Exploration of genetic susceptibility factors for Parkinson's disease

Indian Academy of Sciences (India)

Home; Journals; Journal of Genetics; Volume 89; Issue 2. Exploration of genetic susceptibility factors for Parkinson's disease in a South American sample. Bruno A. Benitez Diego A. Forero Gonzalo H. Arboleda Luis A. Granados Juan J. Yunis William Fernandez Humberto Arboleda. Research Note Volume 89 Issue 2 ...

Genetics of pediatric obesity.

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Manco, Melania; Dallapiccola, Bruno

2012-07-01

Onset of obesity has been anticipated at earlier ages, and prevalence has dramatically increased worldwide over the past decades. Epidemic obesity is mainly attributable to modern lifestyle, but family studies prove the significant role of genes in the individual's predisposition to obesity. Advances in genotyping technologies have raised great hope and expectations that genetic testing will pave the way to personalized medicine and that complex traits such as obesity will be prevented even before birth. In the presence of the pressing offer of direct-to-consumer genetic testing services from private companies to estimate the individual's risk for complex phenotypes including obesity, the present review offers pediatricians an update of the state of the art on genomics obesity in childhood. Discrepancies with respect to genomics of adult obesity are discussed. After an appraisal of findings from genome-wide association studies in pediatric populations, the rare variant-common disease hypothesis, the theoretical soil for next-generation sequencing techniques, is discussed as opposite to the common disease-common variant hypothesis. Next-generation sequencing techniques are expected to fill the gap of "missing heritability" of obesity, identifying rare variants associated with the trait and clarifying the role of epigenetics in its heritability. Pediatric obesity emerges as a complex phenotype, modulated by unique gene-environment interactions that occur in periods of life and are "permissive" for the programming of adult obesity. With the advent of next-generation sequencing techniques and advances in the field of exposomics, sensitive and specific tools to predict the obesity risk as early as possible are the challenge for the next decade.

An association study of 13 SNPs from seven candidate genes with pediatric asthma and a preliminary study for genetic testing by multiple variants in Taiwanese population.

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Wang, Jiu-Yao; Liou, Ya-Huei; Wu, Ying-Jye; Hsiao, Ya-Hsin; Wu, Lawrence Shih-Hsin

2009-03-01

Asthma is one of the most common chronic diseases in children. It is caused by complex interactions between various genetic factors and exposures to environmental allergens and irritants. Because of the heterogeneity of the disease and the genetic and cultural differences among different populations, a proper association study and genetic testing for asthma and susceptibility genes is difficult to perform. We assessed 13 single-nucleotide polymorphisms (SNPs) in seven well-known asthma susceptibility genes and looked for association with pediatric asthma using 449 asthmatic subjects and 512 non-asthma subjects in Taiwanese population. CD14-159 C/T and MS4A2 Glu237Gly were identified to have difference in genotype/allele frequencies between the control group and asthma patients. Moreover, the genotype synergistic analysis showed that the co-contribution of two functional SNPs was riskier or more protective from asthma attack. Our study provided a genotype synergistic method for studying gene-gene interaction on polymorphism basis and genetic testing using multiple polymorphisms.

Interleukin-1 Receptor in Seizure Susceptibility after Traumatic Injury to the Pediatric Brain.

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Semple, Bridgette D; O'Brien, Terence J; Gimlin, Kayleen; Wright, David K; Kim, Shi Eun; Casillas-Espinosa, Pablo M; Webster, Kyria M; Petrou, Steven; Noble-Haeusslein, Linda J

2017-08-16

Epilepsy after pediatric traumatic brain injury (TBI) is associated with poor quality of life. This study aimed to characterize post-traumatic epilepsy in a mouse model of pediatric brain injury, and to evaluate the role of interleukin-1 (IL-1) signaling as a target for pharmacological intervention. Male mice received a controlled cortical impact or sham surgery at postnatal day 21, approximating a toddler-aged child. Mice were treated acutely with an IL-1 receptor antagonist (IL-1Ra; 100 mg/kg, s.c.) or vehicle. Spontaneous and evoked seizures were evaluated from video-EEG recordings. Behavioral assays tested for functional outcomes, postmortem analyses assessed neuropathology, and brain atrophy was detected by ex vivo magnetic resonance imaging. At 2 weeks and 3 months post-injury, TBI mice showed an elevated seizure response to the convulsant pentylenetetrazol compared with sham mice, associated with abnormal hippocampal mossy fiber sprouting. A robust increase in IL-1β and IL-1 receptor were detected after TBI. IL-1Ra treatment reduced seizure susceptibility 2 weeks after TBI compared with vehicle, and a reduction in hippocampal astrogliosis. In a chronic study, IL-1Ra-TBI mice showed improved spatial memory at 4 months post-injury. At 5 months, most TBI mice exhibited spontaneous seizures during a 7 d video-EEG recording period. At 6 months, IL-1Ra-TBI mice had fewer evoked seizures compared with vehicle controls, coinciding with greater preservation of cortical tissue. Findings demonstrate this model's utility to delineate mechanisms underlying epileptogenesis after pediatric brain injury, and provide evidence of IL-1 signaling as a mediator of post-traumatic astrogliosis and seizure susceptibility. SIGNIFICANCE STATEMENT Epilepsy is a common cause of morbidity after traumatic brain injury in early childhood. However, a limited understanding of how epilepsy develops, particularly in the immature brain, likely contributes to the lack of efficacious treatments

Medical genetic issues in clinical of pediatric neurology practice:a history of pediatrics in Peking University First Hospital.

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Wu, Xi-ru

2006-02-18

The Department of Pediatrics of Peking University First Hospital has a long term of outstanding history. It was established about 60 years ago. After the division of pediatric neurology (DPN) had been established in 1960s, it had been assigned to cover genetic disorders. During the recent 20 years, efforts have been put on three aspects: (1) Pediatric neurology clinical service and education; (2) research studies of childhood epilepsies and pediatric neurogenetic disorders; and (3) development of a strong DPN team to establish a comprehensive pediatric neurological program. In this paper, we reviewed the history of the pediatric neurology division in our department, our clinical and research work and achievements for neurogenetic diseases.

CCDC26, CDKN2BAS, RTEL1 and TERT Polymorphisms in pediatric brain tumor susceptibility.

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Adel Fahmideh, Maral; Lavebratt, Catharina; Schüz, Joachim; Röösli, Martin; Tynes, Tore; Grotzer, Michael A; Johansen, Christoffer; Kuehni, Claudia E; Lannering, Birgitta; Prochazka, Michaela; Schmidt, Lisbeth S; Feychting, Maria

2015-08-01

The role of genetic polymorphisms in pediatric brain tumor (PBT) etiology is poorly understood. We hypothesized that single nucleotide polymorphisms (SNPs) identified in genome-wide association studies (GWAS) on adult glioma would also be associated with PBT risk. The study is based on the Cefalo study, a population-based multicenter case-control study. Saliva DNA from 245 cases and 489 controls, aged 7-19 years at diagnosis/reference date, was extracted and genotyped for 29 SNPs reported by GWAS to be significantly associated with risk of adult glioma. Data were analyzed using unconditional logistic regression. Stratified analyses were performed for two histological subtypes: astrocytoma alone and the other tumor types combined. The results indicated that four SNPs, CDKN2BAS rs4977756 (p = 0.036), rs1412829 (p = 0.037), rs2157719 (p = 0.018) and rs1063192 (p = 0.021), were associated with an increased susceptibility to PBTs, whereas the TERT rs2736100 was associated with a decreased risk (p = 0.018). Moreover, the stratified analyses showed a decreased risk of astrocytoma associated with RTEL1 rs6089953, rs6010620 and rs2297440 (p trend = 0.022, p trend = 0.042, p trend = 0.029, respectively) as well as an increased risk of this subtype associated with RTEL1 rs4809324 (p trend = 0.033). In addition, SNPs rs10464870 and rs891835 in CCDC26 were associated with an increased risk of non-astrocytoma tumor subtypes (p trend = 0.009, p trend = 0.007, respectively). Our findings indicate that SNPs in CDKN2BAS, TERT, RTEL1 and CCDC26 may be associated with the risk of PBTs. Therefore, we suggest that pediatric and adult brain tumors might share common genetic risk factors and similar etiological pathways. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Computational Integration of Human Genetic and Toxicological Data to Evaluate AOP-Specific Susceptibility

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Susceptibility to environmental chemicals can be modulated by genetic differences. Direct estimation of the genetic contribution to variability in susceptibility to environmental chemicals is only possible in special cases where there is an observed association between exposure a...

Genetic architecture of intrinsic antibiotic susceptibility.

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Hany S Girgis

2009-05-01

Full Text Available Antibiotic exposure rapidly selects for more resistant bacterial strains, and both a drug's chemical structure and a bacterium's cellular network affect the types of mutations acquired.To better characterize the genetic determinants of antibiotic susceptibility, we exposed a transposon-mutagenized library of Escherichia coli to each of 17 antibiotics that encompass a wide range of drug classes and mechanisms of action. Propagating the library for multiple generations with drug concentrations that moderately inhibited the growth of the isogenic parental strain caused the abundance of strains with even minor fitness advantages or disadvantages to change measurably and reproducibly. Using a microarray-based genetic footprinting strategy, we then determined the quantitative contribution of each gene to E. coli's intrinsic antibiotic susceptibility. We found both loci whose removal increased general antibiotic tolerance as well as pathways whose down-regulation increased tolerance to specific drugs and drug classes. The beneficial mutations identified span multiple pathways, and we identified pairs of mutations that individually provide only minor decreases in antibiotic susceptibility but that combine to provide higher tolerance.Our results illustrate that a wide-range of mutations can modulate the activity of many cellular resistance processes and demonstrate that E. coli has a large mutational target size for increasing antibiotic tolerance. Furthermore, the work suggests that clinical levels of antibiotic resistance might develop through the sequential accumulation of chromosomal mutations of small individual effect.

Experiencing the genetic body: parents' encounters with pediatric clinical genetics.

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Raspberry, Kelly; Skinner, Debra

2007-01-01

Because of advancements in genetic research and technologies, the clinical practice of genetics is becoming a prevalent component of biomedicine. As the genetic basis for more and more diseases are found, it is possible that ways of experiencing health, illness, identity, kin relations, and the body are becoming geneticized, or understood within a genetic model of disease. Yet, other models and relations that go beyond genetic explanations also shape interpretations of health and disease. This article explores how one group of individuals for whom genetic disorder is highly relevant formulates their views of the body in light of genetic knowledge. Using data from an ethnographic study of 106 parents or potential parents of children with known or suspected genetic disorders who were referred to a pediatric genetic counseling and evaluation clinic in the southeastern United States, we find that these parents do, to some degree, perceive of their children's disorders in terms of a genetic body that encompasses two principal qualities: a sense of predetermined health and illness and an awareness of a profound historicity that reaches into the past and extends into the present and future. They experience this genetic body as both fixed and historical, but they also express ideas of a genetic body made less deterministic by their own efforts and future possibilities. This account of parents' experiences with genetics and clinical practice contributes to a growing body of work on the ways in which genetic information and technologies are transforming popular and medical notions of the body, and with it, health, illness, kinship relations, and personal and social identities.

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 industrial based laboratories to meet the rapid development of the science base of toxicology. As the technology to determine genetic susceptibility develops, so scientist will be able to describe altered gene expression provoked by chemicals long before they are able to offer valid interpretations...... to take toxicological data and both interpret and extrapolate it in a manner as to cause exaggerated concern. The challenge to the toxicologist is to explain what data means and in a way that inspires the confidence in those who have to apply data to the assessment of hazard and risk management. It seems...

The role of host genetics in susceptibility to influenza: a systematic review.

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Peter Horby

Full Text Available The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted to summarize the current state of evidence on the role of host genetics in susceptibility to influenza (PROSPERO registration number: CRD42011001380.PubMed, Web of Science, the Cochrane Library, and OpenSIGLE were searched using a pre-defined strategy for all entries up to the date of the search. Two reviewers independently screened the title and abstract of 1,371 unique articles, and 72 full text publications were selected for inclusion. Mouse models clearly demonstrate that host genetics plays a critical role in susceptibility to a range of human and avian influenza viruses. The Mx genes encoding interferon inducible proteins are the best studied but their relevance to susceptibility in humans is unknown. Although the MxA gene should be considered a candidate gene for further study in humans, over 100 other candidate genes have been proposed. There are however no data associating any of these candidate genes to susceptibility in humans, with the only published study in humans being under-powered. One genealogy study presents moderate evidence of a heritable component to the risk of influenza-associated death, and while the marked familial aggregation of H5N1 cases is suggestive of host genetic factors, this remains unproven.The fundamental question "Is susceptibility to severe influenza in humans heritable?" remains unanswered. Not because of a lack of genotyping or analytic tools, nor because of insufficient severe influenza cases, but because of the absence of a coordinated effort to define and assemble cohorts of cases. The recent pandemic and the ongoing epizootic of H5N1 both represent rapidly closing windows of opportunity to increase understanding of the pathogenesis of severe influenza through multi-national host genetic studies.

Bacterial isolates and their antimicrobial susceptibility patterns among pediatric patients with urinary tract infections.

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Ayelign, Birhanu; Abebe, Betelehem; Shibeshi, Adugna; Meshesha, Sosina; Shibabaw, Tewodros; Addis, Zelalem; Gelaw, Aschalew; Dagnew, Mulat

2018-01-01

Urinary tract infection is a common pediatric problem with the potential to produce long-term morbidity. Therefore, appropriate diagnosis and prompt treatment is required. However, studies about magnitude of uropathogenicity and antimicrobial resistance pattern of pediatric urinary tract infection (UTI) are lacking in resource limited countries including Ethiopia. This study was aimed to determine bacterial isolates, antimicrobial susceptibility pattern among pediatric patients with UTI. A cross- sectional study was conducted. Pathogenic bacterial isolates were identified by culture and biochemical methods following standard procedures. Antimicrobial susceptibility testing of the isolates for commonly used antibiotics was done using the standard disc diffusion method on Muller Hinton agar. Associations between dependent and independent variables were measured using chi-square test and within 95% confidence interval. P values pediatric patients were included in the study, and 82 (26.45%) bacterial isolates were detected. Gram- negative bacteria were predominant etiologic agents of UTI in this study. E. coli was the most frequently occurring pathogen (n=45; 54.88%) followed by S. aureus and P.aeruginosa (n=8; 9.75% for both), P. vulgaris , P.aeruginosa (n=4; 4.88%, for both) and Enterococcus species (n=3; 3.66%). All K. pneumoniae , P. mirabilis , and K. ozanae straines were 100% resistance to ampicillin, followed by P. aeruginosa (87.5%) and E. coli (69%). While all Gram- positive bacterial isolates were 100% sensitive to ciprofloxacin. Malnutrition, history of catherization and previous history of UTI were independently associated with UTI (p=0.000). There was a high prevalence of uropathogenic bacteria and drug resistance particularly to ampicillin (72%) and tetracycline (37.80%). This condition indicates that antibiotic selection should be based on knowledge of the local prevalence of bacterial organisms and antibiotic sensitivities rather than empirical

Mediation and modification of genetic susceptibility to obesity by eating behaviors.

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de Lauzon-Guillain, Blandine; Clifton, Emma Ad; Day, Felix R; Clément, Karine; Brage, Soren; Forouhi, Nita G; Griffin, Simon J; Koudou, Yves Akoli; Pelloux, Véronique; Wareham, Nicholas J; Charles, Marie-Aline; Heude, Barbara; Ong, Ken K

2017-10-01

Background: Many genetic variants show highly robust associations with body mass index (BMI). However, the mechanisms through which genetic susceptibility to obesity operates are not well understood. Potentially modifiable mechanisms, including eating behaviors, are of particular interest to public health. Objective: Here we explore whether eating behaviors mediate or modify genetic susceptibility to obesity. Design: Genetic risk scores for BMI (BMI-GRSs) were calculated for 3515 and 2154 adults in the Fenland and EDEN (Etude des déterminants pré et postnatals de la santé et du développement de l'enfant) population-based cohort studies, respectively. The eating behaviors-emotional eating, uncontrolled eating, and cognitive restraint-were measured through the use of a validated questionnaire. The mediating effect of each eating behavior on the association between the BMI-GRS and measured BMI was assessed by using the Sobel test. In addition, we tested for interactions between each eating behavior and the BMI-GRS on BMI. Results: The association between the BMI-GRS and BMI was mediated by both emotional eating (EDEN: P- Sobel = 0.01; Fenland: P- Sobel = 0.02) and uncontrolled eating (EDEN: P- Sobel = 0.04; Fenland: P -Sobel = 0.0006) in both sexes combined. Cognitive restraint did not mediate this association ( P -Sobel > 0.10), except among EDEN women ( P -Sobel = 0.0009). Cognitive restraint modified the relation between the BMI-GRS and BMI among men (EDEN: P -interaction = 0.0001; Fenland: P -interaction = 0.04) and Fenland women ( P -interaction = 0.0004). By tertiles of cognitive restraint, the association between the BMI-GRS and BMI was strongest in the lowest tertile of cognitive restraint, and weakest in the highest tertile. Conclusions: Genetic susceptibility to obesity was partially mediated by the "appetitive" eating behavior traits (uncontrolled and emotional eating) and, in 3 of the 4 population groups studied, was modified by cognitive restraint

Pediatric psoriasis: an update

Directory of Open Access Journals (Sweden)

Nanette B Silverberg

2009-10-01

Full Text Available Nanette B SilverbergPediatric and Adolescent Dermatology, St. Luke’s-Roosevelt Hospital Center, New York, NY, USAAbstract: Pediatric psoriasis consists broadly of 3 age groups of psoriatic patients: infantile psoriasis, a self-limited disease of infancy, psoriasis with early onset, and pediatric psoriasis with psoriatic arthritis. About one-quarter of psoriasis cases begin before the age of 18 years. A variety of clinical psoriasis types are seen in childhood, including plaque-type, guttate, erythrodermic, napkin, and nail-based disease. Like all forms of auto-immunity, susceptibility is likely genetic, but environmental triggers are required to initiate disease activity. The most common trigger of childhood is an upper respiratory tract infection. Once disease has occurred, treatment is determined based on severity and presence of joint involvement. Topical therapies, including corticosteroids and calcipotriene, are the therapies of choice in the initial care of pediatric patients. Ultraviolet light, acitretin and cyclosporine can clear skin symptoms, while methotrexate and etanercept can clear both cutaneous and joint disease. Concern for psychological development is required when choosing psoriatic therapies. This article reviews current concepts in pediatric psoriasis and a rational approach to therapeutics. Keywords: psoriasis, autoimmunity, Streptococcus, etanercept, calcipotriene, topical corticosteroids

Muscle MRI in pediatrics: clinical, pathological and genetic correlation

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Cejas, Claudia P.; Serra, Maria M.; Galvez, David F.G. [Foundation for Neurological Research Dr. Raul Carrea (FLENI), Radiology Department, Buenos Aires (Argentina); Cavassa, Eliana A.; Vazquez, Gabriel A.; Massaro, Mario E.L.; Schteinschneider, Angeles V. [Foundation for Neurological Research Dr. Raul Carrea (FLENI), Department of Neuropediatrics, Buenos Aires (Argentina); Taratuto, Ana L. [Foundation for Neurological Research Dr. Raul Carrea (FLENI), Neuropathology Consultant, Buenos Aires (Argentina)

2017-05-15

Pediatric myopathies comprise a very heterogeneous group of disorders that may develop at different ages and affect different muscle groups. Its diagnosis is sometimes difficult and must be confirmed by muscle biopsy and/or genetic analysis. In recent years, muscle involvement patterns observed on MRI have become a valuable tool, aiding clinical diagnosis and enriching pathological and genetic assessments. We selected eight myopathy cases from our institutional database in which the pattern of muscle involvement observed on MRI was almost pathognomonic and could therefore contribute to establishing diagnosis. Muscle biopsy, genetic diagnosis or both confirmed all cases. (orig.)

Muscle MRI in pediatrics: clinical, pathological and genetic correlation

International Nuclear Information System (INIS)

Cejas, Claudia P.; Serra, Maria M.; Galvez, David F.G.; Cavassa, Eliana A.; Vazquez, Gabriel A.; Massaro, Mario E.L.; Schteinschneider, Angeles V.; Taratuto, Ana L.

2017-01-01

Pediatric myopathies comprise a very heterogeneous group of disorders that may develop at different ages and affect different muscle groups. Its diagnosis is sometimes difficult and must be confirmed by muscle biopsy and/or genetic analysis. In recent years, muscle involvement patterns observed on MRI have become a valuable tool, aiding clinical diagnosis and enriching pathological and genetic assessments. We selected eight myopathy cases from our institutional database in which the pattern of muscle involvement observed on MRI was almost pathognomonic and could therefore contribute to establishing diagnosis. Muscle biopsy, genetic diagnosis or both confirmed all cases. (orig.)

Pediatric vasculitis.

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Barut, Kenan; Sahin, Sezgin; Kasapcopur, Ozgur

2016-01-01

The aim of this review is to define childhood vasculitis and to highlight new causative factors and treatment modalities under the guidance of recently published studies. Childhood vasculitis is difficult to diagnose because of the wide variation in the symptoms and signs. New nomenclature and classification criteria were proposed for the diagnosis of pediatric vasculitis. Recently, progress has been made toward understanding the genetic susceptibility to pediatric vasculitis as it was in other diseases. Various radiological techniques provide great opportunities in establishing the diagnosis of pediatric vasculitis. Mild central nervous system disease can accompany Henoch-Schonlein purpura and can go unnoticed. Antineutrophilic cytoplasmic antibody-associated vasculitis is rare in children. Increased severity of the disease, subglottic stenosis, and renal disease are described more frequently among children. Biological therapies are used with success in children as in adults. Future studies, whose aims are to evaluate treatment responses, prognosis and to design guidelines for activity, and damage index of vasculitis for children are required. Henoch-Schonlein purpura and Kawasaki disease are the most frequent vasculitides of children. Experience from adult studies for treatment and prognosis are usually used because of low incidence of other vasculitides in children. Multicenter studies of pediatric vasculitis should be conducted to detail treatment responses and prognosis in children.

Host genetics in granuloma formation: human-like lung pathology in mice with reciprocal genetic susceptibility to M. tuberculosis and M. avium.

Directory of Open Access Journals (Sweden)

Elena Kondratieva

2010-05-01

Full Text Available Development of lung granulomata is a hallmark of infections caused by virulent mycobacteria, reflecting both protective host response that restricts infection spreading and inflammatory pathology. The role of host genetics in granuloma formation is not well defined. Earlier we have shown that mice of the I/St strain are extremely susceptible to Mycobacterium tuberculosis but resistant to M. avium infection, whereas B6 mice show a reversed pattern of susceptibility. Here, by directly comparing: (i characteristics of susceptibility to two infections in vivo; (ii architecture of lung granulomata assessed by immune staining; and (iii expression of genes encoding regulatory factors of neutrophil influx in the lung tissue, we demonstrate that genetic susceptibility of the host largely determines the pattern of lung pathology. Necrotizing granuloma surrounded by hypoxic zones, as well as a massive neutrophil influx, develop in the lungs of M. avium-infected B6 mice and in the lungs of M. tuberculosis-infected I/St mice, but not in the lungs of corresponding genetically resistant counterparts. The mirror-type lung tissue responses to two virulent mycobacteria indicate that the level of genetic susceptibility of the host to a given mycobacterial species largely determines characteristics of pathology, and directly demonstrate the importance of host genetics in pathogenesis.

Peering into a Chilean black box: parental storytelling in pediatric genetic counseling.

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Ordonez, Jessica; Margarit, Sonia; Downs, Katy; Yashar, Beverly M

2013-12-01

While genetic counseling has expanded to multiple international settings, research about providing culturally sensitive services to non-U.S. patients is limited. To gain insights, we utilized a process study to explore parental communication in pediatric genetics clinics in Chile. We utilized a phenomenological hermeneutic approach to assess storytelling in six pediatric sessions that were conducted in Spanish, and translated into English. The majority of the sessions focused on information gathering (35 %), and providing medical (20 %) and genetics education (18 %). The 14 instances of storytelling we identified usually emerged during information gathering, genetics education, and the closing of the session. Stories illustrated parental efforts to create a cognitive and emotional context for their child's genetic diagnosis. Parents emerged as competent caregivers who discussed the role of the child as a social being in the family and the larger community. Our analysis found that genetic counseling sessions in the U.S. and Chile are structured similarly and although communication is not a balanced process, parents use storytelling to participate as active agents in the session. Via storytelling, we learned that parents are working to understand and gain control over their child's genetic diagnosis by relying on mechanisms that extend beyond the genetics appointment.

Evolution, revolution and heresy in the genetics of infectious disease susceptibility

Science.gov (United States)

Hill, Adrian V. S.

2012-01-01

Infectious pathogens have long been recognized as potentially powerful agents impacting on the evolution of human genetic diversity. Analysis of large-scale case–control studies provides one of the most direct means of identifying human genetic variants that currently impact on susceptibility to particular infectious diseases. For over 50 years candidate gene studies have been used to identify loci for many major causes of human infectious mortality, including malaria, tuberculosis, human immunodeficiency virus/acquired immunodeficiency syndrome, bacterial pneumonia and hepatitis. But with the advent of genome-wide approaches, many new loci have been identified in diverse populations. Genome-wide linkage studies identified a few loci, but genome-wide association studies are proving more successful, and both exome and whole-genome sequencing now offer a revolutionary increase in power. Opinions differ on the extent to which the genetic component to common disease susceptibility is encoded by multiple high frequency or rare variants, and the heretical view that most infectious diseases might even be monogenic has been advocated recently. Review of findings to date suggests that the genetic architecture of infectious disease susceptibility may be importantly different from that of non-infectious diseases, and it is suggested that natural selection may be the driving force underlying this difference. PMID:22312051

Evolution, revolution and heresy in the genetics of infectious disease susceptibility.

Science.gov (United States)

Hill, Adrian V S

2012-03-19

Infectious pathogens have long been recognized as potentially powerful agents impacting on the evolution of human genetic diversity. Analysis of large-scale case-control studies provides one of the most direct means of identifying human genetic variants that currently impact on susceptibility to particular infectious diseases. For over 50 years candidate gene studies have been used to identify loci for many major causes of human infectious mortality, including malaria, tuberculosis, human immunodeficiency virus/acquired immunodeficiency syndrome, bacterial pneumonia and hepatitis. But with the advent of genome-wide approaches, many new loci have been identified in diverse populations. Genome-wide linkage studies identified a few loci, but genome-wide association studies are proving more successful, and both exome and whole-genome sequencing now offer a revolutionary increase in power. Opinions differ on the extent to which the genetic component to common disease susceptibility is encoded by multiple high frequency or rare variants, and the heretical view that most infectious diseases might even be monogenic has been advocated recently. Review of findings to date suggests that the genetic architecture of infectious disease susceptibility may be importantly different from that of non-infectious diseases, and it is suggested that natural selection may be the driving force underlying this difference.

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

Comprehensive Clinical Phenotyping and Genetic Mapping for the Discovery of Autism Susceptibility Genes

Science.gov (United States)

2013-03-14

behavioral teaching strategies and best practice for teaching students with autism spectrum disorders 4.52 Learn strategies for incorporating IEP goals...AFRL-SA-WP-TR-2013-0013 Comprehensive Clinical Phenotyping and Genetic Mapping for the Discovery of Autism Susceptibility Genes...Genetic Mapping for the Discovery of Autism Susceptibility Genes 5a. CONTRACT NUMBER N/A 5b. GRANT NUMBER N/A 5c. PROGRAM ELEMENT NUMBER N/A 6

Seasonal fluctuation in susceptibility to insecticides within natural populations of Drosophila melanogaster. II. Features of genetic variation in susceptibility to organophosphate insecticides within natural populations of D. melanogaster.

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Miyo, Takahiro; Oguma, Yuzuru; Charlesworth, Brian

2006-08-01

To elucidate genetic variation in susceptibility to organophosphate insecticides within natural populations of Drosophila melanogaster, we conducted an analysis of variance for mortality data sets of isofemale lines (10-286 lines) used in the previous studies. Susceptibility of isofemale lines to the three organophosphate insecticides was continuously distributed within each natural population, ranging from susceptible to resistant. Analysis of variance showed highly significant variation among isofemale lines in susceptibility to each insecticide for each natural population. Significant genetic variances in susceptibility to the three chemicals were estimated for the Katsunuma population; 0.0529-0.2722 for malathion, 0.0492-0.1603 for prothiophos, and 0.0469-0.1696 for fenitrothion. Contrary to the consistent seasonal tendency towards an increase in mean susceptibility in the fall, reported in the previous study, genetic variances in susceptibility to the three organophosphates did not change significantly in 1997 but tended to increase by 2- to 5-times in 1998. We tested whether both the observed situations, maintenance and increase in genetic variance in organophosphate resistance, can be generated under circumstances in which the levels of resistance to the three organophosphates tended to decrease, by conducting a simulation analysis, based on the hypothesis that resistant genotypes have lower fitnesses than susceptible ones under the density-independent condition. The simulation analysis generally explained the pattern in the mean susceptibility and genetic variances in susceptibility to the three organophosphates, observed in the Katsunuma population of D. melanogaster. It was suggested that the differences in the frequencies of resistance genes in the summer population could affect the patterns in genetic variance in organophosphate resistance in the fall population.

Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases

Science.gov (United States)

Li, Yun R; Li, Jin; Zhao, Sihai D; Bradfield, Jonathan P; Mentch, Frank D; Maggadottir, S Melkorka; Hou, Cuiping; Abrams, Debra J; Chang, Diana; Gao, Feng; Guo, Yiran; Wei, Zhi; Connolly, John J; Cardinale, Christopher J; Bakay, Marina; Glessner, Joseph T; Li, Dong; Kao, Charlly; Thomas, Kelly A; Qiu, Haijun; Chiavacci, Rosetta M; Kim, Cecilia E; Wang, Fengxiang; Snyder, James; Richie, Marylyn D; Flatø, Berit; Førre, Øystein; Denson, Lee A; Thompson, Susan D; Becker, Mara L; Guthery, Stephen L; Latiano, Anna; Perez, Elena; Resnick, Elena; Russell, Richard K; Wilson, David C; Silverberg, Mark S; Annese, Vito; Lie, Benedicte A; Punaro, Marilynn; Dubinsky, Marla C; Monos, Dimitri S; Strisciuglio, Caterina; Staiano, Annamaria; Miele, Erasmo; Kugathasan, Subra; Ellis, Justine A; Munro, Jane E; Sullivan, Kathleen E; Wise, Carol A; Chapel, Helen; Cunningham-Rundles, Charlotte; Grant, Struan F A; Orange, Jordan S; Sleiman, Patrick M A; Behrens, Edward M; Griffiths, Anne M; Satsangi, Jack; Finkel, Terri H; Keinan, Alon; Prak, Eline T Luning; Polychronakos, Constantin; Baldassano, Robert N; Li, Hongzhe; Keating, Brendan J; Hakonarson, Hakon

2016-01-01

Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ2 meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico–replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases. PMID:26301688

Pediatric Predispositional Genetic Risk Communication: Potential Utility for Prevention and Control of Melanoma Risk as an Exemplar.

Science.gov (United States)

Wu, Yelena P; Mays, Darren; Kohlmann, Wendy; Tercyak, Kenneth P

2017-10-01

Predispositional genetic testing among minor children is intensely debated due to the potential benefits and harms of providing this type of genetic information to children and their families. Existing guidelines on pediatric genetic testing state that predispositional testing could be appropriate for minors if preventive services exist that mitigate children's risk for or severity of the health condition in question. We use the example of hereditary melanoma to illustrate the rationale for and potential application of genetic risk communication for an adult-onset cancer to a pediatric population where childhood behaviors may reduce risk of disease later in life. We draw from the adult melanoma genetic risk communication and pediatric health behavior change literatures to suggest ways in which genetic test reporting and complementary education could be delivered to children who carry a hereditary risk for melanoma and their families in order to foster children's engagement in melanoma preventive behaviors. Genetic discoveries will continue to yield new opportunities to provide predispositional genetic risk information to unaffected individuals, including children, and could be delivered within programs that provide personalized and translational approaches to cancer prevention.

