraju; K. C. H. Fearon

    2014-12-01

    Cancer cachexia is a complex and multifactorial disease. Evolving definitions highlight the fact that a diverse range of biological processes contribute to cancer cachexia. Part of the variation in who will and who will not develop cancer cachexia may be genetically determined. As new definitions, classifications and biological targets continue to evolve, there is a need for reappraisal of the literature for future candidate association studies. This review summarizes genes identified or implicated as well as putative candidate genes contributing to cachexia, identified through diverse technology platforms and model systems to further guide association studies. A systematic search covering 1986–2012 was performed for potential candidate genes / genetic polymorphisms relating to cancer cachexia. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Pathway analysis software was used to reveal possible network associations between genes. Functionality of SNPs/genes was explored based on published literature, algorithms for detecting putative deleterious SNPs and interrogating the database for expression of quantitative trait loci (eQTLs). A total of 154 genes associated with cancer cachexia were identified and explored for functional polymorphisms. Of these 154 genes, 119 had a combined total of 281 polymorphisms with functional and/or clinical significance in terms of cachexia associated with them. Of these, 80 polymorphisms (in 51 genes) were replicated in more than one study with 24 polymorphisms found to influence two or more hallmarks of cachexia (i.e., inflammation, loss of fat mass and/or lean mass and reduced survival). Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides a contemporary basis to select genes and/or polymorphisms for further association studies in cancer cachexia, and

  5. Genetic Factors Affecting Susceptibility to Low Dose & Low Dose-Rate Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Bedford, Joel

    2014-04-18

    Our laboratory has, among other things, developed and used the gamma H2AX focus assay and other chromosomal and cell killing assays to show that differences in this DNA double strand break (dsb) related response can be clearly and distinctly demonstrated for cells which are mildly hyper-radiosensitive such as those associated with A-T heterozygosity. We have found this level of mild hypersensitivity for cells from some 20 to 30 % of apparently normal individuals and from apparently normal parents of Retinoblastoma patients. We found significant differences in gene expression in somatic cells from unaffected parents of Rb patients as compared with normal controls, suggesting that these parents may harbor some as yet unidentified genetic abnormality. In other experiments we sought to determine the extent of differences in normal human cellular reaponses to radiation depending on their irradiation in 2D monolayer vs 3D organized acinar growth conditions. We exmined cell reproductive death, chromosomal aberration induction, and the levels of γ-H2AX foci in cells after single acute gamma-ray doses and immediately after 20 hours of irradiation at a dose rate of 0.0017 Gy/min. We found no significant differences in the dose-responses of these cells under the 2D or 3D growth conditions. While this does not mean such differences cannot occur in other situations, it does mean that they do not generally or necessarily occur. In another series of studies in collaboration with Dr Chuan Li, with supprt from this current grant. We reported a role for apoptotic cell death in promoting wound healing and tissue regeneration in mice. Apoptotic cells released growth signals that stimulated the proliferation of progenitor or stem cells. In yet another collaboration with Dr, B. Chen with funds from this grant, the relative radiosensitivity to cell killing as well as chromosomal instability of 13 DNA-PKcs site-directed mutant cell lines (defective at phosphorylation sites or kinase

  6. Association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with autism: evidence of genetic susceptibility.

    Science.gov (United States)

    Rai, Vandana

    2016-08-01

    Autism (MIM 209850) is a heterogeneous neurodevelopmental disease that manifests within the first 3 years of life. Numerous articles reported that dysfunctional folate-methionine pathway enzymes may play an important role in the pathophysiology of autism. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme of this pathway and MTHFR C677T polymorphism reported as risk factor for autism in several case control studies. However, controversial reports were also published. Hence the present meta-analysis was designed to investigate the relationship of the MTHFR C677T polymorphism with the risk of autism. Electronic databases were searched for case control studies with following search terms - 'MTHFR', 'C677T', in combination with 'Autism'. Pooled OR with its corresponding 95 % CI was calculated and used as association measure to investigate the association between MTHFR C677T polymorphism and risk of autism. Total of thirteen studies were found suitable for the inclusion in the present meta-analysis, which comprises 1978 cases and 7257 controls. Meta-analysis using all four genetic models showed significant association between C677T polymorphism and autism (ORTvs.C = 1.48; 95 % CI: 1.18-1.86; P = 0.0007; ORTT + CT vs. CC = 1.70, 95 % CI = 0.96-2.9, p = 0.05; ORTT vs. CC = 1.84, 95 % CI = 1.12-3.02, p = 0.02; ORCT vs.CC = 1.60, 95 % CI = 1.2-2.1, p = 0.003; ORTT vs.CT+CC = 1.5, 95 % CI = 1.02-2.2, p = 0.03). In total 13 studies, 9 studies were from Caucasian population and 4 studies were from Asian population. The association between C677T polymorphism and autism was significant in Caucasian (ORTvs.C = 1.43; 95 % CI = 1.1-1.87; p = 0.009) and Asian population (ORTvs.C = 1.68; 95 % CI = 1.02-2.77; p = 0.04) using allele contrast model. In conclusion, present meta-analysis strongly suggested a significant association of the MTHFR C677T polymorphism with autism. PMID:26956130

  7. Review: Genetic diversity of HLA-DR and varion of asthma susceptibility; an overview of Asthma in Pregnancy

    Directory of Open Access Journals (Sweden)

    ACHMAD ARMAN SUBIJANTO

    2008-07-01

    Full Text Available Asthma is the most common potentially serious medical condition to complicate pregnancy. To date, many attempts have been done to detect genetic loci contributing to asthma susceptibility. HLA-DR loci may play an important role in the pathophysiology of allergic inflammation by influencing specific IgE responses. Asthma affects almost 7 percent of women in their childbearing years. When women with asthma become pregnant, a third of the patients improve, one third worsen, and the last third remain unchanged. Asthma exacerbations are most likely to appear during the weeks 24 to 36 of gestation, with only occasional patients (10 percent or fewer becoming symptomatic during labor and delivery. Uncontrolled asthma can cause serious complications for mother, including high blood pressure, toxemia and premature delivery. For the baby, complications of uncontrolled asthma include increased risk of stillbirth, fetal growth retardation, premature birth, low birth weight and a low APGAR score at birth. The goal management of asthma during pregnancy is to achieve optimal therapy, maintaining controlled asthma and increased the mother and baby’s quality of life. Most asthma medications are safe during pregnancy.

  8. Impact of a Booklet about Diabetes Genetic Susceptibility and Its Prevention on Attitudes towards Prevention and Perceived Behavioral Change in Patients with Type 2 Diabetes and Their Offspring

    Directory of Open Access Journals (Sweden)

    Masakazu Nishigaki

    2011-01-01

    Full Text Available Background. Offspring of type 2 diabetic patients are at a high risk of type 2 diabetes. Information on diabetes genetic susceptibility and prevention should be supplied to the offspring. Methods. A six-page booklet on diabetes genetic susceptibility and prevention was distributed to 173 patients who ere ordered to hand it to their offspring. The patients answered a self-administered questionnaire on booklet delivery and attitudinal and behavioral changes toward diabetes and its prevention in themselves and their offspring. Results. Valid responses were obtained from 130 patients. Forty-nine patients had actually handed the booklet. Booklet induces more relief than anxiety. From the patient's view, favorable attitudinal and/or behavioral changes occurred in more than half of the offspring who were delivered the booklet. Conclusion. The booklet worked effectively on attitudes and behaviors toward diabetes and its prevention both in patients and their offspring. However, the effectiveness of patients as information deliverers was limited.

  9. BALB/c mice genetically susceptible to proteoglycan-induced arthritis and spondylitis show colony-dependent differences in disease penetrance

    OpenAIRE

    Farkas, Balint; Boldizsar, Ferenc; Tarjanyi, Oktavia; Laszlo, Anna; Lin, Simon M.; Hutas, Gabor; Tryniszewska, Beata; Mangold, Aaron; Nagyeri, Gyorgy; Rosenzweig, Holly L.; Finnegan, Alison; Mikecz, Katalin; Glant, Tibor T.

    2009-01-01

    Introduction The major histocompatibility complex (H-2d) and non-major histocompatibility complex genetic backgrounds make the BALB/c strain highly susceptible to inflammatory arthritis and spondylitis. Although different BALB/c colonies develop proteoglycan-induced arthritis and proteoglycan-induced spondylitis in response to immunization with human cartilage proteoglycan, they show significant differences in disease penetrance despite being maintained by the same vendor at either the same o...

  10. Interaction between arsenic exposure from drinking water and genetic susceptibility in carotid intima–media thickness in Bangladesh

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Fen [Department of Population Health, New York University School of Medicine, New York, NY (United States); Department of Environmental Medicine, New York University School of Medicine, New York, NY (United States); Jasmine, Farzana; Kibriya, Muhammad G. [Department of Health Studies, The University of Chicago, Chicago, IL (United States); The University of Chicago Comprehensive Cancer Center, Chicago, IL (United States); Liu, Mengling; Cheng, Xin [Department of Population Health, New York University School of Medicine, New York, NY (United States); Department of Environmental Medicine, New York University School of Medicine, New York, NY (United States); Parvez, Faruque [Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York City, NY (United States); Paul-Brutus, Rachelle [Department of Health Studies, The University of Chicago, Chicago, IL (United States); The University of Chicago Comprehensive Cancer Center, Chicago, IL (United States); Islam, Tariqul; Paul, Rina Rani; Sarwar, Golam; Ahmed, Alauddin [U-Chicago Research Bangladesh, Ltd., Dhaka (Bangladesh); Jiang, Jieying [Department of Population Health, New York University School of Medicine, New York, NY (United States); Department of Environmental Medicine, New York University School of Medicine, New York, NY (United States); Islam, Tariqul [U-Chicago Research Bangladesh, Ltd., Dhaka (Bangladesh); Slavkovich, Vesna [Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York City, NY (United States); Rundek, Tatjana [Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL (United States); Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL (United States); Demmer, Ryan T.; Desvarieux, Moise [Department of Epidemiology, Mailman School of Public Health, Columbia University, New York City, NY (United States); and others

    2014-05-01

    Epidemiologic studies that evaluated genetic susceptibility for the effects of arsenic exposure from drinking water on subclinical atherosclerosis are limited. We conducted a cross-sectional study of 1078 participants randomly selected from the Health Effects of Arsenic Longitudinal Study in Bangladesh to evaluate whether the association between arsenic exposure and carotid artery intima–media thickness (cIMT) differs by 207 single-nucleotide polymorphisms (SNPs) in 18 genes related to arsenic metabolism, oxidative stress, inflammation, and endothelial dysfunction. Although not statistically significant after correcting for multiple testing, nine SNPs in APOE, AS3MT, PNP, and TNF genes had a nominally statistically significant interaction with well-water arsenic in cIMT. For instance, the joint presence of a higher level of well-water arsenic (≥ 40.4 μg/L) and the GG genotype of AS3MT rs3740392 was associated with a difference of 40.9 μm (95% CI = 14.4, 67.5) in cIMT, much greater than the difference of cIMT associated with the genotype alone (β = − 5.1 μm, 95% CI = − 31.6, 21.3) or arsenic exposure alone (β = 7.2 μm, 95% CI = − 3.1, 17.5). The pattern and magnitude of the interactions were similar when urinary arsenic was used as the exposure variable. Additionally, the at-risk genotypes of the AS3MT SNPs were positively related to the proportion of monomethylarsonic acid (MMA) in urine, which is indicative of arsenic methylation capacity. The findings provide novel evidence that genetic variants related to arsenic metabolism may play an important role in arsenic-induced subclinical atherosclerosis. Future replication studies in diverse populations are needed to confirm the findings. - Highlights: • Nine SNPs had a nominally significant interaction with well-water arsenic in cIMT. • Three SNPs in AS3MT showed nominally significant interactions with urinary arsenic. • cIMT was much higher among subjects with higher arsenic exposure and AS3MT

  11. Interaction between arsenic exposure from drinking water and genetic susceptibility in carotid intima–media thickness in Bangladesh

    International Nuclear Information System (INIS)

    Epidemiologic studies that evaluated genetic susceptibility for the effects of arsenic exposure from drinking water on subclinical atherosclerosis are limited. We conducted a cross-sectional study of 1078 participants randomly selected from the Health Effects of Arsenic Longitudinal Study in Bangladesh to evaluate whether the association between arsenic exposure and carotid artery intima–media thickness (cIMT) differs by 207 single-nucleotide polymorphisms (SNPs) in 18 genes related to arsenic metabolism, oxidative stress, inflammation, and endothelial dysfunction. Although not statistically significant after correcting for multiple testing, nine SNPs in APOE, AS3MT, PNP, and TNF genes had a nominally statistically significant interaction with well-water arsenic in cIMT. For instance, the joint presence of a higher level of well-water arsenic (≥ 40.4 μg/L) and the GG genotype of AS3MT rs3740392 was associated with a difference of 40.9 μm (95% CI = 14.4, 67.5) in cIMT, much greater than the difference of cIMT associated with the genotype alone (β = − 5.1 μm, 95% CI = − 31.6, 21.3) or arsenic exposure alone (β = 7.2 μm, 95% CI = − 3.1, 17.5). The pattern and magnitude of the interactions were similar when urinary arsenic was used as the exposure variable. Additionally, the at-risk genotypes of the AS3MT SNPs were positively related to the proportion of monomethylarsonic acid (MMA) in urine, which is indicative of arsenic methylation capacity. The findings provide novel evidence that genetic variants related to arsenic metabolism may play an important role in arsenic-induced subclinical atherosclerosis. Future replication studies in diverse populations are needed to confirm the findings. - Highlights: • Nine SNPs had a nominally significant interaction with well-water arsenic in cIMT. • Three SNPs in AS3MT showed nominally significant interactions with urinary arsenic. • cIMT was much higher among subjects with higher arsenic exposure and AS3MT

  12. Autism genetic database (AGD: a comprehensive database including autism susceptibility gene-CNVs integrated with known noncoding RNAs and fragile sites

    Directory of Open Access Journals (Sweden)

    Talebizadeh Zohreh

    2009-09-01

    Full Text Available Abstract Background Autism is a highly heritable complex neurodevelopmental disorder, therefore identifying its genetic basis has been challenging. To date, numerous susceptibility genes and chromosomal abnormalities have been reported in association with autism, but most discoveries either fail to be replicated or account for a small effect. Thus, in most cases the underlying causative genetic mechanisms are not fully understood. In the present work, the Autism Genetic Database (AGD was developed as a literature-driven, web-based, and easy to access database designed with the aim of creating a comprehensive repository for all the currently reported genes and genomic copy number variations (CNVs associated with autism in order to further facilitate the assessment of these autism susceptibility genetic factors. Description AGD is a relational database that organizes data resulting from exhaustive literature searches for reported susceptibility genes and CNVs associated with autism. Furthermore, genomic information about human fragile sites and noncoding RNAs was also downloaded and parsed from miRBase, snoRNA-LBME-db, piRNABank, and the MIT/ICBP siRNA database. A web client genome browser enables viewing of the features while a web client query tool provides access to more specific information for the features. When applicable, links to external databases including GenBank, PubMed, miRBase, snoRNA-LBME-db, piRNABank, and the MIT siRNA database are provided. Conclusion AGD comprises a comprehensive list of susceptibility genes and copy number variations reported to-date in association with autism, as well as all known human noncoding RNA genes and fragile sites. Such a unique and inclusive autism genetic database will facilitate the evaluation of autism susceptibility factors in relation to known human noncoding RNAs and fragile sites, impacting on human diseases. As a result, this new autism database offers a valuable tool for the research

  13. Genetic variants on 3q21 and in the Sp8 transcription factor gene (SP8 as susceptibility loci for psychotic disorders: a genetic association study.

    Directory of Open Access Journals (Sweden)

    Kenji Kondo

    Full Text Available BACKGROUND: Recent genome-wide association studies (GWASs investigating bipolar disorder (BD have detected a number of susceptibility genes. These studies have also provided novel insight into shared genetic components between BD and schizophrenia (SCZ, two major psychotic disorders. To examine the replication of the risk variants for BD and the pleiotropic effect of the variants associated with BD, we conducted a genetic association study of single nucleotide polymorphisms (SNPs that were selected based upon previous BD GWASs, which targeted psychotic disorders (BD and SCZ in the Japanese population. METHODS: Forty-eight SNPs were selected based upon previous GWASs. A two-stage analysis was conducted using first-set screening (for all SNPs: BD = 1,012, SCZ = 1,032 and control = 993 and second-set replication samples (for significant SNPs in the screening analysis: BD = 821, SCZ = 1,808 and control = 2,149. We assessed allelic association between BD, SCZ, psychosis (BD+SCZ and the SNPs selected for the analysis. RESULTS: Eight SNPs revealed nominal association signals for all comparisons (Puncorrected<0.05. Among these SNPs, the top two SNPs (associated with psychosis: Pcorrected = 0.048 and 0.037 for rs2251219 and rs2709722, respectively were further assessed in the second-set samples, and we replicated the signals from the initial screening analysis (associated with psychosis: Pcorrected = 0.0070 and 0.033 for rs2251219 and rs2709722, respectively. The meta-analysis between the current and previous GWAS results showed that rs2251219 in Polybromo1 (PBRM1 was significant on genome-wide association level (P = 5×10(-8 only for BD (P = 9.4×10(-9 and psychosis (P = 2.0×10(-10. Although the association of rs2709722 in Sp8 transcription factor (SP8 was suggestive in the Asian population (P = 2.1×10(-7 for psychosis, this signal weakened when the samples size was increased by including data from a

  14. Genetic variant in CD44 confer susceptibility to acute skin reaction in breast cancer patients undergoing radiotherapy

    International Nuclear Information System (INIS)

    Heterogeneity in toxicity to normal tissue is observed in 10% of cancer patients after radiotherapy (RT) which limits the therapeutic outcome. Response to RT is manifested from alterations in gene of vivid pathways involving DNA damage-repair, inflammatory cytokine, cell cycle regulation, antioxidant response etc. Therefore, the common sequence variants in these radioresponsive genes may modify the severity of normal tissue toxicity and identification of the same may have clinical relevance as a predictive biomarker. The present study was aimed to evaluate the potential modifying role of genetic variants in NFE2L2, OGG1, NEIL3, RAD17, PTTG1, REV3L, ALAD, CD44, RAD9A, LIG3, SH3GL1, BAXS, XRCC1, MAD2L2 and TGFBR3 on the individual susceptibility to RT induced acute skin reactions. All the 132 breast cancer patients were treated with a total dose of 50 Gy in case of mastectomy and 60 Gy in breast conservation surgery. The severity of skin damage was scored according to the Radiation Therapy Oncology Group (RTOG) criteria and the toxicity scores were dichotomized as non-over-responders (NOR; RTOG<2) and over-responders (NOR;RTOG>2) for analysis. Out of the 132 subjects, 44 were ORs. Among the 20 studied SNPs of indicated genes, the rs8193 (CD44) polymorphism lying in the miRNA binding site was significantly (p<0.05) associated with the RT induced adverse skin reactions. The non-coding CD44 3'-UTR serves as a competitor for miRNA binding and subsequently inactivates miRNA functions, by freeing the target mRNAs from being repressed. Therefore, though the role of CD44 in radiosensitivity is unknown, the change in the miRNA binding to CD44mRNA transcripts may regulate expression of several genes involved in pathophysiology of normal tissue radiosensitivity leading to the observed outcome. (author)

  15. Genetic susceptibility for acute high altitude disease%急性高原病的遗传易感性

    Institute of Scientific and Technical Information of China (English)

    周文婷; 胡扬

    2013-01-01

    Acute high altitude disease(AHAD), which can be divided into acute mountain disease (AMS), high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE), is one of the special illnesses occurred at high altitude, commonly encountered by travelers to high altitudes (>2 500 m), which affects people's work capacity and health and could be even a life-threatening disease. Despite extensive investigations over the last century, the pathophysiology of AHAD remains elusive. Nevertheless, numerous researches have confirmed the existence of AHAD susceptibility differences. The aim of this paper was to review the epidemiological evidence for a genetic component to the various forms of AHAD so far, as well as to supply helpful reference to its epidemiological studies.%急性高原病(Acute high altitude disease,AHAD)分为急性高原反应、高原肺水肿和高原脑水肿,是高原特发病之一,在高原旅居者中(>2 500 m)具有高发生率,不仅影响人们的工作能力和健康,而且可能危及生命.尽管AHAD 的相关研究已开展百余年,其病理生理机制仍不明确,但大量研究已证实AHAD 存在易感性的差异.文章综述了迄今为止AHAD 的遗传易感性研究进展,以期为AHAD 的流行病学研究提供有益的参考资料.

  16. Genetic, epidemiological and biological analysis of interleukin-10 promoter single-nucleotide polymorphisms suggests a definitive role for -819C/T in leprosy susceptibility.

    Science.gov (United States)

    Pereira, A C; Brito-de-Souza, V N; Cardoso, C C; Dias-Baptista, I M F; Parelli, F P C; Venturini, J; Villani-Moreno, F R; Pacheco, A G; Moraes, M O

    2009-03-01

    Leprosy is a complex infectious disease influenced by genetic and environmental factors. The genetic contributing factors are considered heterogeneous and several genes have been consistently associated with susceptibility like PARK2, tumor necrosis factor (TNF), lymphotoxin-alpha (LTA) and vitamin-D receptor (VDR). Here, we combined a case-control study (374 patients and 380 controls), with meta-analysis (5 studies; 2702 individuals) and biological study to test the epidemiological and physiological relevance of the interleukin-10 (IL-10) genetic markers in leprosy. We observed that the -819T allele is associated with leprosy susceptibility either in the case-control or in the meta-analysis studies. Haplotypes combining promoter single-nucleotide polymorphisms also implicated a haplotype carrying the -819T allele in leprosy susceptibility (odds ratio (OR)=1.40; P=0.01). Finally, we tested IL-10 production in peripheral blood mononuclear cells stimulated with Mycobacterium leprae antigens and found that -819T carriers produced lower levels of IL-10 when compared with non-carriers. Taken together, these data suggest that low levels of IL-10 during the disease outcome can drive patients to a chronic and unprotective response that culminates with leprosy. PMID:19110537

  17. Genetic susceptibility to cancer

    International Nuclear Information System (INIS)

    The normal development and function of tissues are under the regulation of programmed expression of genes involved in the proliferation and differentiation. Tumor development can be identified as the abnormal or deregulated expression of such genes. Two distinct classes of genes have been implicated in cancer development; oncogenes and tumor-suppressor genes. Those genes are potential target for radiation carcinogenesis. However, contemporal view of mutations of oncogenes and tumor-suppressor genes in radiogenic and non-radiogenic human cancers do not match to the spectrum of radiation-induced mutation in the selected genes, and raise the question whether radiations are primarily responsible for the initiation of carcinogenesis by mutation of those genes as primary target. There is now a growing evidence for the radiation to stimulate cell growth, which is followed by suppression. Such stimulatory effects of radiation may evoke the growth-promoting and -suppressing genes, or oncogenes and tumor-suppressor genes. This may lead to a testable proposition that constitutively present gain-of-function mutations in oncogenes and/or loss-of-function mutations in tumor-suppressor genes, accumulated spontaneously or environmentally, may play a significant role in the radiation carcinogenesis. (author)

  18. Individual Genetic Susceptibility

    Energy Technology Data Exchange (ETDEWEB)

    Eric J. Hall

    2008-12-08

    Risk estimates derived from epidemiological studies of exposed populations, as well as the maximum permissible doses allowed for occupational exposure and exposure of the public to ionizing radiation are all based on the assumption that the human population is uniform in its radiosensitivity, except for a small number of individuals, such as ATM homozygotes who are easily identified by their clinical symptoms. The hypothesis upon which this proposal is based is that the human population is not homogeneous in radiosensitiviry, but that radiosensitive sub-groups exist which are not easy to identify. These individuals would suffer an increased incidence of detrimental radiation effects, and distort the shape of the dose response relationship. The radiosensitivity of these groups depend on the expression levels of specific proteins. The plan was to investigate the effect of 3 relatively rare, high penetrate genes available in mice, namely Atm, mRad9 & Brca1. The purpose of radiation protection is to prevent! deterministic effects of clinical significance and limit stochastic effects to acceptable levels. We plan, therefore to compare with wild type animals the radiosensitivity of mice heterozygous for each of the genes mentioned above, as well as double heterozygotes for pairs of genes, using two biological endpoints: a) Ocular cataracts as an important and relevant deterministic effect, and b) Oncogenic transformation in cultured embryo fibroblasts, as a surrogate for carcinogenesis, the most relevant stochastic effect.

  19. Individual Genetic Susceptibility

    International Nuclear Information System (INIS)

    Risk estimates derived from epidemiological studies of exposed populations, as well as the maximum permissible doses allowed for occupational exposure and exposure of the public to ionizing radiation are all based on the assumption that the human population is uniform in its radiosensitivity, except for a small number of individuals, such as ATM homozygotes who are easily identified by their clinical symptoms. The hypothesis upon which this proposal is based is that the human population is not homogeneous in radiosensitiviry, but that radiosensitive sub-groups exist which are not easy to identify. These individuals would suffer an increased incidence of detrimental radiation effects, and distort the shape of the dose response relationship. The radiosensitivity of these groups depend on the expression levels of specific proteins. The plan was to investigate the effect of 3 relatively rare, high penetrate genes available in mice, namely Atm, mRad9 and Brca1. The purpose of radiation protection is to prevent deterministic effects of clinical significance and limit stochastic effects to acceptable levels. We plan, therefore to compare with wild type animals the radiosensitivity of mice heterozygous for each of the genes mentioned above, as well as double heterozygotes for pairs of genes, using two biological endpoints: (a) Ocular cataracts as an important and relevant deterministic effect, and (b) Oncogenic transformation in cultured embryo fibroblasts, as a surrogate for carcinogenesis, the most relevant stochastic effect.

  20. Genetic variation in bacterial kidney disease (BKD) susceptibility in Lake Michigan Chinook Salmon and its progenitor population from the Puget Sound.

    Science.gov (United States)

    Purcell, Maureen K; Hard, Jeffrey J; Neely, Kathleen G; Park, Linda K; Winton, James R; Elliott, Diane G

    2014-03-01

    Mass mortality events in wild fish due to infectious diseases are troubling, especially given the potential for long-term, population-level consequences. Evolutionary theory predicts that populations with sufficient genetic variation will adapt in response to pathogen pressure. Chinook Salmon Oncorhynchus tshawytscha were introduced into Lake Michigan in the late 1960s from a Washington State hatchery population. In the late 1980s, collapse of the forage base and nutritional stress in Lake Michigan were thought to contribute to die-offs of Chinook Salmon due to bacterial kidney disease (BKD). Previously, we demonstrated that Lake Michigan Chinook Salmon from a Wisconsin hatchery have greater survival following BKD challenge relative to their progenitor population. Here, we evaluated whether the phenotypic divergence of these populations in BKD susceptibility was due to selection rather than genetic drift. Comparison of the overall magnitude of quantitative trait to neutral marker divergence between the populations suggested selection had occurred but a direct test of quantitative trait divergence was not significant, preventing the rejection of the null hypothesis of differentiation through genetic drift. Estimates of phenotypic variation (VP ), additive genetic variation (VA ) and narrow-sense heritability (h (2)) were consistently higher in the Wisconsin relative to the Washington population. If selection had acted on the Wisconsin population there was no evidence of a concomitant loss of genetic variation in BKD susceptibility. The Renibacterium salmoninarum exposures were conducted at both 14°C and 9°C; the warmer temperature accelerated time to death in both populations and there was no evidence of phenotypic plasticity or a genotype-by-environment (G × E) interaction. High h (2) estimates for BKD susceptibility in the Wisconsin population, combined with a lack of phenotypic plasticity, predicts that future adaptive gains in BKD resistance are still

  1. MHC Expression on Spleen Lymphocyte Subsets in Genetically Resistant and Susceptible Chickens Infected with Marek's Disease Virus

    DEFF Research Database (Denmark)

    Dalgaard, Tina; Bøving, Mette K.; Handberg, Kurt;

    2009-01-01

    Resistance and susceptibility to Marek's disease (MD) are strongly influenced by the chicken major histocompatibility complex (MHC). In this study, splenic lymphocytes from MD-resistant and MD-susceptible chickens of three MHC genotypes (B21/B21, B19/B21, and B19/B19) were analyzed by flow...

  2. Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology Of Parkinson’s Disease (GEO-PD) consortium

    Science.gov (United States)

    Heckman, Michael G.; Soto-Ortolaza, Alexandra I.; Aasly, Jan O.; Abahuni, Nadine; Annesi, Grazia; Bacon, Justin A.; Bardien, Soraya; Bozi, Maria; Brice, Alexis; Brighina, Laura; Carr, Jonathan; Chartier-Harlin, Marie-Christine; Dardiotis, Efthimios; Dickson, Dennis W.; Diehl, Nancy N.; Elbaz, Alexis; Ferrarese, Carlo; Fiske, Brian; Gibson, J. Mark; Gibson, Rachel; Hadjigeorgiou, Georgios M.; Hattori, Nobutaka; Hentati, Faycal; Ioannidis, John P.A.; Boczarska-Jedynak, Magdalena; Jasinska-Myga, Barbara; Jeon, Beom S.; Kim, Yun Joong; Klein, Christine; Kruger, Rejko; Kyratzi, Elli; Lesage, Suzanne; Lin, Chin-Hsien; Lynch, Timothy; Maraganore, Demetrius M.; Mellick, George D.; Mutez, Eugénie; Nilsson, Christer; Opala, Grzegorz; Park, Sung Sup; Petrucci, Simona; Puschmann, Andreas; Quattrone, Aldo; Sharma, Manu; Silburn, Peter A.; Sohn, Young Ho; Stefanis, Leonidas; Tadic, Vera; Theuns, Jessie; Tomiyama, Hiroyuki; Uitti, Ryan J.; Valente, Enza Maria; Van Broeckhoven, Christine; van de Loo, Simone; Vassilatis, Demetrios K.; Vilariño-Güell, Carles; White, Linda R.; Wirdefeldt, Karin; Wszolek, Zbigniew K.; Wu, Ruey-Meei; Farrer, Matthew J.; Ross, Owen A.

    2014-01-01

    Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson’s disease. Leucine-rich repeat kinase 2 variation related to susceptibility to disease displays many features that reflect the nature of complex late-onset sporadic disorders, such as Parkinson’s disease. The Genetic Epidemiology of Parkinson’s disease consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. Herein we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) reported in the original publication. Simple population allele frequencies can not only provide an insight into the clinical relevance of specific variants but also help genetically define patient groups. Establishing individual patient-based genomic susceptibility profiles incorporating both risk and protective factors will determine future diagnostic and treatment strategies. PMID:23913756

  3. Characteristics of mRNA levels of hepatic key enzymes in cholesterol metabolism of genetically gallstone-susceptible mice

    Institute of Scientific and Technical Information of China (English)

    许国强; 赵力

    2004-01-01

    @@ Our previous study1 indicated that biliary cholesterol hypersecretion was the key pathophysiological defect of gallstone formation. Lith genes determine biliary cholesterol hypersecretion and susceptibility to cholesterol gallstone formation in C57L mice.

  4. Genetics of oxacillin resistance in clinical isolates of Streptococcus pneumoniae that are oxacillin resistant and penicillin susceptible.

    OpenAIRE

    Dowson, C G; Johnson, A P; Cercenado, E.; George, R C

    1994-01-01

    It has recently been reported that penicillin-sensitive pneumococci may exhibit reduced susceptibility to oxacillin, resulting in their misclassification as being penicillin resistant by oxacillin disk testing. Intermediate oxacillin resistance (MIC, 1.0 microgram/ml) in three of these apparently unrelated penicillin-susceptible clinical isolates of Streptococcus pneumoniae isolated in the United Kingdom and in four Spanish isolates was shown to be solely due to the acquisition of a gene enco...

  5. A Genome-Wide Test of the Differential Susceptibility Hypothesis Reveals a Genetic Predictor of Differential Response to Psychological Treatments for Child Anxiety Disorders

    DEFF Research Database (Denmark)

    Keers, Robert; Coleman, Jonathan R I; Lester, Kathryn J;

    2016-01-01

    BACKGROUND: The differential susceptibly hypothesis suggests that certain genetic variants moderate the effects of both negative and positive environments on mental health and may therefore be important predictors of response to psychological treatments. Nevertheless, the identification of such...... variants has so far been limited to preselected candidate genes. In this study we extended the differential susceptibility hypothesis from a candidate gene to a genome-wide approach to test whether a polygenic score of environmental sensitivity predicted response to cognitive behavioural therapy (CBT) in...... children with anxiety disorders. METHODS: We identified variants associated with environmental sensitivity using a novel method in which within-pair variability in emotional problems in 1,026 monozygotic twin pairs was examined as a function of the pairs' genotype. We created a polygenic score of...

  6. Genetic variants in toll-like receptors are not associated with rheumatoid arthritis susceptibility or anti-tumour necrosis factor treatment outcome.

    Directory of Open Access Journals (Sweden)

    Marieke J H Coenen

    Full Text Available BACKGROUND: Several studies point to a role of Toll-like receptors (TLRs in the development of rheumatoid arthritis (RA. We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (anti-TNF medication. METHODOLOGY AND PRINCIPAL FINDINGS: 22 single nucleotide polymorphisms (SNPs in seven TLR genes were genotyped in a Dutch cohort consisting of 378 RA patients and 294 controls. Significantly associated variants were investigated in replication cohorts from The Netherlands, United Kingdom and Sweden (2877 RA patients and 2025 controls. 182 of the Dutch patients were treated with anti-TNF medication. Using these patients and a replication cohort (269 Swedish patients we analysed if genetic variants in TLR genes were associated with anti-TNF outcome. In the discovery phase of the study we found a significant association of SNPs rs2072493 in TLR5 and rs3853839 in TLR7 with RA disease susceptibility. Meta-analysis of discovery and replication cohorts did not confirm these findings. SNP rs2072493 in TLR5 was associated with anti-TNF outcome in the Dutch but not in the Swedish population. CONCLUSION: We conclude that genetic variants in TLRs do not play a major role in susceptibility for developing RA nor in anti-TNF treatment outcome in a Caucasian population.

  7. Genetic Variants of Retinoic Acid Receptor-Related Orphan Receptor Alpha Determine Susceptibility to Type 2 Diabetes Mellitus in Han Chinese

    Science.gov (United States)

    Zhang, Yuwei; Liu, Yulan; Liu, Yin; Zhang, Yanjie; Su, Zhiguang

    2016-01-01

    Retinoic acid receptor-related orphan receptor alpha (RORA) plays a key role in the regulation of lipid and glucose metabolism and insulin expression that are implicated in the development of type 2 diabetes mellitus (T2DM). However, the effects of genetic variants in the RORA gene on the susceptibility to T2DM remain unknown. Nine tagging single-nucleotide polymorphisms (SNPs) were screened by using the SNaPshot method in 427 patients with T2DM and 408 normal controls. Association between genotypes and haplotypes derived from these SNPs with T2DM was analyzed using different genetic models. Allele and genotype frequencies at rs10851685 were significantly different between T2DM patients and control subjects (allele: p = 0.009, Odds ratios (OR) = 1.36 [95% Confidence intervals (CI) = 1.08–1.72]; genotype: p = 0.029). The minor allele T, at rs10851685, was potentially associated with an increased risk of T2DM in the dominant model, displaying OR of 1.38 (95% CI: 1.04–1.82, p = 0.025) in subjects with genotypes TA+TT vs. AA. In haplotype analysis, we observed that haplotypes GGTGTAACT, GGTGTAACC, and GATATAACT were significantly associated with increased risk of T2DM, while haplotypes GATGAAGTT, AGTGAAGTT, and AATGAAATT were protective against T2DM. These data suggest that the genetic variation in RORA might determine a Chinese Han individual’s susceptibility to T2DM. PMID:27556492

  8. Genetic Variants of Retinoic Acid Receptor-Related Orphan Receptor Alpha Determine Susceptibility to Type 2 Diabetes Mellitus in Han Chinese.

    Science.gov (United States)

    Zhang, Yuwei; Liu, Yulan; Liu, Yin; Zhang, Yanjie; Su, Zhiguang

    2016-01-01

    Retinoic acid receptor-related orphan receptor alpha (RORA) plays a key role in the regulation of lipid and glucose metabolism and insulin expression that are implicated in the development of type 2 diabetes mellitus (T2DM). However, the effects of genetic variants in the RORA gene on the susceptibility to T2DM remain unknown. Nine tagging single-nucleotide polymorphisms (SNPs) were screened by using the SNaPshot method in 427 patients with T2DM and 408 normal controls. Association between genotypes and haplotypes derived from these SNPs with T2DM was analyzed using different genetic models. Allele and genotype frequencies at rs10851685 were significantly different between T2DM patients and control subjects (allele: p = 0.009, Odds ratios (OR) = 1.36 [95% Confidence intervals (CI) = 1.08-1.72]; genotype: p = 0.029). The minor allele T, at rs10851685, was potentially associated with an increased risk of T2DM in the dominant model, displaying OR of 1.38 (95% CI: 1.04-1.82, p = 0.025) in subjects with genotypes TA+TT vs. AA. In haplotype analysis, we observed that haplotypes GGTGTAACT, GGTGTAACC, and GATATAACT were significantly associated with increased risk of T2DM, while haplotypes GATGAAGTT, AGTGAAGTT, and AATGAAATT were protective against T2DM. These data suggest that the genetic variation in RORA might determine a Chinese Han individual's susceptibility to T2DM. PMID:27556492

  9. Reversal of Refractory Ulcerative Colitis and Severe Chronic Fatigue Syndrome Symptoms Arising from Immune Disturbance in an HLADR/DQ Genetically Susceptible Individual with Multiple Biotoxin Exposures

    Science.gov (United States)

    Gunn, Shelly R.; Gibson Gunn, G.; Mueller, Francis W.

    2016-01-01

    Patient: Male, 25 Final Diagnosis: Ulcerative colitis and chronic fatigue syndrome Symptoms: Colitis • profound fatigue • multi-joint pain • cognitive impairment • corneal keratitis Medication: — Clinical Procedure: VIP replacement therapy Specialty: Family Medicine Objective: Unusual clinical course Background: Patients with multisymptom chronic conditions, such as refractory ulcerative colitis (RUC) and chronic fatigue syndrome (CFS), present diagnostic and management challenges for clinicians, as well as the opportunity to recognize and treat emerging disease entities. In the current case we report reversal of co-existing RUC and CFS symptoms arising from biotoxin exposures in a genetically susceptible individual. Case Report: A 25-year-old previously healthy male with new-onset refractory ulcerative colitis (RUC) and chronic fatigue syndrome (CFS) tested negative for autoimmune disease biomarkers. However, urine mycotoxin panel testing was positive for trichothecene group and air filter testing from the patient’s water-damaged rental house identified the toxic mold Stachybotrys chartarum. HLA-DR/DQ testing revealed a multisusceptible haplotype for development of chronic inflammation, and serum chronic inflammatory response syndrome (CIRS) biomarker testing was positive for highly elevated TGF-beta and a clinically undetectable level of vasoactive intestinal peptide (VIP). Following elimination of biotoxin exposures, VIP replacement therapy, dental extractions, and implementation of a mind body intervention-relaxation response (MBI-RR) program, the patient’s symptoms resolved. He is off medications, back to work, and resuming normal exercise. Conclusions: This constellation of RUC and CFS symptoms in an HLA-DR/DQ genetically susceptible individual with biotoxin exposures is consistent with the recently described CIRS disease pathophysiology. Chronic immune disturbance (turbatio immuno) can be identified with clinically available CIRS biomarkers and

  10. Reversal of Refractory Ulcerative Colitis and Severe Chronic Fatigue Syndrome Symptoms Arising from Immune Disturbance in an HLA-DR/DQ Genetically Susceptible Individual with Multiple Biotoxin Exposures.