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. Copyright © 2013 Elsevier B.V. All rights reserved.

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

Science.gov (United States)

2011-01-01

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 associated with addiction susceptibility. From meta-data retrieved from 212 publications on candidate gene association studies and 5 GWAS reports, we linked a total of 843 haplotypes to addiction susceptibility. We mapped the SNPs in these haplotypes to functional and regulatory elements in the genome and estimated the magnitude of the contributions of different molecular mechanisms to their effects on addiction susceptibility. In addition to SNPs in coding regions, these data suggest that haplotypes in gene regulatory regions may also contribute to addiction susceptibility. When we compared the lists of genes identified by association studies and those identified by molecular biological studies of drug-regulated genes, we observed significantly higher participation in the same gene interaction networks than expected by chance, despite little overlap between the two gene lists. Conclusions These results appear to offer new insights into the genetic factors underlying drug addiction. PMID:21999673

Antibiotic Susceptibilities and Genetic Characteristics of Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Isolates from Stools of Pediatric Diarrhea Patients in Surabaya, Indonesia.

Science.gov (United States)

Bagus Wasito, Eddy; Shigemura, Katsumi; Osawa, Kayo; Fardah, Alpha; Kanaida, Akiho; Raharjo, Dadik; Kuntaman, K; Hadi, Usman; Harijono, Sugeng; Marto Sudarmo, Subijanto; Nakamura, Tatsuya; Shibayama, Keigo; Fujisawa, Masato; Shirakawa, Toshiro

2017-07-24

The purpose of this study was to investigate extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolates from pediatric (aged 0 to 3 years) diarrhea patients in Surabaya, Indonesia, where this kind of survey is rare; our study included assessment of their antibiotic susceptibilities, as well as ESBL typing, multilocus sequence typing (MLST), and diarrheagenic E. coli (DEC)-typing. ESBL-producing E. coli were detected in 18.8% of all the samples. Many ESBL-producing E. coli had significantly lower susceptibility to gentamicin (p ＜ 0.0001) and the quinolones nalidixic acid (p＝0.004) and ciprofloxacin (p ＜ 0.0001) than non-producers. In ESBL-producing E. coli, 84.0% of strains expressed CTX-M-15 alone or in combination with other ESBL types. MLST revealed that 24.0% of ESBL-producers had sequence type 617, all of which expressed the CTX-M-15 gene; we also detected expression of 3 DEC-related genes: 2 enteroaggregative E. coli genes and 1 enteropathogenic E. coli gene. In conclusion, CTX-M-15-type ESBL-producing E. coli ST617 appear to have spread to Indonesia.

Genetic susceptibility to radiations. Which impact on medical practice

International Nuclear Information System (INIS)

Alapetite, C.; Cosset, J. M.; Bourguignon, M. H.; Masse, R.

2000-01-01

Recent progress especially in the field of gene identification and expression have raised more attention on genetic susceptibility to cancer possibly enhanced by radiation. 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 radiation for better treatment of their malignant tumors. Although only a small percentage of individuals are hypersensitive to radiation effects, all medical specialists using ionising radiation should be aware of this 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 radiation. Then the main tests capable of detecting 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 this specific subset of patients suffering from a genetic disorder with a susceptibility to radiation

Behavioural Susceptibility Theory: Professor Jane Wardle and the Role of Appetite in Genetic Risk of Obesity.

Science.gov (United States)

Llewellyn, Clare H; Fildes, Alison

2017-03-01

There is considerable variability in human body weight, despite the ubiquity of the 'obesogenic' environment. Human body weight has a strong genetic basis and it has been hypothesised that genetic susceptibility to the environment explains variation in human body weight, with differences in appetite being implicated as the mediating mechanism; so-called 'behavioural susceptibility theory' (BST), first described by Professor Jane Wardle. This review summarises the evidence for the role of appetite as a mediator of genetic risk of obesity. Variation in appetitive traits is observable from infancy, drives early weight gain and is highly heritable in infancy and childhood. Obesity-related common genetic variants identified through genome-wide association studies show associations with appetitive traits, and appetite mediates part of the observed association between genetic risk and adiposity. Obesity results from an interaction between genetic susceptibility to overeating and exposure to an 'obesogenic' food environment.

Genetic diversity and in vitro antibiotic susceptibility profile of ...

African Journals Online (AJOL)

We assessed the genetic diversity of forty Salmonella isolates obtained from selected domestic water and waste water sources in the Eastern Cape Province of South Africa using DNA fingerprinting and antibiotic susceptibility profile as test indices. Restriction digests and SDS/PAGE as well as the DNA dendograms of the ...

Canine susceptibility to visceral leishmaniasis: A systematic review upon genetic aspects, considering breed factors and immunological concepts.

Science.gov (United States)

de Vasconcelos, Tassia Cristina Bello; Furtado, Marina Carvalho; Belo, Vínicus Silva; Morgado, Fernanda Nazaré; Figueiredo, Fabiano Borges

2017-10-05

Dogs have different susceptibility degrees to leishmaniasis; however, genetic research on this theme is scarce, manly on visceral form. The aims of this systematic review were to describe and discuss the existing scientific findings on genetic susceptibility to canine leishmaniasis, as well as to show the gaps of the existing knowledge. Twelve articles were selected, including breed immunological studies, genome wide associations or other gene polymorphism or gene sequencing studies, and transcription approaches. As main results of literature, there was a suggestion of genetic clinical resistance background for Ibizan Hound dogs, and alleles associated with protection or susceptibility to visceral leishmaniasis in Boxer dogs. Genetic markers can explain phenotypic variance in both pro- and anti-inflammatory cytokines and in cellular immune responses, including antigen presentation. Many gene segments are involved in canine visceral leishmaniasis phenotype, with Natural Resistance Associated Macrophage Protein 1 (NRAMP1) as the most studied. This was related to both protection and susceptibility. In comparison with murine and human genetic approaches, lack of knowledge in dogs is notorious, with many possibilities for new studies, revealing a wide field to be assessed on canine leishmaniasis susceptibility research. Copyright © 2017 Elsevier B.V. All rights reserved.

Ethical issues of genetic susceptibility testing for occupational diseases: opinions of trainees in a high-risk job

NARCIS (Netherlands)

Visser, M. J.; Rhebergen, M. D. F.; Kezic, S.; van Dijk, F. J. H.; Willems, D. L.; Verberk, M. M.

2013-01-01

Genetic research has opened up possibilities for identification of persons with an increased susceptibility for occupational disease. However, regulations considering the ethical issues that are inevitably associated with the use of genetic tests for susceptibility for occupational diseases are

Pediatric Multiple Sclerosis: Genes, Environment, and a Comprehensive Therapeutic Approach.

Science.gov (United States)

Cappa, Ryan; Theroux, Liana; Brenton, J Nicholas

2017-10-01

Pediatric multiple sclerosis is an increasingly recognized and studied disorder that accounts for 3% to 10% of all patients with multiple sclerosis. The risk for pediatric multiple sclerosis is thought to reflect a complex interplay between environmental and genetic risk factors. Environmental exposures, including sunlight (ultraviolet radiation, vitamin D levels), infections (Epstein-Barr virus), passive smoking, and obesity, have been identified as potential risk factors in youth. Genetic predisposition contributes to the risk of multiple sclerosis, and the major histocompatibility complex on chromosome 6 makes the single largest contribution to susceptibility to multiple sclerosis. With the use of large-scale genome-wide association studies, other non-major histocompatibility complex alleles have been identified as independent risk factors for the disease. The bridge between environment and genes likely lies in the study of epigenetic processes, which are environmentally-influenced mechanisms through which gene expression may be modified. This article will review these topics to provide a framework for discussion of a comprehensive approach to counseling and ultimately treating the pediatric patient with multiple sclerosis. Copyright © 2017 Elsevier Inc. All rights reserved.

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)

Genetic susceptibility to radiation: which impact on medical practice?

International Nuclear Information System (INIS)

Alapetite, C.; Cosset, J.M.; Bourguignon, M.H.; Masse, R.

2001-01-01

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)

Ciliopathies: Genetics in Pediatric Medicine.

Science.gov (United States)

Oud, Machteld M; Lamers, Ideke J C; Arts, Heleen H

2017-03-01

Ciliary disorders , which are also referred to as ciliopathies , are a group of hereditary disorders that result from dysfunctional cilia. The latter are cellular organelles that stick up from the apical plasma membrane. Cilia have important roles in signal transduction and facilitate communications between cells and their surroundings. Ciliary disruption can result in a wide variety of clinically and genetically heterogeneous disorders with overlapping phenotypes. Because cilia occur widespread in our bodies many organs and sensory systems can be affected when they are dysfunctional. Ciliary disorders may be isolated or syndromic, and common features are cystic liver and/or kidney disease, blindness, neural tube defects, brain anomalies and intellectual disability, skeletal abnormalities ranging from polydactyly to abnormally short ribs and limbs, ectodermal defects, obesity, situs inversus , infertility, and recurrent respiratory tract infections. In this review, we summarize the features, frequency, morbidity, and mortality of each of the different ciliopathies that occur in pediatrics. The importance of genetics and the occurrence of genotype-phenotype correlations are indicated, and advances in gene identification are discussed. The use of next-generation sequencing by which a gene panel or all genes can be screened in a single experiment is highlighted as this technology significantly lowered costs and time of the mutation detection process in the past. We discuss the challenges of this new technology and briefly touch upon the use of whole-exome sequencing as a diagnostic test for ciliary disorders. Finally, a perspective on the future of genetics in the context of ciliary disorders is provided.

Genetic control of susceptibility to apoptosis of thymocytes

International Nuclear Information System (INIS)

Mori, N.; Okumoto, M.; Morimoto, J.; Imai, S.; Matsuyama, T.; Takamori, Y.; Yagasaki, O.

1992-01-01

Genetic control of the susceptibility of thymocytes to radiation-induced apoptosis in mice was investigated by counting dead cells in a selected area of thymic cortex on histological specimens after whole-body X-irradiation. The number of dead cells increased almost linearly with doses in BALB/cHeA and STS/A mice. However, dead cell counts in BALB/cHeA mice were more than twice those in STS/A mice at each dose. C57BL/6N and B10.BR mice exhibited a sensitive phenotype similar to BALB/cHeA mice, while C3H/HeMsNrs and NFS/N mice showed a resistant phenotype similar to STS/A mice. Sex difference in the susceptibility of thymocytes to cell death was not recognized in BALB/cHeA and STS/A mice. Resistance was dominant over susceptibility in the progenies of reciprocal crosses between the two strains, indicating an autosomal inheritance. The segregation ratio of susceptible to resistant phenotype in the backcrosses of (BALB/cHeA X STS/A)F 1 with BALB/cHeA was not significantly different from 1 : 1 and all backcrosses of (BALB/cHeA X STS/A)F 1 with STS/A exhibited a resistant phenotype. The results demonstrated that the difference in the susceptibility of thymocytes to radiation-induced apoptosis in the two strains of mice is due to one major autosomal allele. (author)

Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis.

Science.gov (United States)

Venkateswaran, Suresh; Prince, Jarod; Cutler, David J; Marigorta, Urko M; Okou, David T; Prahalad, Sampath; Mack, David; Boyle, Brendan; Walters, Thomas; Griffiths, Anne; Sauer, Cary G; LeLeiko, Neal; Keljo, David; Markowitz, James; Baker, Susan S; Rosh, Joel; Pfefferkorn, Marian; Heyman, Melvin B; Patel, Ashish; Otley, Anthony; Baldassano, Robert; Noe, Joshua; Rufo, Paul; Oliva-Hemker, Maria; Davis, Sonia; Zwick, Michael E; Gibson, Greg; Denson, Lee A; Hyams, Jeffrey; Kugathasan, Subra

2018-03-19

The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84-1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59). To study the genetic contribution to exclusive pediatric onset UC, a GWAS was performed on 466 cases with 2099 healthy controls using UK Biobank array. SNP2HLA was used to impute classical HLA alleles and their corresponding amino acids, and the results are compared with adult onset UC. HLA explained the almost entire association signal, dominated with 191 single nucleotide polymorphisms (SNPs) (p = 5 x 10-8 to 5 x 10-10). Although very small effects, established SNPs in adult onset UC loci had similar direction and magnitude in pediatric onset UC. SNP2HLA imputation identified HLA-DRB1*0103 (odds ratio [OR] = 6.941, p = 1.92*10-13) as the most significant association for pediatric UC compared with adult onset UC (OR = 3.59). Further conditioning showed independent effects for HLA-DRB1*1301 (OR = 2.25, p = 7.92*10-9) and another SNP rs17188113 (OR = 0.48, p = 7.56*10-9). Two HLA-DRB1 causal alleles are shared with adult onset UC, while at least 2 signals are unique to pediatric UC. Subsequent stratified analyses indicated that HLA-DRB1*0103 has stronger association for extensive disease (E4: OR = 8.28, p = 4.66x10-10) and female gender (OR = 8.85, p = 4.82x10-13). In pediatric onset UC, the HLA explains almost the entire genetic associations. In addition, the HLA association is approximately twice as strong in pediatric UC compared with adults, due to a combination of novel and shared effects. We speculate the paramount importance of antigenic stimulation either by infectious or noninfectious stimuli as a causal event in pediatric UC onset.

A Drosophila model for toxicogenomics: Genetic variation in susceptibility to heavy metal exposure.

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Shanshan Zhou

2017-07-01

Full Text Available The genetic factors that give rise to variation in susceptibility to environmental toxins remain largely unexplored. Studies on genetic variation in susceptibility to environmental toxins are challenging in human populations, due to the variety of clinical symptoms and difficulty in determining which symptoms causally result from toxic exposure; uncontrolled environments, often with exposure to multiple toxicants; and difficulty in relating phenotypic effect size to toxic dose, especially when symptoms become manifest with a substantial time lag. Drosophila melanogaster is a powerful model that enables genome-wide studies for the identification of allelic variants that contribute to variation in susceptibility to environmental toxins, since the genetic background, environmental rearing conditions and toxic exposure can be precisely controlled. Here, we used extreme QTL mapping in an outbred population derived from the D. melanogaster Genetic Reference Panel to identify alleles associated with resistance to lead and/or cadmium, two ubiquitous environmental toxins that present serious health risks. We identified single nucleotide polymorphisms (SNPs associated with variation in resistance to both heavy metals as well as SNPs associated with resistance specific to each of them. The effects of these SNPs were largely sex-specific. We applied mutational and RNAi analyses to 33 candidate genes and functionally validated 28 of them. We constructed networks of candidate genes as blueprints for orthologous networks of human genes. The latter not only provided functional contexts for known human targets of heavy metal toxicity, but also implicated novel candidate susceptibility genes. These studies validate Drosophila as a translational toxicogenomics gene discovery system.

Awareness of Cancer Susceptibility Genetic Testing

Science.gov (United States)

Mai, Phuong L.; Vadaparampil, Susan Thomas; Breen, Nancy; McNeel, Timothy S.; Wideroff, Louise; Graubard, Barry I.

2014-01-01

Background Genetic testing for several cancer susceptibility syndromes is clinically available; however, existing data suggest limited population awareness of such tests. Purpose To examine awareness regarding cancer genetic testing in the U.S. population aged ≥25 years in the 2000, 2005, and 2010 National Health Interview Surveys. Methods The weighted percentages of respondents aware of cancer genetic tests, and percent changes from 2000–2005 and 2005–2010, overall and by demographic, family history, and healthcare factors were calculated. Interactions were used to evaluate the patterns of change in awareness between 2005 and 2010 among subgroups within each factor. To evaluate associations with awareness in 2005 and 2010, percentages were adjusted for covariates using multiple logistic regression. The analysis was performed in 2012. Results Awareness decreased from 44.4% to 41.5% (pAwareness increased between 2005 and 2010 in most subgroups, particularly among individuals in the South (p-interaction=0.03) or with a usual place of care (p-interaction=0.01). In 2005 and 2010, awareness was positively associated with personal or family cancer history and high perceived cancer risk, and inversely associated with racial/ethnic minorities, age 25–39 or ≥60 years, male gender, lower education and income levels, public or no health insurance, and no provider contact in 12 months. Conclusions Despite improvement from 2005 to 2010, ≤50% of the U.S. adult population was aware of cancer genetic testing in 2010. Notably, disparities persist for racial/ethnic minorities and individuals with limited health care access or income. PMID:24745633

Comparative study of genetic influence on the susceptibility of exotic ...

African Journals Online (AJOL)

This study investigated comparatively the genetic influence on the susceptibility of exotic cockerels, pullets and broilers to natural infection with infectious bursal disease (IBD) virus in a flock of 150 seven-week-old exotic breed of chickens comprising of 50 Black Harco cockerels, 50 Black Harco pullets and 50 White ...

Genetic Testing for TMEM154 Mutations Associated with Lentivirus Susceptibility in Sheep

Science.gov (United States)

Petrik, Dustin T.; Simpson, Barry; Kijas, James W.; Clawson, Michael L.; Chitko-McKown, Carol G.; Harhay, Gregory P.; Leymaster, Kreg A.

2013-01-01

In sheep, small ruminant lentiviruses cause an incurable, progressive, lymphoproliferative disease that affects millions of animals worldwide. Known as ovine progressive pneumonia virus (OPPV) in the U.S., and Visna/Maedi virus (VMV) elsewhere, these viruses reduce an animal’s health, productivity, and lifespan. Genetic variation in the ovine transmembrane protein 154 gene (TMEM154) has been previously associated with OPPV infection in U.S. sheep. Sheep with the ancestral TMEM154 haplotype encoding glutamate (E) at position 35, and either form of an N70I variant, were highly-susceptible compared to sheep homozygous for the K35 missense mutation. Our current overall aim was to characterize TMEM154 in sheep from around the world to develop an efficient genetic test for reduced susceptibility. The average frequency of TMEM154 E35 among 74 breeds was 0.51 and indicated that highly-susceptible alleles were present in most breeds around the world. Analysis of whole genome sequences from an international panel of 75 sheep revealed more than 1,300 previously unreported polymorphisms in a 62 kb region containing TMEM154 and confirmed that the most susceptible haplotypes were distributed worldwide. Novel missense mutations were discovered in the signal peptide (A13V) and the extracellular domains (E31Q, I74F, and I102T) of TMEM154. A matrix-assisted laser desorption/ionization–time-of flight mass spectrometry (MALDI-TOF MS) assay was developed to detect these and six previously reported missense and two deletion mutations in TMEM154. In blinded trials, the call rate for the eight most common coding polymorphisms was 99.4% for 499 sheep tested and 96.0% of the animals were assigned paired TMEM154 haplotypes (i.e., diplotypes). The widespread distribution of highly-susceptible TMEM154 alleles suggests that genetic testing and selection may improve the health and productivity of infected flocks. PMID:23408992

Genetic testing for TMEM154 mutations associated with lentivirus susceptibility in sheep.

Directory of Open Access Journals (Sweden)

Michael P Heaton

Full Text Available In sheep, small ruminant lentiviruses cause an incurable, progressive, lymphoproliferative disease that affects millions of animals worldwide. Known as ovine progressive pneumonia virus (OPPV in the U.S., and Visna/Maedi virus (VMV elsewhere, these viruses reduce an animal's health, productivity, and lifespan. Genetic variation in the ovine transmembrane protein 154 gene (TMEM154 has been previously associated with OPPV infection in U.S. sheep. Sheep with the ancestral TMEM154 haplotype encoding glutamate (E at position 35, and either form of an N70I variant, were highly-susceptible compared to sheep homozygous for the K35 missense mutation. Our current overall aim was to characterize TMEM154 in sheep from around the world to develop an efficient genetic test for reduced susceptibility. The average frequency of TMEM154 E35 among 74 breeds was 0.51 and indicated that highly-susceptible alleles were present in most breeds around the world. Analysis of whole genome sequences from an international panel of 75 sheep revealed more than 1,300 previously unreported polymorphisms in a 62 kb region containing TMEM154 and confirmed that the most susceptible haplotypes were distributed worldwide. Novel missense mutations were discovered in the signal peptide (A13V and the extracellular domains (E31Q, I74F, and I102T of TMEM154. A matrix-assisted laser desorption/ionization-time-of flight mass spectrometry (MALDI-TOF MS assay was developed to detect these and six previously reported missense and two deletion mutations in TMEM154. In blinded trials, the call rate for the eight most common coding polymorphisms was 99.4% for 499 sheep tested and 96.0% of the animals were assigned paired TMEM154 haplotypes (i.e., diplotypes. The widespread distribution of highly-susceptible TMEM154 alleles suggests that genetic testing and selection may improve the health and productivity of infected flocks.

Additional mechanisms conferring genetic susceptibility to Alzheimer's disease

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Miguel eCalero

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.

A major genetic component of BSE susceptibility

Science.gov (United States)

Juling, Katrin; Schwarzenbacher, Hermann; Williams, John L; Fries, Ruedi

2006-01-01

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. PMID:17014722

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.

Genetic diversity and antifungal susceptibility of Fusarium isolates in onychomycosis.

Science.gov (United States)

Rosa, Priscila D; Heidrich, Daiane; Corrêa, Carolina; Scroferneker, Maria Lúcia; Vettorato, Gerson; Fuentefria, Alexandre M; Goldani, Luciano Z

2017-09-01

Fusarium species have emerged as an important human pathogen in skin disease, onychomycosis, keratitis and invasive disease. Onychomycosis caused by Fusarium spp. The infection has been increasingly described in the immunocompetent and immunosuppressed hosts. Considering onychomycosis is a difficult to treat infection, and little is known about the genetic variability and susceptibility pattern of Fusarium spp., further studies are necessary to understand the pathogenesis and better to define the appropriate antifungal treatment for this infection. Accordingly, the objective of this study was to describe the in vitro susceptibility to different antifungal agents and the genetic diversity of 35 Fusarium isolated from patients with onychomycosis. Fusarium spp. were isolated predominantly from female Caucasians, and the most frequent anatomical location was the nail of the hallux. Results revealed that 25 (71.4%) of isolates belonged to the Fusarium solani species complex, followed by 10 (28.5%) isolates from the Fusarium oxysporum species complex. Noteworthy, the authors report the first case of Neocosmospora rubicola isolated from a patient with onychomycosis. Amphotericin B was the most effective antifungal agent against the majority of isolates (60%, MIC ≤4 μg/mL), followed by voriconazole (34.2%, MIC ≤4 μg/mL). In general, Fusarium species presented MIC values >64 μg/mL for fluconazole, itraconazole and terbinafine. Accurate pathogen identification, characterisation and susceptibility testing provide a better understanding of pathogenesis of Fusarium in onychomycosis. © 2017 Blackwell Verlag GmbH.

Genetic susceptibility testing for chronic disease and intention for behavior change in healthy young adults.

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Vassy, Jason L; Donelan, Karen; Hivert, Marie-France; Green, Robert C; Grant, Richard W

2013-04-01

Genetic testing for chronic disease susceptibility may motivate young adults for preventive behavior change. This nationally representative survey gave 521 young adults hypothetical scenarios of receiving genetic susceptibility results for heart disease, type 2 diabetes, and stroke and asked their (1) interest in such testing, (2) anticipated likelihood of improving diet and physical activity with high- and low-risk test results, and (3) readiness to make behavior change. Responses were analyzed by presence of established disease-risk factors. Respondents with high phenotypic diabetes risk reported increased likelihood of improving their diet and physical activity in response to high-risk results compared with those with low diabetes risk (odds ratio (OR), 1.82 (1.03, 3.21) for diet and OR, 2.64 (1.24, 5.64) for physical activity). In contrast, poor baseline diet (OR, 0.51 (0.27, 0.99)) and poor physical activity (OR, 0.53 (0.29, 0.99)) were associated with decreased likelihood of improving diet. Knowledge of genetic susceptibility may motivate young adults with higher personal diabetes risk for improvement in diet and exercise, but poor baseline behaviors are associated with decreased intention to make these changes. To be effective, genetic risk testing in young adults may need to be coupled with other strategies to enable behavior change.

Are Adolescents with ADHD Interested in Genetic Testing for Nicotine Addiction Susceptibility?

Directory of Open Access Journals (Sweden)

Linda J. Herbert

2010-04-01

Full Text Available It has been well-established that some adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD are at increased risk for cigarette smoking. Current research on the genetic basis of this association could ultimately translate into genetic tests capable of identifying smoking-prone adolescents with ADHD. In this study we examined 81 ADHD affected adolescents’ (age 13–21 interest in genetic testing for nicotine addiction susceptibility. Fifty-seven percent of adolescents indicated a fair amount of interest or more in testing. Most adolescents indicated that the personal information revealed from testing would be either useful (29% or interesting (37%. Implications for genetically-informed smoking prevention and cessation interventions in high risk adolescents with ADHD are discussed.

A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.

Science.gov (United States)

Vissers, Lisenka E L M; van Nimwegen, Kirsten J M; Schieving, Jolanda H; Kamsteeg, Erik-Jan; Kleefstra, Tjitske; Yntema, Helger G; Pfundt, Rolph; van der Wilt, Gert Jan; Krabbenborg, Lotte; Brunner, Han G; van der Burg, Simone; Grutters, Janneke; Veltman, Joris A; Willemsen, Michèl A A P

2017-09-01

Implementation of novel genetic diagnostic tests is generally driven by technological advances because they promise shorter turnaround times and/or higher diagnostic yields. Other aspects, including impact on clinical management or cost-effectiveness, are often not assessed in detail prior to implementation. We studied the clinical utility of whole-exome sequencing (WES) in complex pediatric neurology in terms of diagnostic yield and costs. We analyzed 150 patients (and their parents) presenting with complex neurological disorders of suspected genetic origin. In a parallel study, all patients received both the standard diagnostic workup (e.g., cerebral imaging, muscle biopsies or lumbar punctures, and sequential gene-by-gene-based testing) and WES simultaneously. Our unique study design allowed direct comparison of diagnostic yield of both trajectories and provided insight into the economic implications of implementing WES in this diagnostic trajectory. We showed that WES identified significantly more conclusive diagnoses (29.3%) than the standard care pathway (7.3%) without incurring higher costs. Exploratory analysis of WES as a first-tier diagnostic test indicates that WES may even be cost-saving, depending on the extent of other tests being omitted. Our data support such a use of WES in pediatric neurology for disorders of presumed genetic origin.Genet Med advance online publication 23 March 2017.

Genetic variations of MMP9 gene and intracerebral hemorrhage susceptibility: a case-control study in Chinese Han population.

Science.gov (United States)

Yang, Jie; Wu, Bo; Lin, Sen; Zhou, Junshan; Li, Yingbin; Dong, Wei; Arima, Hisatomi; Zhang, Chanfei; Liu, Yukai; Liu, Ming

2014-06-15

To investigate the association between genetic variations of matrix metalloproteinase 9 (MMP9) gene and intracerebral hemorrhage (ICH) susceptibility in Chinese Han population. The clinical data and peripheral blood samples from the patients with ICH and hypertension, and controlled subjects with hypertension only, were collected. MassARRAY Analyzer was used to genotype the tagger single nucleotide polymorphism (SNP) of MMP9 gene. Haploview4.2 and Unphased3.1.7 were employed to construct haplotypes and to analyze the association between genetic variations (alleles, genotypes and haplotypes) of MMP9 gene and ICH susceptibility. 181 patients with ICH and hypertension, and 197 patients with hypertension only, were recruited between Sep 2009 and Oct 2010. Patients in the ICH group were younger (61.80 ± 13.27 vs. 72.44 ± 12.71 years, ppopulation. Our logistical regression analysis showed that there were no significant associations between genetic variations of the MPP9 gene and ICH susceptibility (all p>0.05). The genetic variations of MMP9 gene were not significantly associated with ICH susceptibility in the Chinese Han population. Copyright © 2014 Elsevier B.V. All rights reserved.

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

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.

Inducible and transmissible genetic events and pediatric tumors of the nervous system

International Nuclear Information System (INIS)

Rice, Jerry M.

2006-01-01

Tumors of the nervous system most often occur in both children and adults as sporadic events with no family history of the disease, but they are also among the clinical manifestations of a significant number of familial cancer syndromes, including familial retinoblastoma, neurofibromatosis 1 and 2, tuberous sclerosis, and Cowden, Turcot, Li-Fraumeni and nevoid basal cell carcinoma (Gorlin) syndromes. All of these syndromes involve transmissible genetic risk resulting from loss of a functional allele, or inheritance of a structurally defective allele, of a specific gene. These genes include RB1, NF1, NF2, TSC1, TSC2, TP53, PTEN, APC, hMLH1, hPSM2, and PTCH, most of which function as tumor suppressor genes. The same genes are also observed in mutated and inactive forms, or are deleted, in tumor cells in sporadic cases of the same tumors. The nature of the mutational events that give rise to these inactivated alleles suggests a possible role of environmental mutagens in their causation. However, only external ionizing radiation at high doses is clearly established as an environmental cause of brain, nerve and meningeal tumors in humans. Transplacental carcinogenesis studies in rodents and other species emphasize the extraordinary susceptibility of the developing mammalian nervous system to carcinogenesis, but the inverse relationship of latency to dose suggests that low transplacental exposures to genotoxicants are more likely to result in brain tumors late in life, rather than in childhood. While not all neurogenic tumor-related genes in humans have similar effects in experimental rodents, genetically engineered mice (GEM) increasingly provide useful insights into the combined effects of multiple tumor suppressor genes and of gene-environment interactions in the genesis of brain tumors, especially pediatric brain tumors such as medulloblastoma. (author)

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

Science.gov (United States)

McKay, James D.; Hung, Rayjean J.; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C.; Caporaso, Neil E.; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A.; Qian, David C.; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N.; Bojesen, Stig E.; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C.; Bush, William S.; Tardon, Adonina; Rennert, Gad; Teare, M. Dawn; Field, John K.; Kiemeney, Lambertus A.; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B.; Andrew, Angeline S.; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C.; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S.; Mellemgaard, Anders; Saliba, Walid; Haiman, Christopher A.; Wilkens, Lynne R.; Fernandez-Somoano, Ana; Fernandez-Tardon, Guillermo; van der Heijden, Henricus F.M.; Kim, Jin Hee; Dai, Juncheng; Hu, Zhibin; Davies, Michael PA; Marcus, Michael W.; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C.; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Doherty, Jennifer A.; Barnett, Matt P.; Chen, Chu; Goodman, Gary E.; Cox, Angela; Taylor, Fiona; Woll, Penella; Brüske, Irene; Wichmann, H.-Erich; Manz, Judith; Muley, Thomas R.; Risch, Angela; Rosenberger, Albert; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A.; Tsao, Ming-Sound; Arnold, Susanne M.; Haura, Eric B.; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M.; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J.; Butler, Lesley M.; Koh, Woon-Puay; Gao, Yu-Tang; Houlston, Richard S.; McLaughlin, John; Stevens, Victoria L.; Joubert, Philippe; Lamontagne, Maxime; Nickle, David C.; Obeidat, Ma’en; Timens, Wim; Zhu, Bin; Song, Lei; Kachuri, Linda; Artigas, María Soler; Tobin, Martin D.; Wain, Louise V.; Rafnar, Thorunn; Thorgeirsson, Thorgeir E.; Reginsson, Gunnar W.; Stefansson, Kari; Hancock, Dana B.; Bierut, Laura J.; Spitz, Margaret R.; Gaddis, Nathan C.; Lutz, Sharon M.; Gu, Fangyi; Johnson, Eric O.; Kamal, Ahsan; Pikielny, Claudio; Zhu, Dakai; Lindströem, Sara; Jiang, Xia; Tyndale, Rachel F.; Chenevix-Trench, Georgia; Beesley, Jonathan; Bossé, Yohan; Chanock, Stephen; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I.