    Science.gov (United States)

    Gunn, Shelly R; Gunn, G Gibson; Mueller, Francis W

    2016-01-01

    BACKGROUND Patients with multisymptom chronic conditions, such as refractory ulcerative colitis (RUC) and chronic fatigue syndrome (CFS), present diagnostic and management challenges for clinicians, as well as the opportunity to recognize and treat emerging disease entities. In the current case we report reversal of co-existing RUC and CFS symptoms arising from biotoxin exposures in a genetically susceptible individual. CASE REPORT A 25-year-old previously healthy male with new-onset refractory ulcerative colitis (RUC) and chronic fatigue syndrome (CFS) tested negative for autoimmune disease biomarkers. However, urine mycotoxin panel testing was positive for trichothecene group and air filter testing from the patient's water-damaged rental house identified the toxic mold Stachybotrys chartarum. HLA-DR/DQ testing revealed a multisusceptible haplotype for development of chronic inflammation, and serum chronic inflammatory response syndrome (CIRS) biomarker testing was positive for highly elevated TGF-beta and a clinically undetectable level of vasoactive intestinal peptide (VIP). Following elimination of biotoxin exposures, VIP replacement therapy, dental extractions, and implementation of a mind body intervention-relaxation response (MBI-RR) program, the patient's symptoms resolved. He is off medications, back to work, and resuming normal exercise. CONCLUSIONS This constellation of RUC and CFS symptoms in an HLA-DR/DQ genetically susceptible individual with biotoxin exposures is consistent with the recently described CIRS disease pathophysiology. Chronic immune disturbance (turbatio immuno) can be identified with clinically available CIRS biomarkers and may represent a treatable underlying disease etiology in a subset of genetically susceptible patients with RUC, CFS, and other immune disorders. PMID:27165859

  11. The effects of selective breeding against scrapie susceptibility on the genetic variability of the Latxa Black-Faced sheep breed

    OpenAIRE

    Legarra Andrés; Parada Analia; Alfonso Leopoldo; Ugarte Eva; Arana Ana

    2006-01-01

    Abstract Breeding sheep populations for scrapie resistance could result in a loss of genetic variability. In this study, the effect on genetic variability of selection for increasing the ARR allele frequency was estimated in the Latxa breed. Two sources of information were used, pedigree and genetic polymorphisms (fifteen microsatellites). The results based on the genealogical information were conditioned by a low pedigree completeness level that revealed the interest of also using the inform...

  12. An X chromosome association scan of the Norfolk Island genetic isolate provides evidence for a novel migraine susceptibility locus at Xq12.

    Directory of Open Access Journals (Sweden)

    Bridget H Maher

    Full Text Available Migraine is a common and debilitating neurovascular disorder with a complex envirogenomic aetiology. Numerous studies have demonstrated a preponderance of women affected with migraine and previous pedigree linkage studies in our laboratory have identified susceptibility loci on chromosome Xq24-Xq28. In this study we have used the genetic isolate of Norfolk Island to further analyse the X chromosome for migraine susceptibility loci.An association approach was employed to analyse 14,124 SNPs spanning the entire X chromosome. Genotype data from 288 individuals comprising a large core-pedigree, of which 76 were affected with migraine, were analysed. Although no SNP reached chromosome-wide significance (empirical α = 1 × 10(-5 ranking by P-value revealed two primary clusters of SNPs in the top 25. A 10 SNP cluster represents a novel migraine susceptibility locus at Xq12 whilst a 11 SNP cluster represents a previously identified migraine susceptibility locus at Xq27. The strongest association at Xq12 was seen for rs599958 (OR = 1.75, P = 8.92 × 10(-4, whilst at Xq27 the strongest association was for rs6525667 (OR = 1.53, P = 1.65 × 10(-4. Further analysis of SNPs at these loci was performed in 5,122 migraineurs from the Women's Genome Health Study and provided additional evidence for association at the novel Xq12 locus (P<0.05.Overall, this study provides evidence for a novel migraine susceptibility locus on Xq12. The strongest effect SNP (rs102834, joint P = 1.63 × 10(-5 is located within the 5'UTR of the HEPH gene, which is involved in iron homeostasis in the brain and may represent a novel pathway for involvement in migraine pathogenesis.

  13. Association between brain-derived neurotrophic factor genetic polymorphism Val66Met and susceptibility to bipolar disorder: a meta-analysis

    OpenAIRE

    Wang, Zuowei; Li, Zezhi; Gao, Keming; Fang, Yiru

    2014-01-01

    Background In view of previous conflicting findings, this meta-analysis was performed to comprehensively determine the overall strength of associations between brain-derived neurotrophic factor (BDNF) genetic polymorphism Val66Met and susceptibility to bipolar disorders (BPD). Methods Literatures published and cited in Pubmed and Wanfang Data was searched with terms of ‘Val66Met’, ‘G196A’, ‘rs6265’, ‘BDNF’, ‘association’, and ‘bipolar disorder’ up to March 2014. All original case–control asso...

  14. Direct-to-consumer genetic testing for addiction susceptibility: a premature commercialisation of doubtful validity and value.

    Science.gov (United States)

    Mathews, Rebecca; Hall, Wayne; Carter, Adrian

    2012-12-01

    Genetic research on addiction liability and pharmacogenetic research on treatments for addiction have identified some genetic variants associated with disease risk and treatment. Genetic testing for addiction liability and treatment response has not been used widely in clinical practice because most of the genes identified only modestly predict addiction risk or treatment response. However, many of these genetic tests have been commercialized prematurely and are available direct to the consumer (DTC). The easy availability of DTC tests for addiction liability and lack of regulation over their use raises a number of ethical concerns. Of paramount concern is the limited predictive power and clinical utility of these tests. Many DTC testing companies do not provide the consumer with the necessary genetic counselling to assist them in interpreting and acting on their test results. They may also engage in misleading marketing to entice consumers to purchase their products. Consumers' genetic information may be vulnerable to misuse by third parties, as there are limited standards to protect the privacy of the genetic information. Non-consensual testing and inappropriate testing of minors may also occur. The United States Food and Drug Administration plans to regulate DTC genetic tests. Based on the ethical concerns we discuss below, we believe there is a strong case for regulation of DTC genetic tests for addiction liability and treatment response. We argue that until this occurs, these tests have more potential to cause harm than to contribute to improved prevention and treatment of addiction. PMID:22510165

  15. Obesity genomics: assessing the transferability of susceptibility loci across diverse populations.

    Science.gov (United States)

    Lu, Yingchang; Loos, Ruth Jf

    2013-01-01

    The prevalence of obesity has nearly doubled worldwide over the past three decades, but substantial differences exist between nations. Although these differences are partly due to the degree of westernization, genetic factors also contribute. To date, little is known about whether the same genes contribute to obesity-susceptibility in populations of different ancestry. We review the transferability of obesity-susceptibility loci (identified by genome-wide association studies) using both single nucleotide polymorphism (SNP) and locus-wide comparisons. SNPs in FTO and near MC4R, obesity-susceptibility loci first identified in Europeans, replicate widely across other ancestries. SNP-to-SNP comparisons suggest that more than half of the 36 body mass index-associated loci are shared across European and East Asian ancestry populations, whereas locus-wide analyses suggest that the transferability might be even more extensive. Furthermore, by taking advantage of differences in haplotype structure, populations of different ancestries can help to narrow down loci, thereby pinpointing causal genes for functional follow-up. Larger-scale genetic association studies in ancestrally diverse populations will be needed for in-depth and locus-wide analyses aimed at determining, with greater confidence, the transferability of loci and allowing fine-mapping. Understanding similarities and differences in genetic susceptibility across populations of diverse ancestries might eventually contribute to a more targeted prevention and customized treatment of obesity. PMID:23806069

  16. Genetic variation between susceptible and non-susceptible snails to Schistosoma infection using random amplified polymorphic DNA analysis (RAPDs Variação genética entre moluscos susceptíveis e não susceptíveis à infecção pelo Schistosoma através da análise do DNA polimórfico amplificado aleatóriamente (RAPDs

    Directory of Open Access Journals (Sweden)

    Abdel-Hamid Zaki ABDEL-HAMID

    1999-09-01

    Full Text Available Susceptibility of snails to infection by certain trematodes and their suitability as hosts for continued development has been a bewildering problem in host-parasite relationships. The present work emphasizes our interest in snail genetics to determine what genes or gene products are specifically responsible for susceptibility of snails to infection. High molecular weight DNA was extracted from both susceptible and non-susceptible snails within the same species Biomphalaria tenagophila. RAPD was undertaken to distinguish between the two types of snails. Random primers (10 mers were used to amplify the extracted DNA by the polymerase chain reaction (PCR followed by polyacrylamide gel electrophoresis (PAGE and silver staining. The results suggest that RAPD represents an efficient means of genome comparison, since many molecular markers were detected as genetic variations between susceptible and non-susceptible snails.A susceptibilidade de moluscos à infecção por certos trematódeos e a sua capacidade como hospedeiro para o contínuo desenvolvimento é o problema mais deslumbrante nas relações parasita hospedeiro. O presente trabalho, focaliza nosso interesse na genética dos moluscos para determinar quais genes ou produtos gênicos são especificamente responsáveis pela susceptibilidade do molusco à infecção. DNA de alto peso molecular, foi extraído de ambos moluscos susceptíveis e não susceptíveis da espécie Biomphalaria tenagophila. Iniciadores aleatórios com 10 pares de bases foram usados na amplificação aleatória (RAPD de ambos os DNAs e análise por eletroforese em gel de poliacrilamida e coloração com prata. Os resultados mostram que a amplificação aleatória do DNA representa um eficiente caminho para a comparação dos genomas desde que marcadores moleculares foram detectados como variantes genéticos entre os moluscos susceptíveis e não susceptíveis.

  17. Thyroid cancer GWAS identifies 10q26.12 and 6q14.1 as novel susceptibility loci and reveals genetic heterogeneity among populations.

    Science.gov (United States)

    Mancikova, Veronika; Cruz, Raquel; Inglada-Pérez, Lucía; Fernández-Rozadilla, Ceres; Landa, Iñigo; Cameselle-Teijeiro, José; Celeiro, Catuxa; Pastor, Susana; Velázquez, Antonia; Marcos, Ricard; Andía, Victor; Álvarez-Escolá, Cristina; Meoro, Amparo; Schiavi, Francesca; Opocher, Giuseppe; Quintela, Inés; Ansede-Bermejo, Juan; Ruiz-Ponte, Clara; Santisteban, Pilar; Robledo, Mercedes; Carracedo, Angel

    2015-10-15

    Thyroid cancer is the most heritable cancer of all those not displaying typical Mendelian inheritance. However, most of the genetic factors that would explain the high heritability remain unknown. Our aim was to identify additional common genetic variants associated with susceptibility to this disease. In order to do so, we performed a genome-wide association study in a series of 398 cases and 502 controls from Spain, followed by a replication in four well-defined Southern European case-control collections contributing a total of 1,422 cases and 1,908 controls. The association between the variation at the 9q22 locus near FOXE1 and thyroid cancer risk was consistent across all series, with several SNPs identified (rs7028661: OR = 1.64, p = 1.0 × 10(-22) , rs7037324: OR = 1.54, p = 1.2 × 10(-17) ). Moreover, the rare alleles of three SNPs (rs2997312, rs10788123 and rs1254167) at 10q26.12 showed suggestive evidence of association with higher risk of the disease (OR = 1.35, p = 1.2 × 10(-04) , OR = 1.26, p = 5.2 × 10(-04) and OR = 1.38, p = 5.9 × 10(-05) , respectively). Finally, the rare allele of rs4075570 at 6q14.1 conferred protection in the series studied (OR = 0.82, p = 2.0 × 10(-04) ). This study suggests that heterogeneity in genetic susceptibility between populations is a key feature to take into account when exploring genetic risk factors related to this disease. PMID:25855579

  18. Genetic and sexual separation between insect resistant and susceptible Barbarea vulgaris plants in Denmark

    DEFF Research Database (Denmark)

    Toneatto, Fiorello; Nielsen, Jens Kvist; Ørgaard, Marian;

    2010-01-01

    cruciferous plant Barbarea vulgaris, some Danish individuals are resistant to herbivory by flea beetles (Phyllotreta nemorum), whereas others are not. The flea beetles are, in parallel, either resistant or susceptible to the plants defenses. To understand the historical-evolutionary framework of these...

  19. Reconstruction of ancestral protein sequences and its applications

    Directory of Open Access Journals (Sweden)

    Grishin Nick V

    2004-09-01

    Full Text Available Abstract Background Modern-day proteins were selected during long evolutionary history as descendants of ancient life forms. In silico reconstruction of such ancestral protein sequences facilitates our understanding of evolutionary processes, protein classification and biological function. Additionally, reconstructed ancestral protein sequences could serve to fill in sequence space thus aiding remote homology inference. Results We developed ANCESCON, a package for distance-based phylogenetic inference and reconstruction of ancestral protein sequences that takes into account the observed variation of evolutionary rates between positions that more precisely describes the evolution of protein families. To improve the accuracy of evolutionary distance estimation and ancestral sequence reconstruction, two approaches are proposed to estimate position-specific evolutionary rates. Comparisons show that at large evolutionary distances our method gives more accurate ancestral sequence reconstruction than PAML, PHYLIP and PAUP*. We apply the reconstructed ancestral sequences to homology inference and functional site prediction. We show that the usage of hypothetical ancestors together with the present day sequences improves profile-based sequence similarity searches; and that ancestral sequence reconstruction methods can be used to predict positions with functional specificity. Conclusions As a computational tool to reconstruct ancestral protein sequences from a given multiple sequence alignment, ANCESCON shows high accuracy in tests and helps detection of remote homologs and prediction of functional sites. ANCESCON is freely available for non-commercial use. Pre-compiled versions for several platforms can be downloaded from ftp://iole.swmed.edu/pub/ANCESCON/.

  20. Genetic variants and increased expression of Parascaris equorum P-glycoprotein-11 in populations with decreased ivermectin susceptibility.

    Directory of Open Access Journals (Sweden)

    I Jana I Janssen

    Full Text Available Macrocyclic lactones (MLs represent the major drug class for control of parasitic infections in humans and animals. However, recently reports of treatment failures became more frequent. In addition to human and ruminant parasitic nematodes this also is the case for the horse-nematode Parascaris equorum. Nevertheless, to date the molecular basis of ML resistance is still not understood. Unspecific resistance mechanisms involving transporters such as P-glycoproteins (Pgps are expected to contribute to ML resistance in nematodes. Here, complete sequences of two P. equorum Pgps were cloned and identified as orthologs of Caenorhabditis elegans Ppg-11 and an unnamed Caenorhabditis briggsae Pgp designated as Pgp-16 using phylogenetic analysis. Quantitative real-time PCR was used to compare expression between tissues. Significantly higher PeqPgp-11 expression was found in the gut for both genders, whereas for PeqPgp-16 the body wall was identified as predominant expression site. Furthermore, Pgps were analyzed regarding their participation in resistance development. Using SeqDoC analyses, Pgp-sequences of P. equorum populations with different ML susceptibility were compared. This approach revealed three single nucleotide polymorphisms (SNPs causing missense mutations in the PeqPgp-11 sequence which correlated with decreased ML susceptibility. However, no resistance associated differences in mRNA expression levels were detected between embryonated eggs of these populations. In contrast, comparison of two pre-adult groups with different ivermectin (IVM susceptibility revealed the presence of the three SNPs and in addition statistically significant PeqPgp-11 overexpression in the group of worms with reduced susceptibility. These results indicate that Pgp-11 might be involved in IVM resistance in P. equorum as it shows increased expression in an IVM exposed life-cycle stage of an IVM resistant population as well as occurrence of putatively resistance

  1. Genetic association of GWAS-supported MAD1L1 gene polymorphism rs12666575 with schizophrenia susceptibility in a Chinese population.

    Science.gov (United States)

    Su, Li; Shen, Tingting; Huang, Guifeng; Long, Jianxiong; Fan, Jingyuan; Ling, Weijun; Jiang, Juan

    2016-01-01

    Schizophrenia (SCZ) is a severe neuropsychiatric disorder with high heritability. A recent European genome-wide association study has reported that mitotic arrest deficient-like 1 (MAD1L1) polymorphism rs12666575 is associated with SCZ susceptibility. This study aims to test the association of MAD1L1 variant rs12666575 with SCZ susceptibility in a Chinese population. A total of 1400 participants, which include 700 SCZ patients and 700 sex- and age-matched controls (Zhuang: 300, Han: 400, respectively), were genotyped using the Sequenom MassARRAY iPLEX platform. 591 SCZ patients underwent positive and negative syndrome scale (PANSS) assessment. Genetic association analysis was performed using the PLINK program. The results showed MAD1L1 rs12666575 polymorphism was significantly associated with SCZ susceptibility in the recessive model (p(adj)=0.013). Also, rs12666575 was significantly associated with general psychopathology sub-scale score (p(adj)=0.043) and thought disturbance factor score (p(adj)=0.045). Our data suggested that MAD1L1 rs12666575 polymorphism may play a protective role against SCZ in the Chinese population. Furthermore, rs12666575 may be associated with general psychopathology and thought disturbance in SCZ patients. PMID:26528791

  2. Ancestral informative marker selection and population structure visualization using sparse Laplacian eigenfunctions.

    Directory of Open Access Journals (Sweden)

    Jun Zhang

    Full Text Available Identification of a small panel of population structure informative markers can reduce genotyping cost and is useful in various applications, such as ancestry inference in association mapping, forensics and evolutionary theory in population genetics. Traditional methods to ascertain ancestral informative markers usually require the prior knowledge of individual ancestry and have difficulty for admixed populations. Recently Principal Components Analysis (PCA has been employed with success to select SNPs which are highly correlated with top significant principal components (PCs without use of individual ancestral information. The approach is also applicable to admixed populations. Here we propose a novel approach based on our recent result on summarizing population structure by graph laplacian eigenfunctions, which differs from PCA in that it is geometric and robust to outliers. Our approach also takes advantage of the priori sparseness of informative markers in the genome. Through simulation of a ring population and the real global population sample HGDP of 650K SNPs genotyped in 940 unrelated individuals, we validate the proposed algorithm at selecting most informative markers, a small fraction of which can recover the similar underlying population structure efficiently. Employing a standard Support Vector Machine (SVM to predict individuals' continental memberships on HGDP dataset of seven continents, we demonstrate that the selected SNPs by our method are more informative but less redundant than those selected by PCA. Our algorithm is a promising tool in genome-wide association studies and population genetics, facilitating the selection of structure informative markers, efficient detection of population substructure and ancestral inference.

  3. Genetic Polymorphisms of TGFB1, TGFBR1, SNAI1 and TWIST1 Are Associated with Endometrial Cancer Susceptibility in Chinese Han Women

    Science.gov (United States)

    Yang, Li; Wang, Ya-Jun; Zheng, Li-Yuan; Jia, Yu-Mian; Chen, Yi-Lin; Chen, Lan; Liu, Dong-Ge; Li, Xiang-Hong; Guo, Hong-Yan; Sun, Ying-Li; Tian, Xin-Xia; Fang, Wei-Gang

    2016-01-01

    Endometrial cancer (EC) is a complex disease involving multiple gene-gene and gene–environment interactions. TGF-β signaling plays pivotal roles in EC development. This study aimed to investigate whether the genetic polymorphisms of TGF-β signaling related genes TGFB1, TGFBR1, SNAI1 and TWIST1 contribute to EC susceptibility. Using the TaqMan Genotyping Assay, 19 tagging-SNPs of these four genes were genotyped in 516 EC cases and 707 controls among Chinese Han women. Logistic regression (LR) showed that the genetic variants of TGFB1 rs1800469, TGFBR1 rs6478974 and rs10733710, TWIST1 rs4721745 were associated with decreased EC risk, and these four loci showed a dose-dependent effect (Ptrend pregnancy intervals (˃11 years) and BMI˂24 (aOR = 0.39, 95% CI = 0.17–0.90, P = 0.0275). These results suggest that polymorphisms in TGFB1, TGFBR1, SNAI1 and TWIST1 may modulate EC susceptibility, both separately and corporately. PMID:27171242

  4. High levels of fish oil enhance neutrophil development and activation and influence colon mucus barrier function in a genetically susceptible mouse model.

    Science.gov (United States)

    Duriancik, David M; Comstock, Sarah S; Langohr, Ingeborg M; Fenton, Jenifer I

    2015-11-01

    Dietary fatty acids influence immunologic homeostasis, but their effect on initiation of colitis, an immune-mediated disease, is not well established. Previously, our laboratory demonstrated that high doses of dietary fish oil (FO) increased colon inflammation and dysplasia in a model of infection-induced colitis. In the current study, we assessed the effects of high-dose dietary FO, 6% by weight, on colon inflammation, neutrophil recruitment and function, and mucus layer integrity in a genetically susceptible, colitis-prone mouse model in the absence of infection. FO-fed SMAD3(-/-) mice had increased colon inflammation evidenced by increased numbers of systemic and local neutrophils and increased neutrophil chemoattractant and inflammatory cytokine gene expression in the colon. Mucus layer thickness in the cecum and goblet cell numbers in the cecum and colon in FO-fed mice were reduced compared to control. FO consumption affected colitis in male and female mice differently. Compared to female control mice, neutrophils from FO-fed female mice had reduced reactive oxygen species (ROS) upon ex vivo stimulation with phorbol myristate acetate while FO-fed male mice produced increased ROS compared to control-fed male mice. In summary, dietary FO impaired mucus layer integrity and was associated with colon inflammation characterized by increased neutrophil numbers and altered neutrophil function. High-dose FO may have detrimental effects in populations genetically susceptible for inflammatory bowel disease and these effects may differ between males and females. PMID:26297475

  5. Genetic susceptibility to chronic wasting disease in free-ranging white-tailed deer: complement component C1q and Prnp polymorphisms

    Science.gov (United States)

    Blanchong, Julie A.; Heisey, Dennis M.; Scribner, Kim T.; Libants, Scot V.; Johnson, Chad; Aiken, Judd M.; Langenberg, Julia A.; Samuel, Michael D.

    2009-01-01

    The genetic basis of susceptibility to chronic wasting disease (CWD) in free-ranging cervids is of great interest. Association studies of disease susceptibility in free-ranging populations, however, face considerable challenges including: the need for large sample sizes when disease is rare, animals of unknown pedigree create a risk of spurious results due to population admixture, and the inability to control disease exposure or dose. We used an innovative matched case–control design and conditional logistic regression to evaluate associations between polymorphisms of complement C1q and prion protein (Prnp) genes and CWD infection in white-tailed deer from the CWD endemic area in south-central Wisconsin. To reduce problems due to admixture or disease-risk confounding, we used neutral genetic (microsatellite) data to identify closely related CWD-positive (n = 68) and CWD-negative (n = 91) female deer to serve as matched cases and controls. Cases and controls were also matched on factors (sex, location, age) previously demonstrated to affect CWD infection risk. For Prnp, deer with at least one Serine (S) at amino acid 96 were significantly less likely to be CWD-positive relative to deer homozygous for Glycine (G). This is the first characterization of genes associated with the complement system in white-tailed deer. No tests for association between any C1q polymorphism and CWD infection were significant at p < 0.05. After controlling for Prnp, we found weak support for an elevated risk of CWD infection in deer with at least one Glycine (G) at amino acid 56 of the C1qC gene. While we documented numerous amino acid polymorphisms in C1q genes none appear to be strongly associated with CWD susceptibility.

  6. Impact of the Method of G6PD Deficiency Assessment on Genetic Association Studies of Malaria Susceptibility

    OpenAIRE

    Johnson, Marla K.; Clark, Tamara D; Njama-Meya, Denise; Rosenthal, Philip J.; Parikh, Sunil

    2009-01-01

    Background Clinical association studies have yielded varied results regarding the impact of glucose-6-phosphate dehydrogenase (G6PD) deficiency upon susceptibility to malaria. Analyses have been complicated by varied methods used to diagnose G6PD deficiency. Methodology/Prinicipal Findings We compared the association between uncomplicated malaria incidence and G6PD deficiency in a cohort of 601 Ugandan children using two different diagnostic methods, enzyme activity and G6PD genotype (G202A, ...

  7. Vascular endothelial growth factor genetic polymorphisms and susceptibility to age-related macular degeneration in Tunisian population

    OpenAIRE

    Habibi, Imen; Sfar, Imen; Chebil, Ahmed; Kort, Fedra; Bouraoui, Rim; Jendoubi-Ayed, Salwa; Makhlouf, Mouna; Abdallah, Taïeb Ben; El Matri, Leila; Gorgi, Yousr

    2014-01-01

    Purpose Three VEGF SNPs (−2578) C/A, (+405) G/C and (+936) C/T were investigated in Tunisian exudative AMD patients in order to determine their association with the disease susceptibility and their influence to intravitreal bevacizumab therapy response. Methods 145 AMD patients and 207 age-matched controls were included. 68 patients were treated with intravitreal bevacizumab. SNPs genotyping were performed using direct sequencing. The serum VEGF was assayed by ELISA (R&D). Results The (+405) ...

  8. MBL2 Genetic Variants in HCV Infection Susceptibility, Spontaneous Viral Clearance and Pegylated Interferon Plus Ribavirin Treatment Response.

    Science.gov (United States)

    Zupin, L; Polesello, V; Alberi, G; Moratelli, G; Crocè, S L; Masutti, F; Pozzato, G; Crovella, S; Segat, L

    2016-07-01

    Hepatitis C is disease that damages the liver, and it is caused by the hepatitis C virus (HCV). The pathology became chronic in about 80% of the cases due to virus persistence in the host organism. The standard of care consists of pegylated interferon plus ribavirin; however, the treatment response is very variable and different host/viral factors may concur in the disease outcome. The mannose-binding protein C (MBL) is a component of the innate immune system, able to recognize HCV and consecutively activating the immune response. MBL is encoded by MBL2 gene, and polymorphisms, two in the promoter region (H/L and X/Y) and three in exon 1 (at codon 52, 54 and 57), have been described as functionally influencing protein expression. In this work, 203 Italian HCV patients and 61 healthy controls were enrolled and genotyped for the five MBL2 polymorphisms mentioned above to investigate their role in HCV infection susceptibility, spontaneous viral clearance and treatment response. MBL2 polymorphisms were not associated with HCV infection susceptibility and with spontaneous viral clearance, while MBL2 O allele, O/O genotype, HYO haplotype and DP combined genotype (all correlated with low or deficient MBL expression) were associated with sustained virological response. Moreover, a meta-analysis to assess the role of MBL2 polymorphisms in HCV infection susceptibility was also performed: YA haplotype could be associated with protection towards HCV infection. PMID:27136459

  9. Genetic susceptibility to S. aureus mastitis in sheep: differential expression of mammary epithelial cells in response to live bacteria or supernatant.

    Science.gov (United States)

    Bonnefont, Cécile M D; Rainard, Pascal; Cunha, Patricia; Gilbert, Florence B; Toufeer, Mehdi; Aurel, Marie-Rose; Rupp, Rachel; Foucras, Gilles

    2012-04-01

    Staphylococcus aureus is a prevalent pathogen for mastitis in dairy ruminants and is responsible for both clinical and subclinical mastitis. Mammary epithelial cells (MEC) represent not only a physical barrier against bacterial invasion but are also active players of the innate immune response permitting infection clearance. To decipher their functions in general and in animals showing different levels of genetic predisposition to Staphylococcus in particular, MEC from ewes undergoing a divergent selection on milk somatic cell count were stimulated by S. aureus. MEC response was also studied according to the stimulation condition with live bacteria or culture supernatant. The early MEC response was studied during a 5 h time course by microarray to identify differentially expressed genes with regard to the host genetic background and as a function of the conditions of stimulation. In both conditions of stimulation, metabolic processes were altered, the apoptosis-associated pathways were considerably modified, and inflammatory and immune responses were enhanced with the upregulation of il1a, il1b, and tnfa and several chemokines known to enhance neutrophil (cxcl8) or mononuclear leukocyte (ccl20) recruitment. Genes associated with oxidative stress were increased after live bacteria stimulation, whereas immune response-related genes were higher after supernatant stimulation in the early phase. Only 20 genes were differentially expressed between Staphylococcus spp-mastitis resistant and susceptible animals without any clearly defined role on the control of infection. To conclude, this suggests that MEC may not represent the cell type at the origin of the difference of mastitis susceptibility, at least as demonstrated in our genetic model. Supernatant or heat-killed S. aureus produce biological effects that are essentially different from those induced by live bacteria. PMID:22337903

  10. Polymorphisms and Plasma Levels of Tissue Inhibitor of Metalloproteinase-3: Impact on Genetic Susceptibility and Clinical Outcome of Oral Cancer.

    Science.gov (United States)

    Su, Chun-Wen; Huang, Yi-Wen; Chen, Mu-Kuan; Su, Shih-Chi; Yang, Shun-Fa; Lin, Chiao-Wen

    2015-11-01

    Oral cancer, the fourth most common cancer among men in Taiwan, is associated with environmental carcinogens. Tissue inhibitor of metalloproteinase-3 (TIMP3), a member of the TIMP family, is the only protein that binds to the extracellular matrix for suppressing cancer cell growth, angiogenesis, migration, and invasion. The association of TIMP3 polymorphism with oral cancer susceptibility, however, has not yet been reported. In this study, 1947 participants-1200 healthy male controls and 747 male patients with oral cancer-were recruited. Allelic discrimination of TIMP3 -1296 T > C (rs9619311), TIMP3 C > T (rs9862), and TIMP3 C > T (rs11547635) polymorphisms were assessed through real-time polymerase chain reaction. The authors discovered that individuals carrying the polymorphic rs9862 allele are more susceptible to oral cancer [odds ratio (OR), 1.5; 95% confidence interval (CI), 1.2-1.9; adjusted OR (AOR), 1.6; 95% CI, 1.2-2.1] after adjustment for betel quid chewing, alcohol, and tobacco consumption. Among 601 betel quid chewers, the TIMP3 polymorphism rs9862 T/T carriers had a 32.2-fold (95% CI, 20.2-51.3) increased oral cancer risk compared with those carrying C/C and not chewing betel quid. In addition, the authors observed a significant association between rs9862 variants and large tumors (OR, 1.5; 95% CI, 1.0-2.3) development. Moreover, TIMP3 plasma levels significantly increased in oral cancer patients who have large tumor or carry T allele rs9862 polymorphism. In conclusion, these results suggest that gene-environment interactions between the TIMP3 rs9862 polymorphisms and betel quid may alter oral cancer susceptibility and tumor growth in Taiwanese men. PMID:26579821

  11. Differential susceptibility of transgenic mice expressing human surfactant protein B genetic variants to Pseudomonas aeruginosa induced pneumonia.

    Science.gov (United States)

    Ge, Lin; Liu, Xinyu; Chen, Rimei; Xu, Yongan; Zuo, Yi Y; Cooney, Robert N; Wang, Guirong

    2016-01-01

    Surfactant protein B (SP-B) is essential for lung function. Previous studies have indicated that a SP-B 1580C/T polymorphism (SNP rs1130866) was associated with lung diseases including pneumonia. The SNP causes an altered N-linked glycosylation modification at Asn129 of proSP-B, e.g. the C allele with this glycosylation site but not in the T allele. This study aimed to generate humanized SP-B transgenic mice carrying either SP-B C or T allele without a mouse SP-B background and then examine functional susceptibility to bacterial pneumonia in vivo. A total of 18 transgenic mouse founders were generated by the DNA microinjection method. These founders were back-crossed with SP-B KO mice to eliminate mouse SP-B background. Four founder lines expressing similar SP-B levels to human lung were chosen for further investigation. After intratracheal infection with 50 μl of Pseudomonas aeruginosa solution (1 × 10(6) CFU/mouse) or saline in SP-B-C, SP-B-T mice the mice were sacrificed 24 h post-infection and tissues were harvested. Analysis of surfactant activity revealed differential susceptibility between SP-B-C and SP-B-T mice to bacterial infection, e.g. higher minimum surface tension in infected SP-B-C versus infected SP-B-T mice. These results demonstrate for the first time that human SP-B C allele is more susceptible to bacterial pneumonia than SP-B T allele in vivo. PMID:26620227

  12. Molecular Basis for Genetic Resistance of Anopheles gambiae to Plasmodium: Structural Analysis of TEP1 Susceptible and Resistant Alleles

    OpenAIRE

    Le, Binh V.; Williams, Marni; Logarajah, Shankar; Baxter, Richard H. G.

    2012-01-01

    Thioester-containing protein 1 (TEP1) is a central component in the innate immune response of Anopheles gambiae to Plasmodium infection. Two classes of TEP1 alleles, TEP1*S and TEP1*R, are found in both laboratory strains and wild isolates, related by a greater or lesser susceptibility, respectively to both P. berghei and P. falciparum infection. We report the crystal structure of the full-length TEP1*S1 allele which, while similar to the previously determined structure of full-length TEP1*R1...

  13. Effect of genetic background and diet on plasma fibrinogen in mice. Possible relation with susceptibility to atherosclerosis

    NARCIS (Netherlands)

    Rezaee, F.; Maas, A.; Maat, M.P.M.de; Verheijen, J.H.; Koopman, J.

    2002-01-01

    Many epidemiological studies suggest that elevated plasma fibrinogen concentrations form one of the most important independent risk factors in blood for cardiovascular disease and particularly atherosclerosis in humans. To clarify the effect of genetic factors, diets and their interactions on plasma

  14. An integrated epigenetic and genetic analysis of DNA methyltransferase genes (DNMTs) in tumor resistant and susceptible chicken lines

    Science.gov (United States)

    Both epigenetic alterations and genetic variations play essential roles in tumorigenesis. The epigenetic modification of DNA methylation is catalyzed and maintained by the DNA methyltransferases (DNMT3a, DNMT3b and DNMT1). DNA mutations and DNA methylation profiles of DNMTs themselves and their rela...

  15. Long-Term Immunity to Lethal Acute or Chronic Type II Toxoplasma gondii Infection Is Effectively Induced in Genetically Susceptible C57BL/6 Mice by Immunization with an Attenuated Type I Vaccine Strain▿

    OpenAIRE

    Gigley, Jason P.; Fox, Barbara A.; Bzik, David J.

    2009-01-01

    C57BL/6 (B6) mice are genetically highly susceptible to chronic type II Toxoplasma gondii infections that invariably cause lethal toxoplasmic encephalitis. We examined the ability of an attenuated type I vaccine strain to elicit long-term immunity to lethal acute or chronic type II infections in susceptible B6 mice. Mice immunized with the type I cps1-1 vaccine strain were not susceptible to a lethal (100-cyst) challenge with the type II strain ME49. Immunized mice challenged with 10 ME49 cys...

  16. Genetics

    Science.gov (United States)

    ... Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers ... The chromosomes are made up of strands of genetic information called DNA. Each chromosome contains sections of ...

  17. Genetic and geographic structure of an insect resistant and a susceptible type of Barbarea vulgaris in western Europe

    DEFF Research Database (Denmark)

    Hauser, Thure Pavlo; Toneatto, Fiorello; Nielsen, Jens Kvist

    2012-01-01

    Abstract Interactions between herbivores and plants are believed to have been important drivers of biodiversity. However, to drive an initial resistance divergence into different evolutionary lineages and taxa, these interactions have probably been embedded in other processes of divergence, like...... allopatric isolation. The cruciferous plant Barbarea vulgaris ssp. arcuata occurs in Denmark in two types: one (G) is resistant to most genotypes of the flea beetle Phyllotreta nemorum, the other (P) is susceptible. The two types additionally differ in hairiness and glucosinolates, they are genetically...... strongly divergent, and reproduction between them is reduced. To determine whether the two plant types and their resistance polymorphisms are also present outside Denmark, and to understand how they have evolved, we analysed 33 European populations of B. vulgaris for resistance, hairiness, glucosinolates...

  18. Association of GST genetic polymorphisms with the susceptibility to hepatocellular carcinoma (HCC in Chinese population evaluated by an updated systematic meta-analysis.

    Directory of Open Access Journals (Sweden)

    Kui Liu

    Full Text Available BACKGROUND: Due to the possible involvement of Glutathione S-transferase Mu-1 (GSTM1 and Glutathione S-transferase theta-1 (GSTT1 in the detoxification of environmental carcinogens, environmental toxins, and oxidative stress products, genetic polymorphisms of these two genes may play important roles in the susceptibility of human being to hepatocellular carcinoma. However, the existing research results are not conclusive. METHODS: A systematic literature search using databases (PubMed, Scopus, Embase, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, Wanfang Data, etc. for the eligible studies meeting the inclusion criteria including case-control studies or cohort studies is evaluated using an updated systematic meta-analysis. RESULTS: Significant increase in the risk of HCC in the Chinese population is found in GSTM1 null genotype (OR = 1.47, 95% CI: 1.21 to 1.79, P<0.001 and GSTT1 null genotype (OR = 1.38, 95% CI: 1.14 to 1.65, P<0.001. Analysis using the random-effects model found an increased risk of HCC in GSTM1-GSTT1 dual null population (OR = 1.79, 95% CI: 1.26 to 2.53, P<0.001. In addition, subgroup analyses showed a significant increase in the association of GST genetic polymorphisms (GSTM1, GSTT1, and GSTM1-GSTT1 with HCC in southeast and central China mainland. However, available data collected by this study fail to show an association between GST genetic polymorphisms and HCC in people from the Taiwan region (for GSTM1: OR = 0.78, 95% CI: 0.60 to 1.01, P = 0.06; for GSTT1: OR = 0.94, 95% CI: 0.78 to 1.14, P = 0.546; for GSTM1-GSTT1: OR = 1.04, 95% CI: 0.81 to 1.32, P = 0.77. Sensitivity analysis and publication bias diagnostics confirmed the reliability and stability of this meta-analysis. CONCLUSIONS: Our results indicate that both GSTM1 and GSTT1 null genotypes are associated with an increased HCC risk in Chinese population. Peoples with dual null genotypes of GSTM1-GSTT1

  19. Population genetics of GYPB and association study between GYPB*S/s polymorphism and susceptibility to P. falciparum infection in the Brazilian Amazon.

    Directory of Open Access Journals (Sweden)

    Eduardo Tarazona-Santos

    Full Text Available BACKGROUND: Merozoites of Plasmodium falciparum invade through several pathways using different RBC receptors. Field isolates appear to use a greater variability of these receptors than laboratory isolates. Brazilian field isolates were shown to mostly utilize glycophorin A-independent invasion pathways via glycophorin B (GPB and/or other receptors. The Brazilian population exhibits extensive polymorphism in blood group antigens, however, no studies have been done to relate the prevalence of the antigens that function as receptors for P. falciparum and the ability of the parasite to invade. Our study aimed to establish whether variation in the GYPB*S/s alleles influences susceptibility to infection with P. falciparum in the admixed population of Brazil. METHODS: Two groups of Brazilian Amazonians from Porto Velho were studied: P. falciparum infected individuals (cases; and uninfected individuals who were born and/or have lived in the same endemic region for over ten years, were exposed to infection but have not had malaria over the study period (controls. The GPB Ss phenotype and GYPB*S/s alleles were determined by standard methods. Sixty two Ancestry Informative Markers were genotyped on each individual to estimate admixture and control its potential effect on the association between frequency of GYPB*S and malaria infection. RESULTS: GYPB*S is associated with host susceptibility to infection with P. falciparum; GYPB*S/GYPB*S and GYPB*S/GYPB*s were significantly more prevalent in the in the P. falciparum infected individuals than in the controls (69.87% vs. 49.75%; P<0.02. Moreover, population genetics tests applied on the GYPB exon sequencing data suggest that natural selection shaped the observed pattern of nucleotide diversity. CONCLUSION: Epidemiological and evolutionary approaches suggest an important role for the GPB receptor in RBC invasion by P. falciparum in Brazilian Amazons. Moreover, an increased susceptibility to infection by this

  20. Genetic analysis of the influence of neuroantigen-complete Freund's adjuvant emulsion structures on the sexual dimorphism and susceptibility to experimental allergic encephalomyelitis.

    Science.gov (United States)

    Fillmore, Parley D; Brace, Matthew; Troutman, Scott A; Blankenhorn, Elizabeth P; Diehl, Sean; Rincon, Mercedes; Teuscher, Cory

    2003-10-01

    The induction of organ-specific autoimmune diseases, such as experimental allergic encephalomyelitis (EAE) the principal animal model of multiple sclerosis (MS), relies on the use of complete Freund's adjuvant (CFA) emulsions. In this study we report that the physical structure of the particles comprising neuroantigen-CFA emulsions significantly influences the genetic control of the incidence and sexual dimorphism seen in EAE. Immunization of (B10.S/SgMcdJ x SJL/J) F(2) mice segregating the quantitative trait loci (QTL) controlling EAE in susceptible SJL/J and resistant B10.S/SgMcdJ mice with emulsions consisting of particles where the Mycobacterium tuberculosis and neuroantigens are localized on the phase surfaces led to severe EAE in 98.8% of the mice, overriding all sex-specific and non-sex-specific genetic checkpoints. In contrast, F(2) mice immunized with emulsions where the bacterial products and encephalitogens are buried inside the water/oil vesicles exhibited a significant reduction in disease incidence (7.5%) and a sexual dimorphism (5% male versus 10% female). A genome scan identified QTL on chromosomes 7 and 11 controlling the sexual dimorphism as a function of the physical structure of the emulsion. The chromosome 11 QTL co-localizes with eae6b, and with Il12b and heptatitis A virus cellular receptor 2 (Havcr2, formerly known as Timd3), both of which are candidate genes for this QTL. Sequence analysis of the SJL/J and B10.S/SgMcdJ alleles indicates that both gene products are structurally monomorphic. Expression analysis also excluded both as candidates for this sex-specific QTL. These results reinforce the importance of gene-environment interactions in initiating and propagating autoimmune disease of the central nervous system, particularly in the context of susceptibility to MS and disease heterogeneity. PMID:14507669

  1. Genetic Analysis of the Influence of Neuroantigen-Complete Freund’s Adjuvant Emulsion Structures on the Sexual Dimorphism and Susceptibility to Experimental Allergic Encephalomyelitis

    Science.gov (United States)

    Fillmore, Parley D.; Brace, Matthew; Troutman, Scott A.; Blankenhorn, Elizabeth P.; Diehl, Sean; Rincon, Mercedes; Teuscher, Cory

    2003-01-01

    The induction of organ-specific autoimmune diseases, such as experimental allergic encephalomyelitis (EAE) the principal animal model of multiple sclerosis (MS), relies on the use of complete Freund’s adjuvant (CFA) emulsions. In this study we report that the physical structure of the particles comprising neuroantigen-CFA emulsions significantly influences the genetic control of the incidence and sexual dimorphism seen in EAE. Immunization of (B10.S/SgMcdJ × SJL/J) F2 mice segregating the quantitative trait loci (QTL) controlling EAE in susceptible SJL/J and resistant B10.S/SgMcdJ mice with emulsions consisting of particles where the Mycobacterium tuberculosis and neuroantigens are localized on the phase surfaces led to severe EAE in 98.8% of the mice, overriding all sex-specific and non-sex-specific genetic checkpoints. In contrast, F2 mice immunized with emulsions where the bacterial products and encephalitogens are buried inside the water/oil vesicles exhibited a significant reduction in disease incidence (7.5%) and a sexual dimorphism (5% male versus 10% female). A genome scan identified QTL on chromosomes 7 and 11 controlling the sexual dimorphism as a function of the physical structure of the emulsion. The chromosome 11 QTL co-localizes with eae6b, and with Il12b and heptatitis A virus cellular receptor 2 (Havcr2, formerly known as Timd3), both of which are candidate genes for this QTL. Sequence analysis of the SJL/J and B10.S/SgMcdJ alleles indicates that both gene products are structurally monomorphic. Expression analysis also excluded both as candidates for this sex-specific QTL. These results reinforce the importance of gene-environment interactions in initiating and propagating autoimmune disease of the central nervous system, particularly in the context of susceptibility to MS and disease heterogeneity. PMID:14507669

  2. Do nuclear-encoded core subunits of mitochondrial complex I confer genetic susceptibility to schizophrenia in Han Chinese populations?