2017-01-01

Summary While several lung cancer susceptibility loci have been identified, much of lung cancer heritability remains unexplained. Here, 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated GWAS analysis of lung cancer on 29,266 patients and 56,450 controls. We identified 18 susceptibility loci achieving genome wide significance, including 10 novel loci. The novel loci highlighted the striking heterogeneity in genetic susceptibility across lung cancer histological subtypes, with four loci associated with lung cancer overall and six with lung adenocarcinoma. Gene expression quantitative trait analysis (eQTL) in 1,425 normal lung tissues highlighted RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes, OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer. PMID:28604730

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

Science.gov (United States)

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

2013-03-01

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 detailed investigation, the landslide inventory was mapped in which 39 landslides, including paleo-landslides, old landslides and recent landslides, were present. Of the 216 slope units, 123 involved landslides. To analyze the mechanism of these landslides, six environmental factors were selected to evaluate landslide occurrence: slope angle, aspect, the height and shape of the slope, distance to river and human activities. These factors were extracted in terms of the slope unit within the ArcGIS software. The spatial analysis demonstrates that most of the landslides are located on convex slopes at an elevation of 100-150 m with slope angles from 135°-225° and 40°-60°. Landslide occurrence was then checked according to these environmental factors using an artificial neural network with back propagation, optimized by genetic algorithms. A dataset of 120 slope units was chosen for training the neural network model, i.e., 80 units with landslide presence and 40 units without landslide presence. The parameters of genetic algorithms and neural networks were then set: population size of 100, crossover probability of 0.65, mutation probability of 0.01, momentum factor of 0.60, learning rate of 0.7, max learning number of 10 000, and target error of 0.000001. After training on the datasets, the susceptibility of landslides was mapped for the land-use plan and hazard mitigation. Comparing the susceptibility map with landslide inventory, it was noted that the prediction accuracy of landslide occurrence

NIH Scientists Map Genetic Changes That Drive Tumors in a Common Pediatric Soft-Tissue Cancer

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... Press Release NIH scientists map genetic changes that drive tumors in a common pediatric soft-tissue cancer ... of Health FOLLOW US Facebook Twitter Instagram YouTube Google+ LinkedIn GovDelivery RSS CONTACT INFORMATION Contact Us LiveHelp ...

Pediatric Obesity-Related Asthma: The Role of Metabolic Dysregulation.

Science.gov (United States)

Vijayakanthi, Nandini; Greally, John M; Rastogi, Deepa

2016-05-01

The burden of obesity-related asthma among children, particularly among ethnic minorities, necessitates an improved understanding of the underlying disease mechanisms. Although obesity is an independent risk factor for asthma, not all obese children develop asthma. Several recent studies have elucidated mechanisms, including the role of diet, sedentary lifestyle, mechanical fat load, and adiposity-mediated inflammation that may underlie the obese asthma pathophysiology. Here, we review these recent studies and emerging scientific evidence that suggest metabolic dysregulation may play a role in pediatric obesity-related asthma. We also review the genetic and epigenetic factors that may underlie susceptibility to metabolic dysregulation and associated pulmonary morbidity among children. Lastly, we identify knowledge gaps that need further exploration to better define pathways that will allow development of primary preventive strategies for obesity-related asthma in children. Copyright © 2016 by the American Academy of Pediatrics.

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.

Genetic susceptibility to infectious disease: lessons from mouse models of leishmaniasis

Czech Academy of Sciences Publication Activity Database

Lipoldová, Marie; Demant, P.

2006-01-01

Roč. 7, č. 4 (2006), s. 294-305 ISSN 1471-0056 R&D Projects: GA ČR(CZ) GA310/03/1381 Grant - others:Howard Hughes Medical Institute(US) HHMI55000323 Institutional research plan: CEZ:AV0Z50520514 Keywords : leishmaniasis * susceptibility to infectious disease * modifying genes Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 22.947, year: 2006

Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease

DEFF Research Database (Denmark)

Baillie, J Kenneth; Bretherick, Andrew; Haley, Christopher S

2018-01-01

Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns...... the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes...... in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn's disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely...

Complex genetics of familial exudative vitreoretinopathy and related pediatric retinal detachments

Science.gov (United States)

Kondo, Hiroyuki

2015-01-01

Familial exudative vitreoretinopathy (FEVR) is a hereditary vitreoretinal disorder that can cause various types of retinal detachments. The abnormalities in eyes with FEVR are caused by poor vascularization in the peripheral retina. The genetics of FEVR is highly heterogeneous, and mutations in the genes for Wnt signaling and a transcription factor have been reported to be responsible for FEVR. These factors have been shown to be the regulators of the pathophysiological pathways of retinal vascular development. Studies conducted to identify the causative genes of FEVR have uncovered a diverse and complex relationship between FEVR and other diseases; for example, Norrie disease, a Mendelian-inherited disease; retinopathy of prematurity, a multifactorial genetic disease; and Coats disease, a nongenetic disease, associated with pediatric retinal detachments. PMID:29018668

Genetic variation may explain why females are less susceptible to dental erosion.

Science.gov (United States)

Uhlen, Marte-Mari; Stenhagen, Kjersti R; Dizak, Piper M; Holme, Børge; Mulic, Aida; Tveit, Anne B; Vieira, Alexandre R

2016-10-01

Not all individuals at risk for dental erosion (DE) display erosive lesions. The prevalence of DE is higher among male subjects. The occurrence of DE may depend on more than just acidic challenge, with genetics possibly playing a role. The aim of this study was to investigate the association of enamel-formation genes with DE. One premolar and a saliva sample were collected from 90 individuals. Prepared teeth were immersed in 0.01 M HCl (pH 2.2), and enamel loss (μm) was measured using white light interferometry. DNA was extracted from saliva, and 15 single-nucleotide polymorphisms were analysed. Allele and genotype frequencies were related to the enamel loss of the specimens. Single-marker and haplotype analyses were performed using sex as a covariate. Mean enamel loss was higher for male donors than for female donors (P = 0.047). Significant associations were found between enamel loss and amelogenin, X-linked (AMELX), tuftelin 1 (TUFT1), and tuftelin-interacting protein 11 (TFIP11). Analyses showed significant associations between variation in enamel-formation genes and a lower susceptibility to DE in female subjects. The results indicate that susceptibility to DE is influenced by genetic variation, and may, in part, explain why some individuals are more susceptible than others to DE, including differences between female subjects and male subjects. © 2016 Eur J Oral Sci.

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. © 2015 by American Society of Clinical Oncology.

Development of a tiered and binned genetic counseling model for informed consent in the era of multiplex testing for cancer susceptibility.

Science.gov (United States)

Bradbury, Angela R; Patrick-Miller, Linda; Long, Jessica; Powers, Jacquelyn; Stopfer, Jill; Forman, Andrea; Rybak, Christina; Mattie, Kristin; Brandt, Amanda; Chambers, Rachelle; Chung, Wendy K; Churpek, Jane; Daly, Mary B; Digiovanni, Laura; Farengo-Clark, Dana; Fetzer, Dominique; Ganschow, Pamela; Grana, Generosa; Gulden, Cassandra; Hall, Michael; Kohler, Lynne; Maxwell, Kara; Merrill, Shana; Montgomery, Susan; Mueller, Rebecca; Nielsen, Sarah; Olopade, Olufunmilayo; Rainey, Kimberly; Seelaus, Christina; Nathanson, Katherine L; Domchek, Susan M

2015-06-01

Multiplex genetic testing, including both moderate- and high-penetrance genes for cancer susceptibility, is associated with greater uncertainty than traditional testing, presenting challenges to informed consent and genetic counseling. We sought to develop a new model for informed consent and genetic counseling for four ongoing studies. Drawing from professional guidelines, literature, conceptual frameworks, and clinical experience, a multidisciplinary group developed a tiered-binned genetic counseling approach proposed to facilitate informed consent and improve outcomes of cancer susceptibility multiplex testing. In this model, tier 1 "indispensable" information is presented to all patients. More specific tier 2 information is provided to support variable informational needs among diverse patient populations. Clinically relevant information is "binned" into groups to minimize information overload, support informed decision making, and facilitate adaptive responses to testing. Seven essential elements of informed consent are provided to address the unique limitations, risks, and uncertainties of multiplex testing. A tiered-binned model for informed consent and genetic counseling has the potential to address the challenges of multiplex testing for cancer susceptibility and to support informed decision making and adaptive responses to testing. Future prospective studies including patient-reported outcomes are needed to inform how to best incorporate multiplex testing for cancer susceptibility into clinical practice.Genet Med 17 6, 485-492.

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

Science.gov (United States)

McKay, James D; Hung, Rayjean J; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C; Caporaso, Neil E; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A; Qian, David C; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N; Bojesen, Stig E; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C; Bush, William S; Tardon, Adonina; Rennert, Gad; Teare, M Dawn; Field, John K; Kiemeney, Lambertus A; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B; Andrew, Angeline S; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S; Mellemgaard, Anders; Saliba, Walid; Haiman, Christopher A; Wilkens, Lynne R; Fernandez-Somoano, Ana; Fernandez-Tardon, Guillermo; van der Heijden, Henricus F M; Kim, Jin Hee; Dai, Juncheng; Hu, Zhibin; Davies, Michael P A; Marcus, Michael W; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Doherty, Jennifer A; Barnett, Matt P; Chen, Chu; Goodman, Gary E; Cox, Angela; Taylor, Fiona; Woll, Penella; Brüske, Irene; Wichmann, H-Erich; Manz, Judith; Muley, Thomas R; Risch, Angela; Rosenberger, Albert; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A; Tsao, Ming-Sound; Arnold, Susanne M; Haura, Eric B; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J; Butler, Lesley M; Koh, Woon-Puay; Gao, Yu-Tang; Houlston, Richard S; McLaughlin, John; Stevens, Victoria L; Joubert, Philippe; Lamontagne, Maxime; Nickle, David C; Obeidat, Ma'en; Timens, Wim; Zhu, Bin; Song, Lei; Kachuri, Linda; Artigas, María Soler; Tobin, Martin D; Wain, Louise V; Rafnar, Thorunn; Thorgeirsson, Thorgeir E; Reginsson, Gunnar W; Stefansson, Kari; Hancock, Dana B; Bierut, Laura J; Spitz, Margaret R; Gaddis, Nathan C; Lutz, Sharon M; Gu, Fangyi; Johnson, Eric O; Kamal, Ahsan; Pikielny, Claudio; Zhu, Dakai; Lindströem, Sara; Jiang, Xia; Tyndale, Rachel F; Chenevix-Trench, Georgia; Beesley, Jonathan; Bossé, Yohan; Chanock, Stephen; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I

2017-07-01

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

Assessing the quality of studies supporting genetic susceptibility and outcomes of ARDS

Directory of Open Access Journals (Sweden)

Marialbert eAcosta-Herrera

2014-02-01

Full Text Available The acute respiratory distress syndrome (ARDS is a severe inflammatory disease manifested as a result of pulmonary and systemic responses to several insults. It is now well accepted that genetic variation influences these responses. However, little is known about the genes that are responsible for patient susceptibility and outcome of ARDS. Methodological flaws are still abundant among genetic association studies with ARDS and here, we aimed to highlight the quality criteria where the standards have not been reached, to expose the associated genes to facilitate replication attempts, and to provide quick-reference guidance for future studies. We conducted a PubMed search from January 2008 to September 2012 for original articles. Studies were considered if a statistically significant association was declared with either susceptibility or outcomes of all-cause ARDS. Fourteen criteria were used for evaluation and results were compared to those from a previous quality assessment report. Significant improvements affecting study design and statistical analysis were detected. However, major issues such as adjustments for the underlying population stratification and replication studies remain poorly addressed.

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

2007-10-01

Full Text Available 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.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.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.

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

NARCIS (Netherlands)

Oostrom, I.I.H. van; Meijers-Heijboer, H.; Duivenvoorden, H.J.; Brocker-Vriends, A.H.; Asperen, C.J. van; Sijmons, R.H.; Seynaeve, C.; Gool, A.R. van; 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

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.; Bröcker-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

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.

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

Genetic diversity within and among two-spotted spider mite resistant and susceptible common bean genotypes

Directory of Open Access Journals (Sweden)

Zeinab YOUSEFI

2017-12-01

Full Text Available Two-spotted spider mite (Tetranychus urticae C. L. Koch, 1836, is one of the most destructive herbivores of common bean. Very little is known about the diversity among resistant sources in this crop. The present study was conducted to characterize 22 resistant and susceptible common bean genotypes by 8 Simple Sequence Repeats (SSRs and 8 Random Amplified Polymorphic DNA (RAPD markers. These SSR and RAPD primers produced 100 % and 81.8 % polymorphic bands. Based on RAPD fingerprints and SSR profiles, pairwise genetic similarity ranged from 0.0 to 0.857 and from 0.125 to 1, respectively. The resistant and susceptible common bean accessions were grouped together in the dendrograms generated from RAPD and SSR clustering analyses. The results indicate that RAPD and SSR analysis could be successfully used for the estimation of genetic diversity among genotypes. SSR markers could group genotypes according to their resistibility and susceptibility to the spotted spider mite but RAPD could not. Therefore, the SSR markers can facilitate the development of resistant common bean cultivars through breeding programs against T. urticae.

Comprehensive Clinical Phenotyping & Genetic Mapping for the Discovery of Autism Susceptibility Genes

Science.gov (United States)

2012-12-05

teaching students with autism spectrum disorders 4.52 Learn strategies for incorporating IEP goals and district standard into daily teaching...W403 Columbus, OH 43205 Final Report Comprehensive Clinical Phenotyping & Genetic Mapping for the Discovery of Autism Susceptibility Genes...QFOXGHDUHDFRGH 1.0 Summary In 2006, the Central Ohio Registry for Autism (CORA) was initiated as a collaboration between Wright-Patterson Air

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...

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

of these interactions, we tested how genetically divergent resistant and susceptible plants are, using microsatellite markers. To test whether they are reproductively fully compatible, resistant and susceptible plants were grown intermixed in an outdoor experiment, and the paternity of open-pollinated offspring......Co-evolution between herbivores and plants is believed to be one of the processes creating Earth’s biodiversity. However, it is difficult to disentangle to what extent diversification is really driven by herbivores or by other historical-geographical processes like allopatric isolation....... In the 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...

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

International Nuclear Information System (INIS)

Mortensen, Holly M.; Euling, Susan Y.

2013-01-01

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

Estimating host genetic effects on susceptibility and infectivity to infectious diseases and their contribution to response to selection

NARCIS (Netherlands)

Anche, M.T.

2016-01-01

Mahlet Teka Anche. (2016). Estimating host genetic effects on susceptibility and infectivity to infectious diseases and their contribution to response to selection. PhD thesis, Wageningen University, the Netherlands

Genetic approaches aiming to reduce the prevalence of an infection in a

Genetic susceptibility to mammary carcinogenesis in rats

Energy Technology Data Exchange (ETDEWEB)

Kamiya, Kenji; Nitta, Yumiko [Hiroshima Univ. (Japan). Research Inst. for Radiation Biology and Medicine

1999-06-01

The Copenhagen (COP) rat strain has previously been shown to be genetically resistant to chemical induction of breast cancer, while Wistar/Furth (WF) and Fischer 344 (F344) animals are relatively susceptible. We have compared the carcinogenic response of these three strains of rats to N-methyl-N-nitrosourea (MNU) with that to {sup 60}Co gamma rays. High incidences of mammary carcinomas were induced by MNU in the F344 and WF rats (100%), whereas the COP strain proved resistant (11.8%). In contrast, radiation-induced mammary carcinomas in COP rats developed in a similar incidence (37.0%) to those in the F344 (22.6%) and WF (26.9%) strains. The low incidence of papillary carcinomas in MNU-treated COP rats appeared to be directly related to the COP genetic resistance controlled by the Mcs genes. Ionizing radiation did, however, induce papillary carcinomas in all the three strains of rats. These carcinomas were more differentiated than MNU-induced cancers with regard to the two mammary differentiation markers, rat milk fat globule membrane (R-MFGM) and {alpha}-smooth muscle actin ({alpha}-SMA). Furthermore, ionizing radiation but not MNU induced mammary adenomas in all three strains, especially in COP rats. Such adenomas had differentiation marker profiles similar to these of carcinomas induced by {sup 60}Co gamma rays. When transplanted into syngenic hosts, growth of adenomas was 17 {beta}-estradiol (E{sub 2})-dependent and they progressed to carcinomas. Furthermore, one microcarcinoma was observed to develop from adenoma tissue in a radiation-exposed COP rat. The findings suggest that radiation and chemical carcinogens are likely to induce mammary cancers through different pathways or from different cell populations. The induction of relatively high incidences of mammary carcinomas and adenomas by radiation in COP rats may correlate with the genetically modulated and highly differentiated physiological status of their mammary glands. (author)

Genetics and genomics of susceptibility and immune response to necrotic enteritis in chicken: a review.

Science.gov (United States)

Zahoor, Imran; Ghayas, Abdul; Basheer, Atia

2018-02-01

Global poultry production is facing many challenges and is currently under pressure due to the presence of several diseases like Necrotic Enteritis (NE). It is estimated that NE-caused global economic losses has increased from 2 billion to 6 billion US$ in 2015 because it is not easy to diagnose and control disease at the earlier stage of occurrence. Additionally, ban on the in-feed antibiotics and some other genetic and non-genetic predisposing factors affect the occurrence of the disease. Though the incidence of the disease can be reduced by minimizing the predisposing factors and through immunization of birds but there is no single remedy to control the disease. Therefore, we suggest that there is need to find out the genetic variants that could help to select the birds resistant to NE. The current review details the pertinent features about the genetic and genomics of susceptibility and immune response of birds to Necrotic Enteritis. We report here the list of candidate gene reported for their involvement with the susceptibility and/or resistance to the disease. However, most of these genes are involved in immune-related functions. For better understanding of the role of Clostridium perfringens and its toxins in the pathogenesis of disease there is need to unveil the association between any specific genetic variation and clinical status of NE. However, the presence of substantial genetic variations among different breeds/strains of chicken shows that it is possible to develop broiler strain with genetic resistant against NE. It would help in the cost-effective and sustainable production of safe broiler meat.

Evaluating the association of allergies with multiple sclerosis susceptibility risk and disease activity in a pediatric population.

Science.gov (United States)

Bourne, Theresa; Waltz, Michael; Casper, T C; Kavak, K; Aaen, G; Belman, A; Benson, L; Candee, M; Chitnis, T; Graves, J; Greenberg, B; Gorman, M; Harris, Y; Krupp, L; Lotze, T; Mar, S; Ness, J; Olsen, C; Roalstad, S; Rodriguez, M; Rose, J; Rubin, J; Schreiner, T; Tillema, J M; Kahn, I; Waldman, A; Barcellos, L; Waubant, E; Weinstock-Guttman, B

2017-04-15

Multiple sclerosis (MS) and allergies are both considered to be related to imbalanced Th1 and Th2 immune responses. Previous studies evaluating the relationship between MS and allergies provide conflicting results. To assess allergies and asthma as risk factors for MS and as predictors of MS relapses in a pediatric cohort. The environment and genetic risk factors for pediatric MS study is a national case-control project with 16 participating US sites. An environmental questionnaire is used that includes history of allergies in the first five years of life. Case-control data are entered in the pediatric MS Network database and cases at 12 of the 16 sites enter relapse data prospectively. Annualized relapse rate was calculated for patients with follow-up and adjusted for age at disease onset, gender, race, ethnicity, and use of disease-modifying therapy (DMT). We included 271 cases (mean age at disease onset of 15.7years and 62% female) and 418 controls. Relapse data were available for 193 cases. There was no difference in prevalence of allergies or asthma between cases and controls. Patients with food allergies had fewer relapses compared to patients without food allergies (0.14 vs 0.48, p=0.01). While allergies and asthma are not associated with pediatric MS, cases with food allergies have fewer relapses compared to those without food allergies. Copyright © 2017 Elsevier B.V. All rights reserved.

Genetic susceptibility to HPV infection and cervical cancer

Directory of Open Access Journals (Sweden)

Maciag P.C.

1999-01-01

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.

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

Science.gov (United States)

Johnson, Wendy; Kyvik, Kirsten Ohm; Mortensen, Erik L; Skytthe, Axel; Batty, G David; Deary, Ian J

2010-04-01

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. 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 Short Form Health Survey. We used quantitative genetic models to examine how genetic and environmental variance in physical health differed with level of education, adjusting for birth-year effects. and Conclusions As expected, greater education was associated with better physical health. 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 less total variance in health primarily because there was less genetic variance. Education apparently reduced expression of genetic susceptibilities to poor health. The patterns of genetic and environmental correlations suggested that this might take place because more educated people manage their environments to protect their health. If so, fostering the personal charactieristics associated with educational attainment could be important in reducing the education-health gradient.

Radiological findings of community-acquired methicillin-resistant and methicillin-susceptible staphylococcus aureus pediatric pneumonia in Hawaii

International Nuclear Information System (INIS)

Erdem, Guliz; Bergert, Lora; Len, Kyra; Melish, Marian; Kon, Kevin; DiMauro, Robert

2010-01-01

Community-acquired Staphylococcus aureus (CA-SA) infections are common among pediatric patients in Hawaii. We wanted to characterize the radiological features of methicillin-susceptible (CA-MSSA) and methicillin-resistant (CA-MRSA) staphylococcal pneumonia in Hawaiian children. We retrospectively reviewed medical records and imaging studies of children with SA pneumonia identified from 1996 through 2007. Of 40 children, 26 (65%) had CA-MRSA pneumonia and 14 patients (35%) had CA-MSSA pneumonia. CA-MRSA patients were significantly younger than CA-MSSA patients (65% younger than 1 year vs. 36% older). In a majority (62%) of CA-MRSA patients, the consolidation was unilateral; in most of the CA-MSSA cases (79%), the consolidation was bilateral. Fifty percent of the patients with CA-MRSA and 21% of those with CA-MSSA had pneumatoceles (P = 0.1). CA-MRSA patients more commonly had pleural effusions (85% vs. 64% for CA-MSSA) and pleural thickening (50% vs. 36% for CA-MSSA). This case series describes the radiologic characteristics of CA-MRSA and CA-MSSA pneumonia in children in a highly endemic area. We found that CA-MRSA pneumonias are unilateral in a majority of pediatric pneumonia cases, are more common in children 1 year or younger, and have higher rates of complications in comparison to CA-MSSA patients. (orig.)

Radiological findings of community-acquired methicillin-resistant and methicillin-susceptible staphylococcus aureus pediatric pneumonia in Hawaii

Energy Technology Data Exchange (ETDEWEB)

Erdem, Guliz; Bergert, Lora; Len, Kyra; Melish, Marian [University of Hawaii, John A. Burns School of Medicine, Department of Pediatrics, Honolulu, HI (United States); Kon, Kevin; DiMauro, Robert [Kapiolani Medical Center for Women and Children, Department of Radiology, Honolulu, HI (United States)

2010-11-15

Community-acquired Staphylococcus aureus (CA-SA) infections are common among pediatric patients in Hawaii. We wanted to characterize the radiological features of methicillin-susceptible (CA-MSSA) and methicillin-resistant (CA-MRSA) staphylococcal pneumonia in Hawaiian children. We retrospectively reviewed medical records and imaging studies of children with SA pneumonia identified from 1996 through 2007. Of 40 children, 26 (65%) had CA-MRSA pneumonia and 14 patients (35%) had CA-MSSA pneumonia. CA-MRSA patients were significantly younger than CA-MSSA patients (65% younger than 1 year vs. 36% older). In a majority (62%) of CA-MRSA patients, the consolidation was unilateral; in most of the CA-MSSA cases (79%), the consolidation was bilateral. Fifty percent of the patients with CA-MRSA and 21% of those with CA-MSSA had pneumatoceles (P = 0.1). CA-MRSA patients more commonly had pleural effusions (85% vs. 64% for CA-MSSA) and pleural thickening (50% vs. 36% for CA-MSSA). This case series describes the radiologic characteristics of CA-MRSA and CA-MSSA pneumonia in children in a highly endemic area. We found that CA-MRSA pneumonias are unilateral in a majority of pediatric pneumonia cases, are more common in children 1 year or younger, and have higher rates of complications in comparison to CA-MSSA patients. (orig.)

Innate Susceptibility to Norovirus Infections Influenced by FUT2 Genotype in a United States Pediatric Population

Science.gov (United States)

Currier, Rebecca L.; Payne, Daniel C.; Staat, Mary A.; Selvarangan, Rangaraj; Shirley, S. Hannah; Halasa, Natasha; Boom, Julie A.; Englund, Janet A.; Szilagyi, Peter G.; Harrison, Christopher J.; Klein, Eileen J.; Weinberg, Geoffrey A.; Wikswo, Mary E.; Parashar, Umesh; Vinjé, Jan; Morrow, Ardythe L.

2015-01-01

Background. Norovirus is a leading cause of acute gastroenteritis (AGE). Noroviruses bind to gut histo-blood group antigens (HBGAs), but only 70%–80% of individuals have a functional copy of the FUT2 (“secretor”) gene required for gut HBGA expression; these individuals are known as “secretors.” Susceptibility to some noroviruses depends on FUT2 secretor status, but the population impact of this association is not established. Methods. From December 2011 to November 2012, active AGE surveillance was performed at 6 geographically diverse pediatric sites in the United States. Case patients aged <5 years were recruited from emergency departments and inpatient units; age-matched healthy controls were recruited at well-child visits. Salivary DNA was collected to determine secretor status and genetic ancestry. Stool was tested for norovirus by real-time reverse transcription polymerase chain reaction. Norovirus genotype was then determined by sequencing. Results. Norovirus was detected in 302 of 1465 (21%) AGE cases and 52 of 826 (6%) healthy controls. Norovirus AGE cases were 2.8-fold more likely than norovirus-negative controls to be secretors (P < .001) in a logistic regression model adjusted for ancestry, age, site, and health insurance. Secretors comprised all 155 cases and 21 asymptomatic infections with the most prevalent norovirus, GII.4. Control children of Meso-American ancestry were more likely than children of European or African ancestry to be secretors (96% vs 74%; P < .001). Conclusions. FUT2 status is associated with norovirus infection and varies by ancestry. GII.4 norovirus exclusively infected secretors. These findings are important to norovirus vaccine trials and design of agents that may block norovirus-HBGA binding. PMID:25744498

Parental genetic diversity of brown trout (Salmo trutta m. fario) brood stock affects offspring susceptibility to whirling disease.

Science.gov (United States)

Eszterbauer, Edit; Forró, Barbara; Tolnai, Zoltán; Guti, Csaba Ferenc; Zsigmond, Gergely; Hoitsy, György; Kallert, Dennis Marc

2015-03-03

Whirling disease, caused by the myxozoan parasite Myxobolus cerebralis, has high economical and ecological importance worldwide. Susceptibility to the disease varies considerably among salmonid species. In brown trout (Salmo trutta) the infection is usually subclinical with low mortality, which increases the risk of parasite dissemination, especially when farm fish are used for stocking natural habitats. The influence of intraspecific genetic differences (especially the level of homozygosity) on susceptibility is unknown. Therefore, we examined the possible correlations between parental genetic diversity and offspring susceptibility of brown trout stocks to whirling disease. Two brown trout brood stocks from a German and a Hungarian fish farm were genetically characterized using microsatellite and lineage-specific genetic markers. The individual inbreeding coefficient f and pairwise relatedness factor r were estimated based on eight microsatellite markers. Brood stock populations were divided into groups according to low and high f and r value estimates and subjected to selective fertilization. The offspring from these separate groups were exposed to M. cerebralis actinospores, and the infection prevalence and intensity was measured and statistically analysed. The analysis of phylogeographic lineage heritage revealed high heterogeneity in the Hungarian brood stock since > 50% of individuals were Atlantic-Danubian hybrids, while only pure Atlantic-descending specimens were detected in the German population. Based on f msat and r msat estimations, classified non-inbred (NIB), inbred (IB) and a group of closely related fish (REL) were created. The susceptibility of their offspring varied considerably. Although there was no significant difference in the prevalence of M. cerebralis infection, the mean intensity of infection differed significantly between NIB and IB groups. In REL and IB groups, a high variability was observed in infection intensity. No external

THE MITOCHONDRIAL PARADIGM FOR CARDIOVASCULAR DISEASE SUSCEPTIBILITY AND CELLULAR FUNCTION: A COMPLEMENTARY CONCEPT TO MENDELIAN GENETICS

OpenAIRE

Kryzwanski, David M.; Moellering, Douglas; Fetterman, Jessica L.; Dunham-Snary, Kimberly J.; Sammy, Melissa J.; Ballinger, Scott W.

2011-01-01

While there is general agreement that cardiovascular disease (CVD) development is influenced by a combination of genetic, environmental, and behavioral contributors, the actual mechanistic basis of how these factors initiate or promote CVD development in some individuals while others with identical risk profiles do not, is not clearly understood. This review considers the potential role for mitochondrial genetics and function in determining CVD susceptibility from the standpoint that the orig...

Pediatric imaging. Rapid fire questions and answers

International Nuclear Information System (INIS)

Quattromani, F.; Lampe, R.

2008-01-01

The book contains the following contributions: Airway, head, neck; allergy, immunology rheumatology; pediatric cardiac imaging; child abuse; chromosomal abnormalities; conscious sedation; contrast agents and radiation protection; pediatric gastrointestinal imaging; genetic disorders in infants and children; pediatric genitourinary imaging; pediatric hematology, oncology imaging; pediatric intenrventional radiology; metabolic and vitamin disorders; muscoskeletal disorders (osteoradiology); neonatology imaging; pediatric neuroimaging; imaging of the respiratory tract in infants and children; vascular anomalies

Pediatric imaging. Rapid fire questions and answers

Energy Technology Data Exchange (ETDEWEB)

Quattromani, F.; Lampe, R. (eds.) [Texas Tech Univ. Health Sciences Center, School of Medicine, Lubbock, TX (United States); Handal, G.A. [Texas Tech Univ. Health Sciences Center, School of Medicine, El Paso, TX (United States)

2008-07-01

The book contains the following contributions: Airway, head, neck; allergy, immunology rheumatology; pediatric cardiac imaging; child abuse; chromosomal abnormalities; conscious sedation; contrast agents and radiation protection; pediatric gastrointestinal imaging; genetic disorders in infants and children; pediatric genitourinary imaging; pediatric hematology, oncology imaging; pediatric intenrventional radiology; metabolic and vitamin disorders; muscoskeletal disorders (osteoradiology); neonatology imaging; pediatric neuroimaging; imaging of the respiratory tract in infants and children; vascular anomalies.

A prospective study of the impact of genetic susceptibility testing for BRCA1/2 or HNPCC on family relationships

NARCIS (Netherlands)

van Oostrom, Iris; Meijers-Heijboer, Hanne; Duivenvoorden, Hugo J.; Brocker-Vriends, Annette H. J. T.; van Asperen, Chhstl J.; Sijmons, Rolf H.; Seynaeve, Caroline; Van Gool, Arthur R.; Klijn, Jan G. M.; Riedijk, Samantha R.; van Dooren, Silvia; Tibben, Aad

This study assessed the impact of genetic testing for cancer susceptibility on family relationships and determinants of adverse consequences for family relationships. Applicants for genetic testing of a known familial pathogenic mutation in BRCA1/2 or a HNPCC related gene (N = 271) rated the

A prospective study of the impact of genetic susceptibility testing for BRCA1/2 or HNPCC on family relationships

NARCIS (Netherlands)

van Oostrom, Iris; Meijers-Heijboer, Hanne; Duivenvoorden, Hugo J.; Bröcker-Vriends, Annette H. J. T.; van Asperen, Christi J.; Sijmons, Rolf H.; Seynaeve, Caroline; van Gool, Arthur R.; Klijn, Jan G. M.; Riedijk, Samantha R.; van Dooren, Silvia; Tibben, Aad

2007-01-01

This study assessed the impact of genetic testing for cancer susceptibility on family relationships and determinants of adverse consequences for family relationships. Applicants for genetic testing of a known familial pathogenic mutation in BRCA1/2 or a HNPCC related gene (N=271) rated the

A prospective study of the impact of genetic susceptibility testing for BRCA1/2 or HNPCC on family relationships.