    OpenAIRE

    Xiao Li; Wen Zhang; Jinsong Tang; Liwen Tan; Xiong-jian Luo; Xiaogang Chen; Yong-Gang Yao

    2015-01-01

    Schizophrenia is one of the most prevalent psychiatric disorders with complex genetic etiology. Accumulating evidence suggests that energy metabolism and oxidative stress play important roles in the pathophysiology of schizophrenia. Dysfunction of mitochondrial respiratory chain and altered expression of complex I subunits were frequently reported in schizophrenia. To investigate whether nuclear-encoded core subunit genes of mitochondrial complex I are associated with schizophrenia, we perfor...

  3. Genetic Association and Gene Expression Analysis Identify FGFR1 as a New Susceptibility Gene for Human Obesity

    OpenAIRE

    Jiao, Hong; Arner, Peter; Dickson, Suzanne L.; Vidal, Hubert; Mejhert, Niklas; Henegar, Corneliu; Taube, Magdalena; Hansson, Caroline; Hinney, Anke; Galan, Pilar; Simon, Chantal; Silveira, Angela; Benrick, Anna; Jansson, John-Olov; Bouloumié, Anne

    2011-01-01

    Context: Previous studies suggest a role for fibroblast growth factor receptor 1 (FGFR1) in the regulation of energy balance. Objective: Our objective was to investigate whether FGFR1 is an obesity gene by genetic association and functional studies. Design: The study was designed to genotype common FGFR1 single-nucleotide polymorphisms (SNP) in large cohorts, confirm significant results in additional cohorts, and measure FGFR1 expression in human adipose tissue and in rodent hypothalamus. Set...

  4. C-reactive protein polymorphisms and genetic susceptibility to ischemic stroke and hemorrhagic stroke in the Chinese Han population

    OpenAIRE

    Wang, Qi; Ding, Hu; Tang, Jia-rong; Zhang, Lan; Xu, Yu-jun; Yan, Jiang-tao; Wang, Wei; Hui, Ru-tai; Wang, Cong-Yi; Wang, Dao-wen

    2009-01-01

    Aim: The inflammatory marker C-reactive protein (CRP) has been strongly correlated with the risk of cardiovascular disease. Some single-nucleotide polymorphisms (SNPs) have been reported to be associated with serum CRP levels. In this study, we assessed the genetic association between SNPs within the CRP gene and ischemic and hemorrhagic stroke in the Han Chinese population. Methods: This study comprises 564 ischemic stroke patients, 220 hemorrhagic stroke patients and 564 controls from the e...

  5. Where chloroquine still works: the genetic make-up and susceptibility of Plasmodium vivax to chloroquine plus primaquine in Bhutan

    OpenAIRE

    Wangchuk, Sonam; Drukpa, Tobgyel; Penjor, Kinley; Peldon, Tashi; Dorjey, Yeshey; Dorji, Kunzang; Chhetri, Vishal; Trimarsanto, Hidayat; To, Sheren; Murphy, Amanda; von Seidlein, Lorenz; Price, Ric N.; Thriemer, Kamala; Auburn, Sarah

    2016-01-01

    Background Bhutan has made substantial progress in reducing malaria incidence. The national guidelines recommend chloroquine (CQ) and primaquine (PQ) for radical cure of uncomplicated Plasmodium vivax, but the local efficacy has not been assessed. The impact of cases imported from India on the genetic make-up of the local vivax populations is currently unknown. Methods Patients over 4 years of age with uncomplicated P. vivax mono-infection were enrolled into a clinical efficacy study and mole...

  6. Longitudinal Pathways from Marital Hostility to Child Anger During Toddlerhood: Genetic Susceptibility and Indirect Effects via Harsh Parenting

    OpenAIRE

    Rhoades, Kimberly A.; Leve, Leslie D.; Harold, Gordon T.; Neiderhiser, Jenae M.; Shaw, Daniel S.; Reiss, David

    2011-01-01

    We examined direct and indirect pathways from marital hostility to toddler anger/frustration via harsh parenting and parental depressive symptoms, with an additional focus on the moderating role of genetic influences as inferred from birth parent anger/frustration. Participants were 361 linked triads of birth mothers, adoptive parents, and adopted children who were 9 (T1) and 18 (T2) months old across the study period. Results indicated an indirect effect from T1 marital hostility to T2 toddl...

  7. Genetic variation in the NBS1, MRE11, RAD50 and BLM genes and susceptibility to non-Hodgkin lymphoma

    OpenAIRE

    Gascoyne Randy D; Connors Joseph M; Gallagher Richard P; Lai Agnes S; Leach Stephen; MacArthur Amy C; Schuetz Johanna M; Spinelli John J; Brooks-Wilson Angela R

    2009-01-01

    Abstract Background Translocations are hallmarks of non-Hodgkin lymphoma (NHL) genomes. Because lymphoid cell development processes require the creation and repair of double stranded breaks, it is not surprising that disruption of this type of DNA repair can cause cancer. The members of the MRE11-RAD50-NBS1 (MRN) complex and BLM have central roles in maintenance of DNA integrity. Severe mutations in any of these genes cause genetic disorders, some of which are characterized by increased risk ...

  8. Genetic variants in microsomal epoxide hydrolase and N-acetyltransferase 2 in susceptibility of IBD in the Danish population

    DEFF Research Database (Denmark)

    Ernst, Anja; Andersen, Vibeke; Østergaard, Mette;

    induce or sustain an immune response. Changes in detoxification of substances that causes epithelial damage may confer susceptibility to IBD. Hence, polymorphic enzymes involved in the detoxification processes may be risk factors of IBD. Methods. The two biotransformation enzymes microsomal epoxide...... hydrolase and N-acetyltransferase 2 were genotyped using TaqMan based Real-Time PCR in 388 patients with Crohn's disease (CD), 565 patients with ulcerative colitis (UC) and 796 healthy Danish controls. Results. No association was found between low microsomal epoxide hydrolase activity or slow N......-acetyltransferase 2 acetylator status and IBD. An association between high activity of microsomal epoxide hydrolase and disease diagnosis before age 40 in CD with an OR of 2.2(1.1- 4.2) P=0.02) was found. No other phenotypic associations were found for the two enzymes and IBD, regarding age at onset, disease location...

  9. Reconstruction of ancestral protein sequences and its applications

    OpenAIRE

    Grishin Nick V; Pei Jimin; Cai Wei

    2004-01-01

    Abstract Background Modern-day proteins were selected during long evolutionary history as descendants of ancient life forms. In silico reconstruction of such ancestral protein sequences facilitates our understanding of evolutionary processes, protein classification and biological function. Additionally, reconstructed ancestral protein sequences could serve to fill in sequence space thus aiding remote homology inference. Results We developed ANCESCON, a package for distance-based phylogenetic ...

  10. Molecular paleontology: a biochemical model of the ancestral ribosome

    OpenAIRE

    Hsiao, Chiaolong; Lenz, Timothy K.; Peters, Jessica K; Fang, Po-Yu; Schneider, Dana M.; Anderson, Eric J.; Preeprem, Thanawadee; Bowman, Jessica C.; O'Neill, Eric B.; Lie, Lively; Athavale, Shreyas S.; Gossett, J. Jared; Trippe, Catherine; Murray, Jason; Anton S. Petrov

    2013-01-01

    Ancient components of the ribosome, inferred from a consensus of previous work, were constructed in silico, in vitro and in vivo. The resulting model of the ancestral ribosome presented here incorporates ∼20% of the extant 23S rRNA and fragments of five ribosomal proteins. We test hypotheses that ancestral rRNA can: (i) assume canonical 23S rRNA-like secondary structure, (ii) assume canonical tertiary structure and (iii) form native complexes with ribosomal protein fragments. Footprinting exp...

  11. Susceptibility Testing

    Science.gov (United States)

    ... page helpful? Also known as: Sensitivity Testing; Drug Resistance Testing; Culture and Sensitivity; C & S; Antimicrobial Susceptibility Formal name: Bacterial and Fungal Susceptibility Testing Related tests: Urine Culture ; ...

  12. Identification of genetic polymorphisms in DNA repair xenoderma pigmentosum group D gene and its association with head and neck cancer susceptibility in rural Indian population: a hospital based case-control study from south-western Maharashtra, India

    Directory of Open Access Journals (Sweden)

    Kailas D. Datkhile

    2016-06-01

    Conclusions: This study indicates that polymorphisms in cd199 of XPD gene could play a role in modifying genetic susceptibility of individual to head and neck cancer in Maharashtra patients. Thus, the case-control study suggest that selected DNA repair genes represent genetic determinants in oral carcinogenesis along with other risk factors in the rural Indian population. [Int J Res Med Sci 2016; 4(6.000: 1997-2005

  13. Interactive effect of genetic susceptibility with height, body mass index, and hormone replacement therapy on the risk of breast cancer

    Directory of Open Access Journals (Sweden)

    Harlid Sophia

    2012-06-01

    Full Text Available Abstract Background Breast cancer today has many established risk factors, both genetic and environmental, but these risk factors by themselves explain only part of the total cancer incidence. We have investigated potential interactions between certain known genetic and phenotypic risk factors, specifically nine single nucleotide polymorphisms (SNPs and height, body mass index (BMI and hormone replacement therapy (HRT. Methods We analyzed samples from three different study populations: two prospectively followed Swedish cohorts and one Icelandic case–control study. Totally 2884 invasive breast cancer cases and 4508 controls were analysed in the study. Genotypes were determined using Mass spectrometry-Maldi-TOF and phenotypic variables were derived from measurements and/or questionnaires. Odds Ratios and 95% confidence intervals were calculated using unconditional logistic regression with the inclusion of an interaction term in the logistic regression model. Results One SNP (rs851987 in ESR1 tended to interact with height, with an increasingly protective effect of the major allele in taller women (p = 0.007 and rs13281615 (on 8q24 tended to confer risk only in non users of HRT (p-for interaction = 0.03. There were no significant interactions after correction for multiple testing. Conclusions We conclude that much larger sample sets would be necessary to demonstrate interactions between low-risk genetic polymorphisms and the phenotypic variables height, BMI and HRT on the risk for breast cancer. However the present hypothesis-generating study has identified tendencies that would be of interest to evaluate for gene-environment interactions in independent materials.

  14. Genetic variants at 1q22 and 10q23 reproducibly associated with gastric cancer susceptibility in a Chinese population

    OpenAIRE

    Zhang, Hanze; Jin, Guangfu; Li, Huizhang; Ren, Chuanli; Ding, Yanbing; Zhang, Qin; Deng, Bin; Wang, Jianming; Hu, Zhibin; Xu, Yaochu; Shen, Hongbing

    2011-01-01

    Two recent genome-wide association studies reported significant associations of genetic variants at 1q22, 10q23 and 20p13 with gastric cancer (GC) risk in Chinese populations. However, these findings have not been confirmed in other independent studies. Here, we performed an independent case–control study in a Chinese population by genotyping three loci (rs4072037A>G at 1q22, rs2274223A>G at 10q23 and rs13042395C>T at 20p13) in 1681 GC cases and 1858 controls. We found that rs4072037 at 1q22 ...

  15. Analysis of Ancestral and Functionally Relevant CD5 Variants in Systemic Lupus Erythematosus Patients

    OpenAIRE

    Maria Carmen Cenit; Mario Martínez-Florensa; Marta Consuegra; Lizette Bonet; Elena Carnero-Montoro; Noelia Armiger; Miguel Caballero-Baños; Maria Teresa Arias; Daniel Benitez; Norberto Ortego-Centeno; Enrique de Ramón; José Mario Sabio; García-Hernández, Francisco J; Carles Tolosa; Ana Suárez

    2014-01-01

    Objective: CD5 plays a crucial role in autoimmunity and is a well-established genetic risk factor of developing RA. Recently, evidence of positive selection has been provided for the CD5 Pro224-Val471 haplotype in East Asian populations. The aim of the present work was to further analyze the functional relevance of non-synonymous CD5 polymorphisms conforming the ancestral and the newly derived haplotypes (Pro224-Ala471 and Pro224-Val471, respectively) as well as to investigate the potential r...

  16. Quantitative genetic study of maximal electroshock seizure threshold in mice: evidence for a major seizure susceptibility locus on distal chromosome 1.

    Science.gov (United States)

    Ferraro, T N; Golden, G T; Smith, G G; Longman, R L; Snyder, R L; DeMuth, D; Szpilzak, I; Mulholland, N; Eng, E; Lohoff, F W; Buono, R J; Berrettini, W H

    2001-07-01

    We conducted a quantitative trait locus (QTL) mapping study to dissect the multifactorial nature of maximal electroshock seizure threshold (MEST) in C57BL/6 (B6) and DBA/2 (D2) mice. MEST determination involved a standard paradigm in which 8- to 12-week-old mice received one shock per day with a daily incremental increase in electrical current until a maximal seizure (tonic hindlimb extension) was induced. Mean MEST values in parental strains were separated by over five standard deviation units, with D2 mice showing lower values than B6 mice. The distribution of MEST values in B6xD2 F2 intercrossed mice spanned the entire phenotypic range defined by parental strains. Statistical mapping yielded significant evidence for QTLs on chromosomes 1, 2, 5, and 15, which together explained over 60% of the phenotypic variance in the model. The chromosome 1 QTL represents a locus of major effect, accounting for about one-third of the genetic variance. Experiments involving a congenic strain (B6.D2-Mtv7(a)/Ty) enabled more precise mapping of the chromosome 1 QTL and indicate that it lies in the genetic interval between markers D1Mit145 and D1Mit17. These results support the hypothesis that the distal portion of chromosome 1 harbors a gene(s) that has a fundamental role in regulating seizure susceptibility. PMID:11472065

  17. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

    Science.gov (United States)

    Huang, Hailiang; Ng, Siew C; Alberts, Rudi; Takahashi, Atsushi; Ripke, Stephan; Lee, James C; Jostins, Luke; Shah, Tejas; Abedian, Shifteh; Cheon, Jae Hee; Cho, Judy; Dayani, Naser E; Franke, Lude; Fuyuno, Yuta; Hart, Ailsa; Juyal, Ramesh C; Juyal, Garima; Kim, Won Ho; Morris, Andrew P; Poustchi, Hossein; Newman, William G; Midha, Vandana; Orchard, Timothy R; Vahedi, Homayon; Sood, Ajit; Sung, Joseph Y; Malekzadeh, Reza; Westra, Harm-Jan; Yamazaki, Keiko; Yang, Suk-Kyun; Barrett, Jeffrey C; Alizadeh, Behrooz Z; Parkes, Miles; BK, Thelma; Daly, Mark J; Kubo, Michiaki; Anderson, Carl A; Weersma, Rinse K

    2016-01-01

    Ulcerative colitis and Crohn’s disease are the two main forms of inflammatory bowel disease (IBD). Here, we report the first trans-ethnic association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East-Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of IBD risk loci, the direction and magnitude of effect is consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by a combination of differences in allele frequencies (NOD2), effect sizes (TNFSF15, ATG16L1) or a combination of both (IL23R, IRGM). Our results provide biological insights into the pathogenesis of IBD, and demonstrate the utility of trans-ethnic association studies for mapping complex disease loci and understanding genetic architecture across diverse populations. PMID:26192919

  18. Genetic diversity of Aspergillus species isolated from onychomycosis and Aspergillus hongkongensis sp. nov., with implications to antifungal susceptibility testing.

    Science.gov (United States)

    Tsang, Chi-Ching; Hui, Teresa W S; Lee, Kim-Chung; Chen, Jonathan H K; Ngan, Antonio H Y; Tam, Emily W T; Chan, Jasper F W; Wu, Andrea L; Cheung, Mei; Tse, Brian P H; Wu, Alan K L; Lai, Christopher K C; Tsang, Dominic N C; Que, Tak-Lun; Lam, Ching-Wan; Yuen, Kwok-Yung; Lau, Susanna K P; Woo, Patrick C Y

    2016-02-01

    Thirteen Aspergillus isolates recovered from nails of 13 patients (fingernails, n=2; toenails, n=11) with onychomycosis were characterized. Twelve strains were identified by multilocus sequencing as Aspergillus spp. (Aspergillus sydowii [n=4], Aspergillus welwitschiae [n=3], Aspergillus terreus [n=2], Aspergillus flavus [n=1], Aspergillus tubingensis [n=1], and Aspergillus unguis [n=1]). Isolates of A. terreus, A. flavus, and A. unguis were also identifiable by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The 13th isolate (HKU49(T)) possessed unique morphological characteristics different from other Aspergillus spp. Molecular characterization also unambiguously showed that HKU49(T) was distinct from other Aspergillus spp. We propose the novel species Aspergillus hongkongensis to describe this previously unknown fungus. Antifungal susceptibility testing showed most Aspergillus isolates had low MICs against itraconazole and voriconazole, but all Aspergillus isolates had high MICs against fluconazole. A diverse spectrum of Aspergillus species is associated with onychomycosis. Itraconazole and voriconazole are probably better drug options for Aspergillus onychomycosis. PMID:26658315

  19. Mitochondrial DNA copy number, but not haplogroup, confers a genetic susceptibility to leprosy in Han Chinese from Southwest China.

    Directory of Open Access Journals (Sweden)

    Dong Wang

    Full Text Available BACKGROUND: Leprosy is a chronic infectious disease caused by Mycobacterium leprae, an unculturable pathogen with an exceptionally eroded genome. The high level of inactivation of gene function in M. leprae, including many genes in its metabolic pathways, has led to a dependence on host energy production and nutritional products. We hypothesized that host cellular powerhouse--the mitochondria--may affect host susceptibility to M. leprae and the onset of clinical leprosy, and this may be reflected by mitochondrial DNA (mtDNA background and mtDNA copy number. METHODS: We analyzed the mtDNA sequence variation of 534 leprosy patients and 850 matched controls from Yunnan Province and classified each subject by haplogroup. mtDNA copy number, taken to be proportional to mtDNA content, was measured in a subset of these subjects (296 patients and 231 controls and 12 leprosy patients upon diagnosis. RESULTS: Comparison of matrilineal components of the case and control populations revealed no significant difference. However, measurement of mtDNA copy number showed that lepromatous leprosy patients had a significantly higher mtDNA content than controls (P = 0.008. Past medical treatments had no effect on the alteration of mtDNA copy number. CONCLUSIONS: Our results suggested that mtDNA content, but not haplogroup, affects leprosy and this influence is limited to the clinical subtype of lepromatous leprosy.

  20. Genetic polymorphism of CCL2-2510 and susceptibility to enterovirus 71 encephalitis in a Chinese population.

    Science.gov (United States)

    Han, Zhen-liang; Li, Ji-an; Chen, Zong-bo

    2014-09-01

    The study was performed in 36 Chinese patients with enterovirus 71 (EV71) encephalitis and 141 patients with EV71-related hand, foot and mouth disease (HFMD) without encephalitis. Genotyping was done by the polymerase chain reaction-restriction fragment length polymorphism technique. Patients with EV71 encephalitis had a significantly higher frequency of the CCL2-2510GG genotypes when compared to patients with EV71-related HFMD without encephalitis (66.7% vs. 41.8%, p=0.028). The frequency of CCL2-2510G alleles was also significantly higher among the patients with EV71 encephalitis than among patients with EV71-related HFMD without encephalitis (79.2% vs. 64.9%, OR=2.1, 95% CI=1.1-3.8, P=0.023). Significant differences were found in gender, age, fever days, white blood cell count, C-reactive protein level, blood glucose concentration, and CCL2 level among genotypes of CCL2-2510A/G in EV71-infected patients, but no significant differences were found in alanine aminotransferase, aspartate aminotransferase, or creatine kinase myocardial isozyme levels or in cerebrospinal fluid evaluations (except monocytes) in patients with EV71 encephalitis. These findings suggest that the CCL2-2510G allele is associated with susceptibility to EV71 encephalitis in Chinese patients. PMID:24788844

  1. Cancer Genetics Services Directory

    Science.gov (United States)

    ... Prevention Overview–for health professionals Research NCI Cancer Genetics Services Directory This directory lists professionals who provide services related to cancer genetics (cancer risk assessment, genetic counseling, genetic susceptibility testing, ...

  2. Genetic variants in insulin-like growth factor binding protein-3 are associated with prostate cancer susceptibility in Eastern Chinese Han men

    Directory of Open Access Journals (Sweden)

    Zhang G

    2015-12-01

    : This study suggests that IGFBP-3 genetic variants are significantly associated with PCa risk in the Chinese population. Keywords: IGFBP-3, polymorphism, case-control study, genetic susceptibility

  3. Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study

    DEFF Research Database (Denmark)

    Milne, Roger L; Gaudet, Mia M; Spurdle, Amanda B;

    2010-01-01

    Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the...... Breast Cancer Association Consortium....

  4. Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study

    DEFF Research Database (Denmark)

    Milne, Roger L; Gaudet, Mia M; Spurdle, Amanda B;

    2010-01-01

    Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in th...

  5. Genetic polymorphisms of GSTM1,GSTP1 and GSTT1 genes and lung cancer susceptibility in the Bangladeshi population

    Institute of Scientific and Technical Information of China (English)

    Mir; Muhammad; Nasir; Uddin; Maizbha; Uddin; Ahmed; Mohammad; Safiqul; Islam; Mohammad; Siddiqul; Islam; Muhammad; Shahdaat; Bin; Sayeed; Yearul; Kabir; Abul; Hasnat

    2014-01-01

    Objective:To verify possible associations between polymorphisms of glutathione S-transferase Mu(GSTM1),glutathione S-transferase θ(GSTT1) and glutathione S-transferase Pi(GSTP1)genes and susceptibility to lung cancer.Methods:A total of 106 lung cancer patients and 116 controls were enrolled in a case-control study.The GSTM1 and GSTT1 were analyzed using PCR while GSTP1 was analyzed using PCR-restriction fragment length polymorphism.Risk of lung cancer was estimated as odds ratio at 95%confidence interval using unconditional logistic regression models adjusting for age,sex,and tobacco use.Results:GSTM1 null and GSTT1 null genotypes did not show a significant risk for developing lung cancer.A significandy elevated lung cancer risk was associated with GSTP1 heterozygous,mutant and combined heterozygous+mutant variants of rs1695.When classified by tobacco consumption status,no association with risk of lung cancer was found in case of tobacco smokers and nonsmokers carrying null and present genotypes of GSTM1 and GSTTL There is a three-fold(approximately) increase in the risk of lung cancer in case of both heterozygous(AG) and heterozygous+mutant homozygous(AG+GG) genotypes whereas there is an eightfold increase in risk of lung cancer in cases of GG with respect to AA genotype in smokers.Conclusions:Carrying the GSTM1 and GSTT1 null genotype is not a risk factor for lung cancer and GSTP1Ile105 Val is associated with elevated risk of lung cancer.

  6. Genetic polymorphisms of GSTM1, GSTP1 and GSTT1 genes and lung cancer susceptibility in the Bangladeshi population

    Institute of Scientific and Technical Information of China (English)

    Mir Muhammad Nasir Uddin; Maizbha Uddin Ahmed; Mohammad Safiqul Islam; Mohammad Siddiqul Islam; Muhammad Shahdaat Bin Sayeed; Yearul Kabir; Abul Hasnat

    2014-01-01

    To verify possible associations between polymorphisms of glutathione S-transferase Mu (GSTM1), glutathione S-transferase θ (GSTT1) and glutathione S-transferase Pi (GSTP1) genes and susceptibility to lung cancer. Methods: A total of 106 lung cancer patients and 116 controls were enrolled in a case-control study. The GSTM1 and GSTT1 were analyzed using PCR while GSTP1 was analyzed using PCR-restriction fragment length polymorphism. Risk of lung cancer was estimated as odds ratio at 95% confidence interval using unconditional logistic regression models adjusting for age, sex, and tobacco use. Results: GSTM1 null and GSTT1 null genotypes did not show a significant risk for developing lung cancer. A significantly elevated lung cancer risk was associated with GSTP1 heterozygous, mutant and combined heterozygous+mutant variants of rs1695. When classified by tobacco consumption status, no association with risk of lung cancer was found in case of tobacco smokers and nonsmokers carrying null and present genotypes of GSTM1 and GSTT1. There is a three-fold (approximately) increase in the risk of lung cancer in case of both heterozygous (AG) and heterozygous+mutant homozygous (AG+GG) genotypes whereas there is an eight-fold increase in risk of lung cancer in cases of GG with respect to AA genotype in smokers. Conclusions: Carrying the GSTM1 and GSTT1 null genotype is not a risk factor for lung cancer and GSTP1Ile105Val is associated with elevated risk of lung cancer.

  7. Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory.

    Science.gov (United States)

    Mitchell, Anna L; Dwyer, Andrew; Pitteloud, Nelly; Quinton, Richard

    2011-07-01

    Idiopathic hypogonadotropic hypogonadism (IHH) is defined by absent or incomplete puberty and characterised biochemically by low levels of sex steroids, with low or inappropriately normal gonadotropin hormones. IHH is frequently accompanied by non-reproductive abnormalities, most commonly anosmia, which is present in 50-60% of cases and defines Kallmann syndrome. The understanding of IHH has undergone rapid evolution, both in respect of genetics and breadth of phenotype. Once considered in monogenic Mendelian terms, it is now more coherently understood as a complex genetic condition. Oligogenic and complex genetic-environmental interactions have now been identified, with physiological and environmental factors interacting in genetically susceptible individuals to alter the clinical course and phenotype. These potentially link IHH to ancient evolutionary pressures on the ancestral human genome. PMID:21511493

  8. The mitochondrial genome structure of Xenoturbella bocki (phylum Xenoturbellida is ancestral within the deuterostomes

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    Lanfear Robert

    2009-05-01

    Full Text Available Abstract Background Mitochondrial genome comparisons contribute in multiple ways when inferring animal relationships. As well as primary sequence data, rare genomic changes such as gene order, shared gene boundaries and genetic code changes, which are unlikely to have arisen through convergent evolution, are useful tools in resolving deep phylogenies. Xenoturbella bocki is a morphologically simple benthic marine worm recently found to belong among the deuterostomes. Here we present analyses comparing the Xenoturbella bocki mitochondrial gene order, genetic code and control region to those of other metazoan groups. Results The complete mitochondrial genome sequence of Xenoturbella bocki was determined. The gene order is most similar to that of the chordates and the hemichordates, indicating that this conserved mitochondrial gene order might be ancestral to the deuterostome clade. Using data from all phyla of deuterostomes, we infer the ancestral mitochondrial gene order for this clade. Using inversion and breakpoint analyses of metazoan mitochondrial genomes, we test conflicting hypotheses for the phylogenetic placement of Xenoturbella and find a closer affinity to the hemichordates than to other metazoan groups. Comparative analyses of the control region reveal similarities in the transcription initiation and termination sites and origin of replication of Xenoturbella with those of the vertebrates. Phylogenetic analyses of the mitochondrial sequence indicate a weakly supported placement as a basal deuterostome, a result that may be the effect of compositional bias. Conclusion The mitochondrial genome of Xenoturbella bocki has a very conserved gene arrangement in the deuterostome group, strikingly similar to that of the hemichordates and the chordates, and thus to the ancestral deuterostome gene order. Similarity to the hemichordates in particular is suggested by inversion and breakpoint analysis. Finally, while phylogenetic analyses of the

  9. Drug resistance and genetic characteristics of clinical isolates of staphylococci in Myanmar: high prevalence of PVL among methicillin-susceptible Staphylococcus aureus belonging to various sequence types

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    M.S. Aung

    2016-03-01

    Full Text Available Prevalence, drug resistance and genetic characteristics were analysed for a total of 128 clinical isolates of staphylococci obtained from a tertiary hospital in Myanmar. The dominant species were S. aureus (39% and S. haemolyticus (35%, followed by S. epidermidis (6% and S. saprophyticus (5%. The majority of S. haemolyticus isolates (71.1% harboured mecA, showing high resistance rates to ampicillin, cephalosporins, erythromycin and levofloxacin, while methicillin-resistant S. aureus (MRSA was only 8% (four isolates among S. aureus with type IV SCCmec. Panton-Valentine leukocidin (PVL genes were detected in 20 isolates of S. aureus (40%, among which only one isolate was MRSA belonging to sequence type (ST 88/agr-III/coa-IIIa, and the other 19 methicillin-susceptible S. aureus (MSSA isolates were classified into six STs (ST88, ST121, ST1153, ST1155, ST1930, ST3206. An ST1153 MSSA isolate with PVL was revealed to belong to a novel coa type, XIIIa. ST121 S. aureus was the most common in the PVL-positive MSSA (47%, 9/19, harbouring genes of bone sialoprotein and variant of elastin binding protein as a distinctive feature. Although PVL-positive MSSA was susceptible to most of the antimicrobial agents examined, ST1930 isolates were resistant to erythromycin and levofloxacin. ST59 PVL-negative MRSA and MSSA had more resistance genes than other MRSA and PVL-positive MSSA, showing resistance to more antimicrobial agents. This study indicated higher prevalence of mecA associated with multiple drug resistance in S. haemolyticus than in S. aureus, and dissemination of PVL genes to multiple clones of MSSA, with ST121 being dominant, among hospital isolates in Myanmar.

  10. Drug resistance and genetic characteristics of clinical isolates of staphylococci in Myanmar: high prevalence of PVL among methicillin-susceptible Staphylococcus aureus belonging to various sequence types.

    Science.gov (United States)

    Aung, M S; Zi, H; Nwe, K M; Maw, W W; Aung, M T; Min, W W; Nyein, N; Kawaguchiya, M; Urushibara, N; Sumi, A; Kobayashi, N

    2016-03-01

    Prevalence, drug resistance and genetic characteristics were analysed for a total of 128 clinical isolates of staphylococci obtained from a tertiary hospital in Myanmar. The dominant species were S. aureus (39%) and S. haemolyticus (35%), followed by S. epidermidis (6%) and S. saprophyticus (5%). The majority of S. haemolyticus isolates (71.1%) harboured mecA, showing high resistance rates to ampicillin, cephalosporins, erythromycin and levofloxacin, while methicillin-resistant S. aureus (MRSA) was only 8% (four isolates) among S. aureus with type IV SCCmec. Panton-Valentine leukocidin (PVL) genes were detected in 20 isolates of S. aureus (40%), among which only one isolate was MRSA belonging to sequence type (ST) 88/agr-III/coa-IIIa, and the other 19 methicillin-susceptible S. aureus (MSSA) isolates were classified into six STs (ST88, ST121, ST1153, ST1155, ST1930, ST3206). An ST1153 MSSA isolate with PVL was revealed to belong to a novel coa type, XIIIa. ST121 S. aureus was the most common in the PVL-positive MSSA (47%, 9/19), harbouring genes of bone sialoprotein and variant of elastin binding protein as a distinctive feature. Although PVL-positive MSSA was susceptible to most of the antimicrobial agents examined, ST1930 isolates were resistant to erythromycin and levofloxacin. ST59 PVL-negative MRSA and MSSA had more resistance genes than other MRSA and PVL-positive MSSA, showing resistance to more antimicrobial agents. This study indicated higher prevalence of mecA associated with multiple drug resistance in S. haemolyticus than in S. aureus, and dissemination of PVL genes to multiple clones of MSSA, with ST121 being dominant, among hospital isolates in Myanmar. PMID:27257489

  11. A Regulatory MDM4 Genetic Variant Locating in the Binding Sequence of Multiple MicroRNAs Contributes to Susceptibility of Small Cell Lung Cancer.

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    Feng Gao

    Full Text Available A functional rs4245739 A>C single nucleotide polymorphism (SNP locating in the MDM43'-untranslated (3'-UTR region creates a miR-191-5p or miR-887-3p targeting sites. This change results in decreased expression of oncogene MDM4. Therefore, we examined the association between this SNP and small cell lung cancer (SCLC risk as well as its regulatory function in SCLC cells. Genotypes were determined in two independent case-control sets consisted of 520SCLC cases and 1040 controls from two regions of China. Odds ratios (ORs and 95% confidence intervals (CIs were estimated by logistic regression. The impact of the rs4245739 SNP on miR-191-5p/miR-887-3p mediated MDM4 expression regulation was investigated using luciferase reporter gene assays. We found that the MDM4 rs4245739AC and CC genotypes were significantly associated with decreased SCLC susceptibility compared with the AA genotype in both case-control sets (Shandong set: OR = 0.53, 95% CI = 0.32-0.89, P = 0.014; Jiangsu set: OR = 0.47, 95% CI = 0.26-0.879, P = 0.017. Stratified analyses indicated that there was a significantly multiplicative interaction between rs4245739 and smoking (Pinteractioin = 0.048. After co-tranfection of miRNAs and different allelic-MDM4 reporter constructs into SCLC cells, we found that the both miR-191-5p and miR-887-3p can lead to significantly decreased MDM4 expression activities in the construct with C-allelic 3'-UTR but not A-allelic 3'-UTR, suggesting a consistent genotype-phenotype correlation. Our data illuminate that the MDM4rs4245739SNP contributes to SCLC risk and support the notion that gene 3'-UTR genetic variants, impacting miRNA-binding, might modify SCLC susceptibility.

  12. Effect of genetic variants in KCNJ11, ABCC8, PPARG and HNF4A loci on the susceptibility of type 2 diabetes in Chinese Han population

    Institute of Scientific and Technical Information of China (English)

    WANG Fang; HAN Xue-yao; REN Qian; ZHANG Xiu-ying; HAN Ling-chuan; LUO Ying-ying; ZHOU Xiang-hai; JI Li-nong

    2009-01-01

    Background KCNJ11, ABCC8, PPARG, and HNF4A have been found to be associated with type 2 diabetes in populations with different genetic backgrounds. The aim of this study was to test, in a Chinese Han population from Beijing, whether the genetic variants in these four genes were associated with genetic predisposition to type 2 diabetes.Methods We studied the association of four representative SNPs in KCNJ11, ABCC8, PPARG and HNF4A by genotyping them using ABI SnaPshot(R) Multiplex System in 400 unrelated type 2 diabetic patients and 400 unrelated normoglycaemic subjects. Results rs5219(E23K) in KCNJ11 was associated with genetic susceptibility to type 2 diabetes (OR=1.400 with 95% Cl 1.117 1.755, P=0.004 under an additive model, OR=-1.652 with 95% Cl 1.086 2.513, P=0.019 under a recessive model,and OR=1.521 with 95% Cl 1.089 2.123, P=0.014 under a dominant model) after adjusting for sex and body mass index (BMI). We did not find evidence of association for ABCC8 rs1799854, PPARG rs1801282 (Pro12Ala) and HNF4A rs2144908. Genotype-phenotype correlation analysis revealed that rs1799854 in ABCC8 was associated with 2-hour postprandial insulin secretion (P=0.005) after adjusting for sex, age and BMI. Although no interactions between the four variants on the risk of type 2 diabetes were detected, the multiplicative interaction between PPARG Pro12Ala and HNF4A rs2144908 was found to be associated with 2-hour postprandial insulin (P=-0.004 under an additive model for rs2144908;and P=0.001 under a dominant model for rs2144908) after adjusting for age, sex and BMI, assuming a dominant model for PPARG Pro12Ala.Conclusions Our study replicated the association of rs5219 in KCNJ11 with type 2 diabetes in Chinese Han population in Beijing. And we also observed that ABCC8 as well as the interaction between PPARG and HNF4A may contribute to post-challenge insulin secretion.

  13. Comparative analysis of rosaceous genomes and the reconstruction of a putative ancestral genome for the family

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    Velasco Riccardo

    2011-01-01

    Full Text Available Abstract Background Comparative genome mapping studies in Rosaceae have been conducted until now by aligning genetic maps within the same genus, or closely related genera and using a limited number of common markers. The growing body of genomics resources and sequence data for both Prunus and Fragaria permits detailed comparisons between these genera and the recently released Malus × domestica genome sequence. Results We generated a comparative analysis using 806 molecular markers that are anchored genetically to the Prunus and/or Fragaria reference maps, and physically to the Malus genome sequence. Markers in common for Malus and Prunus, and Malus and Fragaria, respectively were 784 and 148. The correspondence between marker positions was high and conserved syntenic blocks were identified among the three genera in the Rosaceae. We reconstructed a proposed ancestral genome for the Rosaceae. Conclusions A genome containing nine chromosomes is the most likely candidate for the ancestral Rosaceae progenitor. The number of chromosomal translocations observed between the three genera investigated was low. However, the number of inversions identified among Malus and Prunus was much higher than any reported genome comparisons in plants, suggesting that small inversions have played an important role in the evolution of these two genera or of the Rosaceae.

  14. The Emerging Role of Complement Lectin Pathway in Trypanosomatids: Molecular Bases in Activation, Genetic Deficiencies, Susceptibility to Infection, and Complement System-Based Therapeutics

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    Ingrid Evans-Osses

    2013-01-01

    Full Text Available The innate immune system is evolutionary and ancient and is the pivotal line of the host defense system to protect against invading pathogens and abnormal self-derived components. Cellular and molecular components are involved in recognition and effector mechanisms for a successful innate immune response. The complement lectin pathway (CLP was discovered in 1990. These new components at the complement world are very efficient. Mannan-binding lectin (MBL and ficolin not only recognize many molecular patterns of pathogens rapidly to activate complement but also display several strategies to evade innate immunity. Many studies have shown a relation between the deficit of complement factors and susceptibility to infection. The recently discovered CLP was shown to be important in host defense against protozoan microbes. Although the recognition of pathogen-associated molecular patterns by MBL and Ficolins reveal efficient complement activations, an increase in deficiency of complement factors and diversity of parasite strategies of immune evasion demonstrate the unsuccessful effort to control the infection. In the present paper, we will discuss basic aspects of complement activation, the structure of the lectin pathway components, genetic deficiency of complement factors, and new therapeutic opportunities to target the complement system to control infection.

  15. Genetic variations in DNA repair genes, radiosensitivity to cancer and susceptibility to acute tissue reactions in radiotherapy-treated cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Chistiakov, Dimitry A. (Dept. of Pathology, Univ. of Pittsburgh, Pittsburgh (US)); Voronova, Natalia V. (Dept. of Molecular Diagnostics, National Research Center GosNIIgenetika, Moscow (RU)); Chistiakov, Pavel A. (Dept. of Radiology, Cancer Research Center, Moscow (RU))

    2008-06-15

    Ionizing radiation is a well established carcinogen for human cells. At low doses, radiation exposure mainly results in generation of double strand breaks (DSBs). Radiation-related DSBs could be directly linked to the formation of chromosomal rearrangements as has been proven for radiation-induced thyroid tumors. Repair of DSBs presumably involves two main pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). A number of known inherited syndromes, such as ataxia telangiectasia, ataxia-telangiectasia like-disorder, radiosensitive severe combined immunodeficiency, Nijmegen breakage syndrome, and LIG4 deficiency are associated with increased radiosensitivity and/or cancer risk. Many of them are caused by mutations in DNA repair genes. Recent studies also suggest that variations in the DNA repair capacity in the general population may influence cancer susceptibility. In this paper, we summarize the current status of DNA repair proteins as potential targets for radiation-induced cancer risk. We will focus on genetic alterations in genes involved in HR- and NHEJ-mediated repair of DSBs, which could influence predisposition to radiation-related cancer and thereby explain interindividual differences in radiosensitivity or radioresistance in a general population

  16. Genetic variants in three genes and smoking show strong associations with susceptibility to exudative age-related macular degeneration in a Chinese population

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    cigarette smoking were also related to exudative AMD. After controlling for environmental risk factors, CFH and HTRA1 SNPs were independently associated with exudative AMD, with OR of 3.50 (1.45-8.45) for CT genotype in Y402H, 3.34 (1.33-8.36) for GG genotype in rs1410996 and 3.85 (1.58-9.42) for AA genotype in rs11200638 respectively. The interaction analysis between gene and environmental factors showed that smoking synergistically increased susceptibility of AMD for heterozygotes of rs1410996, with ORinteraction of 7.33 (Pinteraction=0.029). Conclusions In a Han Chinese population, CFH and HTRA1 polymorphisms appear to be independently and possibly additivelv hereditary contributors to exudative AMD. Y402H polymorphism conferred a significant but relatively lower contribution in Chinese than in Caucasians with a low frequency of risk allele. The gene-environment interaction may be a best way to encourage those with a high genetic risk to prevent AMD by avoiding modifiable factors until there is effective treatment for AMD.

  17. Genetic variant rs401681 at 5p15.33 modifies susceptibility to lung cancer but not esophageal squamous cell carcinoma.

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    Man Jiang

    Full Text Available BACKGROUND: The human 5p15.33 locus contains two well-known genes, the telomerase reverse transcriptase (TERT and cleft lip and palate transmembrane 1-like (CLPTM1L genes, which have been implicated in carcinogenesis. A common sequence variant, rs401681, located in an intronic region of CLPTM1L, has been reported to be associated with lung cancer risk based on genome-wide association study. However, subsequent replication studies in diverse populations have yielded inconsistent results. In addition, genetic variants at 5p15.33, including rs401681, have been shown to be involved in the susceptibility to multiple malignancies. Nevertheless, the role of these TERT-CLPTM1L variants in the etiology of esophageal squamous cell carcinoma (ESCC remains unknown. METHODS: We genotyped the rs401681 polymorphism using TaqMan methodology and analyzed its association with the risk of lung cancer and ESCC in a case-control study of 1,479 cancer patients (726 with lung cancer and 753 with ESCC and 860 healthy individuals. RESULTS: Logistic regression analyses revealed that rs401681 T genotypes were associated with a significantly decreased risk of lung cancer (CT vs. CC: adjusted OR=0.782, 95% CI=0.625-0.978, P=0.031; CT/TT vs. CC: adjusted OR=0.786; 95% CI=0.635-0.972, P=0.026. Stratification analysis by histology type indicated that rs401681 T genotypes were associated with a significantly reduced risk of both adenocarcinoma and squamous cell carcinoma. Furthermore, no significant association was observed between rs401681 and the risk of ESCC (CT vs. CC: adjusted OR=0.910, 95% CI=0.734-1.129, P=0.392; TT vs. CC: adjusted OR=0.897, 95%CI=0.624-1.290, P=0.558; CT/TT vs. CC: adjusted OR=0.908, 95% CI=0.740-1.114, P=0.355. CONCLUSIONS: Our findings provide further evidence supporting rs401681 as a genetic variant associated with the risk of lung cancer. In addition, we investigated the correlation between the rs401681 variant and the risk of ESCC in a Han Chinese

  18. Polymorphic allele of human IRGM1 is associated with susceptibility to tuberculosis in African Americans.

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    Katherine Y King

    Full Text Available An ancestral polymorphic allele of the human autophagy-related gene IRGM1 is associated with altered gene expression and a genetic risk for Crohn's Disease (CD. We used the single nucleotide polymorphism rs10065172C/T as a marker of this polymorphic allele and genotyped 370 African American and 177 Caucasian tuberculosis (TB cases and 180 African American and 110 Caucasian controls. Among African Americans, the TB cases were more likely to carry the CD-related T allele of rs10065172 (odds ratio of 1.54; 95% confidence interval, 1.17-2.02; P<0.01 compared to controls. Our finding suggests that this CD-related IRGM1 polymorphic allele is also associated with human susceptibility to TB disease among African Americans.

  19. Isolation of ancestral sylvatic dengue virus type 1, Malaysia.

    Science.gov (United States)

    Teoh, Boon-Teong; Sam, Sing-Sin; Abd-Jamil, Juraina; AbuBakar, Sazaly

    2010-11-01

    Ancestral sylvatic dengue virus type 1, which was isolated from a monkey in 1972, was isolated from a patient with dengue fever in Malaysia. The virus is neutralized by serum of patients with endemic DENV-1 infection. Rare isolation of this virus suggests a limited spillover infection from an otherwise restricted sylvatic cycle. PMID:21029545

  20. Isolation of Ancestral Sylvatic Dengue Virus Type 1, Malaysia

    OpenAIRE

    Teoh, Boon-Teong; Sam, Sing-Sin; Abd-Jamil, Juraina; AbuBakar, Sazaly

    2010-01-01

    Ancestral sylvatic dengue virus type 1, which was isolated from a monkey in 1972, was isolated from a patient with dengue fever in Malaysia. The virus is neutralized by serum of patients with endemic DENV-1 infection. Rare isolation of this virus suggests a limited spillover infection from an otherwise restricted sylvatic cycle.

  1. Are survival processing memory advantages based on ancestral priorities?

    Science.gov (United States)

    Soderstrom, Nicholas C; McCabe, David P

    2011-06-01

    Recent research has suggested that our memory systems are especially tuned to process information according to its survival relevance, and that inducing problems of "ancestral priorities" faced by our ancestors should lead to optimal recall performance (Nairne & Pandeirada, Cognitive Psychology, 2010). The present study investigated the specificity of this idea by comparing an ancestor-consistent scenario and a modern survival scenario that involved threats that were encountered by human ancestors (e.g., predators) or threats from fictitious creatures (i.e., zombies). Participants read one of four survival scenarios in which the environment and the explicit threat were either consistent or inconsistent with ancestrally based problems (i.e., grasslands-predators, grasslands-zombies, city-attackers, city-zombies), or they rated words for pleasantness. After rating words based on their survival relevance (or pleasantness), the participants performed a free recall task. All survival scenarios led to better recall than did pleasantness ratings, but recall was greater when zombies were the threat, as compared to predators or attackers. Recall did not differ for the modern (i.e., city) and ancestral (i.e., grasslands) scenarios. These recall differences persisted when valence and arousal ratings for the scenarios were statistically controlled as well. These data challenge the specificity of ancestral priorities in survival-processing advantages in memory. PMID:21327372

  2. Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the Breast Cancer Association Consortium: a combined case-control study.

    OpenAIRE

    Milne, Roger L.; Gaudet, Mia M.; Spurdle, Amanda B.; Fasching, Peter A.; Couch, Fergus J.; Benitez, Javier; Arias Perez, Jose Ignacio; Zamora, Maria Pilar; Malats, Nuria; dos Santos Silva, Isabel; Gibson, Lorna J.; Fletcher, Olivia; Johnson, Nichola; Anton-Culver, Hoda; Ziogas, Argyrios

    2010-01-01

    Abstract Introduction Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. Methods We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of liv...

  3. Distinctive cellular immunity in genetically susceptible BALB/c mice recovered from Leishmania major infection or after subcutaneous immunization with killed parasites

    Energy Technology Data Exchange (ETDEWEB)

    Liew, F.Y.; Dhaliwal, J.S.

    1987-06-15

    Genetically susceptible BALB/c mice are refractory to further infection after recovery from Leishmania major infection after a sublethal dose of gamma-irradiation. In contrast, mice immunized with killed promastigotes s.c. develop exacerbated lesions after infection. Both groups of mice produce only a low level of specific antibody and no detectable cytotoxic T cells, but do have a strong antigen-specific DTH, which is adoptively transferable with Lyt-1+2-, L3T4+ T cells. Kinetic and histological studies revealed that mice immunized s.c. developed Jones-Mote hypersensitivity, peaking at 15 hr. with little mononuclear cell infiltration at the site of antigen administration; whereas mice that had recovered from infection developed tuberculin-type of reactivity, peaking at 24 to 48 hr, with intense mononuclear cell infiltration. Splenic T cells from recovered mice, when injected into the footpads of normal recipients together with live promastigotes, were able to retard lesion development; whereas T cells from s.c. immunized mice, when similarly transferred, accelerated disease progression. Antigen-specific culture supernatant of spleen cells from recovered mice also activated normal resident peritoneal macrophages to kill intracellular L. major amastigotes and tumor cells. Culture supernatants of spleen cells from s.c. immunized or normal mice were devoid of such activities. Part of the macrophage-activating potential can be inhibited by antibody specific for IFN-gamma. These results therefore demonstrate that whereas the Jones-Mote reaction is correlated with disease exacerbation, the tuberculin-type of DTH may be protective. Furthermore, in vivo immunity is directly related to the capacity of T cells to produce macrophage-activating factor.

  4. DIFFERENTIAL SUSCEPTIBILITY OF HUMAN SP-B GENETIC VARIANTS ON LUNG INJURY CAUSED BY BACTERIAL PNEUMONIA AND THE EFFECT OF A CHEMICALLY MODIFIED CURCUMIN.

    Science.gov (United States)

    Xu, Yongan; Ge, Lin; Abdel-Razek, Osama; Jain, Sumeet; Liu, Zhiyong; Hong, Yucai; Nieman, Gary; Johnson, Francis; Golub, Lorne M; Cooney, Robert N; Wang, Guirong

    2016-04-01

    Staphylococcus aureus is a common cause of nosocomial pneumonia frequently resulting in acute respiratory distress syndrome (ARDS). Surfactant protein B (SP-B) gene expresses two proteins involved in lowering surface tension and host defense. Genotyping studies demonstrate a significant association between human SP-B genetic variants and ARDS. Curcumins have been shown to attenuate host inflammation in many sepsis models. Our hypothesis is that functional differences of SP-B variants and treatment with curcumin (CMC2.24) modulate lung injury in bacterial pneumonia. Humanized transgenic mice, expressing either SP-B T or C allele without mouse SP-B gene, were used. Bioluminescent labeled S. aureus Xen 36 (50 μL) was injected intratracheally to cause pneumonia. Infected mice received daily CMC2.24 (40 mg/kg) or vehicle alone by oral gavage. Dynamic changes of bacteria were monitored using in vivo imaging system. Histological, cellular, and molecular indices of lung injury were studied in infected mice 48 h after infection. In vivo imaging analysis revealed total flux (bacterial number) was higher in the lung of infected SP-B-C mice compared with infected SP-B-T mice (P < 0.05). Infected SP-B-C mice demonstrated increased mortality, lung injury, apoptosis, and NF-κB expression compared with infected SP-B-T mice. Compared with controls, CMC2.24 treatment significantly reduced the following: mortality, total bacterial flux and lung tissue apoptosis, inflammatory cells, NF-κB expression (P < 0.05), and MMPs-2, -9, -12 activities (P < 0.05). We conclude that mice with SP-B-C allele are more susceptible to S. aureus pneumonia than mice with SP-B-T allele, and that CMC2.24 attenuates lung injury thus reducing mortality. PMID:26863117

  5. Distinctive cellular immunity in genetically susceptible BALB/c mice recovered from Leishmania major infection or after subcutaneous immunization with killed parasites

    International Nuclear Information System (INIS)

    Genetically susceptible BALB/c mice are refractory to further infection after recovery from Leishmania major infection after a sublethal dose of gamma-irradiation. In contrast, mice immunized with killed promastigotes s.c. develop exacerbated lesions after infection. Both groups of mice produce only a low level of specific antibody and no detectable cytotoxic T cells, but do have a strong antigen-specific DTH, which is adoptively transferable with Lyt-1+2-, L3T4+ T cells. Kinetic and histological studies revealed that mice immunized s.c. developed Jones-Mote hypersensitivity, peaking at 15 hr. with little mononuclear cell infiltration at the site of antigen administration; whereas mice that had recovered from infection developed tuberculin-type of reactivity, peaking at 24 to 48 hr, with intense mononuclear cell infiltration. Splenic T cells from recovered mice, when injected into the footpads of normal recipients together with live promastigotes, were able to retard lesion development; whereas T cells from s.c. immunized mice, when similarly transferred, accelerated disease progression. Antigen-specific culture supernatant of spleen cells from recovered mice also activated normal resident peritoneal macrophages to kill intracellular L. major amastigotes and tumor cells. Culture supernatants of spleen cells from s.c. immunized or normal mice were devoid of such activities. Part of the macrophage-activating potential can be inhibited by antibody specific for IFN-gamma. These results therefore demonstrate that whereas the Jones-Mote reaction is correlated with disease exacerbation, the tuberculin-type of DTH may be protective. Furthermore, in vivo immunity is directly related to the capacity of T cells to produce macrophage-activating factor

  6. Genetically different clonal isolates of Trichomonas gallinae, obtained from the same bird, can vary in their drug susceptibility, an in vitro evidence.

    Science.gov (United States)

    Zimre-Grabensteiner, Elvira; Arshad, Najma; Amin, Aziza; Hess, Michael

    2011-06-01

    Trichomonas gallinae is a flagellated protozoon which parasitizes in the upper digestive tract of different birds, especially columbiformes (doves and pigeons) and falconiformes. The parasite is also a common inhabitant of the crop of psittacine birds and is frequently detected in budgerigars. The lesions associated with T. gallinae infection of the upper digestive tract range from mild inflammation of the mucosa to large caseous lesions that block the lumen of the oesophagus. Nitroimidazoles are considered to be the drugs of choice for the treatment of trichomonosis. However, only a few studies report the existence of resistant strains of T. gallinae to these drugs. Thus, in the present investigation cloned cultures of T. gallinae obtained from budgerigars and pigeons were analysed for the first time for their in vitro susceptibilities against four 5´-nitroimidazole derivates, including metronidazole, dimetridazole, ronidazole and ornidazole. Significantly different minimal lethal concentrations (MLCs) were observed for them against all four drugs. The lowest MLCs revealed the Trichomonas isolates obtained from two budgerigars, ranging from 2.0 ± 0.3 to 3.0 ± 0.7 μg/ml for metronidazole and dimetridazole, and from 2.0 ± 0.6 to 6.7 ± 1.7 μg/ml for ornidazole and ronidazole. Contrary to this, the highest MLCs were recorded for one Trichomonas isolate obtained from a pigeon, ranging from 83.3 ± 6.7 (for dimetridazole and ronidazole) to 103.3 ± 3.3 μg/ml (for metronidazole and ornidazole). The data obtained for the resistance testing were further compared with already available genetic data of the small subunit rRNA gene sequences and ITS-1, 5.8S rRNA and ITS-2 sequences, indicating a certain correlation between in vitro results and strain relationships. PMID:21345378

  7. Genetic polymorphisms in MMP 2, 3, 7, and 9 genes and the susceptibility and clinical outcome of cervical cancer in a Chinese Han population.

    Science.gov (United States)

    Xie, Beibei; Zhang, Zhen; Wang, Hui; Chen, Zhaojie; Wang, Yongsheng; Liang, Huazheng; Yang, Gaoyuan; Yang, Xingsheng; Zhang, Haiyan

    2016-04-01

    Matrix metalloproteases (MMPs) are proteolytic enzymes that contribute to all stages of tumor progression, including the invasion and metastasis. However, there are no data about the role of MMP polymorphism in the development of cervical cancer. A hospital-based case-control study was conducted in 230 patients with cervical cancer and 230 healthy controls to investigate the possible association between the MMP2 rs243865, MMP3 rs3025058, MMP7 rs11568818, and MMP9 rs3918242 polymorphisms, respectively, and the risk of cervical cancer. Our results suggested that the MMP2 rs243865-1306 C/T was significantly associated with an increased risk of cervical cancer (CT vs. CC, OR = 1.46; 95 % CI 1.18-3.55; P = 0.032; TT vs. CC, OR = 1.72; 95 % CI 1.28-4.02; P = 0.031; CT + TT vs. CC, OR = 1.43; 95 % CI 1.21-3.44; P = 0.029). Similarly, the MMP7 rs11568818-181A/G genotypes can also elevate the risk of cervical cancer in all genetic models. However, the genotype and allele frequencies of MMP3 rs3025058 and MMP9 rs3918242 polymorphisms in cervical cancer patients were not significantly different from controls. Further analysis showed MMP2 rs243865 and MMP7 rs11568818 genotypes were associated with advanced tumor stages of cervical cancer patients. More interestingly, the MMP2 rs243865 and MMP7 rs11568818 genotype was statistically significantly associated with a poor survival in cervical cancer patients. Our results showed that the MMP2 rs243865 and MMP7 rs11568818 genotypes e were associated with increased susceptibility and development of cervical cancer in Chinese Han population. PMID:26526578

  8. Ancestral origin of the ATTCT repeat expansion in spinocerebellar ataxia type 10 (SCA10.

    Directory of Open Access Journals (Sweden)

    Teresa Almeida

    Full Text Available Spinocerebellar ataxia type 10 (SCA10 is an autosomal dominant neurodegenerative disease characterized by cerebellar ataxia and seizures. The disease is caused by a large ATTCT repeat expansion in the ATXN10 gene. The first families reported with SCA10 were of Mexican origin, but the disease was soon after described in Brazilian families of mixed Portuguese and Amerindian ancestry. The origin of the SCA10 expansion and a possible founder effect that would account for its geographical distribution have been the source of speculation over the last years. To unravel the mutational origin and spread of the SCA10 expansion, we performed an extensive haplotype study, using closely linked STR markers and intragenic SNPs, in families from Brazil and Mexico. Our results showed (1 a shared disease haplotype for all Brazilian and one of the Mexican families, and (2 closely-related haplotypes for the additional SCA10 Mexican families; (3 little or null genetic distance in small normal alleles of different repeat sizes, from the same SNP lineage, indicating that they are being originated by a single step mechanism; and (4 a shared haplotype for pure and interrupted expanded alleles, pointing to a gene conversion model for its generation. In conclusion, we show evidence for an ancestral common origin for SCA10 in Latin America, which might have arisen in an ancestral Amerindian population and later have been spread into the mixed populations of Mexico and Brazil.

  9. Genetic Susceptibility to Pancreatic Cancer

    OpenAIRE

    Klein, Alison P

    2012-01-01

    Pancreatic cancer is the fourth leading cause of cancer death in both men and women in the United States. However, it has the poorest prognosis of any major tumor type, with a 5-yr survival rate of approximately 5%. Cigarette smoking, increased body mass index, heavy alcohol consumption, and a diagnosis of diabetes mellitus have all been demonstrated to increase risk of pancreatic cancer. A family history of pancreatic cancer has also been associated with increased risk suggesting inherited g...

  10. Genetic polymorphisms in vitamin D receptor, vitamin D-binding protein, Toll-like receptor 2, nitric oxide synthase 2, and interferon-γ genes and its association with susceptibility to tuberculosis

    Directory of Open Access Journals (Sweden)

    A.C.C.S. Leandro

    2009-04-01

    Full Text Available Mycobacterium tuberculosis kills more people than any other single pathogen, with an estimated one-third of the world's population being infected. Among those infected, only 10% will develop the disease. There are several demonstrations that susceptibility to tuberculosis is linked to host genetic factors in twins, family and associated-based case control studies. In the past years, there has been dramatic improvement in our understanding of the role of innate and adaptive immunity in the human host defense to tuberculosis. To date, attention has been paid to the role of genetic host and parasitic factors in tuberculosis pathogenesis mainly regarding innate and adaptive immune responses and their complex interactions. Many studies have focused on the candidate genes for tuberculosis susceptibility ranging from those expressed in several cells from the innate or adaptive immune system such as Toll-like receptors, cytokines (TNF-α, TGF-β, IFN-γ, IL-1b, IL-1RA, IL-12, IL-10, nitric oxide synthase and vitamin D, both nuclear receptors and their carrier, the vitamin D-binding protein (VDBP. The identification of possible genes that can promote resistance or susceptibility to tuberculosis could be the first step to understanding disease pathogenesis and can help to identify new tools for treatment and vaccine development. Thus, in this mini-review, we summarize the current state of investigation on some of the genetic determinants, such as the candidate polymorphisms of vitamin D, VDBP, Toll-like receptor, nitric oxide synthase 2 and interferon-γ genes, to generate resistance or susceptibility to M. tuberculosis infection.

  11. Multiway admixture deconvolution using phased or unphased ancestral panels.

    Science.gov (United States)

    Churchhouse, Claire; Marchini, Jonathan

    2013-01-01

    We describe a novel method for inferring the local ancestry of admixed individuals from dense genome-wide single nucleotide polymorphism data. The method, called MULTIMIX, allows multiple source populations, models population linkage disequilibrium between markers and is applicable to datasets in which the sample and source populations are either phased or unphased. The model is based upon a hidden Markov model of switches in ancestry between consecutive windows of loci. We model the observed haplotypes within each window using a multivariate normal distribution with parameters estimated from the ancestral panels. We present three methods to fit the model-Markov chain Monte Carlo sampling, the Expectation Maximization algorithm, and a Classification Expectation Maximization algorithm. The performance of our method on individuals simulated to be admixed with European and West African ancestry shows it to be comparable to HAPMIX, the ancestry calls of the two methods agreeing at 99.26% of loci across the three parameter groups. In addition to it being faster than HAPMIX, it is also found to perform well over a range of extent of admixture in a simulation involving three ancestral populations. In an analysis of real data, we estimate the contribution of European, West African and Native American ancestry to each locus in the Mexican samples of HapMap, giving estimates of ancestral proportions that are consistent with those previously reported. PMID:23136122

  12. The imperfect ancestral recombination graph reconstruction problem: upper bounds for recombination and homoplasy.

    Science.gov (United States)

    Lam, Fumei; Tarpine, Ryan; Istrail, Sorin

    2010-06-01

    One of the central problems in computational biology is the reconstruction of evolutionary histories. While models incorporating recombination and homoplasy have been studied separately, a missing component in the theory is a robust and flexible unifying model which incorporates both of these major biological events shaping genetic diversity. In this article, we introduce the first such unifying model and develop algorithms to find the optimal ancestral recombination graph incorporating recombinations and homoplasy events. The power of our framework is the connection between our formulation and the Directed Steiner Arborescence Problem in combinatorial optimization. We implement linear programming techniques as well as heuristics for the Directed Steiner Arborescence Problem, and use our methods to construct evolutionary histories for both simulated and real data sets. PMID:20583925

  13. Genetic mapping of a susceptibility locus for disc herniation and spastic paraplegia on 6q23.3-q24.1

    OpenAIRE

    Zortea, M.; Vettori, A; Trevisan, C; Bellini, S.; Vazza, G.; Armani, M; Simonati, A; Mostacciuolo, M

    2002-01-01

    It has been suggested that a genetic factor(s) or a familial predisposition may contribute to the clinical manifestations of disc herniation; moreover, no genetic linkage between spinal disc herniation and spastic paraplegia has ever been described.

  14. Genotype-based ancestral background consistently predicts efficacy and side effects across treatments in CATIE and STAR*D.

    Directory of Open Access Journals (Sweden)

    Daniel E Adkins

    Full Text Available Only a subset of patients will typically respond to any given prescribed drug. The time it takes clinicians to declare a treatment ineffective leaves the patient in an impaired state and at unnecessary risk for adverse drug effects. Thus, diagnostic tests robustly predicting the most effective and safe medication for each patient prior to starting pharmacotherapy would have tremendous clinical value. In this article, we evaluated the use of genetic markers to estimate ancestry as a predictive component of such diagnostic tests. We first estimated each patient's unique mosaic of ancestral backgrounds using genome-wide SNP data collected in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE (n = 765 and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D (n = 1892. Next, we performed multiple regression analyses to estimate the predictive power of these ancestral dimensions. For 136/89 treatment-outcome combinations tested in CATIE/STAR*D, results indicated 1.67/1.84 times higher median test statistics than expected under the null hypothesis assuming no predictive power (p<0.01, both samples. Thus, ancestry showed robust and pervasive correlations with drug efficacy and side effects in both CATIE and STAR*D. Comparison of the marginal predictive power of MDS ancestral dimensions and self-reported race indicated significant improvements to model fit with the inclusion of MDS dimensions, but mixed evidence for self-reported race. Knowledge of each patient's unique mosaic of ancestral backgrounds provides a potent immediate starting point for developing algorithms identifying the most effective and safe medication for a wide variety of drug-treatment response combinations. As relatively few new psychiatric drugs are currently under development, such personalized medicine offers a promising approach toward optimizing pharmacotherapy for psychiatric conditions.

  15. Thermotolerant Yeast Strains Adapted by Laboratory Evolution Show Trade-Off at Ancestral Temperatures and Preadaptation to Other Stresses

    DEFF Research Database (Denmark)

    Caspeta, Luis; Nielsen, Jens

    2015-01-01

    adaptive laboratory evolution, we previously isolated seven Saccharomyces cerevisiae strains with improved growth at 40°C. Here, we show that genetic adaptations to high temperature caused a growth trade-off at ancestral temperatures, reduced cellular functions, and improved tolerance of other stresses...... proteins showed that the lethal temperature for yeast is around 49°C, as a large fraction of the yeast proteins denature above this temperature. Our analysis also indicated that the number of functions involved in controlling the growth rate decreased in the thermotolerant strains compared with the number...

  16. Long-Term Immunity to Lethal Acute or Chronic Type II Toxoplasma gondii Infection Is Effectively Induced in Genetically Susceptible C57BL/6 Mice by Immunization with an Attenuated Type I Vaccine Strain▿

    Science.gov (United States)

    Gigley, Jason P.; Fox, Barbara A.; Bzik, David J.

    2009-01-01

    C57BL/6 (B6) mice are genetically highly susceptible to chronic type II Toxoplasma gondii infections that invariably cause lethal toxoplasmic encephalitis. We examined the ability of an attenuated type I vaccine strain to elicit long-term immunity to lethal acute or chronic type II infections in susceptible B6 mice. Mice immunized with the type I cps1-1 vaccine strain were not susceptible to a lethal (100-cyst) challenge with the type II strain ME49. Immunized mice challenged with 10 ME49 cysts exhibited significant reductions in brain cyst and parasite burdens compared to naive mice, regardless of the route of challenge infection. Remarkably, cps1-1 strain-immunized B6 mice chronically infected with ME49 survived for at least 12 months without succumbing to the chronic infection. Potent immunity to type II challenge infections persisted for at least 10 months after vaccination. While the cps1-1 strain-elicited immunity did not prevent the establishment of a chronic infection or clear established brain cysts, cps1-1 strain-elicited CD8+ immune T cells significantly inhibited recrudescence of brain cysts during chronic ME49 infection. In addition, we show that uracil starvation of the cps1-1 strain induces early markers of bradyzoite differentiation. Collectively, these results suggest that more effective immune control of chronic type II infection in the genetically susceptible B6 background is established by vaccination with the nonreplicating type I uracil auxotroph cps1-1 strain. PMID:19797073

  17. Long-term immunity to lethal acute or chronic type II Toxoplasma gondii infection is effectively induced in genetically susceptible C57BL/6 mice by immunization with an attenuated type I vaccine strain.

    Science.gov (United States)

    Gigley, Jason P; Fox, Barbara A; Bzik, David J

    2009-12-01

    C57BL/6 (B6) mice are genetically highly susceptible to chronic type II Toxoplasma gondii infections that invariably cause lethal toxoplasmic encephalitis. We examined the ability of an attenuated type I vaccine strain to elicit long-term immunity to lethal acute or chronic type II infections in susceptible B6 mice. Mice immunized with the type I cps1-1 vaccine strain were not susceptible to a lethal (100-cyst) challenge with the type II strain ME49. Immunized mice challenged with 10 ME49 cysts exhibited significant reductions in brain cyst and parasite burdens compared to naive mice, regardless of the route of challenge infection. Remarkably, cps1-1 strain-immunized B6 mice chronically infected with ME49 survived for at least 12 months without succumbing to the chronic infection. Potent immunity to type II challenge infections persisted for at least 10 months after vaccination. While the cps1-1 strain-elicited immunity did not prevent the establishment of a chronic infection or clear established brain cysts, cps1-1 strain-elicited CD8(+) immune T cells significantly inhibited recrudescence of brain cysts during chronic ME49 infection. In addition, we show that uracil starvation of the cps1-1 strain induces early markers of bradyzoite differentiation. Collectively, these results suggest that more effective immune control of chronic type II infection in the genetically susceptible B6 background is established by vaccination with the nonreplicating type I uracil auxotroph cps1-1 strain. PMID:19797073

  18. Influence of common and specific HLA-DRB1/DQB1 haplotypes on genetic susceptibilities of three distinct Arab populations to type 1 diabetes.

    Science.gov (United States)

    Stayoussef, Mouna; Benmansour, Jihen; Al-Jenaidi, Fayza A; Nemr, Rita; Ali, Muhallab E; Mahjoub, Touhami; Almawi, Wassim Y

    2009-01-01

    The contribution of HLA DRB-DQB to type 1 diabetes (T1D) in Bahrainis, Lebanese, and Tunisians was investigated. DRB1*030101-DQB1*0201 was a locus that conferred susceptibility in three populations, while DRB1*040101-DQB1*0302 was a locus that conferred susceptibility only in Tunisians and Bahrainis. The DRB1*100101-DQB1*050101 (Bahrainis) and DRB1*150101-DQB1*060101 (Lebanese) loci were largely protective. The contribution of HLA to T1D must be evaluated with regard to ethnic background. PMID:19005023

  19. Influence of Common and Specific HLA-DRB1/DQB1 Haplotypes on Genetic Susceptibilities of Three Distinct Arab Populations to Type 1 Diabetes▿

    Science.gov (United States)

    Stayoussef, Mouna; Benmansour, Jihen; Al-Jenaidi, Fayza A.; Nemr, Rita; Ali, Muhallab E.; Mahjoub, Touhami; Almawi, Wassim Y.

    2009-01-01

    The contribution of HLA DRB-DQB to type 1 diabetes (T1D) in Bahrainis, Lebanese, and Tunisians was investigated. DRB1*030101-DQB1*0201 was a locus that conferred susceptibility in three populations, while DRB1*040101-DQB1*0302 was a locus that conferred susceptibility only in Tunisians and Bahrainis. The DRB1*100101-DQB1*050101 (Bahrainis) and DRB1*150101-DQB1*060101 (Lebanese) loci were largely protective. The contribution of HLA to T1D must be evaluated with regard to ethnic background. PMID:19005023

  20. Both qualitative and quantitative genetic variation of MHC class II molecules may influence susceptibility to autoimmune diseases: the case of endemic pemphigus foliaceus.

    Science.gov (United States)

    Piovezan, Bruno Zagonel; Petzl-Erler, Maria Luiza

    2013-09-01

    The MHC class II transactivator (CIITA) is a key regulator in expression of the HLA class II genes. It is well known that HLA-DRB1 genotypes have a strong influence on the risk of multifactorial autoimmune diseases, but the effect of CIITA genotypes remains controversial. We tested in a case-control study whether CIITA polymorphisms influence the risk of developing endemic pemphigus foliaceus (EPF) and whether CIITA and HLA-DRB1 interact as regards susceptibility to the disease. The rs4774 SNP is not associated to EPF, while rs3087456 in the CIITA gene promoter is associated with susceptibility [odds ratio (OR) = 2.6, p EPF. PMID:23777927

  1. Genes Suggest Ancestral Colour Polymorphisms Are Shared across Morphologically Cryptic Species in Arctic Bumblebees.

    Directory of Open Access Journals (Sweden)

    Paul H Williams

    Full Text Available Our grasp of biodiversity is fine-tuned through the process of revisionary taxonomy. If species do exist in nature and can be discovered with available techniques, then we expect these revisions to converge on broadly shared interpretations of species. But for the primarily arctic bumblebees of the subgenus Alpinobombus of the genus Bombus, revisions by some of the most experienced specialists are unusual for bumblebees in that they have all reached different conclusions on the number of species present. Recent revisions based on skeletal morphology have concluded that there are from four to six species, while variation in colour pattern of the hair raised questions as to whether at least seven species might be present. Even more species are supported if we accept the recent move away from viewing species as morphotypes to viewing them instead as evolutionarily independent lineages (EILs using data from genes. EILs are recognised here in practice from the gene coalescents that provide direct evidence for their evolutionary independence. We show from fitting both general mixed Yule/coalescent (GMYC models and Poisson-tree-process (PTP models to data for the mitochondrial COI gene that there is support for nine species in the subgenus Alpinobombus. Examination of the more slowly evolving nuclear PEPCK gene shows further support for a previously unrecognised taxon as a new species in northwestern North America. The three pairs of the most morphologically similar sister species are separated allopatrically and prevented from interbreeding by oceans. We also find that most of the species show multiple shared colour patterns, giving the appearance of mimicry among parts of the different species. However, reconstructing ancestral colour-pattern states shows that speciation is likely to have cut across widespread ancestral polymorphisms, without or largely without convergence. In the particular case of Alpinobombus, morphological, colour-pattern, and

  2. Fast phylogeny reconstruction through learning of ancestral sequences

    CERN Document Server

    Mihaescu, Radu; Rao, Satish

    2008-01-01

    Given natural limitations on the length DNA sequences, designing phylogenetic reconstruction methods which are reliable under limited information is a crucial endeavor. There have been two approaches to this problem: reconstructing partial but reliable information about the tree (\\cite{Mo07, DMR08,DHJ06,GMS08}), and reaching "deeper" in the tree through reconstruction of ancestral sequences. In the latter category, \\cite{DMR06} settled an important conjecture of M.Steel, showing that, under the CFN model of evolution, all trees on $n$ leaves with edge lengths bounded by the Ising model phase transition can be recovered with high probability from genomes of length $O(\\log n)$ with a polynomial time algorithm. Their methods had a running time of $O(n^{10})$. Here we enhance our methods from \\cite{DHJ06} with the learning of ancestral sequences and provide an algorithm for reconstructing a sub-forest of the tree which is reliable given available data, without requiring a-priori known bounds on the edge lengths o...

  3. A search for genetic diversity among Italian Greyhounds from Continental Europe and the USA and the effect of inbreeding on susceptibility to autoimmune disease

    OpenAIRE

    Pedersen, Niels C.; Liu, Hongwei; Leonard, Angela; Griffioen, Layle

    2015-01-01

    Background Previous studies documented the problem of inbreeding among Italian Greyhounds (IG) from the USA and its possible role in a multiple autoimmune disease syndrome. The present study is an extension of these earlier experiments and had two objectives: 1) to identify pockets of additional genetic diversity that might still exist among IG from the USA and Continental Europe, and 2) to determine how loss of genetic diversity within the genome and in the dog leukocyte antigen (DLA) comple...

  4. Genetic control of susceptibility to fungal symbionts of juvenile Norway spruce (Picea abies (L.) H. Karsten) in relation to long-term growth performance

    OpenAIRE

    Velmala, Sannakajsa

    2014-01-01

    This study was carried out in order to reveal the degree to which host-tree factors influence the interaction between Norway spruce (Picea abies (L.) Karst.) and the endophytic (EN) and ectomycorrhizal fungi (EMF) found in their needles and roots, respectively. We also explored how susceptibility to fungal infection and the composition and functionality of associated fungal communities relates to seedling growth performance. In multiple glasshouse experiments, we challenged Norway spruce...

  5. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine and quinine in Guinea-Bissau between 2003 and 2012

    DEFF Research Database (Denmark)

    Jovel, Irina Tatiana; Kofoed, Poul-Erik; Rombo, Lars;

    2015-01-01

    BACKGROUND: Guinea-Bissau, West-Africa introduced artemether-lumefantrine in 2008 but quinine has also been commonly prescribed for treatment of uncomplicated Plasmodium falciparum malaria. An efficacious high-dose chloroquine treatment regimen was used previously. Temporal and seasonal changes of.......001). CONCLUSIONS: Following the discontinuation of an effective chloroquine regimen highly artemether-lumefantrine susceptible P. falciparum (with pfcrt 76T) accumulated possibly due to suboptimal use of quinine and despite a fitness cost linked to 76T....

  6. Tumor Induction in Mice After Localized Single- or Fractionated-Dose Irradiation: Differences in Tumor Histotype and Genetic Susceptibility Based on Dose Scheduling

    International Nuclear Information System (INIS)

    Purpose: To investigate differences in tumor histotype, incidence, latency, and strain susceptibility in mice exposed to single-dose or clinically relevant, fractioned-dose γ-ray radiation. Methods and Materials: C3Hf/Kam and C57BL/6J mice were locally irradiated to the right hindlimb with either single large doses between 10 and 70 Gy or fractionated doses totaling 40 to 80 Gy delivered at 2-Gy/d fractions, 5 d/wk, for 4 to 8 weeks. The mice were closely evaluated for tumor development in the irradiated field for 800 days after irradiation, and all tumors were characterized histologically. Results: A total of 210 tumors were induced within the radiation field in 788 mice. An overall decrease in tumor incidence was observed after fractionated irradiation (16.4%) in comparison with single-dose irradiation (36.1%). Sarcomas were the predominant postirradiation tumor observed (n=201), with carcinomas occurring less frequently (n=9). The proportion of mice developing tumors increased significantly with total dose for both single-dose and fractionated schedules, and latencies were significantly decreased in mice exposed to larger total doses. C3Hf/Kam mice were more susceptible to tumor induction than C57BL/6J mice after single-dose irradiation; however, significant differences in tumor susceptibilities after fractionated radiation were not observed. For both strains of mice, osteosarcomas and hemangiosarcomas were significantly more common after fractionated irradiation, whereas fibrosarcomas and malignant fibrous histiocytomas were significantly more common after single-dose irradiation. Conclusions: This study investigated the tumorigenic effect of acute large doses in comparison with fractionated radiation in which both the dose and delivery schedule were similar to those used in clinical radiation therapy. Differences in tumor histotype after single-dose or fractionated radiation exposures provide novel in vivo evidence for differences in tumor

  7. Tumor Induction in Mice After Localized Single- or Fractionated-Dose Irradiation: Differences in Tumor Histotype and Genetic Susceptibility Based on Dose Scheduling

    Energy Technology Data Exchange (ETDEWEB)

    Edmondson, Elijah F., E-mail: elijah.edmondson@colostate.edu [Environmental and Radiological Health Sciences Department, Colorado State University, Fort Collins, Colorado (United States); Hunter, Nancy R. [Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Weil, Michael M. [Environmental and Radiological Health Sciences Department, Colorado State University, Fort Collins, Colorado (United States); Mason, Kathryn A. [Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States)

    2015-07-15

    Purpose: To investigate differences in tumor histotype, incidence, latency, and strain susceptibility in mice exposed to single-dose or clinically relevant, fractioned-dose γ-ray radiation. Methods and Materials: C3Hf/Kam and C57BL/6J mice were locally irradiated to the right hindlimb with either single large doses between 10 and 70 Gy or fractionated doses totaling 40 to 80 Gy delivered at 2-Gy/d fractions, 5 d/wk, for 4 to 8 weeks. The mice were closely evaluated for tumor development in the irradiated field for 800 days after irradiation, and all tumors were characterized histologically. Results: A total of 210 tumors were induced within the radiation field in 788 mice. An overall decrease in tumor incidence was observed after fractionated irradiation (16.4%) in comparison with single-dose irradiation (36.1%). Sarcomas were the predominant postirradiation tumor observed (n=201), with carcinomas occurring less frequently (n=9). The proportion of mice developing tumors increased significantly with total dose for both single-dose and fractionated schedules, and latencies were significantly decreased in mice exposed to larger total doses. C3Hf/Kam mice were more susceptible to tumor induction than C57BL/6J mice after single-dose irradiation; however, significant differences in tumor susceptibilities after fractionated radiation were not observed. For both strains of mice, osteosarcomas and hemangiosarcomas were significantly more common after fractionated irradiation, whereas fibrosarcomas and malignant fibrous histiocytomas were significantly more common after single-dose irradiation. Conclusions: This study investigated the tumorigenic effect of acute large doses in comparison with fractionated radiation in which both the dose and delivery schedule were similar to those used in clinical radiation therapy. Differences in tumor histotype after single-dose or fractionated radiation exposures provide novel in vivo evidence for differences in tumor

  8. Global Alignment of Molecular Sequences via Ancestral State Reconstruction

    CERN Document Server

    Andoni, Alexandr; Hassidim, Avinatan; Roch, Sebastien

    2009-01-01

    Molecular phylogenetic techniques do not generally account for such common evolutionary events as site insertions and deletions (known as indels). Instead tree building algorithms and ancestral state inference procedures typically rely on substitution-only models of sequence evolution. In practice these methods are extended beyond this simplified setting with the use of heuristics that produce global alignments of the input sequences--an important problem which has no rigorous model-based solution. In this paper we consider a new version of the multiple sequence alignment in the context of stochastic indel models. More precisely, we introduce the following {\\em trace reconstruction problem on a tree} (TRPT): a binary sequence is broadcast through a tree channel where we allow substitutions, deletions, and insertions; we seek to reconstruct the original sequence from the sequences received at the leaves of the tree. We give a recursive procedure for this problem with strong reconstruction guarantees at low mut...