NARCIS (Netherlands)

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

2007-01-01

This study assessed the impact of genetic testing for cancer susceptibility on family relationships and determinants of adverse consequences for family relationships. Applicants for genetic testing of a known familial pathogenic mutation in BRCA1/2 or a HNPCC related gene (N=271) rated the

Genetic susceptibility factors for multiple chemical sensitivity revisited

DEFF Research Database (Denmark)

Berg, Nikolaj Drimer; Rasmussen, Henrik Berg; Linneberg, Allan

2010-01-01

of this 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......Multiple chemical sensitivity (MCS) is characterised by adverse effects due to exposure to low levels of chemical substances. Various genes, especially genes of importance to the metabolism of xenobiotic compounds, have been associated with MCS, but findings are inconsistent. The purpose...... significant (OR=1.2, p=0.28). Fast arylamine N-acetyltransferase 2 metaboliser status was associated with severity of chemical sensitivity only in the most severely affected group in the population sample (OR=3.1, p=0.04). The cholecystokinin 2 receptor allele with 21 CT repeats was associated with MCS when...

Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry

DEFF Research Database (Denmark)

Zhao, Zhiguo; Wen, Wanqing; Michailidou, Kyriaki

2016-01-01

PURPOSE: Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. METHODS: We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D suscept...

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

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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.

Genetic susceptibility to bone and soft tissue sarcomas: a field synopsis and meta-analysis.

Science.gov (United States)

Benna, Clara; Simioni, Andrea; Pasquali, Sandro; De Boni, Davide; Rajendran, Senthilkumar; Spiro, Giovanna; Colombo, Chiara; Virgone, Calogero; DuBois, Steven G; Gronchi, Alessandro; Rossi, Carlo Riccardo; Mocellin, Simone

2018-04-06

The genetic architecture of bone and soft tissue sarcomas susceptibility is yet to be elucidated. We aimed to comprehensively collect and meta-analyze the current knowledge on genetic susceptibility in these rare tumors. We conducted a systematic review and meta-analysis of the evidence on the association between DNA variation and risk of developing sarcomas through searching PubMed, The Cochrane Library, Scopus and Web of Science databases. To evaluate result credibility, summary evidence was graded according to the Venice criteria and false positive report probability (FPRP) was calculated to further validate result noteworthiness. Integrative analysis of genetic and eQTL (expression quantitative trait locus) data was coupled with network and pathway analysis to explore the hypothesis that specific cell functions are involved in sarcoma predisposition. We retrieved 90 eligible studies comprising 47,796 subjects (cases: 14,358, 30%) and investigating 1,126 polymorphisms involving 320 distinct genes. Meta-analysis identified 55 single nucleotide polymorphisms (SNPs) significantly associated with disease risk with a high (N=9), moderate (N=38) and low (N=8) level of evidence, findings being classified as noteworthy basically only when the level of evidence was high. The estimated joint population attributable risk for three independent SNPs (rs11599754 of ZNF365/EGR2 , rs231775 of CTLA4 , and rs454006 of PRKCG ) was 37.2%. We also identified 53 SNPs significantly associated with sarcoma risk based on single studies.Pathway analysis enabled us to propose that sarcoma predisposition might be linked especially to germline variation of genes whose products are involved in the function of the DNA repair machinery. We built the first knowledgebase on the evidence linking DNA variation to sarcomas susceptibility, which can be used to generate mechanistic hypotheses and inform future studies in this field of oncology.

Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension.

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Xu, Ke; Ma, Lu; Li, Yang; Wang, Fang; Zheng, Gu-Yan; Sun, Zhijun; Jiang, Feng; Chen, Yundai; Liu, Huirong; Dang, Aimin; Chen, Xi; Chun, Jerold; Tian, Xiao-Li

2015-09-01

Essential hypertension is a complex disease affected by genetic and environmental factors and serves as a major risk factor for cardiovascular diseases. Serum lysophosphatidic acid correlates with an elevated blood pressure in rats, and lysophosphatidic acid interacts with 6 subtypes of receptors. In this study, we assessed the genetic association of lysophosphatidic acid receptors with essential hypertension by genotyping 28 single-nucleotide polymorphisms from genes encoding for lysophosphatidic acid receptors, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 and their flanking sequences, in 3 Han Chinese cohorts consisting of 2630 patients and 3171 controls in total. We identified a single-nucleotide polymorphism, rs531003 in the 3'-flanking genomic region of LPAR1, associated with hypertension (the Bonferroni corrected P=1.09×10(-5), odds ratio [95% confidence interval]=1.23 [1.13-1.33]). The risk allele C of rs531003 is associated with the increased expression of LPAR1 and the susceptibility of hypertension, particularly in those with a shortage of sleep (P=4.73×10(-5), odds ratio [95% confidence interval]=1.75 [1.34-2.28]). We further demonstrated that blood pressure elevation caused by sleep deprivation and phenylephrine-induced vasoconstriction was both diminished in LPAR1-deficient mice. Together, we show that LPAR1 is a novel susceptibility gene for human essential hypertension and that stress, such as shortage of sleep, increases the susceptibility of patients with risk allele to essential hypertension. © 2015 American Heart Association, Inc.

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

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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.

Ethical, legal and social implications of prenatal and preimplantation genetic testing for cancer susceptibility.

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Wang, C-W; Hui, E C

2009-01-01

With the progress in cancer genetics and assisted reproductive technologies, it is now possible for cancer gene mutation carriers not only to reduce cancer mortality through the targeting of surveillance and preventive therapies, but also to avoid the birth of at-risk babies through the choice of different means of reproduction. Thus, the incidence of hereditary cancer syndromes may be decreased in the future. The integration of cancer genetic testing and assisted reproductive technologies raises certain ethical, legal and social issues beyond either genetic testing or assisted reproductive technology itself. In this paper, the reproductive decisions/choices of at-risk young couples and the ethical, legal and social concerns of prenatal genetic testing and preimplantation genetic diagnosis for susceptibility to hereditary cancer syndromes are discussed. Specifically, three ethical principles related to the integration of cancer genetic testing and assisted reproductive technologies, i.e. informed choice, beneficence to children and social justice, and their implications for the responsible translation of these medical techniques into common practice of preventive medicine are highlighted.

Susceptibility Genes in Thyroid Autoimmunity

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Yoshiyuki Ban

2005-01-01

Full Text Available The autoimmune thyroid diseases (AITD are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD and Hashimoto's thyroiditis (HT and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4 and thyroid specific genes (e.g. TSHR, Tg. Most likely, these loci interact and their interactions may influence disease phenotype and severity.

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

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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

Genetic and environmental determinants of the susceptibility of Amerindian derived populations for having hypertriglyceridemia

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Aguilar-Salinas, Carlos A.; Tusie-Luna, Teresa; Pajukanta, Päivi

2014-01-01

Here, we discuss potential explanations for the higher prevalence of hypertriglyceridemia in populations with an Amerindian background. Although environmental factors are the triggers, the search for the ethnic related factors that explains the increased susceptibility of the Amerindians is a promising area for research. The study of the genetics of hypertriglyceridemia in Hispanic populations faces several challenges. Ethnicity could be a major confounding variable to prove genetic associations. Despite that, the study of hypertriglyceridemia in Hispanics has resulted in significant contributions. Two GWAS reports have exclusively included Mexican mestizos. Fifty percent of the associations reported in Caucasians could be generalized to the Mexicans, but in many cases the Mexican lead SNP was different than that reported in Europeans. Both reports included new associations with apo B or triglycerides concentrations. The frequency of susceptibility alleles in Mexicans is higher than that found in Europeans for several of the genes with the greatest effect on triglycerides levels. An example is the SNP rs964184 in APOA5. The same trend was observed for ANGPTL3 and TIMD4 variants. In summary, we postulate that the study of the genetic determinants of hypertriglyceridemia in Amerindian populations which have major changes in their lifestyle, may prove to be a great resource to identify new genes and pathways associated with hypertriglyceridemia. PMID:24768220

Chymotrypsinogen C Genetic Variants, Including c.180TT, Are Strongly Associated With Chronic Pancreatitis in Pediatric Patients.

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Grabarczyk, Alicja Monika; Oracz, Grzegorz; Wertheim-Tysarowska, Katarzyna; Kujko, Aleksandra Anna; Wejnarska, Karolina; Kolodziejczyk, Elwira; Bal, Jerzy; Koziel, Dorota; Kowalik, Artur; Gluszek, Stanislaw; Rygiel, Agnieszka Magdalena

2017-12-01

Genetic studies in adults/adolescent patients with chronic pancreatitis (CP) identified chymotrypsinogen C (CTRC) genetic variants but their association with CP risk has been difficult to replicate. To evaluate the risk of CP associated with CTRC variants in CP pediatric patients-control study. The distribution of CTRC variants in CP pediatric cohort (n = 136, median age at CP onset 8 years) with no history of alcohol/smoking abuse was compared with controls (n = 401, median age 45). We showed that p.Arg254Trp (4.6%) and p.Lys247_Arg254del (5.3%) heterozygous mutations are frequent and significantly associated with CP risk in pediatric patients (odds ratio [OR] = 19.1; 95% CI 2.8-160; P = 0.001 and OR = 5.5; 95% CI 1.6-19.4; P = 0.001, respectively). For the first time, we demonstrated that the c.180TT genotype of common p.Gly60Gly variant is strong, an independent CP risk factor (OR = 23; 95% CI 7.7-70; P A variant, both CA and AA genotype, is significantly underrepresented in CP compared with controls (15% vs 35%; OR = 0.33; 95% CI 0.19-0.59; P risk factors. The c.493+51C>A variant may play a protective role against CP development.

Choosing the correct empirical antibiotic for urinary tract infection in pediatric: Surveillance of antimicrobial susceptibility pattern of Escherichia coli by E-Test method.

OpenAIRE

Iraj Sedighi; Abbas Solgi; Ali Amanati; Mohammad Yousef Alikhani

2014-01-01

Background and Objectives Urinary Tract Infections (UTIs) are of the most common bacterial diseases worldwide. We investigate the antibiotic susceptibility patterns of Escherichia coli (E. coli) strains isolated from pediatric patients with community acquired urinary tract infection (UTI) to find a clinical guidance for choosing a right empirical antibiotic in these patients. Materials and Methods In this cross sectional study, 100 urine specimens which were positive for E. coli had been inve...

Genetic variants in MARCO are associated with the susceptibility to pulmonary tuberculosis in Chinese Han population.

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Mai-Juan Ma

Full Text Available BACKGROUND: Susceptibility to tuberculosis is not only determined by Mycobacterium tuberculosis infection, but also by the genetic component of the host. Macrophage receptor with a collagenous structure (MARCO is essential components required for toll like receptor-signaling in macrophage response to Mycobacterium tuberculosis, which may contribute to tuberculosis risk. PRINCIPAL FINDINGS: To specifically investigated whether single nucleotide polymorphisms (SNPs in MARCO gene are associated with pulmonary tuberculosis in Chinese Han population. By selecting tagging SNPs in MARCO gene, 17 tag SNPs were identified and genotyped in 923 pulmonary tuberculosis patients and 1033 healthy control subjects using a hospital based case-control association study. Single-point and haplotype analysis revealed an association in intron and exon region of MARCO gene. One SNP (rs17009726 was associated with susceptibility to pulmonary tuberculosis, where the carriers of the G allele had a 1.65 fold (95% CI = 1.32-2.05, p(corrected = 9.27E-5 increased risk of pulmonary tuberculosis. Haplotype analysis revealed that haplotype GC containing G allele of 17009726 and haplotype TGCC (rs17795618T/A, rs1371562G/T, rs6761637T/C, rs2011839C/T were also associated with susceptibility to pulmonary tuberculosis (p(corrected = 0.0001 and 0.029, respectively. CONCLUSIONS: Our study suggested that genetic variants in MARCO gene were associated with pulmonary tuberculosis susceptibility in Chinese Han population, and the findings emphasize the importance of MARCO mediated immune responses in the pathogenesis of tuberculosis.

Genetic profiles of ten Dirofilaria immitis isolates susceptible or resistant to macrocyclic lactone heartworm preventives

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Catherine Bourguinat

2017-11-01

Full Text Available Abstract Background For dogs and cats, chemoprophylaxis with macrocyclic lactone (ML preventives for heartworm disease is widely used in the United States and other countries. Since 2005, cases of loss of efficacy (LOE of heartworm preventives have been reported in the U.S. More recently, ML-resistant D. immitis isolates were confirmed. Previous work identified 42 genetic markers that could predict ML response in individual samples. For field surveillance, it would be more appropriate to work on microfilarial pools from individual dogs with a smaller subset of genetic markers. Methods MiSeq technology was used to identify allele frequencies with the 42 genetic markers previously reported. Microfilaria from ten well-characterized new isolates called ZoeKY, ZoeMI, ZoeGCFL, ZoeAL, ZoeMP3, ZoeMO, ZoeAMAL, ZoeLA, ZoeJYD-34, and Metairie were extracted from fresh blood from dogs. DNA were extracted and sequenced with MiSeq technology. Allele frequencies were calculated and compared with the previously reported susceptible, LOE, and resistant D. immitis populations. Results The allele frequencies identified in the current resistant and susceptible isolates were in accordance with the allele frequencies previously reported in related phenotypes. The ZoeMO population, a subset of the ZoeJYD-34 population, showed a genetic profile that was consistent with some reversion towards susceptibility compared with the parental ZoeJYD-34 population. The Random Forest algorithm was used to create a predictive model using different SNPs. The model with a combination of three SNPs (NODE_42411_RC, NODE_21554_RC, and NODE_45689 appears to be suitable for future monitoring. Conclusions MiSeq technology provided a suitable methodology to work with the microfilarial samples. The list of SNPs that showed good predictability for ML resistance was narrowed. Additional phenotypically well characterized D. immitis isolates are required to finalize the best set of SNPs to be

Antibiotic Susceptibility, Genetic Diversity, and the Presence of Toxin Producing Genes in Campylobacter Isolates from Poultry.

Science.gov (United States)

Lee, Jeeyeon; Jeong, Jiyeon; Lee, Heeyoung; Ha, Jimyeong; Kim, Sejeong; Choi, Yukyung; Oh, Hyemin; Seo, Kunho; Yoon, Yohan; Lee, Soomin

2017-11-17

This study examined antibiotic susceptibility, genetic diversity, and characteristics of virulence genes in Campylobacter isolates from poultry. Chicken ( n = 152) and duck ( n = 154) samples were collected from 18 wet markets in Korea. Campylobacter spp. isolated from the carcasses were identified by PCR. The isolated colonies were analyzed for antibiotic susceptibility to chloramphenicol, amikacin, erythromycin, tetracycline, ciprofloxacin, nalidixic acid, and enrofloxacin. The isolates were also used to analyze genetic diversity using the DiversiLab TM system and were tested for the presence of cytolethal distending toxin ( cdt ) genes. Campylobacter spp. were isolated from 45 poultry samples out of 306 poultry samples (14.7%) and the average levels of Campylobacter contamination were 22.0 CFU/g and 366.1 CFU/g in chicken and duck samples, respectively. Moreover, more than 90% of the isolates showed resistance to nalidixic acid and ciprofloxacin. Genetic correlation analysis showed greater than 95% similarity between 84.4% of the isolates, and three cdt genes ( cdtA , cdtB , and cdtC ) were present in 71.1% of Campylobacter isolates. These results indicate that Campylobacter contamination should be decreased to prevent and treat Campylobacter foodborne illness.

Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease

DEFF Research Database (Denmark)

Baillie, J. Kenneth; Bretherick, Andrew; Haley, Christopher S.

2018-01-01

Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcrip...

Causation of nervous system tumors in children: insights from traditional and genetically engineered animal models

International Nuclear Information System (INIS)

Rice, Jerry M.

2004-01-01

Pediatric neurogenic tumors include primitive neuroectodermal tumors (PNETs), especially medulloblastoma; ependymomas and choroid plexus papillomas; astrocytomas; retinoblastoma; and sympathetic neuroblastoma. Meningiomas and nerve sheath tumors, although uncommon in childhood, are also significant because they can result from exposures of children to ionizing radiation. Specific chromosomal loci and specific genes are related to each of these tumor types. Virtually all these genes appear to act as tumor suppressor genes, which are inactivated in tumor cells by mutations or by chromosomal loss. In genetically engineered mice, some genes that are clearly associated with specific human tumors (e.g., RB1 in retinoblastoma and NF2 in meningiomas and schwannomas) have no such effect. Other genetic constructs in mice involving the genes p53, ptc1, and Nf1 have produced tumors remarkably similar to some of the human pediatric neoplasms. Some of these tumors become clinically apparent after only a few weeks, while the mice are still juveniles, especially when two or more tumor suppressor genes are inactivated in the same genetic construct. Conversely, at least one genetic pathway in rodents involving point mutation in the coding region of a transforming gene (neu in malignant schwannomas) does not appear to operate in any human tumors. The nervous system is markedly susceptible to experimental carcinogenesis during early life in rodents, dogs, primates, and other nonhuman species, and there is no obvious reason why this generalization should not also apply to humans. However, except for therapeutic ionizing radiation, no physical, chemical, or biological cause of human pediatric nervous system tumors is known. The failure of experimental transplacental carcinogenesis to mirror human pediatric experience more closely may reflect the need for multiple mutational events in target cells, and for experimental carcinogens that are capable of causing the full spectrum of

THE MITOCHONDRIAL PARADIGM FOR CARDIOVASCULAR DISEASE SUSCEPTIBILITY AND CELLULAR FUNCTION: A COMPLEMENTARY CONCEPT TO MENDELIAN GENETICS

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Kryzwanski, David M.; Moellering, Douglas; Fetterman, Jessica L.; Dunham-Snary, Kimberly J.; Sammy, Melissa J.; Ballinger, Scott W.

2013-01-01

While there is general agreement that cardiovascular disease (CVD) development is influenced by a combination of genetic, environmental, and behavioral contributors, the actual mechanistic basis of how these factors initiate or promote CVD development in some individuals while others with identical risk profiles do not, is not clearly understood. This review considers the potential role for mitochondrial genetics and function in determining CVD susceptibility from the standpoint that the original features that molded cellular function were based upon mitochondrial-nuclear relationships established millions of years ago and were likely refined during prehistoric environmental selection events that today, are largely absent. Consequently, contemporary risk factors that influence our susceptibility to a variety of age-related diseases, including CVD were probably not part of the dynamics that defined the processes of mitochondrial – nuclear interaction, and thus, cell function. In this regard, the selective conditions that contributed to cellular functionality and evolution should be given more consideration when interpreting and designing experimental data and strategies. Finally, future studies that probe beyond epidemiologic associations are required. These studies will serve as the initial steps for addressing the provocative concept that contemporary human disease susceptibility is the result of selection events for mitochondrial function that increased chances for prehistoric human survival and reproductive success. PMID:21647091

Evaluation of shared genetic susceptibility loci between autoimmune diseases and schizophrenia based on genome-wide association studies

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Hoeffding, Louise K E; Rosengren, Anders; Thygesen, Johan H

2017-01-01

Background: Epidemiological studies have documented higher than expected comorbidity (or, in some cases, inverse comorbidity) between schizophrenia and several autoimmune disorders. It remains unknown whether this comorbidity reflects shared genetic susceptibility loci.  Aims: The present study a...

Journal of Genetics | Indian Academy of Sciences

Indian Academy of Sciences (India)

Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus; Department of Pediatrics, Iasis Hospital, 8036 Paphos, Cyprus; Department of Clinical Genetics, The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus; Department of Pediatrics, ...

Identification of Genetic Susceptibility to Childhood Cancer through Analysis of Genes in Parallel

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Plon, Sharon E.; Wheeler, David A.; Strong, Louise C.; Tomlinson, Gail E.; Pirics, Michael; Meng, Qingchang; Cheung, Hannah C.; Begin, Phyllis R.; Muzny, Donna M.; Lewis, Lora; Biegel, Jaclyn A.; Gibbs, Richard A.

2011-01-01

Clinical cancer genetic susceptibility analysis typically proceeds sequentially beginning with the most likely causative gene. The process is time consuming and the yield is low particularly for families with unusual patterns of cancer. We determined the results of in parallel mutation analysis of a large cancer-associated gene panel. We performed deletion analysis and sequenced the coding regions of 45 genes (8 oncogenes and 37 tumor suppressor or DNA repair genes) in 48 childhood cancer patients who also (1) were diagnosed with a second malignancy under age 30, (2) have a sibling diagnosed with cancer under age 30 and/or (3) have a major congenital anomaly or developmental delay. Deleterious mutations were identified in 6 of 48 (13%) families, 4 of which met the sibling criteria. Mutations were identified in genes previously implicated in both dominant and recessive childhood syndromes including SMARCB1, PMS2, and TP53. No pathogenic deletions were identified. This approach has provided efficient identification of childhood cancer susceptibility mutations and will have greater utility as additional cancer susceptibility genes are identified. Integrating parallel analysis of large gene panels into clinical testing will speed results and increase diagnostic yield. The failure to detect mutations in 87% of families highlights that a number of childhood cancer susceptibility genes remain to be discovered. PMID:21356188

Genetic susceptibility markers for a breast-colorectal cancer phenotype: Exploratory results from genome-wide association studies

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Joon, Aron; Brewster, Abenaa M.; Chen, Wei V.; Eng, Cathy; Shete, Sanjay; Casey, Graham; Schumacher, Fredrick; Lin, Yi; Harrison, Tabitha A.; White, Emily; Ahsan, Habibul; Andrulis, Irene L.; Whittemore, Alice S.; Ko Win, Aung; Schmidt, Daniel F.; Kapuscinski, Miroslaw K.; Ochs-Balcom, Heather M.; Gallinger, Steven; Jenkins, Mark A.; Newcomb, Polly A.; Lindor, Noralane M.; Peters, Ulrike; Amos, Christopher I.; Lynch, Patrick M.

2018-01-01

Background Clustering of breast and colorectal cancer has been observed within some families and cannot be explained by chance or known high-risk mutations in major susceptibility genes. Potential shared genetic susceptibility between breast and colorectal cancer, not explained by high-penetrance genes, has been postulated. We hypothesized that yet undiscovered genetic variants predispose to a breast-colorectal cancer phenotype. Methods To identify variants associated with a breast-colorectal cancer phenotype, we analyzed genome-wide association study (GWAS) data from cases and controls that met the following criteria: cases (n = 985) were women with breast cancer who had one or more first- or second-degree relatives with colorectal cancer, men/women with colorectal cancer who had one or more first- or second-degree relatives with breast cancer, and women diagnosed with both breast and colorectal cancer. Controls (n = 1769), were unrelated, breast and colorectal cancer-free, and age- and sex- frequency-matched to cases. After imputation, 6,220,060 variants were analyzed using the discovery set and variants associated with the breast-colorectal cancer phenotype at Pcolorectal cancer phenotype in the discovery and replication data (most significant; rs7430339, Pdiscovery = 1.2E-04; rs7429100, Preplication = 2.8E-03). In meta-analysis of the discovery and replication data, the most significant association remained at rs7429100 (P = 1.84E-06). Conclusion The results of this exploratory analysis did not find clear evidence for a susceptibility locus with a pleiotropic effect on hereditary breast and colorectal cancer risk, although the suggestive association of genetic variation in the region of ROBO1, a potential tumor suppressor gene, merits further investigation. PMID:29698419

Prognostic factors for hereditary cancer distress six months after BRCA1/2 or HNPCC genetic susceptibility testing

NARCIS (Netherlands)

van Oostrom, Iris; Meijers-Heijboer, Hanne; Duivenvoorden, Hugo J.; Brocker-Vriends, Annette H. J. T.; van Asperen, Christi J.; Sijmons, Rolf H.; Seynaeve, Caroline; Van Gool, Arthur R.; Klijn, Jan G. M.; Tibben, Aad

This study explored predictors for hereditary cancer distress six months after genetic susceptibility testing for a known familial BRCA1/2 or HNPCC related mutation, in order to gain insight into aspects relevant for the identification of individuals needing additional psychosocial support. Coping,

Peroxisome Proliferator-Activated Receptor Genetic Polymorphisms and Nonalcoholic Fatty Liver Disease: Any Role in Disease Susceptibility?

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Paola Dongiovanni

2013-01-01

Full Text Available Nonalcoholic fatty liver disease (NAFLD defines a wide spectrum of liver diseases that extend from simple steatosis, that is, increased hepatic lipid content, to nonalcoholic steatohepatitis (NASH, a condition that may progress to cirrhosis with its associated complications. Nuclear hormone receptors act as intracellular lipid sensors that coordinate genetic networks regulating lipid metabolism and energy utilization. This family of transcription factors, in particular peroxisome proliferator-activated receptors (PPARs, represents attractive drug targets for the management of NAFLD and NASH, as well as related conditions such as type 2 diabetes and the metabolic syndrome. The impact on the regulation of lipid metabolism observed for PPARs has led to the hypothesis that genetic variants within the human PPARs genes may be associated with human disease such as NAFLD, the metabolic syndrome, and/or coronary heart disease. Here we review the available evidence on the association between PPARs genetic polymorphism and the susceptibility to NAFLD and NASH, and we provide a meta-analysis of the available evidence. The impact of PPAR variants on the susceptibility to NASH in specific subgroup of patients, and in particular on the response to therapies, especially those targeting PPARs, represents promising new areas of investigation.

Leveraging ethnic group incidence variation to investigate genetic susceptibility to glioma: A novel candidate SNP approach

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Daniel Ian Jacobs

2012-10-01

Full Text Available Objectives: Using a novel candidate SNP approach, we aimed to identify a possible genetic basis for the higher glioma incidence in Whites relative to East Asians and African-Americans. Methods: We hypothesized that genetic regions containing SNPs with extreme differences in allele frequencies across ethnicities are most likely to harbor susceptibility variants. We used International HapMap Project data to identify 3,961 candidate SNPs with the largest allele frequency differences in Whites compared to East Asians and Africans and tested these SNPs for association with glioma risk in a set of White cases and controls. Top SNPs identified in the discovery dataset were tested for association with glioma in five independent replication datasets. Results: No SNP achieved statistical significance in either the discovery or replication datasets after accounting for multiple testing. However, the most strongly associated SNP, rs879471, was found to be in linkage disequilibrium with a previously identified risk SNP, rs6010620, in RTEL1. We estimate rs6010620 to account for a glioma incidence rate ratio of 1.34 for Whites relative to East Asians. Conclusions: We explored genetic susceptibility to glioma using a novel candidate SNP method which may be applicable to other diseases with appropriate epidemiologic patterns.

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 - others: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

Genetic polymorphisms in Toll-like receptors among pediatric patients with renal parenchymal infections of different clinical severities.

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Chi-Hui Cheng

Full Text Available BACKGROUND: Although several studies have suggested single gene defects or variations in the genes associated with host immune response could confer differences in susceptibility to urinary pathogen invasion, no studies have examined the genetic polymorphisms in various toll-like receptors (TLRs that activate innate immune responses in pediatric renal parenchymal infections of different clinical severities, namely acute pyelonephritis and the clinically more severe disease, acute lobar nephronia. METHODOLOGY: Patients who fulfilled the diagnostic criteria for acute pyelonephritis (APN and acute lobar nephronia (ALN without underlying diseases or structural anomalies, except for vesicoureteral reflux (VUR, were enrolled. Genotyping of the single nucleotide polymorphisms (SNPs in the genes encoding TLR-1, TLR-2, TLR-4, TLR-5, and TLR-6 was performed by matrix-assisted laser desorption/ionization time-of-flight-based mini-sequencing analysis. PRINCIPAL FINDINGS: A total of 16 SNPs were selected for genotyping. Analysis of 96 normal and 48 patients' samples revealed that only four SNPs had heterozygosity rates >0.01. These SNPs were selected for further investigation. Hardy-Weinberg equilibrium was satisfied for the observed genotype frequencies. Statistically significant differences in the genotype frequency of TLR-2 (rs3804100, T1350C between controls and ALN or (APN+ALN combined group were identified using the recessive model with the correction for multiple-SNP testing. Further genotype pattern frequency analysis in TLR-2 SNPs (rs3804099 and rs3804100 showed significantly reduced occurrence of the rare allele homozygote (CC+CC in the no-VUR subgroup of APN and ALN cases. CONCLUSIONS: As the inflammatory responses in ALN patients are more severe than those in APN patients (higher CRP levels, longer duration of fever after antibiotic treatment, these findings suggest that the genetic variant in TLR-2 (rs3804100, T1350C may protect the host from

Isotretinoin as a Possible Environmental Trigger to Autoimmunity in Genetically Susceptible Patients

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Jocelyn Nugroho

2017-01-01

Full Text Available Introduction. Isotretinoin is commonly used to treat cystic acne. Definitive mechanisms of action for isotretinoin are not known though despite many side effects having been documented. Various case reports have noted autoimmune diseases succeeding isotretinoin treatment. Case Report. A 16-year-old female presents with symptoms of tremors, lack of focus, sleeplessness, emotional liability, bulging eyes, loose stools, heat intolerance, and missed menstrual periods. Symptoms manifested shortly after the patient finished a course of oral isotretinoin treatment for acne. Physical exam showed resting tremors, bilateral proptosis, hyperactivity, and rapid speech. A diagnosis of Graves’ Disease was made by correlating symptoms, physical exam findings, ultrasound, and positive family history of autoimmune thyroid disease. Conclusion. Emergence of autoimmune thyroid diseases depends upon genetic predisposition and environmental triggers. Mechanism of action for isotretinoin is not known but the drug may play a role in triggering autoimmunity in genetically susceptible individuals.

T-cell receptor variable genes and genetic susceptibility to celiac disease: an association and linkage study.

Science.gov (United States)

Roschmann, E; Wienker, T F; Gerok, W; Volk, B A

1993-12-01

Genetic susceptibility of celiac disease is primarily associated with a particular combination of and HLA-DQA1/DQB1 gene; however, this does not fully account for the genetic predisposition. Therefore, the aim of this study was to examine whether T-cell receptor (TCR) genes may be susceptibility genes in celiac disease. HLA class II typing was performed by polymerase chain reaction amplification in combination with sequence-specific oligonucleotide hybridization. TCR alpha (TCRA), TCR gamma (TCRG), and TCR beta (TCRB) loci were investigated by restriction fragment length polymorphism analysis. Allelic frequencies of TCRA, TCRG, and TCRB variable genes were compared between patients with celiac disease (n = 53) and control patients (n = 67), and relative risk (RR) estimates were calculated. The RR was 1.67 for allele C1 at TCRA1, 3.35 for allele D2 at TCRA2, 1.66 for allele B2 at TCRG, and 1.35 for allele B at TCRB, showing no significant association. Additionally, linkage analysis was performed in 23 families. The logarithm of odd scores for celiac disease vs. the TCR variable genes at TCRA, TCRG, and TCRB showed no significant linkage. These data suggest that the analyzed TCR variable gene segments V alpha 1.2, V gamma 11, and V beta 8 do not play a major role in susceptibility to celiac disease.

Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

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Zhao, Zhiguo; Wen, Wanqing; Michailidou, Kyriaki; Bolla, Manjeet K; Wang, Qin; Zhang, Ben; Long, Jirong; Shu, Xiao-Ou; Schmidt, Marjanka K; Milne, Roger L; García-Closas, Montserrat; Chang-Claude, Jenny; Lindstrom, Sara; Bojesen, Stig E; Ahsan, Habibul; Aittomäki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W; Beeghly-Fadiel, Alicia; Benitez, Javier; Blomqvist, Carl; Bogdanova, Natalia V; Børresen-Dale, Anne-Lise; Brand, Judith; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Cai, Qiuyin; Casey, Graham; Chenevix-Trench, Georgia; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Dörk, Thilo; Dumont, Martine; Fasching, Peter A; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Fostira, Florentia; Gammon, Marilie; Giles, Graham G; Guénel, Pascal; Haiman, Christopher A; Hamann, Ute; Harrington, Patricia; Hartman, Mikael; Hooning, Maartje J; Hopper, John L; Jakubowska, Anna; Jasmine, Farzana; John, Esther M; Johnson, Nichola; Kabisch, Maria; Khan, Sofia; Kibriya, Muhammad; Knight, Julia A; Kosma, Veli-Matti; Kriege, Mieke; Kristensen, Vessela; Le Marchand, Loic; Lee, Eunjung; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Luben, Robert; Lubinski, Jan; Malone, Kathleen E; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; McLean, Catriona; Meijers-Heijboer, Hanne; Meindl, Alfons; Miao, Hui; Muir, Kenneth; Neuhausen, Susan L; Nevanlinna, Heli; Neven, Patrick; Olson, Janet E; Perkins, Barbara; Peterlongo, Paolo; Phillips, Kelly-Anne; Pylkäs, Katri; Rudolph, Anja; Santella, Regina; Sawyer, Elinor J; Schmutzler, Rita K; Schoemaker, Minouk; Shah, Mitul; Shrubsole, Martha; Southey, Melissa C; Swerdlow, Anthony J; Toland, Amanda E; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Ursin, Giske; Van Der Luijt, Rob B; Verhoef, Senno; Wang-Gohrke, Shan; Whittemore, Alice S; Winqvist, Robert; Pilar Zamora, M; Zhao, Hui; Dunning, Alison M; Simard, Jacques; Hall, Per; Kraft, Peter; Pharoah, Paul; Hunter, David; Easton, Douglas F; Zheng, Wei

2016-05-01

Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies. The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.

Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa

Science.gov (United States)

Tosh, Kerrie; Campbell, Sarah J.; Fielding, Katherine; Sillah, Jackson; Bah, Boubacar; Gustafson, Per; Manneh, Kebba; Lisse, Ida; Sirugo, Giorgio; Bennett, Steve; Aaby, Peter; McAdam, Keith P. W. J.; Bah-Sow, Oumou; Lienhardt, Christian; Kramnik, Igor; Hill, Adrian V. S.

2006-01-01

The sst1 locus has been identified in a mouse model to control resistance and susceptibility of Mycobacterium tuberculosis infection. Subsequent studies have now identified Ipr1 (intracellular pathogen resistance 1) to be the gene responsible. Ipr1 is encoded within the sst1 locus and is expressed in the tuberculosis lung lesions and macrophages of sst1-resistant, but not sst1-susceptible mice. We have therefore examined the closest human homologue of Ipr1, SP110, for its ability to control susceptibility to M. tuberculosis infection in humans. In a study of families from The Gambia we have identified three polymorphisms that are associated with disease. On examination of additional families from Guinea-Bissau and the Republic of Guinea, two of these associations were independently replicated. These variants are in strong linkage disequilibrium with each other and lie within a 31-kb block of low haplotypic diversity, suggesting that a polymorphism within this region has a role in genetic susceptibility to tuberculosis in humans. PMID:16803959

Genetic susceptibility factors for alcohol-induced chronic pancreatitis.

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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. Copyright © 2015 IAP and EPC. Published by Elsevier B.V. All rights reserved.

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

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study.

Science.gov (United States)

Kasperaviciūte, Dalia; Catarino, Claudia B; Heinzen, Erin L; Depondt, Chantal; Cavalleri, Gianpiero L; Caboclo, Luis O; Tate, Sarah K; Jamnadas-Khoda, Jenny; Chinthapalli, Krishna; Clayton, Lisa M S; Shianna, Kevin V; Radtke, Rodney A; Mikati, Mohamad A; Gallentine, William B; Husain, Aatif M; Alhusaini, Saud; Leppert, David; Middleton, Lefkos T; Gibson, Rachel A; Johnson, Michael R; Matthews, Paul M; Hosford, David; Heuser, Kjell; Amos, Leslie; Ortega, Marcos; Zumsteg, Dominik; Wieser, Heinz-Gregor; Steinhoff, Bernhard J; Krämer, Günter; Hansen, Jörg; Dorn, Thomas; Kantanen, Anne-Mari; Gjerstad, Leif; Peuralinna, Terhi; Hernandez, Dena G; Eriksson, Kai J; Kälviäinen, Reetta K; Doherty, Colin P; Wood, Nicholas W; Pandolfo, Massimo; Duncan, John S; Sander, Josemir W; Delanty, Norman; Goldstein, David B; Sisodiya, Sanjay M

2010-07-01

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio<1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.

Genetic Variation between Biomphalaria alexandrina Snails Susceptible and Resistant to Schistosoma mansoni Infection

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Suzanne M. F. El-Nassery

2013-01-01

Full Text Available Much effort has been made to control schistosomiasis infection in Egypt. However, enduring effects from such strategies have not yet been achieved. In this study, we sought to determine the genetic variability related to the interaction between Biomphalaria alexandrina snails and Schistosoma mansoni. Using RAPD-PCR with eight (10 mers random primers, we were able to determine the polymorphic markers that differed between snails susceptible and resistant to Schistosoma mansoni infection using five primers out of the eight. Our results suggest that the RAPD-PCR technique is an efficient means by which to compare genomes and to detect genetic variations between schistosomiasis intermediate hosts. The RAPD technique with the above-noted primers can identify genomic markers that are specifically related to the Biomphalaria alexandrina/Schistosoma mansoni relationship in the absence of specific nucleotide sequence information. This approach could be used in epidemiologic surveys to investigate genetic diversity among Biomphalaria alexandrina snails. The ability to determine resistant markers in Biomphalaria alexandrina snails could potentially lead to further studies that use refractory snails as agents to control the spread of schistosomiasis.

Pediatric epilepsy: The Indian experience.

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Gadgil, Pradnya; Udani, Vrajesh

2011-10-01

Epilepsy is a common clinical entity in neurology clinics. The understanding of the genetics of epilepsy has undergone a sea change prompting re-classification by the International league against epilepsy recently. The prevalence rates of epilepsy in India are similar to those of developed nations. However, the large treatment gap is a major challenge to our public health system. Perinatal injuries are a major causative factor in pediatric group. We have discussed a few common etiologies such as neurocysticercosis and newer genetic epilepsy syndromes. We have also briefly touched upon the Indian experience in pediatric epilepsy surgery.

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

International Nuclear Information System (INIS)

Zahedi, F.D.; Rahman, R.A.; Abdullah, A.

2015-01-01

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)

Genetic Predictions of Prion Disease Susceptibility in Carnivore Species Based on Variability of the Prion Gene Coding Region

Science.gov (United States)

Stewart, Paula; Campbell, Lauren; Skogtvedt, Susan; Griffin, Karen A.; Arnemo, Jon M.; Tryland, Morten; Girling, Simon; Miller, Michael W.; Tranulis, Michael A.; Goldmann, Wilfred

2012-01-01

Mammalian species vary widely in their apparent susceptibility to prion diseases. For example, several felid species developed prion disease (feline spongiform encephalopathy or FSE) during the bovine spongiform encephalopathy (BSE) epidemic in the United Kingdom, whereas no canine BSE cases were detected. Whether either of these or other groups of carnivore species can contract other prion diseases (e.g. chronic wasting disease or CWD) remains an open question. Variation in the host-encoded prion protein (PrPC) largely explains observed disease susceptibility patterns within ruminant species, and may explain interspecies differences in susceptibility as well. We sequenced and compared the open reading frame of the PRNP gene encoding PrPC protein from 609 animal samples comprising 29 species from 22 genera of the Order Carnivora; amongst these samples were 15 FSE cases. Our analysis revealed that FSE cases did not encode an identifiable disease-associated PrP polymorphism. However, all canid PrPs contained aspartic acid or glutamic acid at codon 163 which we propose provides a genetic basis for observed susceptibility differences between canids and felids. Among other carnivores studied, wolverine (Gulo gulo) and pine marten (Martes martes) were the only non-canid species to also express PrP-Asp163, which may impact on their prion diseases susceptibility. Populations of black bear (Ursus americanus) and mountain lion (Puma concolor) from Colorado showed little genetic variation in the PrP protein and no variants likely to be highly resistant to prions in general, suggesting that strain differences between BSE and CWD prions also may contribute to the limited apparent host range of the latter. PMID:23236380

Genetic predictions of prion disease susceptibility in carnivore species based on variability of the prion gene coding region.

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Paula Stewart

Full Text Available Mammalian species vary widely in their apparent susceptibility to prion diseases. For example, several felid species developed prion disease (feline spongiform encephalopathy or FSE during the bovine spongiform encephalopathy (BSE epidemic in the United Kingdom, whereas no canine BSE cases were detected. Whether either of these or other groups of carnivore species can contract other prion diseases (e.g. chronic wasting disease or CWD remains an open question. Variation in the host-encoded prion protein (PrP(C largely explains observed disease susceptibility patterns within ruminant species, and may explain interspecies differences in susceptibility as well. We sequenced and compared the open reading frame of the PRNP gene encoding PrP(C protein from 609 animal samples comprising 29 species from 22 genera of the Order Carnivora; amongst these samples were 15 FSE cases. Our analysis revealed that FSE cases did not encode an identifiable disease-associated PrP polymorphism. However, all canid PrPs contained aspartic acid or glutamic acid at codon 163 which we propose provides a genetic basis for observed susceptibility differences between canids and felids. Among other carnivores studied, wolverine (Gulo gulo and pine marten (Martes martes were the only non-canid species to also express PrP-Asp163, which may impact on their prion diseases susceptibility. Populations of black bear (Ursus americanus and mountain lion (Puma concolor from Colorado showed little genetic variation in the PrP protein and no variants likely to be highly resistant to prions in general, suggesting that strain differences between BSE and CWD prions also may contribute to the limited apparent host range of the latter.

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.

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

Pediatric hemiplegic migraine: susceptibility weighted and MR perfusion imaging abnormality

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Altinok, Deniz; Agarwal, Ajay [Children' s Hospital of Michigan, Department of Radiology, Detroit, MI (United States); Ascadi, Gyula; Luat, Aimee; Tapos, Daniela [Children' s Hospital of Michigan, Department of Neurology, Detroit, MI (United States)

2010-12-15

We report on an 11-year-old girl suffering from a typical attack of hemiplegic migraine with characteristic abnormalities in perfusion MR and susceptibility-weighted MR imaging findings. The imaging abnormalities were resolved 48 h after the attack. Susceptibility-weighted MR imaging findings correlated well with the MR perfusion, thus it can be used along with conventional MRI for evaluation of children with complex migraine attacks. Susceptibility-weighted MR imaging might have a diagnostic role in assessing the vascular events in hemiplegic migraine. (orig.)

Pediatric hemiplegic migraine: susceptibility weighted and MR perfusion imaging abnormality

International Nuclear Information System (INIS)

Altinok, Deniz; Agarwal, Ajay; Ascadi, Gyula; Luat, Aimee; Tapos, Daniela

2010-01-01

We report on an 11-year-old girl suffering from a typical attack of hemiplegic migraine with characteristic abnormalities in perfusion MR and susceptibility-weighted MR imaging findings. The imaging abnormalities were resolved 48 h after the attack. Susceptibility-weighted MR imaging findings correlated well with the MR perfusion, thus it can be used along with conventional MRI for evaluation of children with complex migraine attacks. Susceptibility-weighted MR imaging might have a diagnostic role in assessing the vascular events in hemiplegic migraine. (orig.)

Genetic variation of the riparian pioneer tree species populus nigra. II. Variation In susceptibility to the foliar rust melampsora larici-populina

Science.gov (United States)

Legionnet; Muranty; Lefevre

1999-04-01

Partial resistance of Populus nigra L. to three races of the foliar rust Melampsora larici-populina Kleb. was studied in a field trial and in laboratory tests, using a collection of P. nigra originating from different places throughout France. No total resistance was found. The partial resistance was split into epidemiological components, which proved to be under genetic control. Various patterns of association of epidemiological components values were found. Principal components analysis revealed their relationships. Only 24% of the variance of the field susceptibility could be explained by the variation of the epidemiological components of susceptibility. This variable was significantly correlated with susceptibility to the most ancient and widespread race of the pathogen, and with the variables related to the size of the lesions of the different races. Analysis of variance showed significant differences in susceptibility between regions and between stands within one region. Up to 20% of variation was between regions, and up to 22% between stands, so that these genetic factors appeared to be more differentiated than the neutral diversity (up to 3.5% Legionnet & Lefevre, 1996). However, no clear pattern of geographical distribution of diversity was detected.

Choosing the correct empirical antibiotic for urinary tract infection in pediatric: Surveillance of antimicrobial susceptibility pattern of Escherichia coli by E-Test method.

Science.gov (United States)

Sedighi, Iraj; Solgi, Abbas; Amanati, Ali; Alikhani, Mohammad Yousef

2014-12-01

Urinary Tract Infections (UTIs) are of the most common bacterial diseases worldwide. We investigate the antibiotic susceptibility patterns of Escherichia coli (E. coli) strains isolated from pediatric patients with community acquired urinary tract infection (UTI) to find a clinical guidance for choosing a right empirical antibiotic in these patients. In this cross sectional study, 100 urine specimens which were positive for E. coli had been investigated for antibiotics susceptibility pattern. The susceptibility to Co-trimoxazol (25μg), Amikacin (30μg), Ceftriaxone (30μg), Nalidixic Acid (30μg), Cefixime (5μg), and Nitrofurantoin (300μg) tested with Disk diffusion agar and MIC determined with the E-test. Mean age of patients was 38 Months. Girls had greater proportion than boys (74 versus 26%). In Disk diffusion method, 26% of the isolates were susceptible to cotrimoxazole. Susceptibility to amikacin, ceftriaxone, nitrofurantoin, nalidixic acid and cefixime was 94%, 66%, 97%, 62% and 52%, respectively. By E-Test method and according to CLSI criteria susceptibility for co-trimoxazol, amikacin, ceftriaxone and nalidixic acid was 37%, 97%, 67% and 50%, respectively. The highest percentage of agreement between Disk diffusion and E-Test method was found for amikacin (96%) and the lowest percentage for co-trimoxazole (89%). Treatment failure, prolonged or repeated hospitalization, increased costs of care, and increased mortality are some consequence of bacterial resistance in UTIs. Misuse of antibiotics in each geographic location directly affects antibiotic resistance pattern. In the treatment of UTI, proper selection of antimicrobial agents should be relevant to the bacterial susceptibility testing surveillance. According to our results, amikacin as an injectable drug and nitrofurantoin as an oral agent could be used as a drug of choice in our region for children with UTIs.

Inherited behavioral susceptibility to adiposity in infancy: a multivariate genetic analysis of appetite and weight in the Gemini birth cohort.

Science.gov (United States)

Llewellyn, Clare H; van Jaarsveld, Cornelia H M; Plomin, Robert; Fisher, Abigail; Wardle, Jane

2012-03-01

The behavioral susceptibility model proposes that inherited differences in traits such as appetite confer differential risk of weight gain and contribute to the heritability of weight. Evidence that the FTO gene may influence weight partly through its effects on appetite supports this model, but testing the behavioral pathways for multiple genes with very small effects is not feasible. Twin analyses make it possible to get a broad-based estimate of the extent of shared genetic influence between appetite and weight. The objective was to use multivariate twin analyses to test the hypothesis that associations between appetite and weight are underpinned by shared genetic effects. Data were from Gemini, a population-based birth cohort of twins (n = 4804) born in 2007. Infant weights at 3 mo were taken from the records of health professionals. Appetite was assessed at 3 mo for the milk-feeding period by using the Baby Eating Behaviour Questionnaire (BEBQ), a parent-reported measure of appetite [enjoyment of food, food responsiveness, slowness in eating (SE), satiety responsiveness (SR), and appetite size (AS)]. Multivariate quantitative genetic modeling was used to test for shared genetic influences. Significant correlations were found between all BEBQ traits and weight. Significant shared genetic influence was identified for weight with SE, SR, and AS; genetic correlations were between 0.22 and 0.37. Shared genetic effects explained 41-45% of these phenotypic associations. Differences in weight in infancy may be due partly to genetically determined differences in appetitive traits that confer differential susceptibility to obesogenic environments.

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.; Bröcker-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

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. Cancer-related distress, worry and risk perception were assessed in 271

Contact Dermatitis in Pediatrics.

Science.gov (United States)

Pelletier, Janice L; Perez, Caroline; Jacob, Sharon E

2016-08-01

Contact dermatitis is an umbrella term that describes the skin's reaction to contacted noxious or allergenic substances. The two main categories of contact dermatitis are irritant type and allergic type. This review discusses the signs, symptoms, causes, and complications of contact dermatitis. It addresses the testing, treatment, and prevention of contact dermatitis. Proper management of contact dermatitis includes avoidance measures for susceptible children. Implementation of a nickel directive (regulating the use of nickel in jewelry and other products that come into contact with the skin) could further reduce exposure to the most common allergens in the pediatric population. [Pediatr Ann. 2016;45(8):e287-e292.]. Copyright 2016, SLACK Incorporated.

Integrating genetic and toxicogenomic information for determining underlying susceptibility to developmental disorders.

Science.gov (United States)

Robinson, Joshua F; Port, Jesse A; Yu, Xiaozhong; Faustman, Elaine M

2010-10-01

To understand the complex etiology of developmental disorders, an understanding of both genetic and environmental risk factors is needed. Human and rodent genetic studies have identified a multitude of gene candidates for specific developmental disorders such as neural tube defects (NTDs). With the emergence of toxicogenomic-based assessments, scientists now also have the ability to compare and understand the expression of thousands of genes simultaneously across strain, time, and exposure in developmental models. Using a systems-based approach in which we are able to evaluate information from various parts and levels of the developing organism, we propose a framework for integrating genetic information with toxicogenomic-based studies to better understand gene-environmental interactions critical for developmental disorders. This approach has allowed us to characterize candidate genes in the context of variables critical for determining susceptibility such as strain, time, and exposure. Using a combination of toxicogenomic studies and complementary bioinformatic tools, we characterize NTD candidate genes during normal development by function (gene ontology), linked phenotype (disease outcome), location, and expression (temporally and strain-dependent). In addition, we show how environmental exposures (cadmium, methylmercury) can influence expression of these genes in a strain-dependent manner. Using NTDs as an example of developmental disorder, we show how simple integration of genetic information from previous studies into the standard microarray design can enhance analysis of gene-environment interactions to better define environmental exposure-disease pathways in sensitive and resistant mouse strains. © Wiley-Liss, Inc.

Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease.

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Baillie, J Kenneth; Bretherick, Andrew; Haley, Christopher S; Clohisey, Sara; Gray, Alan; Neyton, Lucile P A; Barrett, Jeffrey; Stahl, Eli A; Tenesa, Albert; Andersson, Robin; Brown, J Ben; Faulkner, Geoffrey J; Lizio, Marina; Schaefer, Ulf; Daub, Carsten; Itoh, Masayoshi; Kondo, Naoto; Lassmann, Timo; Kawai, Jun; Mole, Damian; Bajic, Vladimir B; Heutink, Peter; Rehli, Michael; Kawaji, Hideya; Sandelin, Albin; Suzuki, Harukazu; Satsangi, Jack; Wells, Christine A; Hacohen, Nir; Freeman, Thomas C; Hayashizaki, Yoshihide; Carninci, Piero; Forrest, Alistair R R; Hume, David A

2018-03-01

Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn's disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits.

Genetic variants of CD209 associated with Kawasaki disease susceptibility.

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Ho-Chang Kuo

Full Text Available BACKGROUND: Kawasaki disease (KD is a systemic vasculitis with unknown etiology mainly affecting children in Asian countries. Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN, CD209 in humans was showed to trigger an anti-inflammatory cascade and associated with KD susceptibility. This study was conducted to investigate the association between genetic polymorphisms of CD209 and the risk KD. METHODS: A total of 948 subjects (381 KD and 567 controls were recruited. Nine tagging SNPs (rs8112310, rs4804800, rs11465421, rs1544766, rs4804801, rs2287886, rs735239, rs735240, rs4804804 were selected for TaqMan allelic discrimination assay. Clinical phenotypes, coronary artery lesions (CAL and intravenous immunoglobulin (IVIG treatment outcomes were collected for analysis. RESULTS: Significant associations were found between CD209 polymorphisms (rs4804800, rs2287886, rs735240 and the risk of KD. Haplotype analysis for CD209 polymorphisms showed that A/A/G haplotype (P = 0.0002, OR = 1.61 and G/A/G haplotype (P = 0.0365, OR = 1.52 had higher risk of KD as compared with G/G/A haplotype in rs2287886/rs735239/rs735240 pairwise allele analysis. There were no significant association in KD with regards to CAL formation and IVIG treatment responses. CONCLUSION: CD209 polymorphisms were responsible for the susceptibility of KD, but not CAL formation and IVIG treatment responsiveness.

Genetic Variants of CD209 Associated with Kawasaki Disease Susceptibility

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Kuo, Ho-Chang; Huang, Ying-Hsien; Chien, Shu-Chen; Yu, Hong-Ren; Hsieh, Kai-Sheng; Hsu, Yu-Wen; Chang, Wei-Chiao

2014-01-01

Background Kawasaki disease (KD) is a systemic vasculitis with unknown etiology mainly affecting children in Asian countries. Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN, CD209) in humans was showed to trigger an anti-inflammatory cascade and associated with KD susceptibility. This study was conducted to investigate the association between genetic polymorphisms of CD209 and the risk KD. Methods A total of 948 subjects (381 KD and 567 controls) were recruited. Nine tagging SNPs (rs8112310, rs4804800, rs11465421, rs1544766, rs4804801, rs2287886, rs735239, rs735240, rs4804804) were selected for TaqMan allelic discrimination assay. Clinical phenotypes, coronary artery lesions (CAL) and intravenous immunoglobulin (IVIG) treatment outcomes were collected for analysis. Results Significant associations were found between CD209 polymorphisms (rs4804800, rs2287886, rs735240) and the risk of KD. Haplotype analysis for CD209 polymorphisms showed that A/A/G haplotype (P = 0.0002, OR = 1.61) and G/A/G haplotype (P = 0.0365, OR = 1.52) had higher risk of KD as compared with G/G/A haplotype in rs2287886/rs735239/rs735240 pairwise allele analysis. There were no significant association in KD with regards to CAL formation and IVIG treatment responses. Conclusion CD209 polymorphisms were responsible for the susceptibility of KD, but not CAL formation and IVIG treatment responsiveness. PMID:25148534

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

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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.

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.

Multidrug resistance in pediatric urinary tract infections.

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Gaspari, Romolo J; Dickson, Eric; Karlowsky, James; Doern, Gary

2006-01-01

Urinary tract infections (UTIs) represent a common infection in the pediatric population. Escherichia coli is the most common uropathogen in children, and antimicrobial resistance in this species complicates the treatment of pediatric UTIs. Despite the impact of resistance on empiric antibiotic choice, there is little data on multidrug resistance in pediatric patients. In this paper, we describe characteristics of multidrug-resistant E. coli in pediatric patients using a large national database of uropathogens antimicrobial sensitivities. Antimicrobial susceptibility patterns to commonly prescribed antibiotics were performed on uropathogens isolated from children presenting to participating hospitals between 1999 and 2001. Data were analyzed separately for four pediatric age groups. Single and multidrug resistance to ampicillin, amoxicillin-clavulanate, cefazolin, ciprofloxacin, nitrofurantoin, and trimethoprim-sulfamethoxazole (TMP-SMX) were performed on all specimens. There were a total of 11,341 E. coli urine cultures from 343 infants (0-4 weeks), 1,801 toddlers (5 weeks-24 months), 6,742 preteens (2-12 years), and 2,455 teens (13-17 years). E. coli resistance to ampicillin peaked in toddlers (52.8%) but was high in preteens (52.1%), infants (50.4%), and teens (40.6%). Resistance to two or more antibiotics varied across age groups, with toddlers (27%) leading preteens (23.1%), infants (21%), and teens (15.9%). Resistance to three or more antibiotics was low in all age groups (range 3.1-5.2%). The most common co-resistance in all age groups was ampicillin/TMP-SMZ. In conclusion, less than half of all pediatric UTIs are susceptible to all commonly used antibiotics. In some age groups, there is a significant percentage of co-resistance between the two most commonly used antibiotics (ampicillin and TMP-SMZ).

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

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

2014-01-01

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 (h2) 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 h2 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 possible and

Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies.

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Leu, Costin; de Kovel, Carolien G F; Zara, Federico; Striano, Pasquale; Pezzella, Marianna; Robbiano, Angela; Bianchi, Amedeo; Bisulli, Francesca; Coppola, Antonietta; Giallonardo, Anna Teresa; Beccaria, Francesca; Trenité, Dorothée Kasteleijn-Nolst; Lindhout, Dick; Gaus, Verena; Schmitz, Bettina; Janz, Dieter; Weber, Yvonne G; Becker, Felicitas; Lerche, Holger; Kleefuss-Lie, Ailing A; Hallman, Kerstin; Kunz, Wolfram S; Elger, Christian E; Muhle, Hiltrud; Stephani, Ulrich; Møller, Rikke S; Hjalgrim, Helle; Mullen, Saul; Scheffer, Ingrid E; Berkovic, Samuel F; Everett, Kate V; Gardiner, Mark R; Marini, Carla; Guerrini, Renzo; Lehesjoki, Anna-Elina; Siren, Auli; Nabbout, Rima; Baulac, Stephanie; Leguern, Eric; Serratosa, Jose M; Rosenow, Felix; Feucht, Martha; Unterberger, Iris; Covanis, Athanasios; Suls, Arvid; Weckhuysen, Sarah; Kaneva, Radka; Caglayan, Hande; Turkdogan, Dilsad; Baykan, Betul; Bebek, Nerses; Ozbek, Ugur; Hempelmann, Anne; Schulz, Herbert; Rüschendorf, Franz; Trucks, Holger; Nürnberg, Peter; Avanzini, Giuliano; Koeleman, Bobby P C; Sander, Thomas

2012-02-01

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31

Antibiotic Resistance in Pediatric Urinary Tract Infections.

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Stultz, Jeremy S; Doern, Christopher D; Godbout, Emily

2016-12-01

Urinary tract infections (UTIs) are a common problem in pediatric patients. Resistance to common antibiotic agents appears to be increasing over time, although resistance rates may vary based on geographic region or country. Prior antibiotic exposure is a pertinent risk factor for acquiring resistant organisms during a first UTI and recurrent UTI. Judicious prescribing of antibiotics for common pediatric conditions is needed to prevent additional resistance from occurring. Complex pediatric patients with histories of hospitalizations, prior antibiotic exposure, and recurrent UTIs are also at high risk for acquiring UTIs due to extended spectrum beta-lactamase-producing organisms. Data regarding the impact of in vitro antibiotic susceptibility testing interpretation on UTI treatment outcomes is lacking.

Recent progress in the genetics and epigenetics of paraoxonase: why it is relevant to children’s environmental health

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Holland, N; Lizarraga, D; Huen, K

2015-01-01

Purpose of review Children are more susceptible to exposures in utero and during early childhood that may result in developmental problems and chronic diseases. Novel discoveries in the field of molecular epidemiology which can help explain susceptibility to exposures and disease will be demonstrated using the multifunctional enzyme paraoxonase (PON1) as an example. Recent findings The broad PON1 variability in humans, partly due to differences in genetics and age, can confer differential susceptibility because this enzyme can detoxify organophosphate pesticides and has antioxidant properties. Epigenetics plays a significant role in the mediation of the effects of environmental exposure on human health and is hypothesized to be a major contributing factor to the early-life origins of adult disease. Studies highlighted in this review demonstrate the relationship of PON1 polymorphisms with microRNA binding in addition to a link between DNA methylation in the transcriptional regulatory region with changes in PON1 enzyme levels. Other important methodologies such as ancestry informative markers and lactonase activity can enhance studies involving PON1. Summary This PON1 model demonstrates that integrating genetic and epigenetic factors as well as other novel methodologies can improve our understanding of important susceptibility factors linked to pediatric disease. PMID:25635583

Privacy and ethics in pediatric environmental health research-part I: genetic and prenatal testing.

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Fisher, Celia B

2006-10-01

The pressing need for empirically informed public policies aimed at understanding and promoting children's health has challenged environmental scientists to modify traditional research paradigms and reevaluate their roles and obligations toward research participants. Methodologic approaches to children's environmental health research raise ethical challenges for which federal regulations may provide insufficient guidance. In this article I begin with a general discussion of privacy concerns and informed consent within pediatric environmental health research contexts. I then turn to specific ethical challenges associated with research on genetic determinants of environmental risk, prenatal studies and maternal privacy, and data causing inflicted insight or affecting the informational rights of third parties.

Pediatric Obesity: Etiology and Treatment

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Crocker, Melissa K.; Yanovski, Jack A.

2009-01-01

This paper reviews factors that contribute to excessive weight gain in children and outlines current knowledge regarding approaches for treating pediatric obesity. Virtually all of the known genetic causes of obesity primarily increase energy intake. Genes regulating the leptin signaling pathway are particularly important for human energy homeostasis. Obesity is a chronic disorder that requires long-term strategies for management. The foundation for all treatments for pediatric obesity remain...

Genetics of nonsyndromic obesity.

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Lee, Yung Seng

2013-12-01

Common obesity is widely regarded as a complex, multifactorial trait influenced by the 'obesogenic' environment, sedentary behavior, and genetic susceptibility contributed by common and rare genetic variants. This review describes the recent advances in understanding the role of genetics in obesity. New susceptibility loci and genetic variants are being uncovered, but the collective effect is relatively small and could not explain most of the BMI heritability. Yet-to-be identified common and rare variants, epistasis, and heritable epigenetic changes may account for part of the 'missing heritability'. Evidence is emerging about the role of epigenetics in determining obesity susceptibility, mediating developmental plasticity, which confers obesity risk from early life experiences. Genetic prediction scores derived from selected genetic variants, and also differential DNA methylation levels and methylation scores, have been shown to correlate with measures of obesity and response to weight loss intervention. Genetic variants, which confer susceptibility to obesity-related morbidities like nonalcoholic fatty liver disease, were also discovered recently. We can expect discovery of more rare genetic variants with the advent of whole exome and genome sequencing, and also greater understanding of epigenetic mechanisms by which environment influences genetic expression and which mediate the gene-environment interaction.

Genetic determinants of UV-susceptibility in non-melanoma skin cancer.

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Marleen M Welsh

Full Text Available A milieu of cytokines and signaling molecules are involved in the induction of UV-induced immune suppression and thus the etiology of non-melanoma skin cancer (NMSC. Targeting the UV-induced immunosuppression pathway, and using a large population based study of NMSC, we have investigated the risk associated with functional variants in 10 genes (IL10, IL4, IL4R, TNF, TNFR2, HTR2A, HRH2, IL12B, PTGS2, and HAL. The most prominent single genetic effect was observed for IL10. There was increasing risk for both basal cell carcinoma (BCC and squamous cell carcinoma (SCC with increasing number of variant IL10 haplotypes (BCC: p(trend = 0.0048; SCC: p(trend = 0.031. Having two IL10 GC haplotypes was associated with increased odds ratios of BCC and SCC (OR(BCC = 1.5, 95% CI 1.1-1.9; OR(SCC = 1.4, 95% CI 1.0-1.9, and these associations were largely confined to women (OR(BCC = 2.2, 95% CI 1.4-3.4; SCC: OR(SCC = 1.8, 95% CI 1.1-3.0. To examine how combinations of these variants contribute to risk of BCC and SCC, we used multifactor dimensionality reduction (MDR and classification and regression trees (CART. Results from both of these methods found that in men, a combination of skin type, burns, IL10, IL4R, and possibly TNFR2 were important in both BCC and SCC. In women, skin type, burns, and IL10 were the most critical risk factors in SCC, with risk of BCC involving these same factors plus genetic variants in HTR2A, IL12B and IL4R. These data suggest differential genetic susceptibility to UV-induced immune suppression and skin cancer risk by gender.

Bivariate threshold models for genetic evaluation of susceptibility to and ability to recover from mastitis in Danish Holstein cows.