  9. Haplotype ancestral AH8.1 dans la mucoviscidose

    OpenAIRE

    Beucher, Julie

    2012-01-01

    La mucoviscidose est une maladie à transmission autosomique récessive, due à des mutations du gène CFTR. Les patients, partageant de mêmes mutations de CFTR et un même environnement, ont une expression phénotypique variable, suggérant l'influence d'autres gènes modifiant la sévérité de la maladie, appelés gènes modificateurs. L'atteinte respiratoire, caractérisée par une inflammation exacerbée, est un facteur principal de morbimortalité. L'haplotype ancestral AH8.1, impliqué dans la réponse i...

  10. What Is Genetic Ancestry Testing?

    Science.gov (United States)

    ... type of test because Y chromosome and mitochondrial DNA test results, which represent only single ancestral lines, do ... relationships. On a larger scale, combined genetic ancestry test results from many people can be used ... promotes the use of DNA testing in genealogy. The American Society of Human ...

  11. Estimation of hominoid ancestral population sizes under bayesian coalescent models incorporating mutation rate variation and sequencing errors.

    Science.gov (United States)

    Burgess, Ralph; Yang, Ziheng

    2008-09-01

    Estimation of population parameters for the common ancestors of humans and the great apes is important in understanding our evolutionary history. In particular, inference of population size for the human-chimpanzee common ancestor may shed light on the process by which the 2 species separated and on whether the human population experienced a severe size reduction in its early evolutionary history. In this study, the Bayesian method of ancestral inference of Rannala and Yang (2003. Bayes estimation of species divergence times and ancestral population sizes using DNA sequences from multiple loci. Genetics. 164:1645-1656) was extended to accommodate variable mutation rates among loci and random species-specific sequencing errors. The model was applied to analyze a genome-wide data set of approximately 15,000 neutral loci (7.4 Mb) aligned for human, chimpanzee, gorilla, orangutan, and macaque. We obtained robust and precise estimates for effective population sizes along the hominoid lineage extending back approximately 30 Myr to the cercopithecoid divergence. The results showed that ancestral populations were 5-10 times larger than modern humans along the entire hominoid lineage. The estimates were robust to the priors used and to model assumptions about recombination. The unusually low X chromosome divergence between human and chimpanzee could not be explained by variation in the male mutation bias or by current models of hybridization and introgression. Instead, our parameter estimates were consistent with a simple instantaneous process for human-chimpanzee speciation but showed a major reduction in X chromosome effective population size peculiar to the human-chimpanzee common ancestor, possibly due to selective sweeps on the X prior to separation of the 2 species. PMID:18603620

  12. Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP

    NARCIS (Netherlands)

    Zhernakova, Alexandra; Festen, Eleanora M; Franke, Lude; Trynka, Gosia; van Diemen, Cleo C; Monsuur, Alienke J; Bevova, Marianna; Nijmeijer, Rian M; van 't Slot, Ruben; Heijmans, Roel; Boezen, Hendrika; van Heel, David A; van Bodegraven, Adriaan A; Stokkers, Pieter C F; Wijmenga, Cisca; Crusius, J Bart A; Weersma, Rinse K

    2008-01-01

    The two main phenotypes of inflammatory bowel disease (IBD)--Crohn's disease (CD) and ulcerative colitis (UC)--are chronic intestinal inflammatory disorders with a complex genetic background. Using a three-stage design, we performed a functional candidate-gene analysis of innate immune pathway in IB

  13. Genetic association of rs1520333 G/A polymorphism in the IL7 gene with multiple sclerosis susceptibility in Isfahan population

    Directory of Open Access Journals (Sweden)

    Reza Ghavimi

    2014-01-01

    The purpose of the present study is to explore the association of rs1520333 C/T polymorphism in the IL7 gene variants with the risk of MS in a subset of Iranian population. Materials and Methods: In this case - control study, 110 cases with MS and 110 controls were contributed. DNA was extracted from blood samples and to amplify the fragment of interest contain rs1520333 SNP, polymerase chain reaction - restriction fragment length polymorphism method was implemented for genotyping of the DNA samples with a specific restriction enzyme (MwoI. SPSS for Windows software (version 18.0; SPSS, Chicago, IL, USA was used for statistical analysis. Result: We demonstrated the important association between G allele [odds ratio (OR =1.6614, confidence interval (CI =1.12-2.47, P = 0.0124] and GG genotype (OR = 7.45, 95% CI = 2.13-25.97, P 0.0016 of the rs1520333 SNP for susceptibility to MS after adjustment for age, and gender. OR adjusted for age, gender, and body mass index has displayed similar outcomes. Conclusion: These results indicate that the rs1520333 SNP is a significant susceptibility gene variant for development of MS in the Iranian population. Nevertheless, functional studies are required to completely elucidate how this SNP contributed to MS pathogenesis.

  14. Livestock-Associated Methicillin Resistant and Methicillin Susceptible Staphylococcus aureus Sequence Type (CC)1 in European Farmed Animals: High Genetic Relatedness of Isolates from Italian Cattle Herds and Humans

    DEFF Research Database (Denmark)

    Alba, Patricia; Feltrin, Fabiola; Cordaro, Gessica;

    2015-01-01

    Italian dairy cattle herds. The aim of this study was to analyse the differences between ST1 MRSA and methicillin-susceptible S. aureus (MSSA) from cattle and pig herds in Italy and Europe and human isolates. Sixty-tree animal isolates from different holdings and 20 human isolates were characterized by...... pulsed-field gel electrophoresis (PFGE), spa-typing, SCCmec typing, and by micro-array analysis for several virulence, antimicrobial resistance, and strain/host-specific marker genes. Three major PFGE clusters were detected. The bovine isolates shared a high (>= 90% to 100%) similarity with human...... isolates and carried the same SCCmec type IVa. They often showed genetic features typical of human adaptation or present in human-associated CC1: Immune evasion cluster (IEC) genes sak and scn, or sea; sat and aphA3-mediated aminoglycoside resistance. Contrary, typical markers of porcine origin in Italy...

  15. A PCA-based method for ancestral informative markers selection in structured populations

    Institute of Scientific and Technical Information of China (English)

    ZHANG Feng; ZHANG Lei; DENG Hong-Wen

    2009-01-01

    Identification of population structure can help trace population histories and identify disease genes.Structured association (SA) is a commonly used approach for population structure identification and association mapping. A major issue with SA is that its performance greatly depends on the informativeness and the numbers of ancestral informative markers (AIMs). Present major AIM selection methods mostly require prior individual ancestry information, which is usually not available or uncertain in practice. To address this potential weakness, we herein develop a novel approach for AIM selection based on principle component analysis (PCA), which does not require prior ancestry information of study subjects. Our simulation and real genetic data analysis results suggest that, with equivalent AIMs,PCA-based selected AIMs can significantly increase the accuracy of inferred individual ancestries compared with traditionally randomly selected AIMs. Our method can easily be applied to whole genome data to select a set of highly informative AIMs in population structure, which can then be used to identify potential population structure and correct possible statistical biases caused by population stratification.

  16. A PCA-based method for ancestral informative markers selection in structured populations

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Identification of population structure can help trace population histories and identify disease genes. Structured association (SA) is a commonly used approach for population structure identification and association mapping. A major issue with SA is that its performance greatly depends on the informa-tiveness and the numbers of ancestral informative markers (AIMs). Present major AIM selection meth-ods mostly require prior individual ancestry information, which is usually not available or uncertain in practice. To address this potential weakness, we herein develop a novel approach for AIM selection based on principle component analysis (PCA), which does not require prior ancestry information of study subjects. Our simulation and real genetic data analysis results suggest that, with equivalent AIMs, PCA-based selected AIMs can significantly increase the accuracy of inferred individual ancestries compared with traditionally randomly selected AIMs. Our method can easily be applied to whole genome data to select a set of highly informative AIMs in population structure, which can then be used to identify potential population structure and correct possible statistical biases caused by population stratification.

  17. Identification of an SCLC susceptibility rs7963551 genetic polymorphism in a previously GWAS-identified 12p13.33 RAD52 lung cancer risk locus in the Chinese population

    Science.gov (United States)

    Han, Sichong; Gao, Feng; Yang, Wenjun; Ren, Yanli; Liang, Xue; Xiong, Xiangyu; Pan, Wenting; Zhou, Liqing; Zhou, Changchun; Ma, Fei; Yang, Ming

    2015-01-01

    As a well-known DNA repair gene, RAD52 plays an essential role in homologous recombination repair of double strand break, maintenance of genomic stability and prevention of cell malignant transformation. Previous genome-wide association studies (GWASs) have identified common genetic variants at 12p13.33 RAD52 locus associated with lung cancer risk in Caucasians. However, little or nothing has been known about the RAD52 single nucleotide polymorphisms (SNPs) in small cell lung cancer (SCLC) in the Chinese population. As a result, we examined the association between six RAD52 SNPs (rs10849605, rs1051669, rs10774474, rs11571378, rs7963551 and rs6489769) and SCLC susceptibility in Chinese. After 520 SCLC cases and 1040 controls in two independent case-control sets were genotyped, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. We found that only the RAD52 rs7963551 SNP was significantly associated with SCLC risk among six RAD52 SNPs genotyped. The odds of having the rs7963551 CA genotype in SCLC patients was 0.38 (95% CI = 0.24-0.62, P = 1.1×10-4) compared with the CC genotype. Stratified analyses of association between rs7963551 SNP and SCLC risk indicated that the functional polymorphism was only significantly associated with decreased risk among smokers but not nonsmokers. Our results demonstrated that the functional RAD52 rs7963551 SNP contributes to susceptibility to developing SCLC in the Chinese population. PMID:26629180

  18. Phylogenetic analysis of a newfound bat-borne hantavirus supports a laurasiatherian host association for ancestral mammalian hantaviruses.

    Science.gov (United States)

    Witkowski, Peter T; Drexler, Jan F; Kallies, René; Ličková, Martina; Bokorová, Silvia; Mananga, Gael D; Szemes, Tomáš; Leroy, Eric M; Krüger, Detlev H; Drosten, Christian; Klempa, Boris

    2016-07-01

    Until recently, hantaviruses (family Bunyaviridae) were believed to originate from rodent reservoirs. However, genetically distinct hantaviruses were lately found in shrews and moles, as well as in bats from Africa and Asia. Bats (order Chiroptera) are considered important reservoir hosts for emerging human pathogens. Here, we report on the identification of a novel hantavirus, provisionally named Makokou virus (MAKV), in Noack's Roundleaf Bat (Hipposideros ruber) in Gabon, Central Africa. Phylogenetic analysis of the genomic l-segment showed that MAKV was the most closely related to other bat-borne hantaviruses and shared a most recent common ancestor with the Asian hantaviruses Xuan Son and Laibin. Breakdown of the virus load in a bat animal showed that MAKV resembles rodent-borne hantaviruses in its organ distribution in that it predominantly occurred in the spleen and kidney; this provides a first insight into the infection pattern of bat-borne hantaviruses. Ancestral state reconstruction based on a tree of l gene sequences of all relevant hantavirus lineages was combined with phylogenetic fossil host hypothesis testing, leading to a statistically significant rejection of the mammalian superorder Euarchontoglires (including rodents) but not the superorder Laurasiatheria (including shrews, moles, and bats) as potential hosts of ancestral hantaviruses at most basal tree nodes. Our data supports the emerging concept of bats as previously overlooked hantavirus reservoir hosts. PMID:27051047

  19. Genetic Polymorphism of NOS3 with Susceptibility to Deep Vein Thrombosis after Orthopedic Surgery: A Case-Control Study in Chinese Han Population

    OpenAIRE

    Qin, Jizheng; Dai, Jin; Xu, Zhihong; Chen, Dongyang; Qin, Jianghui; Shi, Dongquan; Teng, Huajian; Jiang, Qing

    2013-01-01

    Deep vein thrombosis is one of the common complications of orthopedic surgery. Studies indicated that genetic factors played a considerable role in the pathogenesis of deep vein thrombosis. Endothelial nitric oxide synthase which encoded by nitric oxide synthase 3 (NOS3), can generate nitric oxide in endothelial cells. As a predominant regulator for vascular homeostasis, nitric oxide might be involved in the pathogenesis of thrombosis. It had been proved that the NOS3 polymorphism (rs1799983)...

  20. Confirmation of Genetic Associations at ELMO1 in the GoKinD Collection Supports Its Role as a Susceptibility Gene in Diabetic Nephropathy

    OpenAIRE

    Katavetin, Pisut; Kure, Masahiko; Poznik, G. David; Mychaleckyj, Josyf C.; Rich, Stephen S.; Warram, James H.; Pezzolesi, Marcus Guy; Skupien, Jan Krzysztof; Krolewski, Andrzej Stefan

    2009-01-01

    Objective: To examine the association between single nucleotide polymorphisms (SNPs) in the engulfment and cell motility 1 (ELMO1) gene, a locus previously shown to be associated with diabetic nephropathy in two ethnically distinct type 2 diabetic populations, and the risk of nephropathy in type 1 diabetes. Research Design and Methods: Genotypic data from a genome-wide association scan (GWAS) of the Genetics of Kidneys in Diabetes (GoKinD) study collection were analyzed for associations acros...

  1. Critical Effects of Urbanization on a Charismatic Carnivore: Genetic Change, Disease and Toxicant Exposure, and Disease Susceptibility in Bobcat Populations in an Urban, Fragmented Landscape

    OpenAIRE

    Serieys, Laurel EK

    2014-01-01

    Urbanization has profound ecological impacts that reach beyond city boundaries. Obvious ecological consequences of urbanization include habitat loss and fragmentation. Anthropogenic barriers reduce habitat connectivity, impede gene flow between populations and accelerate the loss of genetic diversity in populations due to drift. Urbanization may have also cryptic consequences such as the effects of human-introduced toxicants on wildlife populations. Toxicants are a leading cause of population...

  2. Human Capital and Genetic Diversity

    OpenAIRE

    Sequeira, Tiago; Santos, Marcelo,; Ferreira-Lopes, Alexandra

    2013-01-01

    The determinants of human capital have been studied sparsely in the literature. Although there is a huge literature on the determinants of schooling linked with the quality of schooling, there are not many contributions that explore the deep determinants of investment in, quantity and quality of human capital. This paper investigates the relationship between human capital and the ancestral genetic diversity of populations. It highlights a strong hump-shaped relationship between genetic divers...

  3. Reconstructing the ancestral germ line methylation state of young repeats.

    Science.gov (United States)

    Feuerbach, Lars; Lyngsø, Rune B; Lengauer, Thomas; Hein, Jotun

    2011-06-01

    One of the key objectives of comparative genomics is the characterization of the forces that shape genomes over the course of evolution. In the last decades, evidence has been accumulated that for vertebrate genomes also epigenetic modifications have to be considered in this context. Especially, the elevated mutation frequency of 5-methylcytosine (5mC) is assumed to facilitate the depletion of CpG dinucleotides in species that exhibit global DNA methylation. For instance, the underrepresentation of CpG dinucleotides in many mammalian genomes is attributed to this effect, which is only neutralized in so-called CpG islands (CGIs) that are preferentially unmethylated and thus partially protected from rapid CpG decay. For primate-specific CpG-rich transposable elements from the ALU family, it is unclear whether their elevated CpG frequency is caused by their small age or by the absence of DNA methylation. In consequence, these elements are often misclassified in CGI annotations. We present a method for the estimation of germ line methylation from pairwise ancestral-descendant alignments. The approach is validated in a simulation study and tested on DNA repeats from the AluSx family. We conclude that a predicted unmethylated state in the germ line is highly correlated with epigenetic activity of the respective genomic region. Thus, CpG-rich repeats can be facilitated as in silico probes for the epigenetic potential of their genomic neighborhood. PMID:21212152

  4. An ancestral HIV-2/simian immunodeficiency virus peptide with potent HIV-1 and HIV-2 fusion inhibitor activity

    OpenAIRE

    Borrego, Pedro; Calado, Rita; Marcelino, José M.; Pereira, Patrícia MR; Quintas, Alexandre; Barroso, Helena; Taveira, Nuno

    2013-01-01

    "Objectives: To produce new fusion inhibitor peptides for HIV-1 and HIV-2 based on ancestral envelope sequences. Methods: HIV-2/simian immunodeficiency virus (SIV) ancestral transmembrane protein sequences were reconstructed and ancestral peptides were derived from the helical region 2 (HR2). The activity of one ancestral peptide (named P3) was examined against a panel of HIV-1 and HIV-2 primary isolates in TZM-bl cells and peripheral blood mononuclear cells and compared to ...

  5. Flavivirus susceptibility in Aedes aegypti.

    Science.gov (United States)

    Black, William C; Bennett, Kristine E; Gorrochótegui-Escalante, Norma; Barillas-Mury, Carolina V; Fernández-Salas, Ildefonso; de Lourdes Muñoz, María; Farfán-Alé, José A; Olson, Ken E; Beaty, Barry J

    2002-01-01

    Aedes aegypti is the primary vector of yellow fever (YF) and dengue fever (DF) flaviviruses worldwide. In this review we focus on past and present research on genetic components and environmental factors in Aedes aegypti that appear to control flavivirus transmission. We review genetic relationships among Ae. aegypti populations throughout the world and discuss how variation in vector competence is correlated with overall genetic differences among populations. We describe current research into how genetic and environmental factors jointly affect distribution of vector competence in natural populations. Based on this information, we propose a population genetic model for vector competence and discuss our recent progress in testing this model. We end with a discussion of approaches being taken to identify the genes that may control flavivirus susceptibility in Ae. aegypti. PMID:12234528

  6. Paraphyly of organelle DNAs in Cycas Sect. Asiorientales due to ancient ancestral polymorphisms

    Directory of Open Access Journals (Sweden)

    Hsu Tsai-Wen

    2009-07-01

    Full Text Available Abstract Background This study addresses the apportionment of genetic diversity between Cycas revoluta and C. taitungensis, species that constitute the section Asiorientales and represent a unique, basal lineage of the Laurasian genus Cycas. Fossil evidence indicates divergence of the section from the rest of Cycas at least 30 million years ago. Geographically, C. taitungensis is limited to Taiwan whereas C. revoluta is found in the Ryukyu Archipelago and on mainland China. Results The phylogenies of ribosomal ITS region of mtDNA and the intergenic spacer between atpB and rbcL genes of cpDNA were reconstructed. Phylogenetic analyses revealed paraphyly of both loci in the two species and also in the section Asiorientales. The lack of reciprocal monophyly between these long isolated sections is likely due to persistent shared ancestral polymorphisms. Molecular dating estimated that mt- and cp DNA lineages coalesced to the most recent common ancestors (TMRCA about 327 (mt and 204 MYA (cp, corresponding with the divergence of cycad sections in the Mesozoic. Conclusion Fates of newly derived mutations of cycads follow Klopfstein et al.'s surfing model where the majority of new mutations do not spread geographically and remain at low frequencies or are eventually lost by genetic drift. Only successful 'surfing mutations' reach very high frequencies and occupy a large portion of a species range. These mutations exist as dominant cytotypes across populations and species. Geographical subdivision is lacking in both species, even though recurrent gene flow by both pollen and seed is severely limited. In total, the contrasting levels between historical and ongoing gene flow, large population sizes, a long lifespan, and slow mutation rates in both organelle DNAs have all likely contributed to the unusually long duration of paraphyly in cycads.

  7. Is Chronic Low Back Pain Associated with the Prevalence of Coronary Heart Disease when Genetic Susceptibility Is Considered? A Co-Twin Control Study of Spanish Twins

    Science.gov (United States)

    Fernandez, Matt; Ordoñana, Juan R.; Hartvigsen, Jan; Ferreira, Manuela L.; Refshauge, Kathryn M.; Sánchez-Romera, Juan F.; Pinheiro, Marina B.; Simpson, Stephen J.; Hopper, John L.; Ferreira, Paulo H.

    2016-01-01

    Objective To investigate the chronic low back pain and coronary heart disease relationship, after adjusting for relevant confounders, including genetics. Methods In a cross-sectional design, 2148 twins were recruited from the Murcia Twin Registry, Spain. The exposure was chronic LBP and the outcomes were myocardial infarction and other coronary heart diseases—lifetime and in the last 2 years–based on standardized health-related questionnaires. First, logistic regression analysis investigated associations of the total sample followed by a matched co-twin control analyses, with all complete twin pairs discordant for chronic LBP utilised, separated for zygosity—dizygotic (DZ) and monozygotic (MZ) pairs, which adjusted for shared familial factors, including genetics. Results Chronic LBP pain is associated with lifetime myocardial infarction [odds ratio (OR) = 2.69, 95% confidence interval (CI) = 1.35–5.36], other coronary heart diseases over a lifetime (OR = 2.58, 95% CI: 1.69–3.93) and in the last two years (OR = 2.19, 95% CI: 1.33–3.60), while there was a borderline association with myocardial infarction in the last 2 years (OR = 2.64, 95% CI: 0.98–7.12). Although the magnitude of the association remained or increased in the co-twin control analyses, none reached statistical significance. Conclusion Chronic LBP is associated with a higher prevalence of myocardial infarction and coronary heart disease. It is possible that this association remains even when controlling for genetics and early shared environment, although this should be investigated with larger samples of twins discordant for LBP. PMID:27171210

  8. Genetic Analysis of the Influence of Neuroantigen-Complete Freund’s Adjuvant Emulsion Structures on the Sexual Dimorphism and Susceptibility to Experimental Allergic Encephalomyelitis

    OpenAIRE

    Fillmore, Parley D.; Brace, Matthew; Troutman, Scott A.; Blankenhorn, Elizabeth P.; Diehl, Sean; Rincon, Mercedes; Teuscher, Cory

    2003-01-01

    The induction of organ-specific autoimmune diseases, such as experimental allergic encephalomyelitis (EAE) the principal animal model of multiple sclerosis (MS), relies on the use of complete Freund’s adjuvant (CFA) emulsions. In this study we report that the physical structure of the particles comprising neuroantigen-CFA emulsions significantly influences the genetic control of the incidence and sexual dimorphism seen in EAE. Immunization of (B10.S/SgMcdJ × SJL/J) F2 mice segregating the qua...

  9. Genetic Analysis of Innate Immunity in Crohn's Disease and Ulcerative Colitis Identifies Two Susceptibility Loci Harboring CARD9 and IL18RAP

    OpenAIRE

    Zhernakova, Alexandra; Festen, Eleanora M.; Franke, Lude; Trynka, Gosia; Diemen, Cleo C van; Monsuur, Alienke J.; Bevova, Marianna; Nijmeijer, Rian M.; van ‘t Slot, Ruben; Heijmans, Roel; Boezen, H. Marike; van Heel, David A; van Bodegraven, Adriaan A.; Stokkers, Pieter C. F.; Wijmenga, Cisca

    2008-01-01

    The two main phenotypes of inflammatory bowel disease (IBD)—Crohn's disease (CD) and ulcerative colitis (UC)—are chronic intestinal inflammatory disorders with a complex genetic background. Using a three-stage design, we performed a functional candidate-gene analysis of innate immune pathway in IBD. In phase I, we typed 354 SNPs from 85 innate immunity genes in 520 Dutch IBD patients (284 CD, 236 UC) and 808 controls. In phase II, ten autosomal SNPs showing association at p < 0.006 in phase I...

  10. Genetic polymorphisms of T-1131C APOA5 and ALOX5AP SG13S114 with the susceptibility of ischemic stroke in Morocco

    Indian Academy of Sciences (India)

    BREHIMA DIAKITE; KHALIL HAMZI; WIAM HMIMECH; SELLAMA NADIFI; GMRAVC

    2016-06-01

    Ischaemic stroke is a multifactorial disease. Genetic polymorphisms involved in lipid, inflammatory and thromboticmetabolisms play an important role in the development of ischaemic stroke. The present study aimed to assess the relationshipbetweenT1131C APOA5andSG13S114 ALOX5APpolymorphisms and the risk of ischemic stroke in 175 cases and 201 con-trols. Genotyping was performed by high resolution melting and polymerase chain reaction restriction fragment length poly-morphism methods. In the case ofT-1131C APOA5 , a modest risk of ischaemic stroke was noticed with CC (OR: 2.86; 95%CI =1.24–6.58; Pc =0.039) and C allele (OR: 1.54; 95% CI =1.01–2.33; Pc =0.014). ForSG13S114 ALOX5AP , a signifi-cant association was observed among subjects with TT (OR: 2.57; 95% CI =1.49–4.83; Pc =0.009) and T allele (OR: 1.59;95% CI =1.16–2.19; Pc =0.008). According to the risk factors of ischaemic stroke, a positive correlation was observed onlybetweenSG13S114variant ofALOX5APgene and hypertension (Pc =0.026). Despite lower sample size,T-1131C APOA5andSG13S114variants could be considered an independent genetic risk factor of ischaemic stroke in Moroccan population

  11. Association study of genetic variants at single nucleotide polymorphism rs109231409 of mannose-binding lectins 1 gene with mastitis susceptibility in Vrindavani crossbred cattle

    Directory of Open Access Journals (Sweden)

    V. N. Muhasin Asaf

    2014-10-01

    Full Text Available Aim: The present study was undertaken to identify whether single nucleotide polymorphism (SNP rs109231409 located on mannose-binding lectins 1 (MBL1 gene was associated with mastitis tolerance/susceptibility. Materials and Methods: After grouping 100 Vrindavani crossbred cattle as mastitis positive and negative animals, they were genotyped using polymerase chain reaction (PCR-restriction fragment length polymorphisms method. Gene and genotype frequencies of different patterns were estimated by standard procedure (POPGENE version 1.32, (University of Alberta, Canada and statistical analysis was carried out by logistic regression methods using STATA 12 software (StataCorp LP, USA. Results: The 588 bp fragment of MBL1 gene was amplified using PCR. PCR product was digested with ApaI restriction enzyme showed two distinct genotypes viz., GG (311 bp and 272 bp fragments and GA (588 bp, 311 bp and 277 bp fragments. The gene, genotype frequencies, average heterozygosity, polymorphic information content and χ2 values for the locus rs109231409 was ascertained. Conclusions: No significant association between SNP “rs109231409” with mastitis tolerance was found. Although there is a lack of association, further studies have to be undertaken in a large population in order to validate the impact of rs109231409 (g.855G >A on mastitis tolerance.

  12. Antimicrobial susceptibility and genetic characteristics of Haemophilus influenzae isolated from community-acquired respiratory tract infection patients in Shanghai City, China.

    Science.gov (United States)

    Qin, Liang; Zhou, Zhaoyan; Hu, Bijie; Yamamoto, Taro; Watanabe, Hiroshi

    2012-08-01

    Haemophilus influenzae is an important causative pathogen of community-acquired respiratory infection in China. In this study we investigated 37 H. influenzae strains isolated from patients with community-acquired respiratory tract infections (CARTI) in Shanghai city between Dec 2008 and Apr 2009. H. influenzae clinical isolates were identified, and b-lactamase production tests were conducted and minimal inhibitory concentrations(MIC) were measured. Pulsed-field gel electrophoresis(PFGE) was introduced as an effective finger printing method. Two isolates (5.4%) were verified as serotype b strains, and 30 strains (81.1%) were nontypeable H. influenzae. Furthermore, 10 (27.0%) were b-lactamase-producing ampicillin-resistance (BLPAR) (TEM-1 type)strains, 11 (29.8%) were low-b-lactamase-nonproducing ampicillin-resistant H. influenzae (Low-BLNAR) strains,and the rest were b-lactamase-negative ampicillin-susceptible(BLNAS) strains. Minimum inhibitory concentrations(MIC90; lg/ml) were 2 for ampicillin/sulbactam, 0.05 force fotaxime, 16 for cefaclor, 2 for azithromycin, 0.12 for levofloxacin, and 4 for imipenem. Fingerprint typing by PFGE revealed 23 independent patterns for the isolates. Pattern A (defined in this study) was predominant in BLPAR strains, and a variety of other patterns were detected in Low-BLNAR and BLNAS strains. Although the incidence of ampicillin resistant H. influenzae is increasing in CARTI patients in China, current antimicrobial chemotherapy seems to be effective. PMID:22302696

  13. Ancient hybridizations among the ancestral genomes of bread wheat

    Czech Academy of Sciences Publication Activity Database

    Marcussen, T.; Sandve, S. R.; Heier, L.; Spannagl, M.; Pfeifer, M.; Rogers, J.; Doležel, Jaroslav; Pozniak, C.; Eversole, K.; Feuillet, C.; Gill, B.; Friebe, B.; Lukaszewski, A.J.; Sourdille, P.; Endo, T. R.; Kubaláková, Marie; Čihalíková, Jarmila; Dubská, Zdeňka; Vrána, Jan; Šperková, Romana; Šimková, Hana; Febrer, M.; Clissold, L.; Jakobsen, K. S.; Wulff, B.H.; Steuernagel, B.; Mayer, K. F. X.; Olsen, O.A.

    2014-01-01

    Roč. 345, č. 6194 (2014). ISSN 0036-8075 Institutional support: RVO:61389030 Keywords : POLYPLOID WHEAT * HYBRID SPECIATION * AEGILOPS-TAUSCHII Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 33.611, year: 2014

  14. Estimating Divergence Time and Ancestral Effective Population Size of Bornean and Sumatran Orangutan Subspecies Using a Coalescent Hidden Markov Model

    DEFF Research Database (Denmark)

    Mailund, Thomas; Dutheil, Julien; Hobolth, Asger;

    2011-01-01

    ue to genetic variation in the ancestor of two populations or two species, the divergence time for DNA sequences from two populations is variable along the genome. Within genomic segments all bases will share the same divergence—because they share a most recent common ancestor—when no recombination...... event has occurred to split them apart. The size of these segments of constant divergence depends on the recombination rate, but also on the speciation time, the effective population size of the ancestral population, as well as demographic effects and selection. Thus, inference of these parameters may...... be possible if we can decode the divergence times along a genomic alignment. Here, we present a new hidden Markov model that infers the changing divergence (coalescence) times along the genome alignment using a coalescent framework, in order to estimate the speciation time, the recombination rate...

  15. Analysis of variations in the glutamate receptor, N-methyl D-aspartate 2A (GRIN2A gene reveals their relative importance as genetic susceptibility factors for heroin addiction.

    Directory of Open Access Journals (Sweden)

    Bin Zhao

    Full Text Available The glutamate receptor, N-methyl D-aspartate 2A (GRIN2A gene that encodes the 2A subunit of the N-methyl D-aspartate (NMDA receptor was recently shown to be involved in the development of opiate addiction. Genetic polymorphisms in GRIN2A have a plausible role in modulating the risk of heroin addiction. An association of GRIN2A single-nucleotide polymorphisms (SNPs with heroin addiction was found earlier in African Americans. To identify markers that contribute to the genetic susceptibility to heroin addiction, we examined the potential association between heroin addiction and forty polymorphisms of the GRIN2A gene using the MassARRAY system and GeneScan in this study. The frequency of the (GT26 repeats (rs3219790 in the heroin addiction group was significantly higher than that in the control group (χ(2 = 5.360, P = 0.021. The allele frequencies of three polymorphisms (rs1102972, rs1650420, and rs3104703 in intron 3 were strongly associated with heroin addiction (P<0.001, 0.0002, and <0.001, after Bonferroni correction. Three additional SNPs from the same intron (rs1071502, rs6497730, and rs1070487 had nominally significant P values for association (P<0.05, but did not pass the threshold value. Haplotype analysis revealed that the G-C-T-C-C-T-A (block 6 and T-T (block 10 haplotypes of the GRIN2A gene displayed a protective effect (P = <0.001 and 0.003. These findings point to a role for GRIN2A polymorphisms in heroin addiction among the Han Chinese from Shaanxi province, and may be informative for future genetic or neurobiological studies on heroin addiction.

  16. Genome-wide inference of ancestral recombination graphs.

    Science.gov (United States)

    Rasmussen, Matthew D; Hubisz, Melissa J; Gronau, Ilan; Siepel, Adam

    2014-01-01

    The complex correlation structure of a collection of orthologous DNA sequences is uniquely captured by the "ancestral recombination graph" (ARG), a complete record of coalescence and recombination events in the history of the sample. However, existing methods for ARG inference are computationally intensive, highly approximate, or limited to small numbers of sequences, and, as a consequence, explicit ARG inference is rarely used in applied population genomics. Here, we introduce a new algorithm for ARG inference that is efficient enough to apply to dozens of complete mammalian genomes. The key idea of our approach is to sample an ARG of [Formula: see text] chromosomes conditional on an ARG of [Formula: see text] chromosomes, an operation we call "threading." Using techniques based on hidden Markov models, we can perform this threading operation exactly, up to the assumptions of the sequentially Markov coalescent and a discretization of time. An extension allows for threading of subtrees instead of individual sequences. Repeated application of these threading operations results in highly efficient Markov chain Monte Carlo samplers for ARGs. We have implemented these methods in a computer program called ARGweaver. Experiments with simulated data indicate that ARGweaver converges rapidly to the posterior distribution over ARGs and is effective in recovering various features of the ARG for dozens of sequences generated under realistic parameters for human populations. In applications of ARGweaver to 54 human genome sequences from Complete Genomics, we find clear signatures of natural selection, including regions of unusually ancient ancestry associated with balancing selection and reductions in allele age in sites under directional selection. The patterns we observe near protein-coding genes are consistent with a primary influence from background selection rather than hitchhiking, although we cannot rule out a contribution from recurrent selective sweeps. PMID:24831947

  17. Genome-wide inference of ancestral recombination graphs.

    Directory of Open Access Journals (Sweden)

    Matthew D Rasmussen

    Full Text Available The complex correlation structure of a collection of orthologous DNA sequences is uniquely captured by the "ancestral recombination graph" (ARG, a complete record of coalescence and recombination events in the history of the sample. However, existing methods for ARG inference are computationally intensive, highly approximate, or limited to small numbers of sequences, and, as a consequence, explicit ARG inference is rarely used in applied population genomics. Here, we introduce a new algorithm for ARG inference that is efficient enough to apply to dozens of complete mammalian genomes. The key idea of our approach is to sample an ARG of [Formula: see text] chromosomes conditional on an ARG of [Formula: see text] chromosomes, an operation we call "threading." Using techniques based on hidden Markov models, we can perform this threading operation exactly, up to the assumptions of the sequentially Markov coalescent and a discretization of time. An extension allows for threading of subtrees instead of individual sequences. Repeated application of these threading operations results in highly efficient Markov chain Monte Carlo samplers for ARGs. We have implemented these methods in a computer program called ARGweaver. Experiments with simulated data indicate that ARGweaver converges rapidly to the posterior distribution over ARGs and is effective in recovering various features of the ARG for dozens of sequences generated under realistic parameters for human populations. In applications of ARGweaver to 54 human genome sequences from Complete Genomics, we find clear signatures of natural selection, including regions of unusually ancient ancestry associated with balancing selection and reductions in allele age in sites under directional selection. The patterns we observe near protein-coding genes are consistent with a primary influence from background selection rather than hitchhiking, although we cannot rule out a contribution from recurrent selective

  18. Ancestral Genomes, Sex, and the Population Structure of Trypanosoma cruzi.

    Directory of Open Access Journals (Sweden)

    2006-03-01

    Full Text Available Acquisition of detailed knowledge of the structure and evolution of Trypanosoma cruzi populations is essential for control of Chagas disease. We profiled 75 strains of the parasite with five nuclear microsatellite loci, 24Salpha RNA genes, and sequence polymorphisms in the mitochondrial cytochrome oxidase subunit II gene. We also used sequences available in GenBank for the mitochondrial genes cytochrome B and NADH dehydrogenase subunit 1. A multidimensional scaling plot (MDS based in microsatellite data divided the parasites into four clusters corresponding to T. cruzi I (MDS-cluster A, T. cruzi II (MDS-cluster C, a third group of T. cruzi strains (MDS-cluster B, and hybrid strains (MDS-cluster BH. The first two clusters matched respectively mitochondrial clades A and C, while the other two belonged to mitochondrial clade B. The 24Salpha rDNA and microsatellite profiling data were combined into multilocus genotypes that were analyzed by the haplotype reconstruction program PHASE. We identified 141 haplotypes that were clearly distributed into three haplogroups (X, Y, and Z. All strains belonging to T. cruzi I (MDS-cluster A were Z/Z, the T. cruzi II strains (MDS-cluster C were Y/Y, and those belonging to MDS-cluster B (unclassified T. cruzi had X/X haplogroup genotypes. The strains grouped in the MDS-cluster BH were X/Y, confirming their hybrid character. Based on these results we propose the following minimal scenario for T. cruzi evolution. In a distant past there were at a minimum three ancestral lineages that we may call, respectively, T. cruzi I, T. cruzi II, and T. cruzi III. At least two hybridization events involving T. cruzi II and T. cruzi III produced evolutionarily viable progeny. In both events, the mitochondrial recipient (as identified by the mitochondrial clade of the hybrid strains was T. cruzi II and the mitochondrial donor was T. cruzi III.

  19. The Korarchaeota: Archaeal orphans representing an ancestral lineage of life

    Energy Technology Data Exchange (ETDEWEB)

    Elkins, James G.; Kunin, Victor; Anderson, Iain; Barry, Kerrie; Goltsman, Eugene; Lapidus, Alla; Hedlund, Brian; Hugenholtz, Phil; Kyrpides, Nikos; Graham, David; Keller, Martin; Wanner, Gerhard; Richardson, Paul; Stetter, Karl O.

    2007-05-01

    Based on conserved cellular properties, all life on Earth can be grouped into different phyla which belong to the primary domains Bacteria, Archaea, and Eukarya. However, tracing back their evolutionary relationships has been impeded by horizontal gene transfer and gene loss. Within the Archaea, the kingdoms Crenarchaeota and Euryarchaeota exhibit a profound divergence. In order to elucidate the evolution of these two major kingdoms, representatives of more deeply diverged lineages would be required. Based on their environmental small subunit ribosomal (ss RNA) sequences, the Korarchaeota had been originally suggested to have an ancestral relationship to all known Archaea although this assessment has been refuted. Here we describe the cultivation and initial characterization of the first member of the Korarchaeota, highly unusual, ultrathin filamentous cells about 0.16 {micro}m in diameter. A complete genome sequence obtained from enrichment cultures revealed an unprecedented combination of signature genes which were thought to be characteristic of either the Crenarchaeota, Euryarchaeota, or Eukarya. Cell division appears to be mediated through a FtsZ-dependent mechanism which is highly conserved throughout the Bacteria and Euryarchaeota. An rpb8 subunit of the DNA-dependent RNA polymerase was identified which is absent from other Archaea and has been described as a eukaryotic signature gene. In addition, the representative organism possesses a ribosome structure typical for members of the Crenarchaeota. Based on its gene complement, this lineage likely diverged near the separation of the two major kingdoms of Archaea. Further investigations of these unique organisms may shed additional light onto the evolution of extant life.

  20. β-Propeller blades as ancestral peptides in protein evolution.

    Directory of Open Access Journals (Sweden)

    Klaus O Kopec

    Full Text Available Proteins of the β-propeller fold are ubiquitous in nature and widely used as structural scaffolds for ligand binding and enzymatic activity. This fold comprises between four and twelve four-stranded β-meanders, the so called blades that are arranged circularly around a central funnel-shaped pore. Despite the large size range of β-propellers, their blades frequently show sequence similarity indicative of a common ancestry and it has been proposed that the majority of β-propellers arose divergently by amplification and diversification of an ancestral blade. Given the structural versatility of β-propellers and the hypothesis that the first folded proteins evolved from a simpler set of peptides, we investigated whether this blade may have given rise to other folds as well. Using sequence comparisons, we identified proteins of four other folds as potential homologs of β-propellers: the luminal domain of inositol-requiring enzyme 1 (IRE1-LD, type II β-prisms, β-pinwheels, and WW domains. Because, with increasing evolutionary distance and decreasing sequence length, the statistical significance of sequence comparisons becomes progressively harder to distinguish from the background of convergent similarities, we complemented our analyses with a new method that evaluates possible homology based on the correlation between sequence and structure similarity. Our results indicate a homologous relationship of IRE1-LD and type II β-prisms with β-propellers, and an analogous one for β-pinwheels and WW domains. Whereas IRE1-LD most likely originated by fold-changing mutations from a fully formed PQQ motif β-propeller, type II β-prisms originated by amplification and differentiation of a single blade, possibly also of the PQQ type. We conclude that both β-propellers and type II β-prisms arose by independent amplification of a blade-sized fragment, which represents a remnant of an ancient peptide world.

  1. β-Propeller Blades as Ancestral Peptides in Protein Evolution

    Science.gov (United States)

    Kopec, Klaus O.; Lupas, Andrei N.