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Welderufael, B G; Janss, L L G; de Koning, D J; Sørensen, L P; Løvendahl, P; Fikse, W F

2017-06-01

Mastitis in dairy cows is an unavoidable problem and genetic variation in recovery from mastitis, in addition to susceptibility, is therefore of interest. Genetic parameters for susceptibility to and recovery from mastitis were estimated for Danish Holstein-Friesian cows using data from automatic milking systems equipped with online somatic cell count measuring units. The somatic cell count measurements were converted to elevated mastitis risk, a continuous variable [on a (0-1) scale] indicating the risk of mastitis. Risk values >0.6 were assumed to indicate that a cow had mastitis. For each cow and lactation, the sequence of health states (mastitic or healthy) was converted to a weekly transition: 0 if the cow stayed within the same state and 1 if the cow changed state. The result was 2 series of transitions: one for healthy to diseased (HD, to model mastitis susceptibility) and the other for diseased to healthy (DH, to model recovery ability). The 2 series of transitions were analyzed with bivariate threshold models, including several systematic effects and a function of time. The model included effects of herd, parity, herd-test-week, permanent environment (to account for the repetitive nature of transition records from a cow) plus two time-varying effects (lactation stage and time within episode). In early lactation, there was an increased risk of getting mastitis but the risk remained stable afterwards. Mean recovery rate was 45% per lactation. Heritabilities were 0.07 [posterior mean of standard deviations (PSD) = 0.03] for HD and 0.08 (PSD = 0.03) for DH. The genetic correlation between HD and DH has a posterior mean of -0.83 (PSD = 0.13). Although susceptibility and recovery from mastitis are strongly negatively correlated, recovery can be considered as a new trait for selection. The Authors. Published by the Federation of Animal Science Societies and Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under

Antimicrobial susceptibility, risk factors and prevalence of bla cefotaximase, temoneira, and sulfhydryl variable genes among Escherichia coli in community-acquired pediatric urinary tract infection.

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Nisha, Kallyadan V; Veena, Shetty A; Rathika, Shenoy D; Vijaya, Shenoy M; Avinash, Shetty K

2017-01-01

The emergence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli has become an important challenge among pediatric patients with community-acquired urinary tract infection (UTI). The aim of this study was to assess the antimicrobial susceptibility patterns, associated risk factors and to survey the frequency of bla cefotaximase (CTX-M), bla temoneira (TEM), and bla sulfhydryl variable (SHV) genotypes in ESBL-producing E. coli isolated from children with community-acquired UTI. This was a prospective study conducted from November 2012 to March 2016 in a tertiary care center. E. coli isolated in urine cultures from children aged ≤18 years was identified and confirmed for ESBL production. ESBL-positive strains were screened for ESBL encoding genes. Chi-square test and Fisher's exact test were used to compare the difference in antibiotic susceptibility with respect to ESBL positive and negative, and binary logistic regression was used to identify the risk factors associated with ESBL production. Among 523 E. coli isolates, 196 (37.5%) were ESBL positive, >90% were resistant to cephalosporins, and 56% were resistant to fluoroquinolones. Least resistance was observed for imipenem, netilmicin, and nitrofurantoin (2%, 8.6%, 15.3%). Association between ESBL production and drug resistance was significant for ceftazidime ( P antibiotics were the common risk factors. ESBL-producing E. coli from community-acquired pediatric UTI carries more than one type of beta-lactamase coding genes correlating their increased antibiotic resistance. Aggressive infection control policy, routine screening for detecting ESBL isolates in clinical samples, and antimicrobial stewardship are the keys to prevent their dissemination in community settings.

Personalized Genetic Testing and Norovirus Susceptibility

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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.

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

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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.

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

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Ewelina Pośpiech

2015-01-01

Full Text Available 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.

Genetic variants of STAT4 are associated with ankylosing spondylitis susceptibility and severity in a Chinese Han population.

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Liu, Zhixiang; Zhang, Peisen; Dong, Jie

2014-01-01

Genetic factors play an important role in ankylosing spondylitis (AS) etiology and signal transducer and activator of transcription 4 (STAT4) gene polymorphisms may be involved. The aim of this study was to test whether STAT4 variants were associated with susceptibility to AS in a Chinese population. A total of 175 subjects who were diagnosed as AS and 249 healthy age-matched controls were enrolled in the present study. The rs7574865 G/T SNP in STAT4 gene was genotyped in all the subjects. The SPSS software was used to investigate the association between the rs7574865 genotypes and AS susceptibility or severity. Rs7574865 G/T was found to be significantly associated with increased risk and severity of AS. Our data demonstrated the STAT4 rs7574865 G/T SNP was significantly associated with increased AS susceptibility and severity in Chinese Han Population.

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

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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.

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

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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.

Association of Genetic Susceptibility Variants for Type 2 Diabetes with Breast Cancer Risk in Women of European Ancestry

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Zhao, Zhiguo; Wen, Wanqing; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Zhang, Ben; Long, Jirong; Shu, Xiao-Ou; Schmidt, Marjanka K.; Milne, Roger L.; García-Closas, Montserrat; Chang-Claude, Jenny; Lindstrom, Sara; Bojesen, Stig E.; Ahsan, Habibul; Aittomäki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Benitez, Javier; Blomqvist, Carl; Bogdanova, Natalia V.; Børresen-Dale, Anne-Lise; Brand, Judith; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Cai, Qiuyin; Casey, Graham; Chenevix-Trench, Georgia; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Dörk, Thilo; Dumont, Martine; Fasching, Peter A.; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Fostira, Florentia; Gammon, Marilie; Giles, Graham G.; Guénel, Pascal; Haiman, Christopher A.; Hamann, Ute; Harrington, Patricia; Hartman, Mikael; Hooning, Maartje J.; Hopper, John L.; Jakubowska, Anna; Jasmine, Farzana; John, Esther M.; Johnson, Nichola; Kabisch, Maria; Khan, Sofia; Kibriya, Muhammad; Knight, Julia A.; Kosma, Veli-Matti; Kriege, Mieke; Kristensen, Vessela; Le Marchand, Loic; Lee, Eunjung; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Luben, Robert; Lubinski, Jan; Malone, Kathleen E.; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; McLean, Catriona; Meijers-Heijboer, Hanne; Meindl, Alfons; Miao, Hui; Muir, Kenneth; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Olson, Janet E.; Perkins, Barbara; Peterlongo, Paolo; Phillips, Kelly-Anne; Pylkäs, Katri; Rudolph, Anja; Santella, Regina; Sawyer, Elinor J.; Schmutzler, Rita K.; Schoemaker, Minouk; Shah, Mitul; Shrubsole, Martha; Southey, Melissa C.; Swerdlow, Anthony J; Toland, Amanda E.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Ursin, Giske; Van Der Luijt, Rob B.; Verhoef, Senno; Wang-Gohrke, Shan; Whittemore, Alice S.; Winqvist, Robert; Zamora, M. Pilar; Zhao, Hui; Dunning, Alison M.; Simard, Jacques; Hall, Per; Kraft, Peter; Pharoah, Paul; Hunter, David; Easton, Douglas F.; Zheng, Wei

2016-01-01

Purpose Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. Methods We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (OR) and 95% confidence intervals (CI) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies. Results The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at P < 0.001), rs9939609 (FTO) (OR = 0.94, 95% CI = 0.92 – 0.95, P = 4.13E-13), rs7903146 (TCF7L2) (OR = 1.04, 95% CI = 1.02 – 1.06, P = 1.26E-05), and rs8042680 (PRC1) (OR = 0.97, 95% CI = 0.95 – 0.99, P = 8.05E-04). Conclusions We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk. PMID:27053251

Genetic variant of miR-4293 rs12220909 is associated with susceptibility to non-small cell lung cancer in a Chinese Han population.

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Lixia Fan

Full Text Available Non-small cell lung cancer is one of the most common cancers and the leading cause of cancer death worldwide. Genetic variants in regulatory regions of some miRNAs might be involved in non-small cell lung cancer susceptibility and survival. rs12220909 (G/C genetic polymorphism in miR-4293 has been shown to be associated with decreased risk of esophageal squamous cell carcinoma. However, the influence of rs12220909 genetic variation on non-small cell lung cancer susceptibility has not been reported. In order to evaluate the potential association between miR-4293 rs12220909 and non-small cell lung cancer risk in a Chinese population, we performed a case-control study among 998 non-small cell lung cancer cases and 1471 controls. The data shows that miR-4293 rs12220909 was significantly associated with decreased susceptibility to non-small cell lung cancer (GC vs.GG: OR = 0.681, 95%CI = 0.555-0.835, P = 2.19E-4; GG vs. GC+CC: OR = 0.687, 95%CI = 0.564-0.837, P = 1.95E-4, which indicates that rs12220909 in miR-4293 may play a significant role in the development of non-small cell lung cancer.

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

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...

Characterization of Shigella Strains by Plasmid Profile Analysis and Antibiotic Susceptibility Patterns in a Pediatric Hospital in Ahvaz

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Amin Sakhaei

2015-11-01

Full Text Available Background: High incidences of dysentery and diarrhea were reported in a pediatric hospital in Ahvaz, Iran during March to April, 2013. Objectives: A cross-sectional study was therefore undertaken to identify the causative agents. Patients and Methods: A total of 230 diarrhea samples were collected from the patients and analyzed by routine bacteriological methods. Bacterial identification, serological assay, antimicrobial susceptibility testing, extended spectrum β-lactamases (ESBLs screening and plasmid profile analysis were performed according to the standard guidelines. Results: A total of 70 Shigella strains including %70 (n = 49 S. sonnei and 30% (n = 21 S. flexneri were isolated from diarrhea samples. Most of the Shigella isolates showed high degrees of resistance to ampicillin, ulafamethoxazole- trimethoprime and cefexim. Concurrent resistance to sulafametoxazole- trimethoprime and ampicillin was the most common resistance pattern. Overall, 11.4% of Shigella isolates showed the ESBL producer criteria. The plasmid profile patterns of all the strains were determined by a modified alkaline lysis method. By plasmid profile analysis 23 genotypes were identified among all the isolates, 14 and 9 genotypes among the S. sonnei and S. Flexneri respectively. S. sonnei and S. flexneri isolates demonstrated unique plasmid profiles. Conclusions: These data demonstrated that S. sonnei strains are the main cause of shigellosis as the prevalent Shigella serotype in Iran. We also found that the antibiotic resistance rates are increasing among Shigella strains. Plasmid profile analysis is more reliable than antibiotic susceptibility patterns in epidemiologic studies.

Genome-wide association study identifies novel breast cancer susceptibility loci

NARCIS (Netherlands)

Easton, Douglas F.; Pooley, Karen A.; Dunning, Alison M.; Pharoah, Paul D. P.; Thompson, Deborah; Ballinger, Dennis G.; Struewing, Jeffery P.; Morrison, Jonathan; Field, Helen; Luben, Robert; Wareham, Nicholas; Ahmed, Shahana; Healey, Catherine S.; Bowman, Richard; Meyer, Kerstin B.; Haiman, Christopher A.; Kolonel, Laurence K.; Henderson, Brian E.; Le Marchand, Loic; Brennan, Paul; Sangrajrang, Suleeporn; Gaborieau, Valerie; Odefrey, Fabrice; Shen, Chen-Yang; Wu, Pei-Ei; Wang, Hui-Chun; Eccles, Diana; Evans, D. Gareth; Peto, Julian; Fletcher, Olivia; Johnson, Nichola; Seal, Sheila; Stratton, Michael R.; Rahman, Nazneen; Chenevix-Trench, Georgia; Bojesen, Stig E.; Nordestgaard, Børge G.; Axelsson, Christen K.; Garcia-Closas, Montserrat; Brinton, Louise; Chanock, Stephen; Lissowska, Jolanta; Peplonska, Beata; Nevanlinna, Heli; Fagerholm, Rainer; Eerola, Hannaleena; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Ahn, Sei-Hyun; Hunter, David J.; Hankinson, Susan E.; Cox, David G.; Hall, Per; Wedren, Sara; Liu, Jianjun; Low, Yen-Ling; Bogdanova, Natalia; Schürmann, Peter; Dörk, Thilo; Tollenaar, Rob A. E. M.; Jacobi, Catharina E.; Devilee, Peter; Klijn, Jan G. M.; Sigurdson, Alice J.; Doody, Michele M.; Alexander, Bruce H.; Zhang, Jinghui; Cox, Angela; Brock, Ian W.; MacPherson, Gordon; Reed, Malcolm W. R.; Couch, Fergus J.; Goode, Ellen L.; Olson, Janet E.; Meijers-Heijboer, Hanne; van den Ouweland, Ans; Uitterlinden, André; Rivadeneira, Fernando; Milne, Roger L.; Ribas, Gloria; Gonzalez-Neira, Anna; Benitez, Javier; Hopper, John L.; McCredie, Margaret; Southey, Melissa; Giles, Graham G.; Schroen, Chris; Justenhoven, Christina; Brauch, Hiltrud; Hamann, Ute; Ko, Yon-Dschun; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana; Day, Nicholas E.; Cox, David R.; Ponder, Bruce A. J.

2007-01-01

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate

Human leptospirosis: seroreactivity and genetic susceptibility in the population of São Miguel Island (Azores, Portugal.

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Lisa M Esteves

Full Text Available 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.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.The present study suggests some degree of long-term protection against leptospires with an attenuation of symptoms in case of reinfection. Moreover, our data supports the genetic

Identification of Candida dubliniensis in a study of HIV-seropositive pediatric dental patients.

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Brown, D M; Jabra-Rizk, M A; Falkler, W A; Baqui, A A; Meiller, T F

2000-01-01

The combination of an immature immune system and suppressed cellular immunity in children with HIV infections provides optimal conditions for rapid disease progression. As a result, pediatric AIDS has become a major epidemiological challenge. Oral fungal colonization remains one of the most common opportunistic infections observed in both adult and pediatric HIV infected patients. Although Candida albicans is the most frequently isolated opportunistic fungal species, a recently characterized Candida species, C. dubliniensis, has gained considerable attention due to its almost exclusive association with HIV-seropositive individuals. The purpose of this study was to prospectively screen for the presence of C. dubliniensis among pediatric HIV+ patients. Oral samples taken from twenty-seven children were cultured for the presence of yeast. All positive yeast isolates obtained were screened for the presence of C. dubliniensis by use of tests for germ tube and chlamydospore production, detection of inability to grow at 45 degrees C, by colony color on CHROMagar Candida medium, coaggregation with Fusobacterium nucleatum ATCC 49256 and by the results of sugar assimilation testing with the API 20C AUX yeast identification system. Among the 27 patients tested, 3 patients were found to harbor C. dubliniensis, one of which also grew C. glabrata; 12 patients were colonized with C. albicans, while the remaining 12 patients were negative for yeast. Identification of the three C. dubliniensis isolates was genetically confirmed by electrophoretic karyotyping. All three C. dubliniensis isolates were found to be susceptible to fluconazole (MIC pediatric HIV seropositive population and support the need for further investigation into the prevalence and pathogenesis of C. dubliniensis.

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

Genetic relatedness, antimicrobial and biocide susceptibility comparative analysis of methicillin-resistant and -susceptible Staphylococcus pseudintermedius from Portugal.

Science.gov (United States)

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

2014-08-01

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 multidrug-resistant. Several antibiotic resistance genes (mecA, blaZ, tet(M), tet(K), aac(6')-Ie-aph(2')-Ia, aph(3')-III, ant(6)-Ia, sat4, erm(B), lnu(A), dfr(G), and catp(C221)) were identified by microarray and double mutations in the gyrA and grlA genes and a single mutation in the rpoB gene were detected by sequence analysis. No differences were detected between MSSP and MRSP in the chlorhexidine acetate (CHA) minimum inhibitory concentrations (MICs). However, two MSSP had elevated MIC to triclosan (TCL) and one to benzalkonium chloride and ethidium bromide. One MSSP isolate harboured a qacA gene, while in another a qacB gene was detected. None of the isolates harboured the sh-fabI gene. Three of the biocide products studied had high bactericidal activity (Otodine(®), Clorexyderm Spot Gel(®), Dermocanis Piocure-M(®)), while Skingel(®) failed to achieve a five log reduction in the bacterial counting. S. pseudintermedius have become a serious therapeutic challenge in particular if methicillin- resistance and/or multidrug-resistance are involved. Biocides, like CHA and TCL, seem to be clinically effective and safe topical therapeutic options.

Diagnosis and treatment of pediatric onset isolated dystonia.

Science.gov (United States)

Zorzi, Giovanna; Carecchio, Miryam; Zibordi, Federica; Garavaglia, Barbara; Nardocci, Nardo

2018-03-01

Isolated dystonia refers to a genetic heterogeneous group of progressive conditions with onset of symptoms during childhood or adolescence, progressive course with frequent generalization and marked functional impairment. There are well-known monogenic forms of isolated dystonia with pediatric onset such as DYT1 and DYT6 transmitted with autosomal dominant inheritance and low penetrance. Genetic findings of the past years have widened the etiological spectrum and the phenotype. The recently discovered genes (GNAL, ANO-3, KTM2B) or variant of already known diseases, such as Ataxia-Teleangectasia, are emerging as another causes of pediatric onset dystonia, sometimes with a more complex phenotype, but their incidence is unknown and still a considerable number of cases remains genetically undetermined. Due to the severe disability of pediatric onset dystonia treatment remains unsatisfactory and still mainly based upon oral pharmacological agents. However, deep brain stimulation is now extensively applied with good to excellent results especially when patients are treated early during the course of the disease. Copyright © 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Cardiomyopathy in the pediatric patients

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Shi-Min Yuan

2018-04-01

Full Text Available Pediatric cardiomyopathies are a group of myocardial diseases with complex taxonomies. Cardiomyopathy can occur in children at any age, and it is a common cause of heart failure and heart transplantation in children. The incidence of pediatric cardiomyopathy is increasing with time. They may be associated with variable comorbidities, which are most often arrhythmia, heart failure, and sudden death. Medical imaging technologies, including echocardiography, cardiac magnetic resonance, and nuclear cardiology, are helpful in reaching a diagnosis of cardiomyopathy. Nevertheless, endomyocardial biopsy is the final diagnostic method of diagnosis. Patients warrant surgical operations, such as palliative operations, bridging operations, ventricular septal maneuvers, and heart transplantation, if pharmaceutical therapies are ineffective. Individual therapeutic regimens due to pediatric characteristics, genetic factors, and pathogenesis may improve the effects of treatment and patients' survival. Key Words: cardiomyopathy, classification, pediatrics

Epidemiology of acute otitis in pediatric patients

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Maddalena Perotti

2011-03-01

Full Text Available Introduction. Acute otitis is one of the most common pediatric infectious diseases that requires an accurate diagnosis in order to direct appropriate therapy to reduce the risk of complications. In this study pathogens collected from pediatric patients and their antibiotic susceptibility patterns were evaluated. Methods. Between May 2009 and May 2010, 739 samples (swabs taken from nasopharynx in case of acute otitis media and/or from ears in case of acute external otitis, collected from 680 patients, suffering of otalgia, admitted to the emergency department of our Hospital were studied.The specimens were submitted for routine bacterial cultures and the susceptibility tests were performed according to Clinical Laboratory Standards. Nitrocefin was used to detect ß-lactamase activity. Results. 316 samples (42.8% of 739 were negative, 102 (13.8% were positive for Streptococcus pneumoniae, 97 (13.1% for Moraxella catarrhalis, 68 (9.2% for Haemophilus influenzae, 62 (8.4% for Pseudomonas aeruginosa, 49 (6.6% for Staphylococcus aureus, 36 (4.9% for Streptococcus pyogenes, 5 (0.7% for Gram negative and 4 (0.5% for Candida spp. Antibiotic susceptibility tests showed that amikacin, ceftazidime, ciprofloxacin, imipenem, meropenem and piperacillin/tazobactam were active against all Gram negative strains isolated.We found one strain of MRSA. Of 102 Streptococcus pneumoniae, 5 (4.9% were penicillin resistant and 25 (24.5% were erythromycin resistant, showing the prevalence of constitutive phenotype (80%. All M. catarrhalis strains were ß-lactamase producers while all H. influenzae were ß-lactamase negatives. Conclusions. The prevalent etiological agents in pediatric acute otitis are S. pneumoniae, M. catharralis, and H. influenzae, as reported in literature. In external acute otitis P. aeruginosa prevails in particular in summer.

Health communication, genetic determinism, and perceived control: the roles of beliefs about susceptibility and severity versus disease essentialism.

Science.gov (United States)

Parrott, Roxanne; Kahl, Mary L; Ndiaye, Khadidiatou; Traeder, Tara

2012-08-01

This research examined the lay public's beliefs about genes and health that might be labeled deterministic. The goals of this research were to sort through the divergent and contested meanings of genetic determinism in an effort to suggest directions for public health genomic communication. A survey conducted in community-based settings of 717 participants included 267 who self-reported race as African American and 450 who self-reported race as Caucasian American. The survey results revealed that the structure of genetic determinism included 2 belief sets. One set aligned with perceived threat, encompassing susceptibility and severity beliefs linked to genes and health. The other set represents beliefs about biological essentialism linked to the role of genes for health. These concepts were found to be modestly positively related. Threat beliefs predicted perceived control over genes. Public health efforts to communicate about genes and health should consider effects of these messages for (a) perceived threat relating to susceptibility and severity and (b) perceptions of disease essentialism. Perceived threat may enhance motivation to act in health protective ways, whereas disease essentialist beliefs may contribute to a loss of motivation associated with control over health.

Genetic Characterization of Spondweni and Zika Viruses and Susceptibility of Geographically Distinct Strains of Aedes aegypti, Aedes albopictus and Culex quinquefasciatus (Diptera: Culicidae to Spondweni Virus.

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Andrew D Haddow

2016-10-01

Full Text Available Zika virus (ZIKV has extended its known geographic distribution to the New World and is now responsible for severe clinical complications in a subset of patients. While substantial genetic and vector susceptibility data exist for ZIKV, less is known for the closest related flavivirus, Spondweni virus (SPONV. Both ZIKV and SPONV have been known to circulate in Africa since the mid-1900s, but neither has been genetically characterized by gene and compared in parallel. Furthermore, the susceptibility of peridomestic mosquito species incriminated or suspected in the transmission of ZIKV to SPONV was unknown.In this study, two geographically distinct strains of SPONV were genetically characterized and compared to nine genetically and geographically distinct ZIKV strains. Additionally, the susceptibility of both SPONV strains was determined in three mosquito species. The open reading frame (ORF of the SPONV 1952 Nigerian Chuku strain, exhibited a nucleotide and amino acid identity of 97.8% and 99.2%, respectively, when compared to the SPONV 1954 prototype South African SA Ar 94 strain. The ORF of the SPONV Chuku strain exhibited a nucleotide and amino acid identity that ranged from 68.3% to 69.0% and 74.6% to 75.0%, respectively, when compared to nine geographically and genetically distinct strains of ZIKV. The ORF of the nine African and Asian lineage ZIKV strains exhibited limited nucleotide divergence. Aedes aegypti, Ae. albopictus and Culex quinquefasciatus susceptibility and dissemination was low or non-existent following artificial infectious blood feeding of moderate doses of both SPONV strains.SPONV and ZIKV nucleotide and amino acid divergence coupled with differences in geographic distribution, ecology and vector species support previous reports that these viruses are separate species. Furthermore, the low degree of SPONV infection or dissemination in Ae. albopictus, Ae. aegypti and Cx. quinquefasciatus following exposure to two

Pediatric medicine and the genetic disorders of the Amish and Mennonite people of Pennsylvania.

Science.gov (United States)

Morton, D Holmes; Morton, Caroline S; Strauss, Kevin A; Robinson, Donna L; Puffenberger, Erik G; Hendrickson, Christine; Kelley, Richard I

2003-08-15

The Clinic for Special Children in Lancaster County, Pennsylvania, is a community-supported, nonprofit pediatric medical practice for Amish and Mennonite children who have genetic disorders. Over a 14-year period, 1988-2002, we have encountered 39 heritable disorders among the Amish and 23 among the Mennonites. We emphasize early recognition and long-term medical care of children with genetic conditions. In the clinic laboratory we perform amino acid analyses by high-performance liquid chromatography (HPLC), organic acid analyses by gas chromatography/mass spectrometry (GC/MS), and molecular diagnoses and carrier tests by polymerase chain reaction (PCR) amplification and sequencing or restriction digestion. Regional hospitals and midwives routinely send whole-blood filter paper neonatal screens for tandem mass spectrometry and other modern analytical methods to detect 14 of the metabolic disorders found in these populations as part of the NeoGen Inc. Supplemental Newborn Screening Program (Pittsburgh, PA). Medical care based on disease pathophysiology reduces morbidity, mortality, and costs for the majority of disorders. Among our patients who are homozygous for the same mutation, differences in disease severity are not unusual. Clinical problems typically arise from the interaction of the underlying genetic disorder with common infections, malnutrition, injuries, and immune dysfunction that act through classical pathophysiological disease mechanisms to influence the natural history of disease. Copyright 2003 Wiley-Liss, Inc.

Genetic variation for maternal effects on parasite susceptibility.

Science.gov (United States)

Stjernman, M; Little, T J

2011-11-01

The expression of infectious disease is increasingly recognized to be impacted by maternal effects, where the environmental conditions experienced by mothers alter resistance to infection in offspring, independent of heritability. Here, we studied how maternal effects (high or low food availability to mothers) mediated the resistance of the crustacean Daphnia magna to its bacterial parasite Pasteuria ramosa. We sought to disentangle maternal effects from the effects of host genetic background by studying how maternal effects varied across 24 host genotypes sampled from a natural population. Under low-food conditions, females produced offspring that were relatively resistant, but this maternal effect varied strikingly between host genotypes, i.e. there were genotype by maternal environment interactions. As infection with P. ramosa causes a substantial reduction in host fecundity, this maternal effect had a large effect on host fitness. Maternal effects were also shown to impact parasite fitness, both because they prevented the establishment of the parasites and because even when parasites did establish in the offspring of poorly fed mothers, and they tended to grow more slowly. These effects indicate that food stress in the maternal generation can greatly influence parasite susceptibility and thus perhaps the evolution and coevolution of host-parasite interactions. © 2011 The Authors. Journal of Evolutionary Biology © 2011 European Society For Evolutionary Biology.

Genetic and Environmental Influences on Retinopathy of Prematurity

Science.gov (United States)

Ortega-Molina, J. M.; Anaya-Alaminos, R.; Uberos-Fernández, J.; Solans-Pérez de Larraya, A.; Chaves-Samaniego, M. J.; Salgado-Miranda, A.; Piñar-Molina, R.; Jerez-Calero, A.; García-Serrano, J. L.

2015-01-01

Objective. The goals were to isolate and study the genetic susceptibility to retinopathy of prematurity (ROP), as well as the gene-environment interaction established in this disease. Methods. A retrospective study (2000–2014) was performed about the heritability of retinopathy of prematurity in 257 infants who were born at a gestational age of ≤32 weeks. The ROP was studied and treated by a single pediatric ophthalmologist. A binary logistic regression analysis was completed between the presence or absence of ROP and the predictor variables. Results. Data obtained from 38 monozygotic twins, 66 dizygotic twins, and 153 of simple birth were analyzed. The clinical features of the cohorts of monozygotic and dizygotic twins were not significantly different. Genetic factors represented 72.8% of the variability in the stage of ROP, environmental factors 23.08%, and random factors 4.12%. The environmental variables representing the highest risk of ROP were the number of days of tracheal intubation (p < 0.001), postnatal weight gain (p = 0.001), and development of sepsis (p = 0.0014). Conclusion. The heritability of ROP was found to be 0.73. The environmental factors regulate and modify the expression of the genetic code. PMID:26089603

Advance MRI for pediatric brain tumors with emphasis on clinical benefits

Energy Technology Data Exchange (ETDEWEB)

Goo, Hyun Woo; Ra, Young Shin [Asan Medical Center, University of Ulsan College of Medicine, Seoul(Korea, Republic of)

2017-01-15

Conventional anatomic brain MRI is often limited in evaluating pediatric brain tumors, the most common solid tumors and a leading cause of death in children. Advanced brain MRI techniques have great potential to improve diagnostic performance in children with brain tumors and overcome diagnostic pitfalls resulting from diverse tumor pathologies as well as nonspecific or overlapped imaging findings. Advanced MRI techniques used for evaluating pediatric brain tumors include diffusion-weighted imaging, diffusion tensor imaging, functional MRI, perfusion imaging, spectroscopy, susceptibility-weighted imaging, and chemical exchange saturation transfer imaging. Because pediatric brain tumors differ from adult counterparts in various aspects, MRI protocols should be designed to achieve maximal clinical benefits in pediatric brain tumors. In this study, we review advanced MRI techniques and interpretation algorithms for pediatric brain tumors.

Genetic and environmental interactions

International Nuclear Information System (INIS)

Strong, L.C.

1977-01-01

Cancer may result from a multistage process occurring over a long period of time. Presumably, initial and progressive stages of carcinogenesis may be modified by both genetic and environmental factors. Theoretically, genetic factors may alter susceptibility to the carcinogenic effects of an environmental agent at the initial exposure due to variation in metabolism of the carcinogen or variation in specific target cell response to the active carcinogen, or during the latent phase due to numerous factors that might increase the probability of tumor expression, including growth-promoting factors or immunodeficiency states. Observed genetic and environmental interactions in carcinogenesis include an association between genetically determined inducibility of aryl hydrocarbon hydroxylase and smoking-related cancers, familial susceptibility to certain environmental carcinogens, an association between hereditary disorders of mutagenesis and carcinogenesis, and enhancement of tissue-specific, dominantly inherited tumor predisposition by radiation. Multiple primary tumors occur frequently in genetically predisposed individuals. Specific markers for susceptibility must be sought in order that high-risk individuals be identified and appropriate measures taken for early cancer detection or prevention. Study of the nature of the genetically determined susceptibility and interactions with environmental agents may be revealing in the understanding of carcinogenesis in general

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

Genetic Biomarkers of Barrett's Esophagus Susceptibility and Progression to Dysplasia and Cancer: A Systematic Review and Meta-Analysis.

Science.gov (United States)

Findlay, John M; Middleton, Mark R; Tomlinson, Ian

2016-01-01

Barrett's esophagus (BE) is a common and important precursor lesion of esophageal adenocarcinoma (EAC). A third of patients with BE are asymptomatic, and our ability to predict the risk of progression of metaplasia to dysplasia and EAC (and therefore guide management) is limited. There is an urgent need for clinically useful biomarkers of susceptibility to both BE and risk of subsequent progression. This study aims to systematically identify, review, and meta-analyze genetic biomarkers reported to predict both. A systematic review of the PubMed and EMBASE databases was performed in May 2014. Study and evidence quality were appraised using the revised American Society of Clinical Oncology guidelines, and modified Recommendations for Tumor Marker Scores. Meta-analysis was performed for all markers assessed by more than one study. A total of 251 full-text articles were reviewed; 52 were included. A total of 33 germline markers of susceptibility were identified (level of evidence II-III); 17 were included. Five somatic markers of progression were identified; meta-analysis demonstrated significant associations for chromosomal instability (level of evidence II). One somatic marker of progression/relapse following photodynamic therapy was identified. However, a number of failings of methodology and reporting were identified. This is the first systematic review and meta-analysis to evaluate genetic biomarkers of BE susceptibility and risk of progression. While a number of limitations of study quality temper the utility of those markers identified, some-in particular, those identified by genome-wide association studies, and chromosomal instability for progression-appear plausible, although robust validation is required.

The Prevalence and Molecular Epidemiology of Multidrug-Resistant Enterobacteriaceae Colonization in a Pediatric Intensive Care Unit.