    2013-01-01

    Proteins of the β-propeller fold are ubiquitous in nature and widely used as structural scaffolds for ligand binding and enzymatic activity. This fold comprises between four and twelve four-stranded β-meanders, the so called blades that are arranged circularly around a central funnel-shaped pore. Despite the large size range of β-propellers, their blades frequently show sequence similarity indicative of a common ancestry and it has been proposed that the majority of β-propellers arose divergently by amplification and diversification of an ancestral blade. Given the structural versatility of β-propellers and the hypothesis that the first folded proteins evolved from a simpler set of peptides, we investigated whether this blade may have given rise to other folds as well. Using sequence comparisons, we identified proteins of four other folds as potential homologs of β-propellers: the luminal domain of inositol-requiring enzyme 1 (IRE1-LD), type II β-prisms, β-pinwheels, and WW domains. Because, with increasing evolutionary distance and decreasing sequence length, the statistical significance of sequence comparisons becomes progressively harder to distinguish from the background of convergent similarities, we complemented our analyses with a new method that evaluates possible homology based on the correlation between sequence and structure similarity. Our results indicate a homologous relationship of IRE1-LD and type II β-prisms with β-propellers, and an analogous one for β-pinwheels and WW domains. Whereas IRE1-LD most likely originated by fold-changing mutations from a fully formed PQQ motif β-propeller, type II β-prisms originated by amplification and differentiation of a single blade, possibly also of the PQQ type. We conclude that both β-propellers and type II β-prisms arose by independent amplification of a blade-sized fragment, which represents a remnant of an ancient peptide world. PMID:24143202

  2. Low pathogenic avian influenza (H9N2) in chicken: Evaluation of an ancestral H9-MVA vaccine.

    Science.gov (United States)

    Ducatez, Mariette F; Becker, Jens; Freudenstein, Astrid; Delverdier, Maxence; Delpont, Mattias; Sutter, Gerd; Guérin, Jean-Luc; Volz, Asisa

    2016-06-30

    Modified Vaccinia Ankara (MVA) has proven its efficacy as a recombinant vector vaccine for numerous pathogens including influenza virus. The present study aimed at evaluating a recombinant MVA candidate vaccine against low pathogenic avian influenza virus subtype H9N2 in the chicken model. As the high genetic and antigenic diversity of H9N2 viruses increases vaccine design complexity, one strategy to widen the range of vaccine coverage is to use an ancestor sequence. We therefore generated a recombinant MVA encoding for the gene sequence of an ancestral hemagglutinin H9 protein (a computationally derived amino acid sequence of the node of the H9N2 G1 lineage strains was obtained using the ANCESCON program). We analyzed the genetics and the growth properties of the MVA vector virus confirming suitability for use under biosafety level 1 and tested its efficacy when applied either as an intra-muscular (IM) or an oral vaccine in specific pathogen free chickens challenged with A/chicken/Tunisia/12/2010(H9N2). Two control groups were studied in parallel (unvaccinated and inoculated birds; unvaccinated and non-inoculated birds). IM vaccinated birds seroconverted as early as four days post vaccination and neutralizing antibodies were detected against A/chicken/Tunisia/12/2010(H9N2) in all the birds before challenge. The role of local mucosal immunity is unclear here as no antibodies were detected in eye drop or aerosol vaccinated birds. Clinical signs were not detected in any of the infected birds even in absence of vaccination. Virus replication was observed in both vaccinated and unvaccinated chickens, suggesting the MVA-ancestral H9 vaccine may not stop virus spread in the field. However vaccinated birds showed less histological damage, fewer influenza-positive cells and shorter virus shedding than their unvaccinated counterparts. PMID:27259828

  3. PhyloBot: A Web Portal for Automated Phylogenetics, Ancestral Sequence Reconstruction, and Exploration of Mutational Trajectories

    Science.gov (United States)

    Hanson-Smith, Victor; Johnson, Alexander

    2016-01-01

    The method of phylogenetic ancestral sequence reconstruction is a powerful approach for studying evolutionary relationships among protein sequence, structure, and function. In particular, this approach allows investigators to (1) reconstruct and “resurrect” (that is, synthesize in vivo or in vitro) extinct proteins to study how they differ from modern proteins, (2) identify key amino acid changes that, over evolutionary timescales, have altered the function of the protein, and (3) order historical events in the evolution of protein function. Widespread use of this approach has been slow among molecular biologists, in part because the methods require significant computational expertise. Here we present PhyloBot, a web-based software tool that makes ancestral sequence reconstruction easy. Designed for non-experts, it integrates all the necessary software into a single user interface. Additionally, PhyloBot provides interactive tools to explore evolutionary trajectories between ancestors, enabling the rapid generation of hypotheses that can be tested using genetic or biochemical approaches. Early versions of this software were used in previous studies to discover genetic mechanisms underlying the functions of diverse protein families, including V-ATPase ion pumps, DNA-binding transcription regulators, and serine/threonine protein kinases. PhyloBot runs in a web browser, and is available at the following URL: http://www.phylobot.com. The software is implemented in Python using the Django web framework, and runs on elastic cloud computing resources from Amazon Web Services. Users can create and submit jobs on our free server (at the URL listed above), or use our open-source code to launch their own PhyloBot server. PMID:27472806

  4. PhyloBot: A Web Portal for Automated Phylogenetics, Ancestral Sequence Reconstruction, and Exploration of Mutational Trajectories.

    Science.gov (United States)

    Hanson-Smith, Victor; Johnson, Alexander

    2016-07-01

    The method of phylogenetic ancestral sequence reconstruction is a powerful approach for studying evolutionary relationships among protein sequence, structure, and function. In particular, this approach allows investigators to (1) reconstruct and "resurrect" (that is, synthesize in vivo or in vitro) extinct proteins to study how they differ from modern proteins, (2) identify key amino acid changes that, over evolutionary timescales, have altered the function of the protein, and (3) order historical events in the evolution of protein function. Widespread use of this approach has been slow among molecular biologists, in part because the methods require significant computational expertise. Here we present PhyloBot, a web-based software tool that makes ancestral sequence reconstruction easy. Designed for non-experts, it integrates all the necessary software into a single user interface. Additionally, PhyloBot provides interactive tools to explore evolutionary trajectories between ancestors, enabling the rapid generation of hypotheses that can be tested using genetic or biochemical approaches. Early versions of this software were used in previous studies to discover genetic mechanisms underlying the functions of diverse protein families, including V-ATPase ion pumps, DNA-binding transcription regulators, and serine/threonine protein kinases. PhyloBot runs in a web browser, and is available at the following URL: http://www.phylobot.com. The software is implemented in Python using the Django web framework, and runs on elastic cloud computing resources from Amazon Web Services. Users can create and submit jobs on our free server (at the URL listed above), or use our open-source code to launch their own PhyloBot server. PMID:27472806

  5. Analysis of the stone ancestral hall of Guo’s tomb on Xiaotang mountainin Han dynasty architectural features

    Institute of Scientific and Technical Information of China (English)

    刘国庆

    2014-01-01

    The stone ancestral hall of Guo’s tomb in Xiaotang mountain is the earliest existing buildings on the ground in China. It has a very high historical, cultural and artistic value, and it was described by the ancient and modern scholars and experts in their books and articles. But the study of architectural of ancestral hall was emphasized from 1930s, and became a brilliant star in the Chinese historic buildings. In this article, the architectural characteristics of the stone ancestral hall are discussed through fieldworks, in order to clarify the real architecture appearance of the ancestral hall and refer more informations for comprehensive study of Xiaotang stone ancestral hall.

  6. Genetic polymorphism of glutathion S-transferase P1 (GSTP1 Ile105Val and susceptibility to atherogenesis in patients with type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Grubiša Ivana

    2013-01-01

    Full Text Available One of the characteristics of type 2 diabetes mellitus (T2DM is the state of persistent oxidative stress (OS that has been implicated in the pathogenesis of diseases such is atherosclerosis mainly through chronic hyperglycemia that stimulates production of reactive oxygen species (ROS and increases OS. Glutathione S-transferase P1 (GSTP1 is a member of the cytosolic GST superfamily. It plays an important role in neutralizing OS as an enzyme. Also, it participates in regulation of stress signaling and protects cells against apoptosis via its noncatalytic ligand-binding activity. GSTP1 Ile105Val functional polymorphism influences protein catalytic activity and stability and the aim of this study was to determine whether this gene variation influences susceptibility to atherogenesis in T2DM patients. A total of 240 individuals (140 patients with T2DM, accompanied with clinical manifestations of atherosclerosis, and 100 healthy controls were included in this study. Genomic DNA was isolated from peripheral blood cells and genotyping was performed using polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP analysis. We obtained no statistically significant differences in the distribution of alleles and genotypes between cases and controls (P>0.05 but association between Ile/Val (OR=0.6, 95%CI=0.35-1.05, P=0.08 and Val/Val (OR=0.45, 95%CI=0.18-1.11, P=0.08 genotypes and disease approached significance (P=0.08. Our results indicated that a larger study group is needed to establish the true relationship between potentialiy protective allele Val and the disease, and to determine the influence of other GSTP1 polymorphisms on atherogenesis in T2DM patients. [Projekat Ministarstva nauke Republike Srbije, br. 175075

  7. Genetic Variation in miR-146a Is Not Associated with Susceptibility to IgA Nephropathy in Adults from a Chinese Han Population.

    Directory of Open Access Journals (Sweden)

    Bin Yang

    Full Text Available MicroRNA 146a (miR-146a is a 19 to 23 nucleotide long, small non-coding RNA with gene regulatory functions that has influence on the pathogenesis of many diseases. A single nucleotide polymorphism (rs2910164 C>G in pre-miR-146a is correlated with the expression of miR-146a. The aim of this study was to perform an association analysis of rs2910164 with IgA nephropathy in adult patients from a Chinese Han population.A total of 145 patients with renal biopsy-proved IgA nephropathy (IgAN and 179 healthy controls were recruited to the current study. rs2910164 was genotyped by the polymerase chain reaction (PCR and high-resolution melting methods (HRM. Clinical characteristics and pathology grading of patients with IgAN were recorded at the time of kidney biopsy.There were significant differences among the population of patients grouped by different age of onset in a co-dominant model (CG vs. CC vs. GG (p = 0.033 and a recessive model (CG+CC vs. GG (p = 0.001. However, no significant difference was observed in the distribution of genotypes between cases and controls (p = 0.144. There was also no significant difference between rs2910164 and patient quantitative traits (all p > 0.003 or different pathology grading (Lee's grading system and tubular atrophy/interstitial fibrosis in the Oxford classification (all p > 0.05.There was no association of rs2910164 with susceptibility to IgAN in adults from a Chinese Han population. However, rs2910164 was correlated with the age of onset of IgAN in adult patients.

  8. An ancestral role for the mitochondrial pyruvate carrier in glucose-stimulated insulin secretion

    Directory of Open Access Journals (Sweden)

    Kyle S. McCommis

    2016-08-01

    Conclusions: Altogether, these studies suggest that the MPC plays an important and ancestral role in insulin-secreting cells in mediating glucose sensing, regulating insulin secretion, and controlling systemic glycemia.

  9. Mapping ancestral genomes with massive gene loss: a matrix sandwich problem.

    OpenAIRE

    Gavranović, Haris; Chauve, Cedric; Salse, Jérôme; Tannier, Eric

    2011-01-01

    MOTIVATION: Ancestral genomes provide a better way to understand the structural evolution of genomes than the simple comparison of extant genomes. Most ancestral genome reconstruction methods rely on universal markers, that is, homologous families of DNA segments present in exactly one exemplar in every considered species. Complex histories of genes or other markers, undergoing duplications and losses, are rarely taken into account. It follows that some ancestors are inaccessible by these met...

  10. Number of ancestral human species: a molecular perspective.

    Science.gov (United States)

    Curnoe, D; Thorne, A

    2003-01-01

    Despite the remarkable developments in molecular biology over the past three decades, anthropological genetics has had only limited impact on systematics in human evolution. Genetics offers the opportunity to objectively test taxonomies based on morphology and may be used to supplement conventional approaches to hominid systematics. Our analyses, examining chromosomes and 46 estimates of genetic distance, indicate there may have been only around 4 species on the direct line to modern humans and 5 species in total. This contrasts with current taxonomies recognising up to 23 species. The genetic proximity of humans and chimpanzees has been used to suggest these species are congeneric. Our analysis of genetic distances between them is consistent with this proposal. It is time that chimpanzees, living humans and all fossil humans be classified in Homo. The creation of new genera can no longer be a solution to the complexities of fossil morphologies. Published genetic distances between common chimpanzees and bonobos, along with evidence for interbreeding, suggest they should be assigned to a single species. The short distance between humans and chimpanzees also places a strict limit on the number of possible evolutionary 'side branches' that might be recognised on the human lineage. All fossil taxa were genetically very close to each other and likely to have been below congeneric genetic distances seen for many mammals. Our estimates of genetic divergence suggest that periods of around 2 million years are required to produce sufficient genetic distance to represent speciation. Therefore, Neanderthals and so-called H. erectus were genetically so close to contemporary H. sapiens they were unlikely to have been separate species. Thus, it is likely there was only one species of human (H. sapiens) for most of the last 2 million years. We estimate the divergence time of H. sapiens from 16 genetic distances to be around 1.7 Ma which is consistent with evidence for the earliest

  11. hOGG1基因多态性与胃癌遗传易感性的关系%Relationship between polymorphism in hOGG1 and XPD and genetic susceptibility to gastric cancer

    Institute of Scientific and Technical Information of China (English)

    于兆亚; 汤静

    2013-01-01

    Objective To investigate the relationship between polymorphism in human 8-oxoguanine DNA glycosylase 1(hOGG1) and xeroderma pigmentosum group D (XPD) and genetic susceptibility to gastric cancer. Methods The peripheral blood samples of 98 cases of gastric cancer and 80 non-tumor volunteers(control group) in Zhengzhou and Kaifeng of Henan were collected, the peripheral DNA repair enzyme gene polymorphism in gastric cancer populations were detected by using polymerase chain reaction restriction fragment length polymorphism(PCR-RFLP), and it's relationship with genetic susceptibility to cancer was analyzed. Results There were significant differences in genotypes frequency of hOGG1Ser326Cys and XPD Lys751Gln between gastric cancer group and control group (P 1, API=0.38). Conclusion The Lys751Gln genotype and susceptibility to gastric cancer in individuals can be relevant. The interaction between carrying Cys or Gln gene-gene and alcohol can increase the susceptibility to gastric cancer.%目的:探讨人类8-羟基鸟嘌呤DNA糖苷酶1(hOGG 1)基因多态性与胃癌遗传易感性的关系。方法收集河南郑州和开封地区98例胃癌患者和80例非肿瘤对照组志愿者外周血样,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)检测法检测胃癌人群的外周血中DNA损伤修复酶基因多态性,分析其与肿瘤遗传易感性的关系。结果 hOGG1Ser326Cys基因的各基因型频率在胃癌组和对照组间的分布差异有统计学意义(P<0.05)。携带Cys326Cys基因型者胃癌的发病风险增加1.7倍(OR=1.706,95%CI=0.341~2.462,P=0.002)。hOGG1Ser 326Cys基因多态性与酒的交互作用增加胃癌的发病风险(S>1,API=0.38)。结论Cys326Cys基因型是胃癌发病的危险基因型,携带Cys易感基因与饮酒交互作用时可能增加患胃癌的易感性。

  12. Novel Gentic Variations Contributing to Asthma Susceptability in Saudi Arabia

    Science.gov (United States)

    2014-04-13

    Collection of Clinical Data That Will be Used in This Study and Will Form a Data Bank for Asthma in Saudi Arabia; Identify Known and NOVEL Genetic Risk Factors Contributing to Asthma Susceptibility; Study the Mechanistic Roles of the Genetic Variants Within Major Asthma Susceptibility Genes

  13. Susceptibility of Children to Sapovirus Infections, Nicaragua, 2005–2006

    OpenAIRE

    Bucardo, Filemón; Carlsson, Beatrice; Nordgren, Johan; Larson, Göran; Blandon, Patricia; Vilchez, Samuel; Svensson, Lennart

    2012-01-01

    We describe the genetic diversity of sapovirus (SaV) in children in Nicaragua and investigate the role of host genetic factors and susceptibility to SaV infections. Our results indicate that neither ABO blood group, Lewis phenotype, nor secretor status affects susceptibility to SaV infection in Nicaragua.

  14. Multi-variant pathway association analysis reveals the importance of genetic determinants of estrogen metabolism in breast and endometrial cancer susceptibility.

    Directory of Open Access Journals (Sweden)

    Yen Ling Low

    2010-07-01

    Full Text Available Despite the central role of estrogen exposure in breast and endometrial cancer development and numerous studies of genes in the estrogen metabolic pathway, polymorphisms within the pathway have not been consistently associated with these cancers. We posit that this is due to the complexity of multiple weak genetic effects within the metabolic pathway that can only be effectively detected through multi-variant analysis. We conducted a comprehensive association analysis of the estrogen metabolic pathway by interrogating 239 tagSNPs within 35 genes of the pathway in three tumor samples. The discovery sample consisted of 1,596 breast cancer cases, 719 endometrial cancer cases, and 1,730 controls from Sweden; and the validation sample included 2,245 breast cancer cases and 1,287 controls from Finland. We performed admixture maximum likelihood (AML-based global tests to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three sub-pathways for androgen synthesis, androgen-to-estrogen conversion, and estrogen removal. In the discovery sample, although no single polymorphism was significant after correction for multiple testing, the pathway-based AML global test suggested association with both breast (p(global = 0.034 and endometrial (p(global = 0.052 cancers. Further testing revealed the association to be focused on polymorphisms within the androgen-to-estrogen conversion sub-pathway, for both breast (p(global = 0.008 and endometrial cancer (p(global = 0.014. The sub-pathway association was validated in the Finnish sample of breast cancer (p(global = 0.015. Further tumor subtype analysis demonstrated that the association of the androgen-to-estrogen conversion sub-pathway was confined to postmenopausal women with sporadic estrogen receptor positive tumors (p(global = 0.0003. Gene-based AML analysis suggested CYP19A1 and UGT2B4 to be the major players within the sub-pathway. Our study indicates that the composite

  15. Molecular epidemiology and in-vitro antifungal susceptibility of Aspergillus terreus species complex isolates in Delhi, India: evidence of genetic diversity by amplified fragment length polymorphism and microsatellite typing.

    Directory of Open Access Journals (Sweden)

    Shallu Kathuria

    Full Text Available Aspergillus terreus is emerging as an etiologic agent of invasive aspergillosis in immunocompromised individuals in several medical centers in the world. Infections due to A. terreus are of concern due to its resistance to amphotericin B, in vivo and in vitro, resulting in poor response to antifungal therapy and high mortality. Herein we examined a large collection of molecularly characterized, geographically diverse A. terreus isolates (n = 140 from clinical and environmental sources in India for the occurrence of cryptic A. terreus species. The population structure of the Indian A. terreus isolates and their association with those outside India was determined using microsatellite based typing (STR technique and Amplified Fragment Length Polymorphism analysis (AFLP. Additionally, in vitro antifungal susceptibility of A. terreus isolates was determined against 7 antifungals. Sequence analyses of the calmodulin locus identified the recently described cryptic species A. hortai, comprising 1.4% of Aspergillus section Terrei isolates cultured from cases of aspergilloma and probable invasive aspergillosis not reported previously. All the nine markers used for STR typing of A. terreus species complex proved to be highly polymorphic. The presence of high genetic diversity revealing 75 distinct genotypes among 101 Indian A. terreus isolates was similar to the marked heterogeneity noticed in the 47 global A. terreus population exhibiting 38 unique genotypes mainly among isolates from North America and Europe. Also, AFLP analysis showed distinct banding patterns for genotypically diverse A. terreus isolates. Furthermore, no correlation between a particular genotype and amphotericin B susceptibility was observed. Overall, 8% of the A. terreus isolates exhibited low MICs of amphotericin B. All the echinocandins and azoles (voriconazole, posaconazole and isavuconazole demonstrated high potency against all the isolates. The study emphasizes the need of

  16. Genetic variants in PARP1 (rs3219090) and IRF4 (rs12203592) genes associated with melanoma susceptibility in a Spanish population

    International Nuclear Information System (INIS)

    Few high penetrance genes are known in Malignant Melanoma (MM), however, the involvement of low-penetrance genes such as MC1R, OCA2, ASIP, SLC45A2 and TYR has been observed. Lately, genome-wide association studies (GWAS) have been the ideal strategy to identify new common, low-penetrance susceptibility loci. In this case–control study, we try to validate in our population nine melanoma associated markers selected from published GWAS in melanoma predisposition. We genotyped the 9 markers corresponding to 8 genes (PARP1, MX2, ATM, CCND1, NADSYN1, CASP8, IRF4 and CYP2R1) in 566 cases and 347 controls from a Spanish population using KASPar probes. Genotypes were analyzed by logistic regression and adjusted by phenotypic characteristics. We confirm the protective role in MM of the rs3219090 located on the PARP1 gene (p-value 0.027). Additionally, this SNP was also associated with eye color (p-value 0.002). A second polymorphism, rs12203592, located on the IRF4 gene was associated with protection to develop MM for the dominant model (p-value 0.037). We have also observed an association of this SNP with both lentigines (p-value 0.014) and light eye color (p-value 3.76 × 10-4). Furthermore, we detected a novel association with rs1485993, located on the CCND1 gene, and dark eye color (p-value 4.96 × 10-4). Finally, rs1801516, located on the ATM gene, showed a trend towards a protective role in MM similar to the one firstly described in a GWAS study. To our knowledge, this is the first time that these SNPs have been associated with MM in a Spanish population. We confirmed the proposed role of rs3219090, located on the PARP1 gene, and rs12203592, located on the IRF4 gene, as protective to MM along the same lines as have previous genome-wide associated works. Finally, we have seen associations between IRF4, PARP1, and CCND1 and phenotypic characteristics, confirming previous results for the IRF4 gene and presenting novel data for the last two, suggesting that pigmentation

  17. Genetic risk factors for human susceptibility to infections of relevance in dermatology Fatores de risco genético para a suscetibilidade humana à infecções de relevância em dermatologia

    Directory of Open Access Journals (Sweden)

    José Felipe Jardim Sardinha

    2011-08-01

    Full Text Available BACKGROUND: In the pre-microbiological era, it was widely accepted that diseases, today known to be infectious, were hereditary. With the discovery of microorganisms and their role in the pathogenesis of several diseases, it was suggested that exposure to the pathogen was enough to explain infection. Nowadays, it is clear that infection is the result of a complex interplay between pathogen and host, therefore dependant on the genetic make-up of the two organisms. Dermatology offers several examples of infectious diseases in different stages of understanding of their molecular basis. In this review, we summarize the main advances towards dissecting the genetic component controlling human susceptibility to infectious diseases of interest in dermatology. Widely investigated diseases such as leprosy and leishmaniasis are discussed from the genetic perspective of both host and pathogen. Others, such as rare mycobacterioses, fungal infections and syphilis, are presented as good opportunities for research in the field of genetics of infection.INTRODUÇÃO: Durante a era pré-microbiológica, era comum a visão de que doenças, hoje sabidamente infecciosas, eram hereditárias. Com a descoberta dos microorganismos e seu papel na patogênese de diversas patologias, chegou-se a propor que a exposição ao patógeno era condição suficiente para explicar infecção. Hoje, está claro que infecção é o resultado de uma complexa interação entre patógeno e hospedeiro, dependendo portanto, em última análise, do make-up genético de ambos os organismos. A dermatologia oferece diversos exemplos de doenças infecciosas em diferentes graus de entendimento de suas bases moleculares. Nesta revisão, resumimos os principais avanços na direção da dissecção do componente genético controlando suscetibilidade do ser humano a doenças infecciosas de importância na dermatologia. Doenças amplamente estudadas, como a hanseníase e a leishmaniose, s

  18. Genetic Study of Population Mixture and Its Role in Human History

    OpenAIRE

    Moorjani, Priya

    2013-01-01

    Mixture between populations is an evolutionary process that shapes genetic variation. Intermixing between groups of distinct ancestries creates mosaics of chromosomal segments inherited from multiple ancestral populations. Studying populations of mixed ancestry (admixed populations) is of special interest in population genetics as it not only provides insights into the history of admixed groups but also affords an opportunity to reconstruct the history of the ancestral populations, some of wh...

  19. CAPN -10基因多态性与妊娠期糖尿病遗传易感性的关系%Relationship between polymorphism of CAPN - 10 gene and genetic susceptibility of gestational diabetes mellitus

    Institute of Scientific and Technical Information of China (English)

    周龙; 费樱; 王焰; 谭玉洁

    2012-01-01

    目的:探讨CAPN-10基因19、43及63位点多态性与妊娠期糖尿病遗传易感性的关系.方法:采用病例对照研究方法及PCR-RFLP技术对100例葡萄糖耐量正常的妊娠妇女(NGT组)和100例妊娠期糖耐量受损患者(GIGT组)及100例妊娠期糖尿病患者(GDM组)的CAPN-10基因19、43及63多态性位点进行基因分型.结果:①CAPN-10基因的19、43、63位点的基因型频率经Hardy-Weinberg平衡定律检验,均符合遗传平衡法则,表明各基因频率满足遗传平衡(P>0.05),基因型频率分布具有群体代表性.②43位点GG基因型频率及G等位基因频率在GDM组均显著高于NGT组,差异有统计学意义(P<0.05),而在GIGT组与NGT组间差异无统计学意义.③19位点和63位点的基因型频率、等位基因频率在GDM组、GIGT组与NGT组差异均无统计学意义;19、43、63位点的基因型频率、等位基因频率在GIGT组与GDM组差异无统计学意义.结论:CAPN-10基因多态性可能与GDM遗传易感性有关;CAPN-10基因SNP43位点G等位基因可能与GDM的发生有关,其16和63位点则与GDM的发生无关.%Objective: To explore the relationship between the polymorphisms of 19 locus, 43 locus, and 63 locus in CAPN - 10 gene and genetic susceptibility of gestational diabetes mellitus (COM) . Methods: Case - control study and PCR - RFLP technique were used for genolyping of 19 locus, 43 locus, and 63 locus in CAPN - 10 gene of 100 pregnant women with normal glucose tolerance (NGT) (NGT group), 100 patients with gestational impaired glucose tolerance (GIGT) ( GIGT group), and 100 patients with GDM ( GDM group) . Results: The frequencies of genotypes of 19 locus, 43 locus, and 63 locus in CAPN -10 gene were detected by Hardy - Weinberg equation law, all of them were coincidence with genetic equation law, which indicated that all the frequencies of genotypes satisfied genetic e-quation (P > 0.05), the distribution of genotyping frequency had colonial

  20. SUSCEPTIBILIDAD GENÉTICA AL CÁNCER: ALGUNAS CONSIDERACIONES BIOÉTICAS BAJO EL MARCO LEGAL VENEZOLANO GENETIC SUSCEPTIBILITY TO CANCER: SOME BIOETHICAL CONSIDERATIONS IN VENEZUELAN LEGAL FRAMEWORK

    Directory of Open Access Journals (Sweden)

    Carlos JG Flores-Angulo

    environmental conditions, the base of carcinogenesis is the non lethal genetic damage. In this sense, the study of genetic susceptibility markers acquires capital importance, because it allows the identification of high genetic risk individuals, estimate their prognosis and their answer to treatment, obtaining a more predictive and preventive position of the medical practice. None the less this could unleash a great deal of ethical problems, especially difficult to solve in a society without an adequate legal context. That is why it is important to carry out an analysis of the Venezuelan Legal System (VLS that protects the information of human genome and its bioethical repercussions. For that, a search and interpretation of the valid Venezuelan normative was made, concerning publications about cancer, its susceptibility and technological diagnosis. The conclusions that were obtained were that 1 Their massive offer is not recommended because of its psychosocial and labor repercussions, 2 The normative of the VLS about the genome protection is quite limited, and 3 The adaptation of the VLS is necessary to the imminent scientific development, in order to control the bioethical impact of the obtained information and guarantee the access to a genetic, psychological and legal advisement so that the context of responsibilities can be established.

  1. Exome Array Analysis of Susceptibility to Pneumococcal Meningitis

    Science.gov (United States)

    Kloek, Anne T.; van Setten, Jessica; van der Ende, Arie; Bots, Michiel L.; Asselbergs, Folkert W.; Serón, Mercedes Valls; Brouwer, Matthijs C.; van de Beek, Diederik; Ferwerda, Bart

    2016-01-01

    Host genetic variability may contribute to susceptibility of bacterial meningitis, but which genes contribute to the susceptibility to this complex disease remains undefined. We performed a genetic association study in 469 community-acquired pneumococcal meningitis cases and 2072 population-based controls from the Utrecht Health Project in order to find genetic variants associated with pneumococcal meningitis susceptibility. A HumanExome BeadChip was used to genotype 102,097 SNPs in the collected DNA samples. Associations were tested with the Fisher exact test. None of the genetic variants tested reached Bonferroni corrected significance (p-value pathophysiology of pneumococcal meningitis. PMID:27389768

  2. Molecular cloning of ion channels in Felis catus that are related to periodic paralyses in man: a contribution to the understanding of the genetic susceptibility to feline neck ventroflexion and paralysis

    Directory of Open Access Journals (Sweden)

    Marlyn Zapata

    2014-07-01

    Full Text Available Neck ventroflexion in cats has different causes; however, the most common is the hypokalemia associated with flaccid paralysis secondary to chronic renal failure. In humans, the most common causes of acute flaccid paralysis are hypokalemia precipitated by thyrotoxicosis and familial forms linked to mutations in sodium, potassium, and calcium channel genes. Here, we describe the sequencing and analysis of skeletal muscle ion channels in Felis catus that could be related to periodic paralyses in humans, contributing to the understanding of the genetic susceptibility to feline neck ventroflexion and paralysis. We studied genomic DNA from eleven cats, including five animals that were hyperthyroid with hypokalemia, although only one presented with muscle weakness, and six healthy control domestic cats. We identified the ion channel ortholog genes KCNJ2, KCNJ12, KCNJ14, CACNA1S and SCN4A in the Felis catus genome, together with several polymorphic variants. Upon comparative alignment with other genomes, we found that Felis catus provides evidence for a high genomic conservation of ion channel sequences. Although we hypothesized that neck ventroflexion in cats could be associated with a thyrotoxic or familial periodic paralysis channel mutation, we did not identify any previously detected human channel mutation in the hyperthyroid cat presenting hypokalemia. However, based on the small number of affected cats in this study, we cannot yet rule out this molecular mechanism. Notwithstanding, hyperthyroidism should still be considered as a differential diagnosis in hypokalemic feline paralysis.

  3. Molecular cloning of ion channels in Felis catus that are related to periodic paralyses in man: a contribution to the understanding of the genetic susceptibility to feline neck ventroflexion and paralysis.

    Science.gov (United States)

    Zapata, Marlyn; Kunii, Ilda S; Paninka, Rolf M; Simões, Denise M N; Castillo, Víctor A; Reche, Archivaldo; Maciel, Rui M B; Dias da Silva, Magnus R

    2014-01-01

    Neck ventroflexion in cats has different causes; however, the most common is the hypokalemia associated with flaccid paralysis secondary to chronic renal failure. In humans, the most common causes of acute flaccid paralysis are hypokalemia precipitated by thyrotoxicosis and familial forms linked to mutations in sodium, potassium, and calcium channel genes. Here, we describe the sequencing and analysis of skeletal muscle ion channels in Felis catus that could be related to periodic paralyses in humans, contributing to the understanding of the genetic susceptibility to feline neck ventroflexion and paralysis. We studied genomic DNA from eleven cats, including five animals that were hyperthyroid with hypokalemia, although only one presented with muscle weakness, and six healthy control domestic cats. We identified the ion channel ortholog genes KCNJ2, KCNJ12, KCNJ14, CACNA1S and SCN4A in the Felis catus genome, together with several polymorphic variants. Upon comparative alignment with other genomes, we found that Felis catus provides evidence for a high genomic conservation of ion channel sequences. Although we hypothesized that neck ventroflexion in cats could be associated with a thyrotoxic or familial periodic paralysis channel mutation, we did not identify any previously detected human channel mutation in the hyperthyroid cat presenting hypokalemia. However, based on the small number of affected cats in this study, we cannot yet rule out this molecular mechanism. Notwithstanding, hyperthyroidism should still be considered as a differential diagnosis in hypokalemic feline paralysis. PMID:25063199

  4. Pedigree study of five patients with inflammatory bowel disease and its genetic susceptibility%5例炎症性肠病患者的家系调查及其与遗传易感关系分析

    Institute of Scientific and Technical Information of China (English)

    王丽英; 王江滨; 王哲

    2008-01-01

    目的 探讨我国炎症性肠病患者的遗传易感倾向.方法 在广泛进行流行病学调查的基础上,采用系谱分析方法,对5例具有家族聚集现象的炎症性肠病患者家系进行病史、临床表现、X线、结肠镜及病理组织学检查、治疗状况、家族成员死亡原因、有无近亲结婚史等的详细调查.结果 2个克罗恩病家族分别有兄弟、母子患病;3个溃疡性结肠炎家族分别有姐弟、母子和祖孙三人患病.患者的一级亲属更易受累,同胞受累最多见,其特点是发病年龄较早、后代发病年龄早且病情重.男女均可发病,患病类型相同,病变部位相似.结论 该调查中的炎症性肠病患者存在着遗传易感倾向,发病人数少,推测可能为多基因遗传或常染色体隐性遗传.%Objective To investigate the genetic susceptibility to inflammatory bowel disease in China.Methods The pedigree of 5 probands with inflammatory bowel disease (2 with Crohn's disease and 3 with ulcerative colitis) were analyzed including familial history,clinical features,radiographic,endoscopic and pathological findings.A detailed family pedigree and information of the whereabouts of each relative were obtained.Results Crohn's disease was found in 2 families,each with two affected patients (two brothers or mother and a child).Ulcerative colitis was i'ound in 3 families,each with two or more affected patients (an elder sister and younger brother in the first family,mother and a child in the second family and grandparent and 2 grandchildren in the third family ).First-degree relatives were susceptibility to inflammatory bowel disease and siblings were affected more frequently.The member of the later generation was younger at diagnosis than the preceding generation. Offsprings had an earlier onset and more severe than affected parents. A high concordance for type and localization was found between males and females.Conclusions The patients with inflammatory bowel

  5. Immunogenetic Susceptibilities in Inflammatory Bowel Disease

    OpenAIRE

    Rotter, Jerome I

    1990-01-01

    It is now clear that the major identified risk factor for the inflammatory bowel diseases (IBDs) is a positive family history. Furthermore, the available data in spouses and twins indicate that the genetic susceptibility is due in large measure to shared familial predisposition. This emphasizes the importance of identifying the actual familial susceptibilities. Given the data for immunopathogenetic etiologies in the genesis of IBD, the logical candidate genes are those that involve the immune...

  6. An ancestral bacterial division system is widespread in eukaryotic mitochondria

    Czech Academy of Sciences Publication Activity Database

    Leger, M.M.; Petrů, M.; Žárský, V.; Eme, L.; Vlček, Čestmír; Harding, T.; Lang, B.F.; Eliáš, M.; Doležal, P.; Roger, A. J.

    2015-01-01

    Roč. 112, č. 33 (2015), s. 10239-10246. ISSN 0027-8424 R&D Projects: GA ČR GA13-24983S; GA MŠk(CZ) ED1.1.00/02.0109 Grant ostatní: GA ČR GA13-29423S; GA MŠk(CZ) CZ.1.05/1.1.00/02.0109 Institutional support: RVO:68378050 Keywords : mitochondria * Min proteins * MinCDE * mitochondrial fission * mitochondrial division Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 9.674, year: 2014

  7. Sequence divergence of Mus spretus and Mus musculus across a skin cancer susceptibility locus

    Directory of Open Access Journals (Sweden)

    Balmain Allan

    2008-12-01

    Full Text Available Abstract Background Mus spretus diverged from Mus musculus over one million years ago. These mice are genetically and phenotypically divergent. Despite the value of utilizing M. musculus and M. spretus for quantitative trait locus (QTL mapping, relatively little genomic information on M. spretus exists, and most of the available sequence and polymorphic data is for one strain of M. spretus, Spret/Ei. In previous work, we mapped fifteen loci for skin cancer susceptibility using four different M. spretus by M. musculus F1 backcrosses. One locus, skin tumor susceptibility 5 (Skts5 on chromosome 12, shows strong linkage in one cross. Results To identify potential candidate genes for Skts5, we sequenced 65 named and unnamed genes and coding elements mapping to the peak linkage area in outbred spretus, Spret/EiJ, FVB/NJ, and NIH/Ola. We identified polymorphisms in 62 of 65 genes including 122 amino acid substitutions. To look for polymorphisms consistent with the linkage data, we sequenced exons with amino acid polymorphisms in two additional M. spretus strains and one additional M. musculus strain generating 40.1 kb of sequence data. Eight candidate variants were identified that fit with the linkage data. To determine the degree of variation across M. spretus, we conducted phylogenetic analyses. The relatedness of the M. spretus strains at this locus is consistent with the proximity of region of ascertainment of the ancestral mice. Conclusion Our analyses suggest that, if Skts5 on chromosome 12 is representative of other regions in the genome, then published genomic data for Spret/EiJ are likely to be of high utility for genomic studies in other M. spretus strains.

  8. Social capital and health: evidence that ancestral trust promotes health among children of immigrants.

    Science.gov (United States)

    Ljunge, Martin

    2014-12-01

    This paper presents evidence that generalized trust promotes health. Children of immigrants in a broad set of European countries with ancestry from across the world are studied. Individuals are examined within country of residence using variation in trust across countries of ancestry. The approach addresses reverse causality and concerns that the trust measure picks up institutional factors in the individual's contextual setting. There is a significant positive estimate of ancestral trust in explaining self-assessed health. The finding is robust to accounting for individual, parental, and extensive ancestral country characteristics. Individuals with higher ancestral trust are also less likely to be hampered by health problems in their daily life, providing evidence of trust influencing real life outcomes. Individuals with high trust feel and act healthier, enabling a more productive life. PMID:25464341

  9. Reconstructed Ancestral Enzymes Impose a Fitness Cost upon Modern Bacteria Despite Exhibiting Favourable Biochemical Properties.

    Science.gov (United States)

    Hobbs, Joanne K; Prentice, Erica J; Groussin, Mathieu; Arcus, Vickery L

    2015-10-01

    Ancestral sequence reconstruction has been widely used to study historical enzyme evolution, both from biochemical and cellular perspectives. Two properties of reconstructed ancestral proteins/enzymes are commonly reported--high thermostability and high catalytic activity--compared with their contemporaries. Increased protein stability is associated with lower aggregation rates, higher soluble protein abundance and a greater capacity to evolve, and therefore, these proteins could be considered "superior" to their contemporary counterparts. In this study, we investigate the relationship between the favourable in vitro biochemical properties of reconstructed ancestral enzymes and the organismal fitness they confer in vivo. We have previously reconstructed several ancestors of the enzyme LeuB, which is essential for leucine biosynthesis. Our initial fitness experiments revealed that overexpression of ANC4, a reconstructed LeuB that exhibits high stability and activity, was only able to partially rescue the growth of a ΔleuB strain, and that a strain complemented with this enzyme was outcompeted by strains carrying one of its descendants. When we expanded our study to include five reconstructed LeuBs and one contemporary, we found that neither in vitro protein stability nor the catalytic rate was correlated with fitness. Instead, fitness showed a strong, negative correlation with estimated evolutionary age (based on phylogenetic relationships). Our findings suggest that, for reconstructed ancestral enzymes, superior in vitro properties do not translate into organismal fitness in vivo. The molecular basis of the relationship between fitness and the inferred age of ancestral LeuB enzymes is unknown, but may be related to the reconstruction process. We also hypothesise that the ancestral enzymes may be incompatible with the other, contemporary enzymes of the metabolic network. PMID:26349578

  10. Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium.

    Science.gov (United States)

    Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B; Behrens, Sabine; Goode, Ellen L; Bolla, Manjeet K; Dennis, Joe; Dunning, Alison M; Easton, Douglas F; Wang, Qin; Benitez, Javier; Hopper, John L; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Fasching, Peter A; Haeberle, Lothar; Peto, Julian; Dos-Santos-Silva, Isabel; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marmé, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; Nielsen, Sune F; Nordestgaard, Børge G; González-Neira, Anna; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Fagerholm, Rainer; Dörk, Thilo; Bogdanova, Natalia V; Mannermaa, Arto; Hartikainen, Jaana M; Van Dijck, Laurien; Smeets, Ann; Flesch-Janys, Dieter; Eilber, Ursula; Radice, Paolo; Peterlongo, Paolo; Couch, Fergus J; Hallberg, Emily; Giles, Graham G; Milne, Roger L; Haiman, Christopher A; Schumacher, Fredrick; Simard, Jacques; Goldberg, Mark S; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Beeghly-Fadiel, Alicia; Winqvist, Robert; Grip, Mervi; Andrulis, Irene L; Glendon, Gord; García-Closas, Montserrat; Figueroa, Jonine; Czene, Kamila; Brand, Judith S; Darabi, Hatef; Eriksson, Mikael; Hall, Per; Li, Jingmei; Cox, Angela; Cross, Simon S; Pharoah, Paul D P; Shah, Mitul; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Ademuyiwa, Foluso; Ambrosone, Christine B; Swerdlow, Anthony; Jones, Michael; Chang-Claude, Jenny

    2016-01-01

    Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 × 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10(-3) and 7.0 × 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10(-3), 4.5 × 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry. PMID:26621531

  11. Biomarkers: The Clues to Genetic Susceptibility.

    OpenAIRE

    Zeiger, M

    1994-01-01

    There are approximately 500,000 cancer-related deaths annually in the United States. Scientists believe as that many as 80% of those deaths could be prevented due to the fact that most malignancies are a result of external factors rather than inherent biological conditions. With recent advances in molecular biology, a new field that combines highly sensitive and specific techniques for detecting early damage associated with cancer has emerged. By combining knowledge about external factors rel...