Science.gov (United States)

Suwantarat, Nuntra; Logan, Latania K; Carroll, Karen C; Bonomo, Robert A; Simner, Patricia J; Rudin, Susan D; Milstone, Aaron M; Tekle, Tsigereda; Ross, Tracy; Tamma, Pranita D

2016-05-01

To determine the prevalence and acquisition of extended-spectrum β-lactamases (ESBLs), plasmid-mediated AmpCs (pAmpCs), and carbapenemases ("MDR Enterobacteriaceae") colonizing children admitted to a pediatric intensive care unit (PICU). Prospective study. 40-bed PICU. Admission and weekly thereafter rectal surveillance swabs were collected on all pediatric patients during a 6-month study period. Routine phenotypic identification and antibiotic susceptibility testing were performed. Enterobacteriaceae displaying characteristic resistance profiles underwent further molecular characterization to identify genetic determinants of resistance likely to be transmitted on mobile genetic elements and to evaluate relatedness of strains including DNA microarray, multilocus sequence typing, repetitive sequence-based PCR, and hsp60 sequencing typing. Evaluating 854 swabs from unique children, the overall prevalence of colonization with an MDR Enterobacteriaceae upon admission to the PICU based on β-lactamase gene identification was 4.3% (n=37), including 2.8% ESBLs (n=24), 1.3% pAmpCs (n=11), and 0.2% carbapenemases (n=2). Among 157 pediatric patients contributing 603 subsequent weekly swabs, 6 children (3.8%) acquired an incident MDR Enterobacteriaceae during their PICU stay. One child acquired a pAmpC (E. coli containing bla DHA) related to an isolate from another patient. Approximately 4% of children admitted to a PICU were colonized with MDR Enterobacteriaceae (based on β-lactamase gene identification) and an additional 4% of children who remained in the PICU for at least 1 week acquired 1 of these organisms during their PICU stay. The acquired MDR Enterobacteriaceae were relatively heterogeneous, suggesting that a single source was not responsible for the introduction of these resistance mechanisms into the PICU setting.

Human growth hormone-related latrogenic Creutzfeldt-Jakob disease: Search for a genetic susceptibility by analysis of the PRNP coding region

Energy Technology Data Exchange (ETDEWEB)

Jaegly, A.; Boussin, F.; Deslys, J.P. [CEA/CRSSA/DSV/DPTE, Fontenay-aux-Roses (France)] [and others

1995-05-20

The human PRNP gene encoding PrP is located on chromosome 20 and consists of two exons and a single intron. The open reading frame is entirely fitted into the second exon. Genetic studies indicate that all of the familial and several sporadic forms of TSSEs are associated with mutations in the PRNP 759-bp coding region. Moreover, homozygosity at codon 129, a locus harboring a polymorphism among the general population, was proposed as a genetic susceptibility marker for both sporadic and iatrogenic CJD. To assess whether additional genetic predisposition markers exist in the PRNP gene, the authors sequenced the PRNP coding region of 17 of the 32 French patients who developed a hGH-related CJD.

NALP3 inflammasome functional polymorphisms and gout susceptibility.

Science.gov (United States)

Miao, Zhi-Min; Zhao, Shi-Hua; Yan, Sheng-Li; Li, Chang-Gui; Wang, Yan-Gang; Meng, Dong-Mei; Zhou, Li; Mi, Qing-Sheng

2009-01-01

Gout is the most common autoinflammatory arthritis characterized by elevated serum urate and recurrent attacks of intra-articular crystal deposition of monosodium urate (MSU). Although the pathogenesis of gout is still unclear, accumulated studies indicate that genetic factors trigger gout development, including some susceptibility genes that control the production and clearance of urate and lead to hyperuricemia. However, the epidemiological evidence suggests that only less than 10% of hyperuricemia patients develop gout, indicating that other genes unrelated to the urate metabolism may also contribute to the diseases susceptibility. Accumulated evidences have implied that MSU crystal-induced inflammation is a paradigm of innate immunity and that NALP3 inflammasome, an innate immune complex containing NALP3, ASC and CARD-8, is involved in gout development. Recent studies suggest that NALP3 and CARD-8 functional mutations contribute to the development of autoinflammatory diseases including hereditary periodic fever syndrome, arthritis as well as hypertension susceptibility. Taking into account these genetic findings, here we would like to propose a novel hypothesis that functional mutations in NALP3 inflammasome may make NALP3 inflammasome as attractive susceptibility candidates and genetic markers for gout. Further clinical genetic studies need to be performed to confirm the role of NALP3 inflammasome in the etiology of gout.

Genetic diversity and antifungal susceptibility profiles in causative agents of sporotrichosis

Science.gov (United States)

2014-01-01

Background Sporotrichosis is a chronic subcutaneous mycosis of humans and animals, which is typically acquired by traumatic inoculation of plant material contaminated with Sporothrix propagules, or via animals, mainly felines. Sporothrix infections notably occur in outbreaks, with large epidemics currently taking place in southeastern Brazil and northeastern China. Pathogenic species include Sporothrix brasiliensis, Sporothrix schenckii s. str., Sporothrix globosa, and Sporothrix luriei, which exhibit differing geographical distribution, virulence, and resistance to antifungals. The phylogenetically remote species Sporothrix mexicana also shows a mild pathogenic potential. Methods We assessed a genetically diverse panel of 68 strains. Susceptibility profiles of medically important Sporothrix species were evaluated by measuring the MICs and MFCs for amphotericin B (AMB), fluconazole (FLC), itraconazole (ITC), voriconazole (VRC), posaconazole (PCZ), flucytosine (5FC), and caspofungin (CAS). Haplotype networks were constructed to reveal interspecific divergences within clinical Sporothrix species to evaluate genetically deviant isolates. Results ITC and PCZ were moderately effective against S. brasiliensis (MIC90 = 2 and 2 μg/mL, respectively) and S. schenckii (MIC90 = 4 and 2 μg/mL, respectively). PCZ also showed low MICs against the rare species S. mexicana. 5FC, CAS, and FLC showed no antifungal activity against any Sporothrix species. The minimum fungicidal concentration ranged from 2 to >16 μg/mL for AMB against S. brasiliensis and S. schenckii, while the MFC90 was >16 μg/mL for ITC, VRC, and PCZ. Conclusion Sporothrix species in general showed high degrees of resistance against antifungals. Evaluating a genetically diverse panel of strains revealed evidence of multidrug resistant phenotypes, underlining the need for molecular identification of etiologic agents to predict therapeutic outcome. PMID:24755107

Genetic susceptibility for specific cancers. Medical liability of the clinician.

Science.gov (United States)

Severin, M J

1999-12-01

The use of genetic profiling techniques to detect individuals with an increased susceptibility to heritable cancers has provoked recent legal interest in the duties of the attending physician and in the rights of patients and their families. In the current study specific prima facie and recently litigated cases are presented and explored to delineate the issues facing physicians and to illustrate the prerogatives of patients who are caught up in a heritable cancer enigma. Various courts have attempted to answer questions involving lawsuits in which incidents of breast/ovarian carcinoma and colon carcinoma have provoked claims of negligence against health care providers. Health care workers involved in the care of these patients have specific duties to these individuals. It would appear that physicians are being forced to assume the additional duty of delving into a patient's family history of cancer through multiple generations. This duty is followed by a responsibility to provide detailed counseling to those patients in whom such activity impacts the diagnosis and management of familial cancer.

[Association between HRE-2 gene polymorphism at codon 655 and genetic susceptibility of colorectal cancer].

Science.gov (United States)

Liang, Xia; Zhang, Yong-jing; Liu, Bing; Ni, Qin; Jin, Ming-juan; Ma, Xin-yuan; Yao, Kai-yan; Li, Qi-long; Chen, Kun

2009-06-01

To explore the distribution of HER-2 genetic polymorphism at codon 655 and its association with susceptibility of colorectal cancer in Chinese. A population-based case-control study was carried out. 292 patients with colorectal cancer and 842 healthy controls were interviewed. Meanwhile, the genetic polymorphism of HRE-2 was detected using polymerase chain reaction-restriction fragment length polymorphism. The frequencies of Ile/Val+Val/Val genotypes and Val allele were both higher in cases (25.34% and 13.36%) than those in controls (18.41% and 9.74%) (P<0.05). Compared with Ile/Ile genotype, Ile/Val+Val/Val genotypes were significantly associated with colorectal cancer [ORadjusted=1.54, 95% CI: 1.11-2.14]. The adjusted odds ratio of interactions between this polymorphism and smoking, alcohol drinking were 1.43 (95%CI: 0.88-2.30) and 1.29 (95%CI: 0.73-2.29), respectively. The present findings suggest that HER-2 genetic polymorphism at codon 655 may be associated with the risk of colorectal cancer in Chinese. In addition, there are no interactions between this polymorphism and smoking, alcohol drinking, respectively.

Genetic variants of ADAM33 are associated with asthma susceptibility in the Punjabi population of Pakistan.

Science.gov (United States)

Sabar, Muhammad Farooq; Ghani, Muhammad Usman; Shahid, Mariam; Sumrin, Aleena; Ali, Amjad; Akram, Muhammad; Tariq, Muhammad Akram; Bano, Iqbal

2016-01-01

A disintegrin and metalloproteinase 33 (ADAM33) gene has been considered as an asthma susceptibility gene due to its possible role in airway remodeling, abnormal cell proliferation, and differentiation. Association of this gene with asthma has been reported in several genetic studies on various populations. The current study aims to evaluate the association of ADAM33 gene polymorphisms with the risk of asthma in the Punjabi population of Pakistan. A total of 101 asthma patients and 102 age-matched healthy controls from Lahore, a city in Punjab, were recruited. ADAM33 single nucleotide polymorphisms (SNPs) T + 1[rs2280089], T2[rs2280090], T1[rs2280091], ST + 5[rs597980], ST + 4[rs44707], S2[rs528557], Q - 1[rs612709], and F + 1[rs511898] were genotyped in both patients and controls using single base extension and capillary electrophoresis-based genetic analyzer. The basic allelic and genotypic model was analyzed for association of the SNPs with asthma using SHEsis software. Haploview software was used to calculate pairwise linkage disequilibrium (LD) among six of the genotyped SNPs. Of the 8 SNPs genotyped, only S2[rs528557] showed significant association with asthma (Allele p = 0.0189, Genotype p = 0.021). SNPs T + 1[rs2280089], T2[rs2280090], T1[rs2280091], ST + 4[rs44707], S2[rs528557], and Q - 1[rs612709] were found to be in moderate to strong LD. The significantly higher frequency of haplotype "AAGTCG" in healthy controls suggests a protective effect against asthma risk in the studied population (p = 0.0059). These findings suggest that genetic variants of ADAM33 gene may play important roles in asthma susceptibility in the Punjabi population of Pakistan.

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...... 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....... 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...

Genetics and epigenetics of obesity

OpenAIRE

Herrera, Blanca M.; Keildson, Sarah; Lindgren, Cecilia M.

2011-01-01

Obesity results from interactions between environmental and genetic factors. Despite a relatively high heritability of common, non-syndromic obesity (40?70%), the search for genetic variants contributing to susceptibility has been a challenging task. Genome wide association (GWA) studies have dramatically changed the pace of detection of common genetic susceptibility variants. To date, more than 40 genetic variants have been associated with obesity and fat distribution. However, since these v...

Liver Proteome of Mice with Distinct Genetic Susceptibilities to Fluorosis Treated with Different Concentrations of F in the Drinking Water.

Science.gov (United States)

Khan, Zohaib Nisar; Sabino, Isabela Tomazini; de Souza Melo, Carina Guimarães; Martini, Tatiana; da Silva Pereira, Heloísa Aparecida Barbosa; Buzalaf, Marília Afonso Rabelo

2018-04-29

Appropriate doses of fluoride (F) have therapeutic action against dental caries, but higher levels can cause disturbances in soft and mineralized tissues. Interestingly, the susceptibility to the toxic effects of F is genetically determined. This study evaluated the effects of F on the liver proteome of mice susceptible (A/J) or resistant (129P3/J) to the effects of F. Weanling male A/J (n = 12) and 129P3/J (n = 12) mice were housed in pairs and assigned to two groups given low-F food and drinking water containing 15 or 50 ppm F for 6 weeks. Liver proteome profiles were examined using nano-LC-ESI-MS/MS. Difference in expression among the groups was determined using the PLGS software. Treatment with the lower F concentration provoked more pronounced alterations in fold change in liver proteins in comparison to the treatment with the higher F concentration. Interestingly, most of the proteins with fold change upon treatment with 15 ppm F were increased in the A/J mice compared with their 129P3/J counterparts, suggesting an attempt of the former to fight the deleterious effects of F. However, upon treatment with 50 ppm F, most proteins with fold change were decreased in the A/J mice compared with their 129P3/J counterparts, especially proteins related to oxidative stress and protein folding, which might be related to the higher susceptibility of the A/J animals to the deleterious effects of F. Our findings add light into the mechanisms underlying genetic susceptibility to fluorosis.

Pediatric central nervous system vascular malformations

Energy Technology Data Exchange (ETDEWEB)

Burch, Ezra A. [Brigham and Women' s Hospital, Department of Radiology, Boston, MA (United States); Orbach, Darren B. [Boston Children' s Hospital, Neurointerventional Radiology, Boston, MA (United States)

2015-09-15

Pediatric central nervous system (CNS) vascular anomalies include lesions found only in the pediatric population and also the full gamut of vascular lesions found in adults. Pediatric-specific lesions discussed here include infantile hemangioma, vein of Galen malformation and dural sinus malformation. Some CNS vascular lesions that occur in adults, such as arteriovenous malformation, have somewhat distinct manifestations in children, and those are also discussed. Additionally, children with CNS vascular malformations often have associated broader vascular conditions, e.g., PHACES (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, eye anomalies and sternal anomalies), hereditary hemorrhagic telangiectasia, and capillary malformation-arteriovenous malformation syndrome (related to the RASA1 mutation). The treatment of pediatric CNS vascular malformations has greatly benefited from advances in endovascular therapy, including technical advances in adult interventional neuroradiology. Dramatic advances in therapy are expected to stem from increased understanding of the genetics and vascular biology that underlie pediatric CNS vascular malformations. (orig.)

Pediatric central nervous system vascular malformations

International Nuclear Information System (INIS)

Burch, Ezra A.; Orbach, Darren B.

2015-01-01

Pediatric central nervous system (CNS) vascular anomalies include lesions found only in the pediatric population and also the full gamut of vascular lesions found in adults. Pediatric-specific lesions discussed here include infantile hemangioma, vein of Galen malformation and dural sinus malformation. Some CNS vascular lesions that occur in adults, such as arteriovenous malformation, have somewhat distinct manifestations in children, and those are also discussed. Additionally, children with CNS vascular malformations often have associated broader vascular conditions, e.g., PHACES (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, eye anomalies and sternal anomalies), hereditary hemorrhagic telangiectasia, and capillary malformation-arteriovenous malformation syndrome (related to the RASA1 mutation). The treatment of pediatric CNS vascular malformations has greatly benefited from advances in endovascular therapy, including technical advances in adult interventional neuroradiology. Dramatic advances in therapy are expected to stem from increased understanding of the genetics and vascular biology that underlie pediatric CNS vascular malformations. (orig.)

How the environment shapes genetically induced seizure activity in rats

NARCIS (Netherlands)

Schridde, U.; Luijtelaar, E.L.J.M. van; Takahashi, T.; Fukuyama, Y.

2008-01-01

Underling biology that governs the age-dependent seizure susceptibility is a new, exciting research field for every pediatric epileptologists and developmental nouroscientists. From daily practice, clinicians are well aware about a close correlation between the degree of seizure susceptibility and

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

Genetic susceptibility, colony size, and water temperature drive white-pox disease on the coral Acropora palmata.

Science.gov (United States)

Muller, Erinn M; van Woesik, Robert

2014-01-01

Outbreaks of coral diseases are one of the greatest threats to reef corals in the Caribbean, yet the mechanisms that lead to coral diseases are still largely unknown. Here we examined the spatial-temporal dynamics of white-pox disease on Acropora palmata coral colonies of known genotypes. We took a Bayesian approach, using Integrated Nested Laplace Approximation algorithms, to examine which covariates influenced the presence of white-pox disease over seven years. We showed that colony size, genetic susceptibility of the coral host, and high-water temperatures were the primary tested variables that were positively associated with the presence of white-pox disease on A. palmata colonies. Our study also showed that neither distance from previously diseased individuals, nor colony location, influenced the dynamics of white-pox disease. These results suggest that white-pox disease was most likely a consequence of anomalously high water temperatures that selectively compromised the oldest colonies and the most susceptible coral genotypes.

Genetic susceptibility, colony size, and water temperature drive white-pox disease on the coral Acropora palmata.

Directory of Open Access Journals (Sweden)

Erinn M Muller

Full Text Available Outbreaks of coral diseases are one of the greatest threats to reef corals in the Caribbean, yet the mechanisms that lead to coral diseases are still largely unknown. Here we examined the spatial-temporal dynamics of white-pox disease on Acropora palmata coral colonies of known genotypes. We took a Bayesian approach, using Integrated Nested Laplace Approximation algorithms, to examine which covariates influenced the presence of white-pox disease over seven years. We showed that colony size, genetic susceptibility of the coral host, and high-water temperatures were the primary tested variables that were positively associated with the presence of white-pox disease on A. palmata colonies. Our study also showed that neither distance from previously diseased individuals, nor colony location, influenced the dynamics of white-pox disease. These results suggest that white-pox disease was most likely a consequence of anomalously high water temperatures that selectively compromised the oldest colonies and the most susceptible coral genotypes.

Frequency of Usher syndrome in two pediatric populations: Implications for genetic screening of deaf and hard of hearing children.

Science.gov (United States)

Kimberling, William J; Hildebrand, Michael S; Shearer, A Eliot; Jensen, Maren L; Halder, Jennifer A; Trzupek, Karmen; Cohn, Edward S; Weleber, Richard G; Stone, Edwin M; Smith, Richard J H

2010-08-01

Usher syndrome is a major cause of genetic deafness and blindness. The hearing loss is usually congenital and the retinitis pigmentosa is progressive and first noticed in early childhood to the middle teenage years. Its frequency may be underestimated. Newly developed molecular technologies can detect the underlying gene mutation of this disorder early in life providing estimation of its prevalence in at risk pediatric populations and laying a foundation for its incorporation as an adjunct to newborn hearing screening programs. A total of 133 children from two deaf and hard of hearing pediatric populations were genotyped first for GJB2/6 and, if negative, then for Usher syndrome. Children were scored as positive if the test revealed > or =1 pathogenic mutations in any Usher gene. Fifteen children carried pathogenic mutations in one of the Usher genes; the number of deaf and hard of hearing children carrying Usher syndrome mutations was 15/133 (11.3%). The population prevalence was estimated to be 1/6000. Usher syndrome is more prevalent than has been reported before the genome project era. Early diagnosis of Usher syndrome has important positive implications for childhood safety, educational planning, genetic counseling, and treatment. The results demonstrate that DNA testing for Usher syndrome is feasible and may be a useful addition to newborn hearing screening programs.

Changes to perceptions of the pros and cons of genetic susceptibility testing after APOE genotyping for Alzheimer disease risk

Science.gov (United States)

Christensen, Kurt D.; Roberts, J. Scott; Uhlmann, Wendy R.; Green, Robert C.

2011-01-01

Purpose Perceptions about the pros and cons of genetic susceptibility testing are among the best predictors of test utilization. How actual testing changes such perceptions has yet to be examined. Methods In a clinical trial, first-degree relatives of patients with Alzheimer disease received genetic risk assessments for Alzheimer disease including APOE disclosure. Participants rated 11 possible benefits associated with genetic testing (pros) and 10 risks or limitations (cons) before genetic risk disclosure and again 12 months afterward. Results Pros were rated higher than cons at baseline (3.53 vs. 1.83, P cons did not change (1.88 vs. 1.83, P = 0.199) except for a three-item discrimination subscale which increased (2.07 vs. 1.92, P = 0.012). Among specific pros and cons, three items related to prevention and treatment changed the most. Conclusion The process of APOE genetic risk assessment for Alzheimer disease sensitizes some to its limitations and the risks of discrimination; however, 1-year after disclosure, test recipients still consider the pros to strongly outweigh the cons. PMID:21270636

Phenylketonuria Genetic Screening Simulation

Science.gov (United States)

Erickson, Patti

2012-01-01

After agreeing to host over 200 students on a daylong genetics field trip, the author needed an easy-to-prepare genetics experiment to accompany the DNA-necklace and gel-electrophoresis activities already planned. One of the student's mothers is a pediatric physician at the local hospital, and she suggested exploring genetic-disease screening…

Cancer Genetics Services Directory

Science.gov (United States)

... Services Directory Cancer Prevention Overview 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, ...

The role of genetic background in susceptibility to chemical warfare nerve agents across rodent and non-human primate models.

Science.gov (United States)

Matson, Liana M; McCarren, Hilary S; Cadieux, C Linn; Cerasoli, Douglas M; McDonough, John H

2018-01-15

Genetics likely play a role in various responses to nerve agent exposure, as genetic background plays an important role in behavioral, neurological, and physiological responses to environmental stimuli. Mouse strains or selected lines can be used to identify susceptibility based on background genetic features to nerve agent exposure. Additional genetic techniques can then be used to identify mechanisms underlying resistance and sensitivity, with the ultimate goal of developing more effective and targeted therapies. Here, we discuss the available literature on strain and selected line differences in cholinesterase activity levels and response to nerve agent-induced toxicity and seizures. We also discuss the available cholinesterase and toxicity literature across different non-human primate species. The available data suggest that robust genetic differences exist in cholinesterase activity, nerve agent-induced toxicity, and chemical-induced seizures. Available cholinesterase data suggest that acetylcholinesterase activity differs across strains, but are limited by the paucity of carboxylesterase data in strains and selected lines. Toxicity and seizures, two outcomes of nerve agent exposure, have not been fully evaluated for genetic differences, and thus further studies are required to understand baseline strain and selected line differences. Published by Elsevier B.V.

Diagnosing ARVC in Pediatric Patients Applying the Revised Task Force Criteria: Importance of Imaging, 12-Lead ECG, and Genetics.

Science.gov (United States)

Steinmetz, Michael; Krause, Ulrich; Lauerer, Peter; Konietschke, Frank; Aguayo, Randolph; Ritter, Christian Oliver; Schuster, Andreas; Lotz, Joachim; Paul, Thomas; Staab, Wieland

2018-05-12

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a potentially lethal disease that is well described in adults. In pediatric patients, however, identification of patients at risk of adverse events of ARVC remains a challenge. We aimed to determine which criteria of the revised Task Force Criteria (rTFC), alone or combined, have an impact on diagnosis of ARVC when compared to disease-specific genetic mutations in pediatric patients ≤ 18 years. Between September 2010 and December 2013, 48 consecutive young patients ≤ 18 years of age (mean 14, range of 12.9-15.1 years) underwent contrast-enhanced magnetic resonance imaging (CMR), genetic testing, and comprehensive clinical work-up for ARVC criteria to test for clinically suspected ARVC. As specified by the rTFC, patients were grouped into four categories: "definite," "borderline," "possible," and "none" ARVC. Of the 48 patients, 12 were found to have gene mutations of either the desmoplakin (9/12) or plakophilin (3/12) locus. According to rTFC 12/48 patients were considered as "definite" ARVC (25%), while 10/12 (83.3%) had an ARVC-specific gene mutation. Of the remaining 36 patients, 6 (12.5%) were grouped as "borderline" ARVC, 7 (14.6%) as "possible" ARVC (including the remaining two genetic mutations), and 22 (45.8%) as "none" ARVC, respectively. Statistical analysis of ARVC criteria in patients diagnosed with "definite" ARVC revealed high prevalence of positive findings by imaging (CMR and echocardiography) and positive genetics. The positive predictive value to detect "definite" ARVC by genotyping was 83.3%, while the negative predictive value was 94%. Logistic regression analyses for different criteria combinations revealed that imaging modalities (echo and CMR combined) and abnormalities of 12-lead ECG were significant markers (p < 0.01). Positive results of endomyocardial biopsies or arrhythmia on ECG or Holter as defined by the rTFC were not significant in this analysis. The rTFC for

The Role of Abcb5 Alleles in Susceptibility to Haloperidol-Induced Toxicity in Mice and Humans

Science.gov (United States)

Zheng, Ming; Zhang, Haili; Dill, David L.; Clark, J. David; Tu, Susan; Yablonovitch, Arielle L.; Tan, Meng How; Zhang, Rui; Rujescu, Dan; Wu, Manhong; Tessarollo, Lino; Vieira, Wilfred; Gottesman, Michael M.; Deng, Suhua; Eberlin, Livia S.; Zare, Richard N.; Billard, Jean-Martin; Gillet, Jean-Pierre; Li, Jin Billy; Peltz, Gary

2015-01-01

Background We know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS) toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT), which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study. Methods and Findings A whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5) affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite) levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered

The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.

KAUST Repository

Zheng, Ming

2015-02-03

We know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS) toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT), which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study.A whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5) affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite) levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered.ABCB5 alleles alter susceptibility to

Pediatric obesity. An introduction ☆

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Yanovski, Jack A.

2015-01-01

The prevalence of child and adolescent obesity in the United States increased dramatically between 1970 and 2000, and there are few indications that the rates of childhood obesity are decreasing. Obesity is associated with myriad medical, psychological, and neurocognitive abnormalities that impact children’s health and quality of life. Genotypic variation is important in determining the susceptibility of individual children to undue gains in adiposity; however, the rapid increase in pediatric obesity prevalence suggests that changes to children’s environments and/or to their learned behaviors may dramatically affect body weight regulation. This paper presents an overview of the epidemiology, consequences, and etiopathogenesis of pediatric obesity, serving as a general introduction to the subsequent papers in this Special Issue that address aspects of childhood obesity and cognition in detail. PMID:25836737

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

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Steffens, M.; Leu, C.; Ruppert, A. K.

2012-01-01

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3 and account for 2030 of all epilepsies. Despite their high heritability of 80, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a ...

Susceptibility to radiation-induced mammary carcinoma in genetically resistant Copenhagen rats

International Nuclear Information System (INIS)

Kamiya, Kenji; Nitta, Yumiko; Gould, M.N.

2000-01-01

The objective of this experiment was to compare the cellular basis of mammary cancer induction by a chemical carcinogen with induction by ionizing radiation in three strains of rats (inbred that have different genetic susceptibilities: COP rats, F344 rats, and WF rats). Rats were given a single intraperitoneal injection of 50 mg MNU/kg body weight as a mammary-tumor-inducing chemical carcinogen and were irradiated with a 3.0 Gy dose of 60 Co gamma rays at a dose rate of 26.58±1.19 cGy/min. The rats were inspected weekly, and they were killed and necropsied whenever palpable tumors were detected or they became moribund. The histopathological and immunohistochemical characteristics of the mammary tumors were investigated. A transplantation experiment using selected primary mammary tumors that developed in COP rats exposed to gamma rays was also performed to investigate the transplantability of mammary tumors induced by ionizing radiation. The sensitivity of the WF and F344 rats and the resistance of the COP rats to mammary carcinoma induction by the chemical carcinogen MNU was confirmed. In contrast to the chemical carcinogens, no difference in susceptibility to radiation induction of mammary carcinomas was detected among the three strains of rats, and immunohistochemical examination indicated that the radiation-induced carcinomas consisted of more highly differentiated cells than the MNU-induced cancers. The results of the experiment appear to support the hypothesis that differentiated mammary gland tissue is more resistant to chemical carcinogens than to cancer induction by radiation. The authors conclude that radiation-induced cancers in rats may develop via different pathways or from different cell populations than chemically induced cancers. (K.H.)

Susceptibility to radiation-induced mammary carcinoma in genetically resistant Copenhagen rats

Energy Technology Data Exchange (ETDEWEB)

Kamiya, Kenji; Nitta, Yumiko [Hiroshima Univ. (Japan). Research Inst. for Radiation Biology and Medicine; Gould, M.N.

2000-07-01

The objective of this experiment was to compare the cellular basis of mammary cancer induction by a chemical carcinogen with induction by ionizing radiation in three strains of rats (inbred that have different genetic susceptibilities: COP rats, F344 rats, and WF rats). Rats were given a single intraperitoneal injection of 50 mg MNU/kg body weight as a mammary-tumor-inducing chemical carcinogen and were irradiated with a 3.0 Gy dose of {sup 60} Co gamma rays at a dose rate of 26.58{+-}1.19 cGy/min. The rats were inspected weekly, and they were killed and necropsied whenever palpable tumors were detected or they became moribund. The histopathological and immunohistochemical characteristics of the mammary tumors were investigated. A transplantation experiment using selected primary mammary tumors that developed in COP rats exposed to gamma rays was also performed to investigate the transplantability of mammary tumors induced by ionizing radiation. The sensitivity of the WF and F344 rats and the resistance of the COP rats to mammary carcinoma induction by the chemical carcinogen MNU was confirmed. In contrast to the chemical carcinogens, no difference in susceptibility to radiation induction of mammary carcinomas was detected among the three strains of rats, and immunohistochemical examination indicated that the radiation-induced carcinomas consisted of more highly differentiated cells than the MNU-induced cancers. The results of the experiment appear to support the hypothesis that differentiated mammary gland tissue is more resistant to chemical carcinogens than to cancer induction by radiation. The authors conclude that radiation-induced cancers in rats may develop via different pathways or from different cell populations than chemically induced cancers. (K.H.)

Patient Susceptibility to Candidiasis—A Potential for Adjunctive Immunotherapy

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Davidson, Linda; Netea, Mihai G.; Kullberg, Bart Jan

2018-01-01

Candida spp. are colonizing fungi of human skin and mucosae of the gastrointestinal and genitourinary tract, present in 30–50% of healthy individuals in a population at any given moment. The host defense mechanisms prevent this commensal fungus from invading and causing disease. Loss of skin or mucosal barrier function, microbiome imbalances, or defects of immune defense mechanisms can lead to an increased susceptibility to severe mucocutaneous or invasive candidiasis. A comprehensive understanding of the immune defense against Candida is essential for developing adjunctive immunotherapy. The important role of underlying genetic susceptibility to Candida infections has become apparent over the years. In most patients, the cause of increased susceptibility to fungal infections is complex, based on a combination of immune regulation gene polymorphisms together with other non-genetic predisposing factors. Identification of patients with an underlying genetic predisposition could help determine which patients could benefit from prophylactic antifungal treatment or adjunctive immunotherapy. This review will provide an overview of patient susceptibility to mucocutaneous and invasive candidiasis and the potential for adjunctive immunotherapy. PMID:29371502

Patient Susceptibility to Candidiasis—A Potential for Adjunctive Immunotherapy

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Linda Davidson

2018-01-01

Full Text Available Candida spp. are colonizing fungi of human skin and mucosae of the gastrointestinal and genitourinary tract, present in 30–50% of healthy individuals in a population at any given moment. The host defense mechanisms prevent this commensal fungus from invading and causing disease. Loss of skin or mucosal barrier function, microbiome imbalances, or defects of immune defense mechanisms can lead to an increased susceptibility to severe mucocutaneous or invasive candidiasis. A comprehensive understanding of the immune defense against Candida is essential for developing adjunctive immunotherapy. The important role of underlying genetic susceptibility to Candida infections has become apparent over the years. In most patients, the cause of increased susceptibility to fungal infections is complex, based on a combination of immune regulation gene polymorphisms together with other non-genetic predisposing factors. Identification of patients with an underlying genetic predisposition could help determine which patients could benefit from prophylactic antifungal treatment or adjunctive immunotherapy. This review will provide an overview of patient susceptibility to mucocutaneous and invasive candidiasis and the potential for adjunctive immunotherapy.

[Genetic factors in myocardial infarction].

Science.gov (United States)

Hara, Masahiko; Sakata, Yasuhiko; Sato, Hiroshi

2013-02-01

One of the main mechanisms of acute myocardial infarction (AMI) is plaque rupture or erosion followed by intraluminal thrombus formation and occlusion of the coronary arteries. Thus far, many underlying conditions or environmental factors, such as hypertension, diabetes, dyslipidemia, smoking or obesity, as well as a family history of coronary artery diseases have been identified as risks for the onset of AMI. These risks suggest that AMI occurs due to interactions between underlying conditions and multiple genetic susceptibilities. For this reason, many target gene-disease association studies have been performed with the recent introduction of genome-wide association studies (GWAS) that have further revealed new genetic susceptibilities for AMI. GWAS is a way to examine many common genetic variants in different individuals to see if any variant is associated with a trait in a case-control fashion, and typically focuses on associations between single-nucleotide polymorphisms (SNP) and traits. SNP on chromosome 9p21 is one of the robust susceptibility variants for AMI which has been identified by many GWAS. In this review, we overview the methodology of GWAS, introduce genetic variants identified by GWAS as those with susceptibility for AMI, and describe the foresight of using GWAS to investigate genetic susceptibility to AMI.