  12. Human genetic studies in areas of high natural radiation VI. Genetical load and ethnic group

    International Nuclear Information System (INIS)

    The load of mutations disclosed by inbreeding, according to the ethnic group of the parents, has been analyzed in our data. Besides the total of the population, a sample with no alien ancestrals has also been analyzed. Genetic load has been studied for absortions, still births, pos-natal mortality, total mortality, anomalies, total mortality + anomalies, and abnormalities in general

  13. A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts

    Science.gov (United States)

    Irum, Bushra; Khan, Arif O.; Wang, Qiwei; Li, David; Khan, Asma A.; Husnain, Tayyab; Akram, Javed; Riazuddin, Sheikh

    2016-01-01

    Purpose This study was performed to investigate the genetic determinants of autosomal recessive congenital cataracts in large consanguineous families. Methods Affected individuals underwent a detailed ophthalmological examination and slit-lamp photographs of the cataractous lenses were obtained. An aliquot of blood was collected from all participating family members and genomic DNA was extracted from white blood cells. Initially, a genome-wide scan was performed with genomic DNAs of family PKCC025 followed by exclusion analysis of our familial cohort of congenital cataracts. Protein-coding exons of CRYBB1, CRYBB2, CRYBB3, and CRYBA4 were sequenced bidirectionally. A haplotype was constructed with SNPs flanking the causal mutation for affected individuals in all four families, while the probability that the four familial cases have a common founder was estimated using EM and CHM-based algorithms. The expression of Crybb3 in the developing murine lens was investigated using TaqMan assays. Results The clinical and ophthalmological examinations suggested that all affected individuals had nuclear cataracts. Genome-wide linkage analysis localized the causal phenotype in family PKCC025 to chromosome 22q with statistically significant two-point logarithm of odds (LOD) scores. Subsequently, we localized three additional families, PKCC063, PKCC131, and PKCC168 to chromosome 22q. Bidirectional Sanger sequencing identified a missense variation: c.493G>C (p.Gly165Arg) in CRYBB3 that segregated with the disease phenotype in all four familial cases. This variation was not found in ethnically matched control chromosomes, the NHLBI exome variant server, or the 1000 Genomes or dbSNP databases. Interestingly, all four families harbor a unique disease haplotype that strongly suggests a common founder of the causal mutation (p<1.64E-10). We observed expression of Crybb3 in the mouse lens as early as embryonic day 15 (E15), and expression remained relatively steady throughout

  14. Clinical characteristics, prognosis and genetic susceptibility of herpes simplex encephalitis in children%儿童单纯疱疹病毒脑炎的临床特征、预后及遗传易感性

    Institute of Scientific and Technical Information of China (English)

    冯文雅; 陈天明; 胡冰; 万佳彬; 刘钢

    2015-01-01

    Objective To summarize the clinical characteristics and long-term prognosis of herpes simplex virus encephalitis (HSE) in childhood and to analyze genotype of UNC93B1 and TLR3.Method Data of a total of 30 HSE patients admitted to Beijing Children's Hospital from January 2008 to September 2013 were retrospectively analyzed,the data included clinical manifestations,physical sign,auxiliary examination,therapy and long-term clinical prognosis.The family history obtained during follow-up visit was also analyzed for genetic predisposition.With parents' agreement,the blood specimens of patients were collected in EDTA anticoagulant tubes,the first 2 genetic etiologies UNC93B1 and TLR3 were sequenced,and the genetic susceptibility to HSE in childhood was summarized.Result (1)All the 30 patients (100%) had fever,28 (93%) had seizure,25 (83%)had altered state of consciousness,only 11 (37%) had personality changes,and in 8 (73%) appeared at or after 2 weeks of onset.(2) During the long-term follow up,2 (7%) patients died after discharge,23 patients (82%) had neurological sequelae,13 patients (57%) had moderate,severe disability and vegetative state.(3) After sequencing of UNC93B1,and TLR3,one patient was found homozygous for a single-nucleotide substitution at position C.414C > G in exon 4 of UNC93B1 which affected the expression of UNC93B1,and may block or decrease the production of interferon.(4) Six single nucleotide polymorphisms (SNPs) were found in this study,their genotype frequency and gene frequency of Chinese were respectively searched in Genomes Project in NCBI and defined 1 000 genomes group.The genotype frequency of UNC93B1 rs7149 between 1 000 genomes group and HSE group was significantly different (x2 =55.37,P < 0.05).The frequency of CC type and C type was higher in HSE group,both of them had significant difference (x2 =93.90,P <0.05,OR =61.563;x2 =134.40,P < 0.05,OR =12.491).Conclusion HSE lacks specific clinical manifestations,the long

  15. Genetic association mapping via evolution-based clustering of haplotypes.

    Directory of Open Access Journals (Sweden)

    Ioanna Tachmazidou

    2007-07-01

    Full Text Available Multilocus analysis of single nucleotide polymorphism haplotypes is a promising approach to dissecting the genetic basis of complex diseases. We propose a coalescent-based model for association mapping that potentially increases the power to detect disease-susceptibility variants in genetic association studies. The approach uses Bayesian partition modelling to cluster haplotypes with similar disease risks by exploiting evolutionary information. We focus on candidate gene regions with densely spaced markers and model chromosomal segments in high linkage disequilibrium therein assuming a perfect phylogeny. To make this assumption more realistic, we split the chromosomal region of interest into sub-regions or windows of high linkage disequilibrium. The haplotype space is then partitioned into disjoint clusters, within which the phenotype-haplotype association is assumed to be the same. For example, in case-control studies, we expect chromosomal segments bearing the causal variant on a common ancestral background to be more frequent among cases than controls, giving rise to two separate haplotype clusters. The novelty of our approach arises from the fact that the distance used for clustering haplotypes has an evolutionary interpretation, as haplotypes are clustered according to the time to their most recent common ancestor. Our approach is fully Bayesian and we develop a Markov Chain Monte Carlo algorithm to sample efficiently over the space of possible partitions. We compare the proposed approach to both single-marker analyses and recently proposed multi-marker methods and show that the Bayesian partition modelling performs similarly in localizing the causal allele while yielding lower false-positive rates. Also, the method is computationally quicker than other multi-marker approaches. We present an application to real genotype data from the CYP2D6 gene region, which has a confirmed role in drug metabolism, where we succeed in mapping the location

  16. A skull might lie: modelling ancestral ranges and diet from genes and shape of tree squirrels

    Czech Academy of Sciences Publication Activity Database

    Pečnerová, Patrícia; Moravec, Jiří C.; Martínková, Natália

    2015-01-01

    Roč. 64, č. 6 (2015), s. 1074-1088. ISSN 1063-5157 EU Projects: European Commission(XE) CZ.1.07/2.4.00/17.0138 Institutional support: RVO:68081766 Keywords : Sciurini * multilocus phylogeny * geometric morphometry * speciation * ancestral range reconstruction * diet modelling Subject RIV: EG - Zoology Impact factor: 14.387, year: 2014

  17. Investigating the potential of ancestral state reconstruction algorithms in historical linguistics

    OpenAIRE

    Jäger, Gerhard; List, Johann-Mattis

    2016-01-01

    Current efforts in computational historical linguistics are predominantly concerned with phylogenetic inference. However, methods for ancestral state reconstruction have been only sporadically applied. This is surprising since reconstruction is considered essential both in evolutionary biology and in classical historical linguistics. In contradistinction to phylogenetic algorithms, automatic reconstruction methods presuppose phylogenetic information in order to explain what has evolved whe...

  18. Inheritance of the 8.1 ancestral haplotype in recurrent pregnancy loss

    OpenAIRE

    Kolte, Astrid M.; Nielsen, Henriette S.; Steffensen, Rudi; Crespi, Bernard; Christiansen, Ole B

    2015-01-01

    A segment of DNA called the 8.1 ancestral haplotype is hypothesized to cause fetal loss due to a ‘selfish gene’ effect. The hypothesis was not supported, although the haplotype tended to be inherited more often than expected among girls (p=0.11) in a study of 110 mother-child pairs. Further studies are warranted.

  19. Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis.

    Science.gov (United States)

    Jawaheer, Damini; Li, Wentian; Graham, Robert R; Chen, Wei; Damle, Aarti; Xiao, Xiangli; Monteiro, Joanita; Khalili, Houman; Lee, Annette; Lundsten, Robert; Begovich, Ann; Bugawan, Teodorica; Erlich, Henry; Elder, James T; Criswell, Lindsey A; Seldin, Michael F; Amos, Christopher I; Behrens, Timothy W; Gregersen, Peter K

    2002-09-01

    Rheumatoid arthritis (RA) is an inflammatory disease with a complex genetic component. An association between RA and the human leukocyte antigen (HLA) complex has long been observed in many different populations, and most studies have focused on a direct role for the HLA-DRB1 "shared epitope" in disease susceptibility. We have performed an extensive haplotype analysis, using 54 markers distributed across the entire HLA complex, in a set of 469 multicase families with RA. The results show that, in addition to associations with the DRB1 alleles, at least two additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral A1-B8-DRB1*03 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB1*0404 haplotypes. These data emphasize the importance of defining haplotypes when trying to understand the HLA associations with disease, and they clearly demonstrate that such associations with RA are complex and cannot be completely explained by the DRB1 locus. PMID:12181776

  20. Genetic Variations in Vesicoureteral Reflux Sequelae.

    Science.gov (United States)

    Hains, David S; Schwaderer, Andrew L

    2016-01-01

    Urinary tract infections (UTI) are a common condition in children. Vesicoureteral reflux (VUR) represents a common associated condition with childhood UTI. UTI susceptibility appears to have a genetic component based on family and UTI cohort studies. Targeted analysis of innate immune system genetic variations indicate that these variations are important in UTI susceptibility. In this overview, we discuss how current cohorts and genetic strategies can be implemented to discover new susceptibility loci in patients with UTI. PMID:26848692

  1. Frequency of carriers of 8.1 ancestral haplotype and its fragments in two Caucasian populations.

    Science.gov (United States)

    Kiszel, Petra; Kovács, Margit; Szalai, Csaba; Yang, Yan; Pozsonyi, Eva; Blaskó, Bernadett; Laki, Judit; Prohászka, Zoltán; Fazakas, Adám; Pánczél, Pál; Hosszúfalusi, Nóra; Rajczy, Katalin; Wu, Yee-Ling; Chung, Erwin K; Zhou, Bi; Blanchong, Carol A; Vatay, Agnes; Yu, C Yung; Füst, G

    2007-01-01

    Within the human MHC region larger stretches of conserved DNA, called conserved ancestral haplotypes exist. However, many MHC haplotypes contain only fragments of an ancestral haplotype. Little is known, however, on relative distribution of the ancestral haplotypes to their fragments. Therefore we determined the frequency of carriers of the whole ancestral haplotype 8.1 (AH8.1) and its fragments in 127 healthy Hungarian people, 101 healthy Ohioian females, and in nine Hungarian families. The HLA-DQ2, HLA-DR3(17), RAGE -429C allele, the mono-S-C4B genotype, the HSP70-2 1267G allele and the TNF -308A (TNF2) allele were used as markers of the AH8.1. Frequency of carriers of the whole AH8.1 and its fragments was similar in the both populations. 18% of the subjects carried the whole AH8.1 in at least one chromosome, while 17-20%, 36-39%, and 24-29%, respectively carried two or three constituents of the haplotype, only one constituent or none of them. Similar results were obtained in the family study. In addition, marked differences were found in the relationship of the constituents' alleles to the whole AH8.1. In both populations, 29%, 50-59%, 52-56% and 76-96%, respectively of the carriers of HSP70-2 1267G, RAGE-429C, TNF2, and mono-S carriers carried the whole 8.1 haplotype. These findings may have important implications for studies of the disease associations with different MHC ancestral haplotypes. PMID:17558713

  2. Genetic influence on the age at onset of asthma

    DEFF Research Database (Denmark)

    Thomsen, Simon Francis; Duffy, David Lorenzo; Kyvik, Kirsten Ohm; Backer, Vibeke

    2010-01-01

    Although the genetics of asthma susceptibility have been frequently explored, little is known about genetic factors that influence the age at onset of asthma.......Although the genetics of asthma susceptibility have been frequently explored, little is known about genetic factors that influence the age at onset of asthma....

  3. The genetic architecture of Parkinson's disease : emphasis on genetic susceptibility

    OpenAIRE

    Brás, José Miguel Tomás

    2010-01-01

    A Doença de Parkinson (DP) é a segunda doença neurodegenerativa mais frequente, seguindo a Doença de Alzheimer, tendo sido frequentemente designada como uma doença esporádica com potenciais causas ambientais. Até à data, o factor de risco mais relevante para o desenvolvimento da DP é a idade. Uma vez que a proporção da população idosa tem vindo a aumentar, devido ao aumento da longevidade, o número de indivíduos afectados por doenças neurodegenerativas, incluindo DP é, també...

  4. Segregation of a Latent High Adiposity Phenotype in Families with a History of Type 2 Diabetes Mellitus Implicates Rare Obesity-Susceptibility Genetic Variants with Large Effects in Diabetes-Related Obesity

    OpenAIRE

    Jenkins, Arthur B.; Batterham, Marijka; Samocha-Bonet, Dorit; Tonks, Katherine; Greenfield, Jerry R.; Campbell, Lesley V.

    2013-01-01

    Background We recently reported significantly greater weight gain in non-diabetic healthy subjects with a 1st degree family history (FH+) of type 2 diabetes mellitus (T2DM) than in a matched control group without such history (FH−) during voluntary overfeeding, implying co-inheritance of susceptibilities to T2DM and obesity. We have estimated the extent and mode of inheritance of susceptibility to increased adiposity in FH+. Methods Normoglycaemic participants were categorised either FH+ (≥1 ...

  5. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer

    Czech Academy of Sciences Publication Activity Database

    Wolpin, B. M.; Rizzato, C.; Kraft, P.; Kooperberg, Ch.; Petersen, G. M.; Wang, Z.; Arslan, A. A.; Beane-Freeman, L.; Bracci, P. M.; Buring, J.; Canzian, F.; Duell, E. J.; Gallinger, S.; Giles, G.G.; Goodman, G. E.; Goodman, P. J.; Jacobs, E. J.; Kamineni, A.; Klein, A. P.; Kolonel, L. N.; Kulke, M. H.; Li, D.; Malats, N.; Olson, S. H.; Risch, H. A.; Sesso, H. D.; Visvanathan, K.; White, E.; Zheng, W.; Abnet, Ch. C.; Albanes, D.; Andreotti, G.; Austin, M. A.; Barfield, R.; Basso, D.; Berndt, S. I.; Boutron-Ruault, M. Ch.; Brotzman, M.; Büchler, M. W.; Bueno-de-Mesquita, H. B.; Bugert, P.; Burdette, L.; Campa, D.; Caporaso, N. E.; Capurso, G.; Chung, Ch.; Cotterchio, M.; Costello, E.; Elena, J.; Funel, N.; Gaziano, J. M.; Giese, N. A.; Giovannucci, E. L.; Goggins, M.; Gorman, M. J.; Gross, M.; Haiman, Ch. A.; Hassan, M.; Helzlsouer, K. J.; Henderson, B. E.; Holly, E. A.; Hu, N.; Hunter, D. J.; Innocenti, F.; Jenab, M.; Kaaks, R.; Key, T. J.; Khaw, K. T.; Klein, E. A.; Kogevinas, M.; Krogh, V.; Kupcinskas, J.; Kurtz, R. C.; LaCroix, A.; Landi, M. T.; Landi, S.; Le Marchand, L.; Mambrini, A.; Mannisto, S.; Milne, R. L.; Nakamura, Y.; Oberg, A. L.; Owzar, K.; Patel, A. V.; Peeters, P. H. M.; Peters, U.; Pezzilli, R.; Piepoli, A.; Porta, M.; Real, F. X.; Riboli, E.; Rothman, N.; Scarpa, A.; Shu, X. O.; Silverman, D. T.; Souček, P.; Sund, M.; Talar-Wojnarowska, R.; Taylor, P. R.; Theodoropoulos, G. E.; Thornquist, M.; Tjonneland, A.; Tobias, G. S.; Trichopoulos, D.; Vodička, Pavel; Wactawski-Wende, J.; Wentzensen, N.; Wu, Ch.; Yu, H.; Yu, K.; Zeleniuch-Jacquotte, A.; Hoover, R.; Hartge, P.; Fuchs, Ch.; Chanock, S. J.; Stolzenberg-Solomon, R. S.; Amundadottir, L. T.

    2014-01-01

    Roč. 46, č. 9 (2014), s. 994-1000. ISSN 1061-4036 Institutional support: RVO:68378041 Keywords : disease * variants * genetic susceptibility Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 29.352, year: 2014

  6. Punctuated evolution and transitional hybrid network in an ancestral cell cycle of fungi

    Science.gov (United States)

    Medina, Edgar M; Turner, Jonathan J; Gordân, Raluca; Skotheim, Jan M; Buchler, Nicolas E

    2016-01-01

    Although cell cycle control is an ancient, conserved, and essential process, some core animal and fungal cell cycle regulators share no more sequence identity than non-homologous proteins. Here, we show that evolution along the fungal lineage was punctuated by the early acquisition and entrainment of the SBF transcription factor through horizontal gene transfer. Cell cycle evolution in the fungal ancestor then proceeded through a hybrid network containing both SBF and its ancestral animal counterpart E2F, which is still maintained in many basal fungi. We hypothesize that a virally-derived SBF may have initially hijacked cell cycle control by activating transcription via the cis-regulatory elements targeted by the ancestral cell cycle regulator E2F, much like extant viral oncogenes. Consistent with this hypothesis, we show that SBF can regulate promoters with E2F binding sites in budding yeast. DOI: http://dx.doi.org/10.7554/eLife.09492.001 PMID:27162172

  7. Diaspora of diaspora: Adyge-Abkhaz returnees in the ancestral homeland

    OpenAIRE

    Erciyes, Cemre

    2008-01-01

    Focusing on the diasporic characteristics shown by ancestral return migrants, this case study looks at the Abkhaz-Adyge (Circassian) returnees from Turkey to the Caucasus and how they become the “diaspora of the diaspora.” The next generations of diasporans continue to dream of return, and, with recent developments in communication technologies and cheaper transportation, many find ways to realize this dream. There are many different forms of return, but some “return-migrate” and settle in an...

  8. COMPONENTES NUTRICIONALES Y ANTIOXIDANTES DE DOS ESPECIES DE GUAJE (Leucaena spp.): UN RECURSO ANCESTRAL SUBUTILIZADO

    OpenAIRE

    Nallely Román-Cortés; María del Rosario García-Mateos; Ana María Castillo-González; Jaime Sahagún-Castellanos; Adelina Jiménez-Arellanes

    2014-01-01

    El guaje ( Leucaena spp.) es una planta de vaina y semillas comestibles, un recurso ancestral subutilizado por los pueblos mesoamericanos. El valor nutricional y nutracéutico del guaje se desconoce pese a su consumo vigente en las poblaciones rurales. El objetivo de este trabajo fue evaluar el contenido de minerales, compo - nentes nutricionales y antioxidantes para contribuir a la revalorización alimentaria del guaje rojo ( L. esculenta Benth.) y verde ( L. leucocephala Lam.). Los contenidos...

  9. Distinct actions of ancestral vinclozolin and juvenile stress on neural gene expression in the male rat

    Directory of Open Access Journals (Sweden)

    Ross eGillette

    2015-03-01

    Full Text Available Exposure to the endocrine disrupting chemical vinclozolin during gestation of an F0 generation and/or chronic restraint stress during adolescence of the F3 descendants affects behavior, physiology, and gene expression in the brain. Genes related to the networks of growth factors, signaling peptides and receptors, steroid hormone receptors and enzymes, and epigenetic related factors were measured using quantitative polymerase chain reaction via Taqman low density arrays targeting 48 genes in the central amygdaloid nucleus, medial amygdaloid nucleus, medial preoptic area, lateral hypothalamus, and the ventromedial nucleus of the hypothalamus. We found that growth factors are particularly vulnerable to ancestral exposure in the central and medial amygdala; restraint stress during adolescence affected neural growth factors in the medial amygdala. Signaling peptides were affected by both ancestral exposure and stress during adolescence primarily in hypothalamic nuclei. Steroid hormone receptors and enzymes were strongly affected by restraint stress in the medial preoptic area. Epigenetic related genes were affected by stress in the ventromedial hypothalamus and by both ancestral exposure and stress during adolescence independently in the central amygdala. It is noteworthy that the lateral hypothalamus showed no effects of either manipulation. Gene expression is discussed in the context of behavioral and physiological measures previously published.

  10. AAV ancestral reconstruction library enables selection of broadly infectious viral variants.

    Science.gov (United States)

    Santiago-Ortiz, J; Ojala, D S; Westesson, O; Weinstein, J R; Wong, S Y; Steinsapir, A; Kumar, S; Holmes, I; Schaffer, D V

    2015-12-01

    Adeno-associated virus (AAV) vectors have achieved clinical efficacy in treating several diseases. However, enhanced vectors are required to extend these landmark successes to other indications and protein engineering approaches may provide the necessary vector improvements to address such unmet medical needs. To generate new capsid variants with potentially enhanced infectious properties and to gain insights into AAV's evolutionary history, we computationally designed and experimentally constructed a putative ancestral AAV library. Combinatorial variations at 32 amino acid sites were introduced to account for uncertainty in their identities. We then analyzed the evolutionary flexibility of these residues, the majority of which have not been previously studied, by subjecting the library to iterative selection on a representative cell line panel. The resulting variants exhibited transduction efficiencies comparable to the most efficient extant serotypes and, in general, ancestral libraries were broadly infectious across the cell line panel, indicating that they favored promiscuity over specificity. Interestingly, putative ancestral AAVs were more thermostable than modern serotypes and did not use sialic acids, galactose or heparan sulfate proteoglycans for cellular entry. Finally, variants mediated 19- to 31-fold higher gene expression in the muscle compared with AAV1, a clinically used serotype for muscle delivery, highlighting their promise for gene therapy. PMID:26186661

  11. Ancestral sleep.

    Science.gov (United States)

    de la Iglesia, Horacio O; Moreno, Claudia; Lowden, Arne; Louzada, Fernando; Marqueze, Elaine; Levandovski, Rosa; Pilz, Luisa K; Valeggia, Claudia; Fernandez-Duque, Eduardo; Golombek, Diego A; Czeisler, Charles A; Skene, Debra J; Duffy, Jeanne F; Roenneberg, Till

    2016-04-01

    While we do not yet understand all the functions of sleep, its critical role for normal physiology and behaviour is evident. Its amount and temporal pattern depend on species and condition. Humans sleep about a third of the day with the longest, consolidated episode during the night. The change in lifestyle from hunter-gatherers via agricultural communities to densely populated industrialized centres has certainly affected sleep, and a major concern in the medical community is the impact of insufficient sleep on health [1,2]. One of the causal mechanisms leading to insufficient sleep is altered exposure to the natural light-dark cycle. This includes the wide availability of electric light, attenuated exposure to daylight within buildings, and evening use of light-emitting devices, all of which decrease the strength of natural light-dark signals that entrain circadian systems [3]. PMID:27046809

  12. Efectos genéticos de la formación de calosa en ápices radicales de líneas de maíz resistentes y susceptibles a suelos ácidos Genetic effects in callose content in root apex of inbred resistant and susceptible corn lines to acid soils

    Directory of Open Access Journals (Sweden)

    Alba Lucía Arcos

    2007-01-01

    Full Text Available El objetivo de este trabajo fue estudiar la herencia de la producción de calosa utilizando líneas endogámicas de maíz. Seleccionando 14 líneas (7 tolerantes y 7 susceptibles a suelos ácidos se formó un dialelo que fue probado en campo y en invernadero. Se determinó el contenido de calosa en los 91 cruzamientos resultantes y los 14 progenitores. Para ello se colocaron las semillas en cámara de crecimiento en condiciones controladas. Después de 4-5 días las plántulas fueron transferidas a cubetas que contenían solución nutritiva con aireación constante. Luego de 48 horas se adicionaron 25 µM de aluminio (AlCl3 a cada una de las cubetas y se mantuvieron por 12 horas. Se cortaron tres ápices radicales de cada genotipo y se mantuvieron en etanol 96%. Para medir el contenido de calosa se utilizó Methyl blue como colorante, este forma un complejo con la calosa llamado Siruflúor-calosa, que es medido con el espectrofotómetro de fluorescencia. Se encontraron diferencias significativas para los progenitores, los cruzamientos y los progenitores Vs cruzamientos. El contenido de calosa de los progenitores varió de 0.746 a 2.035 µg PE/cm ápice de raíz. La heterosis varió desde -21.2% a 276.3%. La Habilidad Combinatoria General (HCG y la Habilidad Combinatoria Específica (HCE fueron altamente significativas, lo que indica que tanto los efectos genéticos aditivos y no aditivos fueron importantes en la herencia de calosa. El 46% de SC entre cruzamientos correspondió a la HCG y el 54% a la HCE. El coeficiente de correlación entre el contenido de calosa y la producción de grano del maíz en el campo fue negativo aunque no significativo (r = -0.38.The main objective of this work was to identify genetic parameters that are related to callose accumulation using tropical inbreeds corn. Fourteen inbreed lines selected for different levels of tolerance to acid soils were chosen and a diallel among them was generated. The seeds were grown

  13. Genetic effects in callose content in root apex of inbred resistant and susceptible corn lines to acid soils Efectos genéticos de la formación de calosa en ápices radicales de líneas de maíz resistentes y susceptibles a suelos ácidos

    Directory of Open Access Journals (Sweden)

    Arcos Alba Lucía

    2007-12-01

    Full Text Available

    The main objective of this work was to identify genetic parameters that are related to callose accumulation using tropical inbreeds corn. Fourteen inbreed lines selected for different levels of tolerance to acid soils were chosen and a diallel among them was generated. The seeds were grown under controlled environmental conditions in a growth chamber and transferred to a nutrient solution at pH 4.3. After 12 hours of 25 µM Al (AlCl3 treatment was applied, callose contents of 1 cm root apex were determined with fluorescence spectrophotometer. Significant differences were found for parents, crosses and parents vs crosses. Average callose content varied from 0.746 to 2.035 (µg PE/cm root apex. Heterosis varied from –21.2% to 276.3%. General combining ability (GCA and specific combining ability (SCA were highly significant indicating that both, additive and non–additive gene effects were important for callose inheritance. SCA and GCA sum of squares accounted for 54% and 46%, respectively of crosses of squares sum. Correlation coefficient between callose content and corn grain yield in the field was negative but not significant (r = –0.38.

    Key words: Zea mays; callose; inheritance; diallel; heterosis; acid soils.

    El objetivo de este trabajo fue estudiar la herencia de la producción de calosa utilizando líneas endogámicas de maíz. Seleccionando 14 líneas (7 tolerantes y 7 susceptibles a suelos ácidos se formó un dialelo que fue probado en campo y en invernadero. Se determinó el contenido de calosa en los 91 cruzamientos resultantes y los 14 progenitores. Para ello se colocaron las semillas en cámara de crecimiento en condiciones controladas. Después de 4–5 días las plántulas fueron transferidas a cubetas que contenían solución nutritiva con aireación constante. Luego de 48 horas se adicionaron 25 µM de aluminio (AlCl3 a cada una de las cubetas y se mantuvieron por 12 horas. Se cortaron tres ápices radicales de

  14. Genetic variants and multiple myeloma risk

    DEFF Research Database (Denmark)

    Martino, Alessandro; Campa, Daniele; Jurczyszyn, Artur;

    2014-01-01

    BACKGROUND: Genetic background plays a role in multiple myeloma susceptibility. Several single-nucleotide polymorphisms (SNP) associated with genetic susceptibility to multiple myeloma were identified in the last years, but only a few of them were validated in independent studies. METHODS: With t...

  15. Genetic epidemiology: Systemic lupus erythematosus

    OpenAIRE

    Ahmad, Yasmeen A.; Bruce, Ian N.

    2001-01-01

    Systemic lupus erythematosus is the prototype multisystem autoimmune disease. A strong genetic component of susceptibility to the disease is well established. Studies of murine models of systemic lupus erythematosus have shown complex genetic interactions that influence both susceptibility and phenotypic expression. These models strongly suggest that several defects in similar pathways, e.g. clearance of immune complexes and/or apoptotic cell debris, can all result in disease expression. Stud...

  16. Further Evidence of Subphenotype Association with Systemic Lupus Erythematosus Susceptibility Loci: A European Cases Only Study

    Czech Academy of Sciences Publication Activity Database

    Alonso-Perez, E.; Suarez-Gestal, M.; Calaza, M.; Ordi-Ros, J.; Bijl, M.; Papasteriades, Ch.; Carreira, P.; Skopouli, F.N.; Witte, T.; Marchini, M.; Migliaresi, S.; Santos, M.J.; Růžičková, Šárka; Pullmann, R.; Sebastiani, G.D.; Suarez, A.; Blanco, F.J.

    2012-01-01

    Roč. 7, č. 9 (2012), e45356. E-ISSN 1932-6203 Institutional research plan: CEZ:AV0Z50520701 Keywords : GENOME-WIDE ASSOCIATION * GENETIC SUSCEPTIBILITY * DISEASE SUSCEPTIBILITY Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.730, year: 2012

  17. Modeling susceptibility to periodontitis

    NARCIS (Netherlands)

    M.L. Laine; V. Moustakis; L. Koumakis; G. Potamias; B.G. Loos

    2013-01-01

    Chronic inflammatory diseases like periodontitis have a complex pathogenesis and a multifactorial etiology, involving complex interactions between multiple genetic loci and infectious agents. We aimed to investigate the influence of genetic polymorphisms and bacteria on chronic periodontitis risk. W

  18. Variation in Effects of Non-Hodgkin Lymphoma Risk Factors According to the Human Leukocyte Antigen (HLA)-DRB1*01:01 Allele and Ancestral Haplotype 8.1

    OpenAIRE

    Wang, Sophia S.; Lu, Yani; Rothman, Nathaniel; Amr M Abdou; Cerhan, James R.; De Roos, Anneclaire; Davis, Scott; Richard K Severson; Cozen, Wendy; Chanock, Stephen J.; Bernstein, Leslie; Morton, Lindsay M.; Hartge, Patricia

    2011-01-01

    Genetic variations in human leukocyte antigens (HLA) are critical in host responses to infections, transplantation, and immunological diseases. We previously identified associations with non-Hodgkin lymphoma (NHL) and the HLA-DRB1*01:01 allele and extended ancestral haplotype (AH) 8.1 (HLA-A*01-B*08-DR*03-TNF-308A). To illuminate how HLA alleles and haplotypes may influence NHL etiology, we examined potential interactions between HLA-DRB1*01:01 and AH 8.1, and a wide range of NHL risk factors...

  19. Chromosome painting in three-toed sloths: a cytogenetic signature and ancestral karyotype for Xenarthra

    Directory of Open Access Journals (Sweden)

    Azevedo Nathália F

    2012-03-01

    Full Text Available Abstract Background Xenarthra (sloths, armadillos and anteaters represent one of four currently recognized Eutherian mammal supraorders. Some phylogenomic studies point to the possibility of Xenarthra being at the base of the Eutherian tree, together or not with the supraorder Afrotheria. We performed painting with human autosomes and X-chromosome specific probes on metaphases of two three-toed sloths: Bradypus torquatus and B. variegatus. These species represent the fourth of the five extant Xenarthra families to be studied with this approach. Results Eleven human chromosomes were conserved as one block in both B. torquatus and B. variegatus: (HSA 5, 6, 9, 11, 13, 14, 15, 17, 18, 20, 21 and the X chromosome. B. torquatus, three additional human chromosomes were conserved intact (HSA 1, 3 and 4. The remaining human chromosomes were represented by two or three segments on each sloth. Seven associations between human chromosomes were detected in the karyotypes of both B. torquatus and B. variegatus: HSA 3/21, 4/8, 7/10, 7/16, 12/22, 14/15 and 17/19. The ancestral Eutherian association 16/19 was not detected in the Bradypus species. Conclusions Our results together with previous reports enabled us to propose a hypothetical ancestral Xenarthran karyotype with 48 chromosomes that would differ from the proposed ancestral Eutherian karyotype by the presence of the association HSA 7/10 and by the split of HSA 8 into three blocks, instead of the two found in the Eutherian ancestor. These same chromosome features point to the monophyly of Xenarthra, making this the second supraorder of placental mammals to have a chromosome signature supporting its monophyly.

  20. Chromosome painting in three-toed sloths: a cytogenetic signature and ancestral karyotype for Xenarthra

    Science.gov (United States)

    2012-01-01

    Background Xenarthra (sloths, armadillos and anteaters) represent one of four currently recognized Eutherian mammal supraorders. Some phylogenomic studies point to the possibility of Xenarthra being at the base of the Eutherian tree, together or not with the supraorder Afrotheria. We performed painting with human autosomes and X-chromosome specific probes on metaphases of two three-toed sloths: Bradypus torquatus and B. variegatus. These species represent the fourth of the five extant Xenarthra families to be studied with this approach. Results Eleven human chromosomes were conserved as one block in both B. torquatus and B. variegatus: (HSA 5, 6, 9, 11, 13, 14, 15, 17, 18, 20, 21 and the X chromosome). B. torquatus, three additional human chromosomes were conserved intact (HSA 1, 3 and 4). The remaining human chromosomes were represented by two or three segments on each sloth. Seven associations between human chromosomes were detected in the karyotypes of both B. torquatus and B. variegatus: HSA 3/21, 4/8, 7/10, 7/16, 12/22, 14/15 and 17/19. The ancestral Eutherian association 16/19 was not detected in the Bradypus species. Conclusions Our results together with previous reports enabled us to propose a hypothetical ancestral Xenarthran karyotype with 48 chromosomes that would differ from the proposed ancestral Eutherian karyotype by the presence of the association HSA 7/10 and by the split of HSA 8 into three blocks, instead of the two found in the Eutherian ancestor. These same chromosome features point to the monophyly of Xenarthra, making this the second supraorder of placental mammals to have a chromosome signature supporting its monophyly. PMID:22429690

  1. Ancestral polymorphism and recent invasion of transposable elements in Drosophila species

    Directory of Open Access Journals (Sweden)

    Dias Elaine

    2012-07-01

    Full Text Available Abstract Background During the evolution of transposable elements, some processes, such as ancestral polymorphisms and horizontal transfer of sequences between species, can produce incongruences in phylogenies. We investigated the evolutionary history of the transposable elements Bari and 412 in the sequenced genomes of the Drosophila melanogaster group and in the sibling species D. melanogaster and D. simulans using traditional phylogenetic and network approaches. Results Maximum likelihood (ML phylogenetic analyses revealed incongruences and unresolved relationships for both the Bari and 412 elements. The DNA transposon Bari within the D. ananassae genome is more closely related to the element of the melanogaster complex than to the sequence in D. erecta, which is inconsistent with the species phylogeny. Divergence analysis and the comparison of the rate of synonymous substitutions per synonymous site of the Bari and host gene sequences explain the incongruence as an ancestral polymorphism that was inherited stochastically by the derived species. Unresolved relationships were observed in the ML phylogeny of both elements involving D. melanogaster, D. simulans and D. sechellia. A network approach was used to attempt to resolve these relationships. The resulting tree suggests recent transfers of both elements between D. melanogaster and D. simulans. The divergence values of the elements between these species support this conclusion. Conclusions We showed that ancestral polymorphism and recent invasion of genomes due to introgression or horizontal transfer between species occurred during the evolutionary history of the Bari and 412 elements in the melanogaster group. These invasions likely occurred in Africa during the Pleistocene, before the worldwide expansion of D. melanogaster and D. simulans.

  2. Contrasting determinants of abundance in ancestral and colonized ranges of an invasive brood parasite

    Science.gov (United States)

    Hahn, D.C.; O'Connor, R.J.

    2002-01-01

    Avian species distributions are typically regarded as constrained by spatially extensive variables such as climate, habitat, spatial patchiness, and microhabitat attributes. We hypothesized that the distribution of a brood parasite depends as strongly on host distribution patterns as on biophysical factors and examined this hypothesis with respect to the national distribution of the Brown-headed Cowbird (Molothrus ater). We applied a classification and regression (CART) analysis to data from the Breeding Bird Survey (BBS) and the Christmas Bird Count (CBC) and derived hierarchically organized statistical models of the influence of climate and weather, cropping and land use, and host abundance and distribution on the distribution of the Brown-headed Cowbird within the conterminous United States. The model accounted for 47.2% of the variation in cowbird incidence, and host abundance was the top predictor with an R2 of 18.9%. The other predictors identified by the model (crops 15.7%, weather and climate 14.3%, and region 9.6%) fit the ecological profile of this cowbird. We showed that host abundance was independent of these environmental predictors of cowbird distribution. At the regional scale host abundance played a very strong role in determining cowbird abundance in the cowbird?s colonized range east and west of their ancestral range in the Great Plains (26.6%). Crops were not a major predictor for cowbirds in their ancestral range, although they are the most important predictive factor (33%) for the grassland passerines that are the cowbird?s ancestral hosts. Consequently our findings suggest that the distribution of hosts does indeed take precedence over habitat attributes in shaping the cowbird?s distribution at a national scale, within an envelope of constraint set by biophysical factors.

  3. Spread of pedigree versus genetic ancestry in spatially distributed populations

    OpenAIRE

    Kelleher, J; Etheridge, AM; Véber, A.; Barton, NH

    2016-01-01

    Ancestral processes are fundamental to modern population genetics and spatial structure has been the subject of intense interest for many years. Despite this interest, almost nothing is known about the distribution of the locations of pedigree or genetic ancestors. Using both spatially continuous and stepping-stone models, we show that the distribution of pedigree ancestors approaches a travelling wave, for which we develop two alternative approximations. The speed and width of the wave are s...

  4. Ancestral heritage saves tribes during 1 April 2007 Solomon Islands tsunami

    Science.gov (United States)

    Fritz, Hermann M.; Kalligeris, Nikos

    2008-01-01

    The 1 April 2007 magnitude Ms 8.1 earthquake off the New Georgia Group in the Solomon Islands generated a tsunami that killed 52 with locally focused run-up heights of 12 m, local flow depths of 5 m as well as tectonic uplift up to 3.6 m and subsidence down to -1.5 m. A reconnaissance team deployed within one week investigated 65 coastal settlements on 13 remote Islands. The ancestral heritage ``run to high ground after an earthquake'' passed on to younger generations by survivors of smaller historic tsunamis triggered an immediate spontaneous self evacuation containing the death toll.

  5. Genetic epidemiology: Psoriatic arthritis

    OpenAIRE

    Barton, Anne C

    2002-01-01

    The existence of psoriatic arthritis as a distinct clinical entity remains a topic of debate; some authors propose that it is simply the co-occurrence of psoriasis and inflammatory arthritis. However, a distinct entity is likely to have distinct susceptibility factors in addition to those that contribute to psoriasis and inflammatory arthritis alone. These aetiological factors may be genetic and/or environmental, and in this review, the evidence for distinct psoriatic arthritis genetic suscep...

  6. Consistency and inconsistency of consensus methods for inferring species trees from gene trees in the presence of ancestral population structure.

    Science.gov (United States)

    DeGiorgio, Michael; Rosenberg, Noah A

    2016-08-01

    In the last few years, several statistically consistent consensus methods for species tree inference have been devised that are robust to the gene tree discordance caused by incomplete lineage sorting in unstructured ancestral populations. One source of gene tree discordance that has only recently been identified as a potential obstacle for phylogenetic inference is ancestral population structure. In this article, we describe a general model of ancestral population structure, and by relying on a single carefully constructed example scenario, we show that the consensus methods Democratic Vote, STEAC, STAR, R(∗) Consensus, Rooted Triple Consensus, Minimize Deep Coalescences, and Majority-Rule Consensus are statistically inconsistent under the model. We find that among the consensus methods evaluated, the only method that is statistically consistent in the presence of ancestral population structure is GLASS/Maximum Tree. We use simulations to evaluate the behavior of the various consensus methods in a model with ancestral population structure, showing that as the number of gene trees increases, estimates on the basis of GLASS/Maximum Tree approach the true species tree topology irrespective of the level of population structure, whereas estimates based on the remaining methods only approach the true species tree topology if the level of structure is low. However, through simulations using species trees both with and without ancestral population structure, we show that GLASS/Maximum Tree performs unusually poorly on gene trees inferred from alignments with little information. This practical limitation of GLASS/Maximum Tree together with the inconsistency of other methods prompts the need for both further testing of additional existing methods and development of novel methods under conditions that incorporate ancestral population structure. PMID:27086043

  7. ABO (histo) blood group phenotype development and human reproduction as they relate to ancestral IgM formation: A hypothesis.

    Science.gov (United States)

    Arend, Peter

    2016-01-01

    The formation of a histo (blood) group) ABO phenotype and the exclusion of an autoreactive IgM or isoagglutinin activity arise apparently in identical glycosylation of complementary domains on cell surfaces and plasma proteins. The fundamental O-glycan emptiness of the circulating IgM, which during the neonatal amino acid sequencing of the variable regions is exerting germline-specific O-GalNAc glycan-reactive serine/threonine residues that in the plasma of the adult human blood group O individuals apparently remain associated with the open glycosidic sites on the ABOH convertible red cell surface, must raise suggestions on a transient expression of developmental glycans, which have been "lost" over the course of maturation. In fact, while the mammalian non-somatic, embryogenic stem cell (ESC)- germ cell (GC) transformation is characterized by a transient and genetically as-yet-undefined trans-species-functional O-GalNAc glycan expression, in the C57BL/10 mouse such expression was potentially identified in growth-dependent, blood group A-like GalNAc glycan-bearing, ovarian glycolipids complementary with the syngeneic anti-A reactive IgM, which does not appear in early ovariectomized animals. This non-somatically encoded, polyreactive, ancestral IgM molecule has not undergone clonal selection and does primarily not differentiate between self and non-self and might, due to amino acid hydroxyl groups, highly suggest substrate competition with subsequent O-glycosylations in ongoing ESC-GC transformations and affecting GC maturation. However, the membrane-bound somatic N/O-glycotransferases, which initiate, after formation of the zygote, the complex construction of the human ABO phenotypes in the trans cisternae of the Golgi apparatus, are associated and/or completed with soluble enzyme versions exerting identical specificities in plasma and likely competing vice versa by glycosylation of neonatal IgM amino acids, where they suggest to accomplish the clearance of anti

  8. Genetic Variations in Vesicoureteral Reflux Sequelae

    OpenAIRE

    Hains, David S.; Schwaderer, Andrew L.

    2016-01-01

    Urinary tract infections (UTI) are a common condition in children. Vesicoureteral reflux (VUR) represents a common associated condition with childhood UTI. UTI susceptibility appears to have a genetic component based on family and UTI cohort studies. Targeted analysis of innate immune system genetic variations indicate that these variations are important in UTI susceptibility. In this overview, we discuss how current cohorts and genetic strategies can be implemented to discover new susceptibi...

  9. Bearing the unbearable: ancestral transmission through dreams and moving metaphors in the analtyic field.

    Science.gov (United States)

    Pickering, Judith

    2012-11-01

    This paper explores how untold and unresolved intergenerational trauma may be transmitted through unconscious channels of communication, manifesting in the dreams of descendants. Unwitting carriers for that which was too horrific for their ancestors to bear, descendants may enter analysis through an unconscious need to uncover past secrets, piece together ancestral histories before the keys to comprehending their terrible inheritance die with their forebears. They seek the relational containment of the analytic relationship to provide psychological conditions to bear the unbearable, know the unknowable, speak the unspeakable and redeem the unredeemable. In the case of 'Rachael', initial dreams gave rise to what Hobson (1984) called 'moving metaphors of self' in the analytic field. Dream imagery, projective and introjective processes in the transference-countertransference dynamics gradually revealed an unknown ancestral history. I clarify the back and forth process from dream to waking dream thoughts to moving metaphors and differentiate the moving metaphor from a living symbol. I argue that the containment of the analytic relationship nested within the security of the analytic space is a necessary precondition for such healing processes to occur. PMID:23130614

  10. RNA-DNA differences in human mitochondria restore ancestral form of 16S ribosomal RNA.

    Science.gov (United States)

    Bar-Yaacov, Dan; Avital, Gal; Levin, Liron; Richards, Allison L; Hachen, Naomi; Rebolledo Jaramillo, Boris; Nekrutenko, Anton; Zarivach, Raz; Mishmar, Dan

    2013-11-01

    RNA transcripts are generally identical to the underlying DNA sequences. Nevertheless, RNA-DNA differences (RDDs) were found in the nuclear human genome and in plants and animals but not in human mitochondria. Here, by deep sequencing of human mitochondrial DNA (mtDNA) and RNA, we identified three RDD sites at mtDNA positions 295 (C-to-U), 13710 (A-to-U, A-to-G), and 2617 (A-to-U, A-to-G). Position 2617, within the 16S rRNA, harbored the most prevalent RDDs (>30% A-to-U and ∼15% A-to-G of the reads in all tested samples). The 2617 RDDs appeared already at the precursor polycistrone mitochondrial transcript. By using traditional Sanger sequencing, we identified the A-to-U RDD in six different cell lines and representative primates (Gorilla gorilla, Pongo pigmaeus, and Macaca mulatta), suggesting conservation of the mechanism generating such RDD. Phylogenetic analysis of more than 1700 vertebrate mtDNA sequences supported a thymine as the primate ancestral allele at position 2617, suggesting that the 2617 RDD recapitulates the ancestral 16S rRNA. Modeling U or G (the RDDs) at position 2617 stabilized the large ribosomal subunit structure in contrast to destabilization by an A (the pre-RDDs). Hence, these mitochondrial RDDs are likely functional. PMID:23913925

  11. In silico resurrection of the major vault protein suggests it is ancestral in modern eukaryotes.

    Science.gov (United States)

    Daly, Toni K; Sutherland-Smith, Andrew J; Penny, David

    2013-01-01

    Vaults are very large oligomeric ribonucleoproteins conserved among a variety of species. The rat vault 3D structure shows an ovoid oligomeric particle, consisting of 78 major vault protein monomers, each of approximately 861 amino acids. Vaults are probably the largest ribonucleoprotein structures in eukaryote cells, being approximately 70 nm in length with a diameter of 40 nm--the size of three ribosomes and with a lumen capacity of 50 million Å(3). We use both protein sequences and inferred ancestral sequences for in silico virtual resurrection of tertiary and quaternary structures to search for vaults in a wide variety of eukaryotes. We find that the vault's phylogenetic distribution is widespread in eukaryotes, but is apparently absent in some notable model organisms. Our conclusion from the distribution of vaults is that they were present in the last eukaryote common ancestor but they have apparently been lost from a number of groups including fungi, insects, and probably plants. Our approach of inferring ancestral 3D and quaternary structures is expected to be useful generally. PMID:23887922

  12. Identification of the ancestral haplotype for apolipoprotein B suggests an African origin of Homo sapiens sapiens and traces their subsequent migration to Europe and the Pacific.

    OpenAIRE

    Rapacz, J; Chen, L.; Butler-Brunner, E; Wu, M J; Hasler-Rapacz, J O; Butler, R.; Schumaker, V N

    1991-01-01

    The probable ancestral haplotype for human apolipoprotein B (apoB) has been identified through immunological analysis of chimpanzee and gorilla serum and sequence analysis of their DNA. Moreover, the frequency of this ancestral apoB haplotype among different human populations provides strong support for the African origin of Homo sapiens sapiens and their subsequent migration from Africa to Europe and to the Pacific. The approach used here for the identification of the ancestral human apoB ha...

  13. Markov chain Monte Carlo sampling of gene genealogies conditional on observed genetic data

    OpenAIRE

    Burkett, Kelly

    2011-01-01

    The gene genealogy is a tree describing the ancestral relationships among genes sampled from unrelated individuals. Knowledge of the tree is useful for inference of population-genetic parameters such as the mutation or recombination rate. It also has potential application in genomic mapping, as individuals with similar trait values will tend to be more closely related genetically at the location of a trait-influencing mutation. One way to incorporate genealogical trees in genetic applications...

  14. Ancestral state reconstruction of body size in the Caniformia (Carnivora, Mammalia): the effects of incorporating data from the fossil record.

    Science.gov (United States)

    Finarelli, John A; Flynn, John J

    2006-04-01

    A recent molecular phylogeny of the mammalian order Carnivora implied large body size as the ancestral condition for the caniform subclade Arctoidea using the distribution of species mean body sizes among living taxa. "Extant taxa-only" approaches such as these discount character state observations for fossil members of living clades and completely ignore data from extinct lineages. To more rigorously reconstruct body sizes of ancestral forms within the Caniformia, body size and first appearance data were collected for 149 extant and 367 extinct taxa. Body sizes were reconstructed for four ancestral nodes using weighted squared-change parsimony on log-transformed body mass data. Reconstructions based on extant taxa alone favored large body sizes (on the order of 10 to 50 kg) for the last common ancestors of both the Caniformia and Arctoidea. In contrast, reconstructions incorporating fossil data support small body sizes (fossil data was discarded, body size reconstructions became ambiguous, demonstrating that incorporating both character state and temporal information from fossil taxa unambiguously supports a small ancestral body size, thereby falsifying hypotheses derived from extant taxa alone. Body size reconstructions for Caniformia, Arctoidea, and Musteloidea were not sensitive to potential errors introduced by uncertainty in the position of extinct lineages relative to the molecular topology, or to missing body size data for extinct members of an entire major clade (the aquatic Pinnipedia). Incorporating character state observations and temporal information from the fossil record into hypothesis testing has a significant impact on the ability to reconstruct ancestral characters and constrains the range of potential hypotheses of character evolution. Fossil data here provide the evidence to reliably document trends of both increasing and decreasing body size in several caniform clades. More generally, including fossils in such analyses incorporates evidence of

  15. ReAS: Recovery of ancestral sequences for transposable elements from the unassembled reads of a whole genome shotgun.

    Directory of Open Access Journals (Sweden)

    Ruiqiang Li

    2005-09-01

    Full Text Available We describe an algorithm, ReAS, to recover ancestral sequences for transposable elements (TEs from the unassembled reads of a whole genome shotgun. The main assumptions are that these TEs must exist at high copy numbers across the genome and must not be so old that they are no longer recognizable in comparison to their ancestral sequences. Tested on the japonica rice genome, ReAS was able to reconstruct all of the high copy sequences in the Repbase repository of known TEs, and increase the effectiveness of RepeatMasker in identifying TEs from genome sequences.

  16. Genetic influence on the age at onset of asthma: a twin study

    DEFF Research Database (Denmark)

    Thomsen, Simon Francis; Duffy, David Lorenzo; Kyvik, Kirsten Ohm; Backer, Vibeke

    2010-01-01

    Although the genetics of asthma susceptibility have been frequently explored, little is known about genetic factors that influence the age at onset of asthma.......Although the genetics of asthma susceptibility have been frequently explored, little is known about genetic factors that influence the age at onset of asthma....

  17. Genetics and Pathogenesis of Inflammatory Bowel Disease.

    Science.gov (United States)

    Liu, Ta-Chiang; Stappenbeck, Thaddeus S

    2016-05-23

    We are currently in an exciting time when our understanding of genetic underpinnings of inflammatory bowel disease (IBD) has undergone a revolution, based in large part on novel genotyping and sequencing technologies. With >160 susceptible loci identified for IBD, the goal is now to understand at a fundamental level the function of these susceptibility alleles. Determining the clinical relevance of how these susceptible genes shape the development of IBD is also a high priority. The main challenge is to understand how the environment and microbiome play a role in triggering disease in genetically susceptible individuals, as the interactions may be complex. To advance the field, novel in vitro and mouse models that are designed to interrogate complex genetics and functionally test hypotheses are needed. Ultimately, the goal of genetics studies will be to translate genetics to patients with IBD and improve their care. PMID:26907531

  18. 中国汉人 X染色体上情感障碍易感性基因的遗传学研究及关联分析%Susceptible gene for affection disorder of chromosome X in Han people of Chinese:genetical study and relative analysis

    Institute of Scientific and Technical Information of China (English)

    吴怀安; 闫小华; 邓小敏; 沈其杰

    2002-01-01

    Objective In order to detect the Susceptible gene on X chromosome for Han nationality of Chinese who suffer from affective disorder(AD),to explore the association between DXS1114 polymorphism and AD and the feature of genetics.Method We used the technique of the amplified fragment length polymorphism(Amp FLP)to detect the polymorphism distribution of DXS1114 for 40 patients with AD and 40 normal controls.Results We found that there were 4 polymorphism fragments of DXS1114 on the γ -chromosome in AD and normal controls.The result of statistics showed that four polymorphism fragments(117bp.113bp.111bp 109bp)had not significant difference(P>0.05)between patients and normal controls.Conclusion We report that the DXS1114 is not associated with Chinese who suffer from AD.The results indicate that there maybe no a susceptible gene of AD on xq26.1 in our research simples.

  19. Where did the chili get its spice? Biogeography of capsaicinoid production in ancestral wild chili species.

    Science.gov (United States)

    Tewksbury, Joshua J; Manchego, Carlos; Haak, David C; Levey, Douglas J

    2006-03-01

    The biogeography of pungency in three species of wild chili in the chaco and surrounding highland habitats of southeastern Bolivia is described. We report that Capsicum chacoense, C. baccatum, and C. eximium are polymorphic for production of capsaicin and its analogs, such that completely pungent and completely nonpungent individuals co-occur in some populations. In C. chacoense, the density of plants and the proportion of pungent plants increased with elevation. Above 900 m, all individuals in all populations except two were pungent; nonpungent individuals in at least one of the two polymorphic populations were likely a result of spreading by humans. The occurrence of pungent and nonpungent individuals in three species of ancestral Capsicum and the geographic variation of pungency within species suggest that production of capsaicin and its analogs entails both costs and benefits, which shift from one locality to another. Determining the selection pressures behind such shifts is necessary to understand the evolution of pungency in chilies. PMID:16572297

  20. Magmatism and Epithermal Gold-Silver Deposits of the Southern Ancestral Cascade Arc, Western Nevada and Eastern California

    Science.gov (United States)

    John, David A.; du Bray, Edward A.; Henry, Christopher D., (compiler); Vikre, Peter

    2015-01-01

    Many epithermal gold-silver deposits are temporally and spatially associated with late Oligocene to Pliocene magmatism of the southern ancestral Cascade arc in western Nevada and eastern California. These deposits, which include both quartz-adularia (low- and intermediate-sulfidation; Comstock Lode, Tonopah, Bodie) and quartz-alunite (high-sulfidation; Goldfield, Paradise Peak) types, were major producers of gold and silver. Ancestral Cascade arc magmatism preceded that of the modern High Cascades arc and reflects subduction of the Farallon plate beneath North America. Ancestral arc magmatism began about 45 Ma, continued until about 3 Ma, and extended from near the Canada-United States border in Washington southward to about 250 km southeast of Reno, Nevada. The ancestral arc was split into northern and southern segments across an inferred tear in the subducting slab between Mount Shasta and Lassen Peak in northern California. The southern segment extends between 42°N in northern California and 37°N in western Nevada and was active from about 30 to 3 Ma. It is bounded on the east by the northeast edge of the Walker Lane. Ancestral arc volcanism represents an abrupt change in composition and style of magmatism relative to that in central Nevada. Large volume, caldera-forming, silicic ignimbrites associated with the 37 to 19 Ma ignimbrite flareup are dominant in central Nevada, whereas volcanic centers of the ancestral arc in western Nevada consist of andesitic stratovolcanoes and dacitic to rhyolitic lava domes that mostly formed between 25 and 4 Ma. Both ancestral arc and ignimbrite flareup magmatism resulted from rollback of the shallowly dipping slab that began about 45 Ma in northeast Nevada and migrated south-southwest with time. Most southern segment ancestral arc rocks have oxidized, high potassium, calc-alkaline compositions with silica contents ranging continuously from about 55 to 77 wt%. Most lavas are porphyritic and contain coarse plagioclase

  1. Evolutionary history of assassin bugs (insecta: hemiptera: Reduviidae: insights from divergence dating and ancestral state reconstruction.

    Directory of Open Access Journals (Sweden)

    Wei Song Hwang

    Full Text Available Assassin bugs are one of the most successful clades of predatory animals based on their species numbers (∼6,800 spp. and wide distribution in terrestrial ecosystems. Various novel prey capture strategies and remarkable prey specializations contribute to their appeal as a model to study evolutionary pathways involved in predation. Here, we reconstruct the most comprehensive reduviid phylogeny (178 taxa, 18 subfamilies to date based on molecular data (5 markers. This phylogeny tests current hypotheses on reduviid relationships emphasizing the polyphyletic Reduviinae and the blood-feeding, disease-vectoring Triatominae, and allows us, for the first time in assassin bugs, to reconstruct ancestral states of prey associations and microhabitats. Using a fossil-calibrated molecular tree, we estimated divergence times for key events in the evolutionary history of Reduviidae. Our results indicate that the polyphyletic Reduviinae fall into 11-14 separate clades. Triatominae are paraphyletic with respect to the reduviine genus Opisthacidius in the maximum likelihood analyses; this result is in contrast to prior hypotheses that found Triatominae to be monophyletic or polyphyletic and may be due to the more comprehensive taxon and character sampling in this study. The evolution of blood-feeding may thus have occurred once or twice independently among predatory assassin bugs. All prey specialists evolved from generalist ancestors, with multiple evolutionary origins of termite and ant specializations. A bark-associated life style on tree trunks is ancestral for most of the lineages of Higher Reduviidae; living on foliage has evolved at least six times independently. Reduviidae originated in the Middle Jurassic (178 Ma, but significant lineage diversification only began in the Late Cretaceous (97 Ma. The integration of molecular phylogenetics with fossil and life history data as presented in this paper provides insights into the evolutionary history of

  2. Characterisation of monotreme caseins reveals lineage-specific expansion of an ancestral casein locus in mammals.

    Science.gov (United States)

    Lefèvre, Christophe M; Sharp, Julie A; Nicholas, Kevin R

    2009-01-01

    Using a milk-cell cDNA sequencing approach we characterised milk-protein sequences from two monotreme species, platypus (Ornithorhynchus anatinus) and echidna (Tachyglossus aculeatus) and found a full set of caseins and casein variants. The genomic organisation of the platypus casein locus is compared with other mammalian genomes, including the marsupial opossum and several eutherians. Physical linkage of casein genes has been seen in the casein loci of all mammalian genomes examined and we confirm that this is also observed in platypus. However, we show that a recent duplication of beta-casein occurred in the monotreme lineage, as opposed to more ancient duplications of alpha-casein in the eutherian lineage, while marsupials possess only single copies of alpha- and beta-caseins. Despite this variability, the close proximity of the main alpha- and beta-casein genes in an inverted tail-tail orientation and the relative orientation of the more distant kappa-casein genes are similar in all mammalian genome sequences so far available. Overall, the conservation of the genomic organisation of the caseins indicates the early, pre-monotreme development of the fundamental role of caseins during lactation. In contrast, the lineage-specific gene duplications that have occurred within the casein locus of monotremes and eutherians but not marsupials, which may have lost part of the ancestral casein locus, emphasises the independent selection on milk provision strategies to the young, most likely linked to different developmental strategies. The monotremes therefore provide insight into the ancestral drivers for lactation and how these have adapted in different lineages. PMID:19874726

  3. Ancestral genetic diversity associated with the rapid spread of stress-tolerant coral symbionts in response to Holocene climate change

    OpenAIRE

    Hume, Benjamin C C; VOOLSTRA, CHRISTIAN R.; Arif, Chatchanit; D'Angelo, Cecilia; Burt, John A.; Eyal, Gal; Loya, Yossi; Wiedenmann, Jörg

    2016-01-01

    Coral communities in the Persian/Arabian Gulf (PAG) withstand unusually high salinity levels and regular summer temperature maxima of up to ?35 °C that kill conspecifics elsewhere. Due to the recent formation of the PAG and its subsequent shift to a hot climate, these corals have had only 5,000 km of the PAG, the Gulf of Oman, and the Red Sea coastline, we show that S. thermophilum is a member of a highly diverse, ancient group of symbionts cryptically distributed outside the PAG. We argue th...

  4. Antiquity of Ediacaran Fossils, Early Shelled Organisms, Recent Radiometric Age-Dates from India and Ancestral Biota

    Science.gov (United States)

    Basu, A.

    2008-03-01

    U-Pb zircon ages and Pb-Pb limestone ages assign Ediacaran and shelly fossils reported from India between 1750 and 950 Ma indicating ancestral diversification of metazoans. Simple bacterial life must have began earlier and may be found in meteorites.

  5. ReAS: Recovery of ancestral sequences for transposable elements from the unassembled reads of a whole genome shotgun

    DEFF Research Database (Denmark)

    Li, Ruiqiang; Ye, Jia; Li, Songgang;

    2005-01-01

    in comparison to their ancestral sequences. Tested on the japonica rice genome, ReAS was able to reconstruct all of the high copy sequences in the Repbase repository of known TEs, and increase the effectiveness of RepeatMasker in identifying TEs from genome sequences. Udgivelsesdato: 2005-Sep...

  6. Susceptibility to anchoring effects

    OpenAIRE

    Todd McElroy; Keith Dowd

    2007-01-01

    Previous research on anchoring has shown this heuristic to be a very robust psychological phenomenon ubiquitous across many domains of human judgment and decision-making. Despite the prevalence of anchoring effects, researchers have only recently begun to investigate the underlying factors responsible for how and in what ways a person is susceptible to them. This paper examines how one such factor, the Big-Five personality trait of openness-to-experience, influences the effect of previously p...

  7. Seleção genética de Biomphalaria glabrata e Biomphalaria tenagophila visando a alteração da suscetibilidade e resistência ao Schistosoma mansoni Genetic selection of Biomphalaria glabrata and Biomphalaria tenagophila seeking the alteration of the susceptibility and resistance to the Schistosoma mansoni

    Directory of Open Access Journals (Sweden)

    Nádia Regina Borim Zuim

    2005-10-01

    Full Text Available Gerações de Biomphalaria glabrata e Biomphalaria tenagophila selecionadas geneticamente para resistência e suscetibilidade ao Schistosoma mansoni das linhagens BH e SJ foram utilizadas no estudo da adaptação do trematódeo ao hospedeiro intermediário. As gerações dos planorbídeos foram obtidas por autofecundação dos moluscos que se apresentaram suscetíveis ou resistentes após a exposição aos miracídios de Schistosoma mansoni. Para Biomphalaria glabrata foram obtidas as gerações: Parental, F1S (Suscetível, F1R (Resistente, F2S e F2R. Para a Biomphalaria tenagophila foram estudadas as gerações: Parental, F1S, F1R e F50S. A comparação das taxas de infecção apresentadas pelas diferentes gerações mostrou que, em ambas as espécies, o aumento da suscetibilidade foi mais facilmente obtido do que o aumento da resistência. A dificuldade em aumentar a resistência do molusco ao S. mansoni tem fortes implicações epidemiológicas.Generations of Biomphalaria glabrata and Biomphalaria tenagophila selected genetically for resistance and susceptibility to Schistosoma mansoni of strains BH and SJ were used in a study of the trematode adaptation to the intermediate host. Descendants of the planorbids were obtained by self-fertilization of the mollusks that became susceptible or resistant after exposure to the miracidia of Schistosoma mansoni. For Biomphalaria glabrata they were obtained from the following generations: Parental, F1S (Susceptible, F1R (Resistant, F2S and F2R. For Biomphalaria tenagophila the studied generations were: Parental, F1S, F1R and F50S. The comparison of the infection rates presented by the different generations showed that the increase in susceptibility was more easily obtained in both species. The difficulty in increasing the resistance of the mollusks to Schistosoma mansoni has important epidemiologic implications.

  8. Genetics of otitis media.

    Science.gov (United States)

    Post, J Christopher

    2011-01-01

    There is a growing body of evidence, both from animal and human studies, that host genetic factors can influence the risk of developing otitis media (OM). The role of genetics in OM has been elucidated through studies with monozygotic and dizygotic twins, analyses linking genetic polymorphisms to OM susceptibility, and genome scans. Several twin studies have shown a strong genetic component to middle ear effusion risk, with the estimate of the role of heredity for the proportion of time with middle ear effusions being around 0.7. Genetic polymorphisms in plasminogen activator inhibitor-1, interleukin-6, tumor necrosis factor-α, human leukocyte antigen, and mannose-binding lectin have been variously linked with OM and upper respiratory infection susceptibility. Several genome linkage studies have identified chromosomal regions associated with chronic OM, including 3p, 10q, 10q22.3, 17q12 and 19q. A number of candidate genes are associated with these sites. Given the current state of understanding of the role of genetics in OM, a family history of OM should be ascertained for all patients. Children with a strong family history of OM should be considered as candidates for a more aggressive early treatment of OM, particularly if other risk factors are present. These children may be earlier candidates for the placement of tympanostomy tubes and/or adenoidectomy. Existing data do not support routine genetic testing to determine a child's susceptibility to OM; however, given the advances in whole genome sequencing, such testing may someday play a role in the management of the OM patient. PMID:21358196

  9. 周代宗庙礼制考%The Research on the Etiquettes of Zhou Dynasty’s Ancestral Temple

    Institute of Scientific and Technical Information of China (English)

    王启敏

    2015-01-01

    周代社会中与宗庙相关的礼制多种多样。宗庙始成要举行落成典礼,作歌诗以纪之。祭庙的形式可谓五花八门,而且祭者的态度要十分的恭敬、严谨。诸侯有丧事了,要在宗庙吊唁,规矩也很多。此外,如天子即位,天子(或诸侯)娶妻、嫁女、出国、归国、出征、凯旋等都要在宗庙举行郑重的祭告仪式。在宗庙的守护、装饰、迁移等方面,在当时也有着严格的、不同的礼节制度要遵守。%In Zhou dynasty the related ancestral temple customs are various. After the completion of ancestral temple, it should be inaugurated and poems should be made to memorize. The forms of memorial temples are varied. The attitude of the emperor and monarch muse be very respectful. The same was the monarch’s condolences at the ancestral temple. In addition, the ascending to the throne as emperor, or monarch, getting married or married abroad, returning to the homeland and triumphing must be held in the ancestral temple solemnly and be reported to ancestral temple. The temple’s guardian, decoration, migration and the others also have restricted rules to obey.

  10. Population genetic structure and colony breeding system in dampwood termites (Zootermopsis angusticollis and Z. nevadensis nuttingi)

    Science.gov (United States)

    Studies describing the population genetic structure and breeding system of basal lineages of termite species remain rare. Such species, however, may reveal ancestral life history attributes potentially influential in the evolution of eusociality within the Order Isoptera. Through the development and...

  11. Detection and Characterization of Infections and Infection Susceptibility

    Science.gov (United States)

    2016-08-31

    Immune Disorders; Chronic Granulomatous Disease; Genetic Immunological Deficiencies; Hyperimmunoglobulin-E Recurrent Infection Syndrome; Recurrent Infections; Unknown Immune Deficiency; GATA2 Deficiency (MonoMAC),; Nontuberculous Mycobacterial Infections; Hyper IgE (Job s) Syndrome; Leukocyte Adhesion Deficiency; Susceptibility to Disseminated Infections; Primary Immune Deficiency Disease (PIDD)

  12. Susceptibility of Mycobacterium bovis BCG Vaccine Strains to Antituberculous Antibiotics▿

    OpenAIRE

    Ritz, Nicole; Tebruegge, Marc; Connell, Tom G.; Sievers, Aina; Robins-Browne, Roy; Curtis, Nigel

    2008-01-01

    Mycobacterium bovis BCG is one of the most commonly administered vaccines. Complications, including disseminated BCG disease, are rare but increasingly reported in immunodeficient children. There is growing recognition of the importance of differences between BCG vaccine strains. We determined the susceptibilities of five genetically distinct BCG vaccine strains to 12 antituberculous drugs.

  13. TERT gene harbors multiple variants associated with pancreatic cancer susceptibility

    Czech Academy of Sciences Publication Activity Database

    Campa, D.; Rizzato, C.; Stolzenberg-Solomon, R.; Pacetti, P.; Vodička, Pavel; Cleary, S.P.; Capurso, G.; Bueno-de-Mesquita, H. B.; Werner, J.; Gazouli, M.; Butterbach, K.; Ivanauskas, A.; Giese, N.; Petersen, G. M.; Fogar, P.; Wang, Z.; Bassi, C.; Ryska, M.; Theodoropoulos, G.E.; Kooperberg, Ch.; Li, D.; Greenhalf, W.; Pasquali, C.; Hackert, T.; Fuchs, Ch.S.; Mohelníková-Duchoňová, B.; Sperti, C.; Funel, N.; Dieffenbach, A.K.; Wareham, N.J.; Buring, J.; Holcátová, I.; Costello, E.; Zambon, C.F.; Kupcinskas, J.; Risch, H.A.; Kraft, P.; Bracci, P.M.; Pezzilli, R.; Olson, S.H.; Sesso, H. D.; Hartge, P.; Strobel, O.; Malecka-Panas, E.; Visvanathan, K.; Arslan, A. A.; Pedrazzoli, S.; Souček, P.; Gioffreda, D.; Key, T.J.; Talar-Wojnarowska, R.; Scarpa, A.; Mambrini, A.; Jacobs, E.J.; Jamroziak, K.; Klein, A.; Tavano, F.; Bambi, F.; Landi, S.; Austin, M. A.; Vodičková, Ludmila; Brenner, H.; Chanock, S. J.; Fave, G.D.; Piepoli, A.; Cantore, M.; Zheng, W.; Wolpin, B.M.; Amundadottir, L. T.; Canzian, F.

    2015-01-01

    Roč. 137, č. 9 (2015), s. 2175-2183. ISSN 0020-7136 R&D Projects: GA ČR GAP301/12/1734 Institutional support: RVO:68378041 Keywords : pancreatic cancer * polymorphisms * telomerase * susceptibility Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.085, year: 2014

  14. Analysis on the reconstruction accuracy of the Fitch method for inferring ancestral states

    Directory of Open Access Journals (Sweden)

    Grünewald Stefan

    2011-01-01

    Full Text Available Abstract Background As one of the most widely used parsimony methods for ancestral reconstruction, the Fitch method minimizes the total number of hypothetical substitutions along all branches of a tree to explain the evolution of a character. Due to the extensive usage of this method, it has become a scientific endeavor in recent years to study the reconstruction accuracies of the Fitch method. However, most studies are restricted to 2-state evolutionary models and a study for higher-state models is needed since DNA sequences take the format of 4-state series and protein sequences even have 20 states. Results In this paper, the ambiguous and unambiguous reconstruction accuracy of the Fitch method are studied for N-state evolutionary models. Given an arbitrary phylogenetic tree, a recurrence system is first presented to calculate iteratively the two accuracies. As complete binary tree and comb-shaped tree are the two extremal evolutionary tree topologies according to balance, we focus on the reconstruction accuracies on these two topologies and analyze their asymptotic properties. Then, 1000 Yule trees with 1024 leaves are generated and analyzed to simulate real evolutionary scenarios. It is known that more taxa not necessarily increase the reconstruction accuracies under 2-state models. The result under N-state models is also tested. Conclusions In a large tree with many leaves, the reconstruction accuracies of using all taxa are sometimes less than those of using a leaf subset under N-state models. For complete binary trees, there always exists an equilibrium interval [a, b] of conservation probability, in which the limiting ambiguous reconstruction accuracy equals to the probability of randomly picking a state. The value b decreases with the increase of the number of states, and it seems to converge. When the conservation probability is greater than b, the reconstruction accuracies of the Fitch method increase rapidly. The reconstruction

  15. Eleven ancestral gene families lost in mammals and vertebrates while otherwise universally conserved in animals

    Directory of Open Access Journals (Sweden)

    Danchin Etienne GJ

    2006-01-01

    Full Text Available Abstract Background Gene losses played a role which may have been as important as gene and genome duplications and rearrangements, in modelling today species' genomes from a common ancestral set of genes. The set and diversity of protein-coding genes in a species has direct output at the functional level. While gene losses have been reported in all the major lineages of the metazoan tree of life, none have proposed a focus on specific losses in the vertebrates and mammals lineages. In contrast, genes lost in protostomes (i.e. arthropods and nematodes but still present in vertebrates have been reported and extensively detailed. This probable over-anthropocentric way of comparing genomes does not consider as an important phenomena, gene losses in species that are usually described as "higher". However reporting universally conserved genes throughout evolution that have recently been lost in vertebrates and mammals could reveal interesting features about the evolution of our genome, particularly if these losses can be related to losses of capability. Results We report 11 gene families conserved throughout eukaryotes from yeasts (such as Saccharomyces cerevisiae to bilaterian animals (such as Drosophila melanogaster or Caenorhabditis elegans. This evolutionarily wide conservation suggests they were present in the last common ancestors of fungi and metazoan animals. None of these 11 gene families are found in human nor mouse genomes, and their absence generally extends to all vertebrates. A total of 8 out of these 11 gene families have orthologs in plants, suggesting they were present in the Last Eukaryotic Common Ancestor (LECA. We investigated known functional information for these 11 gene families. This allowed us to correlate some of the lost gene families to loss of capabilities. Conclusion Mammalian and vertebrate genomes lost evolutionary conserved ancestral genes that are probably otherwise not dispensable in eukaryotes. Hence, the human

  16. Elongation Factor-Tu (EF-Tu) proteins structural stability and bioinformatics in ancestral gene reconstruction

    Science.gov (United States)

    Dehipawala, Sunil; Nguyen, A.; Tremberger, G.; Cheung, E.; Schneider, P.; Lieberman, D.; Holden, T.; Cheung, T.

    2013-09-01

    A paleo-experimental evolution report on elongation factor EF-Tu structural stability results has provided an opportunity to rewind the tape of life using the ancestral protein sequence reconstruction modeling approach; consistent with the book of life dogma in current biology and being an important component in the astrobiology community. Fractal dimension via the Higuchi fractal method and Shannon entropy of the DNA sequence classification could be used in a diagram that serves as a simple summary. Results from biomedical gene research provide examples on the diagram methodology. Comparisons between biomedical genes such as EEF2 (elongation factor 2 human, mouse, etc), WDR85 in epigenetics, HAR1 in human specificity, DLG1 in cognitive skill, and HLA-C in mosquito bite immunology with EF Tu DNA sequences have accounted for the reported circular dichroism thermo-stability data systematically; the results also infer a relatively less volatility geologic time period from 2 to 3 Gyr from adaptation viewpoint. Comparison to Thermotoga maritima MSB8 and Psychrobacter shows that Thermus thermophilus HB8 EF-Tu calibration sequence could be an outlier, consistent with free energy calculation by NUPACK. Diagram methodology allows computer simulation studies and HAR1 shows about 0.5% probability from chimp to human in terms of diagram location, and SNP simulation results such as amoebic meningoencephalitis NAF1 suggest correlation. Extensions to the studies of the translation and transcription elongation factor sequences in Megavirus Chiliensis, Megavirus Lba and Pandoravirus show that the studied Pandoravirus sequence could be an outlier with the highest fractal dimension and lowest entropy, as compared to chicken as a deviant in the DNMT3A DNA methylation gene sequences from zebrafish to human and to the less than one percent probability in computer simulation using the HAR1 0.5% probability as reference. The diagram methodology would be useful in ancestral gene

  17. Interrogating the complex role of chromosome 16p13.13 in multiple sclerosis susceptibility: independent genetic signals in the CIITA-CLEC16A-SOCS1 gene complex.

    Science.gov (United States)

    Zuvich, Rebecca L; Bush, William S; McCauley, Jacob L; Beecham, Ashley H; De Jager, Philip L; Ivinson, Adrian J; Compston, Alastair; Hafler, David A; Hauser, Stephen L; Sawcer, Stephen J; Pericak-Vance, Margaret A; Barcellos, Lisa F; Mortlock, Douglas P; Haines, Jonathan L

    2011-09-01

    Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease of the central nervous system, and numerous studies have shown that MS has a strong genetic component. Independent studies to identify MS-associated genes have often indicated multiple signals in physically close genomic regions, although by their proximity it is not always clear if these data indicate redundant or truly independent genetic signals. Recently, three MS study samples were genotyped in parallel using an Illumina Custom BeadChip. These revealed multiple significantly associated single-nucleotide polymorphisms within a 600 kb stretch on chromosome 16p13. Here we present a detailed analysis of variants in this region that clarifies the independent nature of these signals. The linkage disequilibrium patterns in the region and logistic regression analysis of the associations suggest that this region likely harbors three independent MS disease loci. Further, we examined cis-expression QTLs, histone modifications and CCCTC-binding factor (CTCF) binding data in the region. We also tested for correlated expression of the genes from the region using whole-genome expression array data from lymphoblastoid cell lines. Three of the genes show expression correlations across loci. Furthermore, in the GM12878 lymphoblastoid cell line, these three genes are in a continuous region devoid of H3K27 methylation, suggesting an open chromatin configuration. This region likely only contributes minimal risk to MS; however, investigation of this region will undoubtedly provide insight into the functional mechanisms of these genes. These data highlight the importance of taking a closer look at the expression and function of chromosome 16p13 in the pathogenesis of MS. PMID:21653641

  18. [Genetics and genetic counseling].

    Science.gov (United States)

    Izzi, Claudia; Liut, Francesca; Dallera, Nadia; Mazza, Cinzia; Magistroni, Riccardo; Savoldi, Gianfranco; Scolari, Francesco

    2016-01-01

    Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most frequent genetic disease, characterized by progressive development of bilateral renal cysts. Two causative genes have been identified: PKD1 and PKD2. ADPKD phenotype is highly variable. Typically, ADPKD is an adult onset disease. However, occasionally, ADPKD manifests as very early onset disease. The phenotypic variability of ADPKD can be explained at three genetic levels: genic, allelic and gene modifier effects. Recent advances in molecular screening for PKD gene mutations and the introduction of the new next generation sequencing (NGS)- based genotyping approach have generated considerable improvement regarding the knowledge of genetic basis of ADPKD. The purpose of this article is to provide a comprehensive review of the genetics of ADPKD, focusing on new insights in genotype-phenotype correlation and exploring novel clinical approach to genetic testing. Evaluation of these new genetic information requires a multidisciplinary approach involving a nephrologist and a clinical geneticist. PMID:27067213

  19. A recurrent laminin 5 mutation in British patients with lethal (Herlitz) junctional epidermolysis bullosa: evidence for a mutational hotspot rather than propagation of an ancestral allele.

    Science.gov (United States)

    Ashton, G H; Mellerio, J E; Dunnill, M G; Pulkkinen, L; Christiano, A M; Uitto, J; Eady, R A; McGrath, J A

    1997-05-01

    The three genes (LAMA3, LAB3 and LAMC2) that encode the anchoring filament protein, laminin 5, may all harbour pathogenetic mutations in the autosomal recessive blistering skin disorder, junctional epidermolysis bullosa (JEB). Recently, one particular mutation, R635X in the LAMB3 gene, has been found to account for approximately 40% of all JEB laminin 5 mutations (Kivirikko et al., Hum Mol Genet 1996; 5: 231-7). In this study, we assessed the frequency of this mutation in 12 British patients with lethal (Herlitz) JEB using PCR amplification of genomic DNA and restriction endonuclease digestion. The mutation R635X was fond in seven of 24 (29%) mutant alleles, confirming its relative frequency within the British gene pool. In addition, haplotype analysis using intragenic polymorphisms showed that the mutation arose on at least four different haplotype backgrounds, suggesting it represents a mutational hotspot rather than propagation of a common British ancestral allele. These findings support the hypermutable nature of this CpG dinucleotide and have implications in screening for laminin 5 gene mutations in British and other patients with JEB. PMID:9205497

  20. Travelling in time with networks: Revealing present day hybridization versus ancestral polymorphism between two species of brown algae, Fucus vesiculosus and F. spiralis

    Directory of Open Access Journals (Sweden)

    Pearson Gareth A

    2011-01-01

    Full Text Available Abstract Background Hybridization or divergence between sympatric sister species provides a natural laboratory to study speciation processes. The shared polymorphism in sister species may either be ancestral or derive from hybridization, and the accuracy of analytic methods used thus far to derive convincing evidence for the occurrence of present day hybridization is largely debated. Results Here we propose the application of network analysis to test for the occurrence of present day hybridization between the two species of brown algae Fucus spiralis and F. vesiculosus. Individual-centered networks were analyzed on the basis of microsatellite genotypes from North Africa to the Pacific American coast, through the North Atlantic. Two genetic distances integrating different time steps were used, the Rozenfeld (RD; based on alleles divergence and the Shared Allele (SAD; based on alleles identity distances. A diagnostic level of genotype divergence and clustering of individuals from each species was obtained through RD while screening for exchanges through putative hybridization was facilitated using SAD. Intermediate individuals linking both clusters on the RD network were those sampled at the limits of the sympatric zone in Northwest Iberia. Conclusion These results suggesting rare hybridization were confirmed by simulation of hybrids and F2 with directed backcrosses. Comparison with the Bayesian method STRUCTURE confirmed the usefulness of both approaches and emphasized the reliability of network analysis to unravel and study hybridization