Antimicrobial Resistant Pattern of Escherichia Coli Strains Isolated from Pediatric Patients in Jordan

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Mohammad Alshara

2011-05-01

Full Text Available The present study was conducted to investigate antimicrobial resistant pattern of Escherichia coli (E. coli strains isolated from clinical specimens of Jordanian pediatric patients during the period from January to December 2008. A total of 444 E. coli strains were isolated from clinical specimens and tested for their susceptibility to different antimicrobial drugs. Overall, high resistance rate was observed for ampicillin (84%, followed by amoxicillin-clavulanic acid (74.3%, cotrimoxazole (71%, nalidixic acid (47.3%, cephalothin (41%. Lower resistance rates were observed for amikacin (0% followed by Cefotaxime (11%, Ceftriaxone (11.7%, ciprofloxacin (14.5%, Norfloxacin (16.5%, gentamicin (17.3% cephalexin (20.9%, Ceftazidime (22.5%, cefixime (29.6%, and cefaclor (32.8%. Ampicillin, amoxicillin-clavulanic acid and cotrimoxazole were found to be ineffective at in vitro inhibition of the E. coli of pediatric origin. Amikacin was highly effective for E. coli with susceptibility rate of 100%. The majority of E. coli strains were susceptible to third generation cephalosporins and fluoroquinolones.

Pediatric Orthogenomics: The Latest Trends and Controversies

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Neha Sinha

2017-05-01

Full Text Available The advent of molecular biology has paved way for an era of personalized medicine. Though medical disciplines such as oncology and cardiology are advanced in their use of genomics, implementation has been slower in other specialties, such as orthopaedics. Recent advances in genomic technology have shed light on the underlying genetic basis of various pediatric orthopaedic disorders. Prior understanding of the genetic makeup of a patient may help individualize care in patients with conditions including idiopathic scoliosis, congenital talipes equinovarus and congenital limb deformities. The fastpaced growth of information in orthogenomics often makes it challenging for an orthopaedic surgeon to effectively use this information for patient care. Genetic characterization of a patient will help indicate risk of progression of a condition, recurrence and/or response to a treatment modality, and a collaborative approach between an orthopaedic surgeon and a geneticist can help tailor patient care. The following review article summarizes current understanding in molecular genomics of common pediatric orthopaedic disorders.

The Prevalence and Molecular Epidemiology of Multidrug-Resistant Enterobacteriaceae Colonization in a Pediatric Intensive Care Unit

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Suwantarat, Nuntra; Logan, Latania K.; Carroll, Karen C.; Bonomo, Robert A.; Simner, Patricia J.; Rudin, Susan D.; Milstone, Aaron M.; Tekle, Tsigereda; Ross, Tracy; Tamma, Pranita D.

2016-01-01

OBJECTIVE To determine the prevalence and acquisition of extended-spectrum β-lactamases (ESBLs), plasmid-mediated AmpCs (pAmpCs), and carbapenemases (“MDR Enterobacteriaceae”) colonizing children admitted to a pediatric intensive care unit (PICU). DESIGN Prospective study. SETTING 40-bed PICU. METHODS Admission and weekly thereafter rectal surveillance swabs were collected on all pediatric patients during a 6-month study period. Routine phenotypic identification and antibiotic susceptibility testing were performed. Enterobacteriaceae displaying characteristic resistance profiles underwent further molecular characterization to identify genetic determinants of resistance likely to be transmitted on mobile genetic elements and to evaluate relatedness of strains including DNA microarray, multilocus sequence typing, repetitive sequence-based PCR, and hsp60 sequencing typing. Results Evaluating 854 swabs from unique children, the overall prevalence of colonization with an MDR Enterobacteriaceae upon admission to the PICU based on β-lactamase gene identification was 4.3% (n = 37), including 2.8% ESBLs (n =24), 1.3% pAmpCs (n =11), and 0.2% carbapenemases (n =2). Among 157 pediatric patients contributing 603 subsequent weekly swabs, 6 children (3.8%) acquired an incident MDR Enterobacteriaceae during their PICU stay. One child acquired a pAmpC (E. coli containing blaDHA) related to an isolate from another patient. Conclusions Approximately 4% of children admitted to a PICU were colonized with MDR Enterobacteriaceae (based on β-lactamase gene identification) and an additional 4% of children who remained in the PICU for at least 1 week acquired 1 of these organisms during their PICU stay. The acquired MDR Enterobacteriaceae were relatively heterogeneous, suggesting that a single source was not responsible for the introduction of these resistance mechanisms into the PICU setting. PMID:26856439

Etiology and antimicrobial resistance patterns in pediatric urinary tract infection.

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Wang, Jun; He, Lijiao; Sha, Jintong; Zhu, Haobo; Huang, Liqu; Zhu, Xiaojiang; Dong, Jun; Li, Guogen; Ge, Zheng; Lu, Rugang; Ma, Geng; Shi, Yaqi; Guo, Yunfei

2018-02-02

Urinary tract infection (UTI) is one of most common pediatric infections. The aim of this study was to investigate the etiology and antimicrobial resistance patterns in children hospitalized at Children's Hospital of Nanjing Medical University. We conducted a retrospective, descriptive study of all UTI from 1 January 2013 to 30 November 2016 in children discharged from Nanjing Children's Hospital. The isolated pathogens and their resistance patterns were examined using midstream urine culture. A total of 2,316 children with UTI were included in the study. The occurrence rates of isolated pathogens were as follows: Enterococcus spp., 35.15%; Escherichia coli, 22.32%; Staphylococcus aureus spp., 7.73%; Streptococcus spp., 7.51%; and Klebsiella spp., 6.95%. Uropathogens had a low susceptibility to linezolid (3.47%), vancomycin (0.92%), imipenem (5.74%), and amikacin (3.17%), but they had a high susceptibility to erythromycin (90.52%), penicillin G (74.01%), cefotaxime (71.41%), cefazolin (73.41%), cefuroxime (72.52%), and aztreonam (70.11%). There is high antibiotic resistance in hospitalized children with UTI. Susceptibility testing should be carried out on all clinical isolates, and the empirical antibiotic treatment should be altered accordingly. © 2018 Japan Pediatric Society.

Genetic susceptibility loci, environmental exposures, and Parkinson's disease: a case-control study of gene-environment interactions.

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Chung, Sun Ju; Armasu, Sebastian M; Anderson, Kari J; Biernacka, Joanna M; Lesnick, Timothy G; Rider, David N; Cunningham, Julie M; Ahlskog, J Eric; Frigerio, Roberta; Maraganore, Demetrius M

2013-06-01

Prior studies causally linked mutations in SNCA, MAPT, and LRRK2 genes with familial Parkinsonism. Genome-wide association studies have demonstrated association of single nucleotide polymorphisms (SNPs) in those three genes with sporadic Parkinson's disease (PD) susceptibility worldwide. Here we investigated the interactions between SNPs in those three susceptibility genes and environmental exposures (pesticides application, tobacco smoking, coffee drinking, and alcohol drinking) also associated with PD susceptibility. Pairwise interactions between environmental exposures and 18 variants (16 SNPs and two variable number tandem repeats, or "VNTRs") in SNCA, MAPT and LRRK2, were investigated using data from 1098 PD cases from the upper Midwest, USA and 1098 matched controls. Environmental exposures were assessed using a validated telephone interview script. Five pairwise interactions had uncorrected P-values coffee drinking × MAPT H1/H2 haplotype or MAPT rs16940806, and alcohol drinking × MAPT rs2435211. None of these interactions remained significant after Bonferroni correction. Secondary analyses in strata defined by type of control (sibling or unrelated), sex, or age at onset of the case also did not identify significant interactions after Bonferroni correction. This study documented limited pairwise interactions between established genetic and environmental risk factors for PD; however, the associations were not significant after correction for multiple testing. Copyright © 2013 Elsevier Ltd. All rights reserved.

Tumor Necrosis Factor B (TNFB) Genetic Variants and Its Increased Expression Are Associated with Vitiligo Susceptibility

Science.gov (United States)

Laddha, Naresh C.; Dwivedi, Mitesh; Gani, Amina R.; Mansuri, Mohmmad Shoab; Begum, Rasheedunnisa

2013-01-01

Genetic polymorphisms in TNFB are involved in the regulation of its expression and are found to be associated with various autoimmune diseases. The aim of the present study was to determine whether TNFB +252A/G (rs909253) and exon 3 C/A (rs1041981) polymorphisms are associated with vitiligo susceptibility, and expression of TNFB and ICAM1 affects the disease onset and progression. We have earlier reported the role of TNFA in autoimmune pathogenesis of vitiligo, and we now show the involvement of TNFB in vitiligo pathogenesis. The two polymorphisms investigated in the TNFB were in strong linkage disequilibrium and significantly associated with vitiligo. TNFB and ICAM1 transcripts were significantly increased in patients compared to controls. Active vitiligo patients showed significant increase in TNFB transcripts compared to stable vitiligo. The genotype-phenotype analysis revealed that TNFB expression levels were higher in patients with GG and AA genotypes as compared to controls. Patients with the early age of onset and female patients showed higher TNFB and ICAM1 expression. Overall, our findings suggest that the increased TNFB transcript levels in vitiligo patients could result, at least in part, from variations at the genetic level which in turn leads to increased ICAM1 expression. For the first time, we show that TNFB +252A/G and exon 3 C/A polymorphisms are associated with vitiligo susceptibility and influence the TNFB and ICAM1 expression. Moreover, the study also emphasizes influence of TNFB and ICAM1 on the disease progression, onset and gender bias for developing vitiligo. PMID:24312346

Recurrent MET fusion genes represent a drug target in pediatric glioblastoma

DEFF Research Database (Denmark)

Sehested, Astrid Marie

2016-01-01

Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously unidentified gene fusions involving the MET oncogene in ∼10% of cases. These MET...

Genetic susceptibility and neurotransmitters in Tourette syndrome.

Science.gov (United States)

Paschou, Peristera; Fernandez, Thomas V; Sharp, Frank; Heiman, Gary A; Hoekstra, Pieter J

2013-01-01

Family studies have consistently shown that Tourette syndrome (TS) is a familial disorder and twin studies have clearly indicated a genetic contribution in the etiology of TS. Whereas early segregation studies of TS suggested a single-gene autosomal dominant disorder, later studies have pointed to more complex models including additive and multifactorial inheritance and likely interaction with genetic factors. While the exact cellular and molecular base of TS is as yet elusive, neuroanatomical and neurophysiological studies have pointed to the involvement of cortico-striato-thalamocortical circuits and abnormalities in dopamine, glutamate, gamma-aminobutyric acid, and serotonin neurotransmitter systems, with the most consistent evidence being available for involvement of dopamine-related abnormalities, that is, a reduction in tonic extracellular dopamine levels along with hyperresponsive spike-dependent dopamine release, following stimulation. Genetic and gene expression findings are very much supportive of involvement of these neurotransmitter systems. Moreover, intriguingly, genetic work on a two-generation pedigree has opened new research pointing to a role for histamine, a so far rather neglected neurotransmitter, with the potential of the development of new treatment options. Future studies should be aimed at directly linking neurotransmitter-related genetic and gene expression findings to imaging studies (imaging genetics), which enables a better understanding of the pathways and mechanisms through which the dynamic interplay of genes, brain, and environment shapes the TS phenotype. © 2013 Elsevier Inc. All rights reserved.

[Genetics and susceptibility to human papillomaviruses: epidermodysplasia verruciformis, a disease model].

Science.gov (United States)

Orth, Gérard

2010-06-01

The outcomes of infection by human papillomaviruses (HPV), both oncogenic and non oncogenic, show major interindividual variability The underlying genetic factors and mechanisms are poorly known, but their complexity is illustrated by epidermodysplasia verruciformis (EV), a rare autosomal recessive genodermatosis associated with a high risk of non melanoma skin cancer. This model disease is characterized by abnormal susceptibility to widespread betapapillomaviruses, including HPV-5, a virus associated with EV cancers. Most cases of EV are caused by a mutation that inactivates either of two related genes, EVER1 and EVER2. This inactivation likely compensates for the absence of a viral gene (E5 or E8) essential for HPV pathogenicity. Proteins E5 and E8 interfere with the interaction between EVER proteins and ZnT1, a zinc transporter EV is thus likely to represent a primary defect of intrinsic (constitutive) immunity or innate immunity to betapapillomaviruses, involving modulation of zinc homeostasis upon keratinocyte infection. It remains to be established which cellular genes are involved in intrinsic, innate or acquired immune responses to other human papillomaviruses, including oncogenic genital types.

Using case-control designs for genome-wide screening for associations between genetic markers and disease susceptibility loci.

Science.gov (United States)

Yang, Q; Khoury, M J; Atkinson, M; Sun, F; Cheng, R; Flanders, W D

1999-01-01

We used a case-control design to scan the genome for any associations between genetic markers and disease susceptibility loci using the first two replicates of the Mycenaean population from the GAW11 (Problem 2) data. Using a case-control approach, we constructed a series of 2-by-3 tables for each allele of every marker on all six chromosomes. Odds ratios (ORs) and 95% confidence intervals (95% CI) were estimated for all alleles of every marker. We selected the one allele for which the estimated OR had the minimum p-value to plot in the graph. Among these selected ORs, we calculated 95% CI for those that had a p-value Mycenaean population, the case-control design identified allele number 1 of marker 24 on chromosome 1 to be associated with a disease susceptibility gene, OR = 2.10 (95% CI 1.66-2.62). Our approach failed to show any other significant association between case-control status and genetic markers. Stratified analysis on the environmental risk factor (E1) provided no further evidence of significant association other than allele 1 of marker 24 on chromosome 1. These data indicate the absence of linkage disequilibrium for markers flanking loci A, B, and C. Finally, we examined the effect of gene x environment (G x E) interaction for the identified allele. Our results provided no evidence of G x E interaction, but suggested that the environmental exposure alone was a risk factor for the disease.

Relationship between HTRA1 polymorphism and genetic susceptibility of wet age-related macular degeneration in Han population

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Nan Yang

2018-05-01

Full Text Available AIM: To investigate the relationship between high temperature essential factor A-1(HTRA1polymorphism and genetic susceptibility of wet age-related macular degeneration(AMDin Han population. METHODS: Totally 201 patients of wet AMD in Han population were selected from May 2014 to January 2017 in our hospital as disease group, and 201 healthy persons of Han were selected as health group. Blood samples of peripheral vein were collected and genomic DNA was extracted. HTRA1 polymorphism loci were detected, and the rs11200638 and rs2248799 loci of HTRA1 gene were detected by Sequenom mass spectrometry platform. Then the relationship between HTRA1 polymorphism and genetic susceptibility of wet AMD were analyzed. RESULTS: The grade distributions of the genotype of the rs11200638 and rs2248799 loci in the two groups subjects had significant differences(PPPOR values of rs11200638 genotype AA and AG were respectively 5.36 and 3.45, which were the risk factors of wet AMD(POR values of rs2248799 genotype TT and TC were respectively 2.36 and 1.98, which were the risk factors of wet AMD(PCONCLUSION: The rs11200638 and rs2248799 polymorphisms of HTRA1 gene are associated with the incidence of wet AMD, and the genotype AA and TT are closely related to the risk of wet AMD in Han population, of which the higher frequencies can increase the risk of wet AMD.

Use of propolis in pediatric dentistry

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Seema Malhotra

2014-01-01

Full Text Available Pediatric age groups are the ones that are more susceptible to a drug. Complications/side effects due to the use of man-made drugs have paved way for the natural products for pharmacotherapeutic purposes. Propolis, a natural resinous substance shows dental application based on its antimicrobial, anti-inflammatory and immunomodulating effects. An alternative to gold standard drugs propolis is easy to use, patient friendly, and easily accessible.

Genetics and epigenetics of obesity.

Science.gov (United States)

Herrera, Blanca M; Keildson, Sarah; Lindgren, Cecilia M

2011-05-01

Obesity results from interactions between environmental and genetic factors. Despite a relatively high heritability of common, non-syndromic obesity (40-70%), the search for genetic variants contributing to susceptibility has been a challenging task. Genome wide association (GWA) studies have dramatically changed the pace of detection of common genetic susceptibility variants. To date, more than 40 genetic variants have been associated with obesity and fat distribution. However, since these variants do not fully explain the heritability of obesity, other forms of variation, such as epigenetics marks, must be considered. Epigenetic marks, or "imprinting", affect gene expression without actually changing the DNA sequence. Failures in imprinting are known to cause extreme forms of obesity (e.g. Prader-Willi syndrome), but have also been convincingly associated with susceptibility to obesity. Furthermore, environmental exposures during critical developmental periods can affect the profile of epigenetic marks and result in obesity. We review the most recent evidence for genetic and epigenetic mechanisms involved in the susceptibility and development of obesity. Only a comprehensive understanding of the underlying genetic and epigenetic mechanisms, and the metabolic processes they govern, will allow us to manage, and eventually prevent, obesity. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Intraoperative mechanical ventilation for the pediatric patient.

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Kneyber, Martin C J

2015-09-01

Invasive mechanical ventilation is required when children undergo general anesthesia for any procedure. It is remarkable that one of the most practiced interventions such as pediatric mechanical ventilation is hardly supported by any scientific evidence but rather based on personal experience and data from adults, especially as ventilation itself is increasingly recognized as a harmful intervention that causes ventilator-induced lung injury. The use of low tidal volume and higher levels of positive end-expiratory pressure became an integral part of lung-protective ventilation following the outcomes of clinical trials in critically ill adults. This approach has been readily adopted in pediatric ventilation. However, a clear association between tidal volume and mortality has not been ascertained in pediatrics. In fact, experimental studies have suggested that young children might be less susceptible to ventilator-induced lung injury. As such, no recommendations on optimal lung-protective ventilation strategy in children with or without lung injury can be made. Copyright © 2015 Elsevier Ltd. All rights reserved.

Awareness of cancer susceptibility genetic testing: the 2000, 2005, and 2010 National Health Interview Surveys.

Science.gov (United States)

Mai, Phuong L; Vadaparampil, Susan Thomas; Breen, Nancy; McNeel, Timothy S; Wideroff, Louise; Graubard, Barry I

2014-05-01

Genetic testing for several cancer susceptibility syndromes is clinically available; however, existing data suggest limited population awareness of such tests. To examine awareness regarding cancer genetic testing in the U.S. population aged ≥25 years in the 2000, 2005, and 2010 National Health Interview Surveys. The weighted percentages of respondents aware of cancer genetic tests, and percent changes from 2000-2005 and 2005-2010, overall and by demographic, family history, and healthcare factors were calculated. Interactions were used to evaluate the patterns of change in awareness between 2005 and 2010 among subgroups within each factor. To evaluate associations with awareness in 2005 and 2010, percentages were adjusted for covariates using multiple logistic regression. The analysis was performed in 2012. Awareness decreased from 44.4% to 41.5% (pAwareness increased between 2005 and 2010 in most subgroups, particularly among individuals in the South (pinteraction=0.03) or with a usual place of care (pinteraction=0.01). In 2005 and 2010, awareness was positively associated with personal or family cancer history and high perceived cancer risk, and inversely associated with racial/ethnic minorities, age 25-39 or ≥60 years, male gender, lower education and income levels, public or no health insurance, and no provider contact in 12 months. Despite improvement from 2005 to 2010, ≤50% of the U.S. adult population was aware of cancer genetic testing in 2010. Notably, disparities persist for racial/ethnic minorities and individuals with limited health care access or income. Published by Elsevier Inc.

Characteristics of Japanese inflammatory bowel disease susceptibility loci.

Science.gov (United States)

Arimura, Yoshiaki; Isshiki, Hiroyuki; Onodera, Kei; Nagaishi, Kanna; Yamashita, Kentaro; Sonoda, Tomoko; Matsumoto, Takayuki; Takahashi, Atsushi; Takazoe, Masakazu; Yamazaki, Keiko; Kubo, Michiaki; Fujimiya, Mineko; Imai, Kohzoh; Shinomura, Yasuhisa

2014-08-01

There are substantial differences in inflammatory bowel disease (IBD) genetics depending on the populations examined. We aimed to identify Japanese population-specific or true culprit susceptibility genes through a meta-analysis of past genetic studies of Japanese IBD. For this study, we reviewed 2,703 articles. The review process consisted of three screening stages: we initially searched for relevant studies and then relevant single nucleotide polymorphisms (SNPs). Finally, we adjusted them for the meta-analysis. To maximize our chances of analysis, we introduced proxy SNPs during the first stage. To minimize publication bias, no significant SNPs and solitary SNPs without pairs were combined to be reconsidered during the third stage. Additionally, two SNPs were newly genotyped. Finally, we conducted a meta-analysis of 37 published studies in 50 SNPs located at 22 loci corresponding to the total number of 4,853 Crohn's disease (CD), 5,612 ulcerative colitis (UC) patients, and 14,239 healthy controls. We confirmed that the NKX2-3 polymorphism is associated with common susceptibility to IBD and that HLA-DRB1*0450 alleles increase susceptibility to CD but reduce risk for UC while HLA-DRB1*1502 alleles increase susceptibility to UC but reduce CD risk. Moreover, we found individual disease risk loci: TNFSF15 and TNFα to CD and HLA-B*5201, and NFKBIL1 to UC. The genetic risk of HLA was substantially high (odds ratios ranged from 1.54 to 2.69) while that of common susceptibility loci to IBD was modest (odds ratio ranged from 1.13 to 1.24). Results indicate that Japanese IBD susceptibility loci identified by the meta-analysis are closely associated with the HLA regions.

HSD17B12 gene rs11037575 C>T polymorphism confers neuroblastoma susceptibility in a Southern Chinese population

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Zhang ZR

2017-04-01

Full Text Available Zhuorong Zhang,1,2 Yan Zou,2 Jinhong Zhu,3 Ruizhong Zhang,2 Tianyou Yang,2 Fenghua Wang,2 Huimin Xia,1,2 Jing He,2 Zhichun Feng1,4–6 1Southern Medical University, Guangzhou, Guangdong, 2Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, 3Molecular Epidemiology Laboratory, Department of Laboratory Medicine, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 4Division of Neonatology, Affiliated BaYi Children’s Hospital, Clinical Medical College in PLA Army General Hospital, Southern Medical University, 5National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, 6Beijing Key Laboratory of Pediatric Organ Failure, Beijing, People’s Republic of China Abstract: A previous genome-wide association study (GWAS identified four genetic polymorphisms (rs1027702 near DUSP12, rs10055201 in IL31RA, rs2619046 in DDX4, and rs11037575 in HSD17B12 gene that were associated with neuroblastoma susceptibility, especially for low-risk subjects. The aim of this study was to examine the association between these four polymorphisms and neuroblastoma susceptibility in a Southern Chinese population composed of 256 cases and 531 controls. Overall, among all the polymorphisms, single-locus analysis only revealed significant association between the HSD17B12 rs11037575 C>T polymorphism and neuroblastoma susceptibility (CT vs CC: adjusted odds ratio [OR] =0.71, 95% confidence interval [CI] =0.51–0.97, P=0.030. Moreover, stratified analysis indicated that the rs11037575 T allele was associated with decreased neuroblastoma risk among the children aged 0–18 months (adjusted OR =0.60, 95% CI =0.37–0.97, P=0.036; regarding the tumor site, this polymorphism protected against tumor in the mediastinum (adjusted OR =0.59, 95% CI =0.37–0.94, P=0.025. When risk genotypes were combined, we found that girls with

Bridging Adult Experience to Pediatrics in Oncology Drug Development.

Science.gov (United States)

Leong, Ruby; Zhao, Hong; Reaman, Gregory; Liu, Qi; Wang, Yaning; Stewart, Clinton F; Burckart, Gilbert

2017-10-01

Pediatric drug development in the United States has grown under the current regulations made permanent by the Food and Drug Administration Safety and Innovation Act of 2012. Over 1200 pediatric studies have now been submitted to the US FDA, but there is still a high rate of failure to obtain pediatric labeling for the indication pursued. Pediatric oncology represents special problems in that the disease is most often dissimilar to any cancer found in the adult population. Therefore, the development of drug dosing in pediatric oncology patients represents a special challenge. Potential approaches to pediatric dosing in oncology patients include extrapolation of efficacy from adult studies in those few cases where the disease is similar, inclusion of adolescent patients in adult trials when possible, and bridging the adult dose to the pediatric dose. An analysis of the recommended phase 2 dose for 40 molecularly targeted agents in pediatric patients provides some insight into current practices. Increased knowledge of tumor biology and efforts to identify and validate molecular targets and genetic abnormalities that drive childhood cancers can lead to increased opportunities for precision medicine in the treatment of pediatric cancers. © 2017, The American College of Clinical Pharmacology.

Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study.

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Allen, Richard J; Porte, Joanne; Braybrooke, Rebecca; Flores, Carlos; Fingerlin, Tasha E; Oldham, Justin M; Guillen-Guio, Beatriz; Ma, Shwu-Fan; Okamoto, Tsukasa; John, Alison E; Obeidat, Ma'en; Yang, Ivana V; Henry, Amanda; Hubbard, Richard B; Navaratnam, Vidya; Saini, Gauri; Thompson, Norma; Booth, Helen L; Hart, Simon P; Hill, Mike R; Hirani, Nik; Maher, Toby M; McAnulty, Robin J; Millar, Ann B; Molyneaux, Philip L; Parfrey, Helen; Rassl, Doris M; Whyte, Moira K B; Fahy, William A; Marshall, Richard P; Oballa, Eunice; Bossé, Yohan; Nickle, David C; Sin, Don D; Timens, Wim; Shrine, Nick; Sayers, Ian; Hall, Ian P; Noth, Imre; Schwartz, David A; Tobin, Martin D; Wain, Louise V; Jenkins, R Gisli

2017-11-01

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high mortality, uncertain cause, and few treatment options. Studies have identified a significant genetic risk associated with the development of IPF; however, mechanisms by which genetic risk factors promote IPF remain unclear. We aimed to identify genetic variants associated with IPF susceptibility and provide mechanistic insight using gene and protein expression analyses. We used a two-stage approach: a genome-wide association study in patients with IPF of European ancestry recruited from nine different centres in the UK and controls selected from UK Biobank (stage 1) matched for age, sex, and smoking status; and a follow-up of associated genetic variants in independent datasets of patients with IPF and controls from two independent US samples from the Chicago consortium and the Colorado consortium (stage 2). We investigated the effect of novel signals on gene expression in large transcriptomic and genomic data resources, and examined expression using lung tissue samples from patients with IPF and controls. 602 patients with IPF and 3366 controls were selected for stage 1. For stage 2, 2158 patients with IPF and 5195 controls were selected. We identified a novel genome-wide significant signal of association with IPF susceptibility near A-kinase anchoring protein 13 (AKAP13; rs62025270, odds ratio [OR] 1·27 [95% CI 1·18-1·37], p=1·32 × 10 -9 ) and confirmed previously reported signals, including in mucin 5B (MUC5B; rs35705950, OR 2·89 [2·56-3·26], p=1·12 × 10 -66 ) and desmoplakin (DSP; rs2076295, OR 1·44 [1·35-1·54], p=7·81 × 10 -28 ). For rs62025270, the allele A associated with increased susceptibility to IPF was also associated with increased expression of AKAP13 mRNA in lung tissue from patients who had lung resection procedures (n=1111). We showed that AKAP13 is expressed in the alveolar epithelium and lymphoid follicles from patients with IPF, and AKAP

Cumulative role of rare and common putative functional genetic variants at NPAS3 in schizophrenia susceptibility.

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González-Peñas, Javier; Arrojo, Manuel; Paz, Eduardo; Brenlla, Julio; Páramo, Mario; Costas, Javier

2015-10-01

Schizophrenia may be considered a human-specific disorder arisen as a maladaptive by-product of human-specific brain evolution. Therefore, genetic variants involved in susceptibility to schizophrenia may be identified among those genes related to acquisition of human-specific traits. NPAS3, a transcription factor involved in central nervous system development and neurogenesis, seems to be implicated in the evolution of human brain, as it is the human gene with most human-specific accelerated elements (HAEs), i.e., .mammalian conserved regulatory sequences with accelerated evolution in the lineage leading to humans after human-chimpanzee split. We hypothesize that any nucleotide variant at the NPAS3 HAEs may lead to altered susceptibility to schizophrenia. Twenty-one variants at these HAEs detected by the 1000 genomes Project, as well as five additional variants taken from psychiatric genome-wide association studies, were genotyped in 538 schizophrenic patients and 539 controls from Galicia. Analyses at the haplotype level or based on the cumulative role of the variants assuming different susceptibility models did not find any significant association in spite of enough power under several plausible scenarios regarding direction of effect and the specific role of rare and common variants. These results suggest that, contrary to our hypothesis, the special evolution of the NPAS3 HAEs in Homo relaxed the strong constraint on sequence that characterized these regions during mammalian evolution, allowing some sequence changes without any effect on schizophrenia risk. © 2015 Wiley Periodicals, Inc.

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

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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.

Possible individual variation in susceptibility to radiation-induced genetic changes

International Nuclear Information System (INIS)

Gentner, N.E.; Walker, J.A.

1990-01-01

Several studies have shown variation between individuals in radiosensitivity. A person could have a high level of cytogenetic indicator because of high exposure or high susceptibility. To relate spontaneous cytogenetic end-points to dose it is advisable to have a measure of both the spontaneous level and of induced susceptibility. These end points need to be compared in irradiated persons who have developed cancer versus those who have not, as a guide to what end points are appropriate for susceptibility to radiogenic cancer. The use of inbred rodent strains may not be appropriate to derive specific locus mutation data relevant to the human situation, in which large differences in susceptibility appear to exist. Variability in response because of differential DNA repair capacity should be kept in mind when evaluating existing human data. For accident situations, using acute exposures for testing susceptibility may be appropriate, but to be relevant to low dose, low dose rate exposures, more use of protracted dose delivery in testing is recommended. There is a need for international collaborative study where these different tests are done on the same donors at the same time. It might now be prudent for radiation protection to take into account the occurrence of critical groups in the population on the basis of their increased radiation sensitivity. (12 refs., 3 figs.)

Clinical and genetic features of pediatric acute lymphoblastic leukemia in Down syndrome in the Nordic countries

Science.gov (United States)

2014-01-01

Background Children with Down syndrome (DS) have an increased risk for acute lymphoblastic leukemia (ALL). Although previous studies have shown that DS-ALL differs clinically and genetically from non-DS-ALL, much remains to be elucidated as regards genetic and prognostic factors in DS-ALL. Methods To address clinical and genetic differences between DS-ALL and non-DS-ALL and to identify prognostic factors in DS-ALL, we ascertained and reviewed all 128 pediatric DS-ALL diagnosed in the Nordic countries between 1981 and 2010. Their clinical and genetic features were compared with those of the 4,647 B-cell precursor (BCP) ALL cases diagnosed during the same time period. Results All 128 DS-ALL were BCP ALL, comprising 2.7% of all such cases. The 5-year event-free survival (EFS) and overall survival (OS) were significantly (P = 0.026 and P = 0.003, respectively) worse for DS-ALL patients with white blood cell counts ≥50 × 109/l. The age distributions varied between the DS and non-DS cases, with age peaks at 2 and 3 years, respectively; none of the DS patients had infant ALL (P = 0.029). The platelet counts were lower in the DS-ALL group (P = 0.005). Abnormal karyotypes were more common in non-DS-ALL (P < 0.0001), and there was a significant difference in the modal number distribution, with only 2% high hyperdiploid DS-ALL cases (P < 0.0001). The 5-year EFS and 5-year OS were significantly worse for DS-ALL (0.574 and 0.691, respectively) compared with non-DS-ALL (0.783 and 0.894, respectively) in the NOPHO ALL-1992/2000 protocols (P < 0.001). Conclusions The present study adds further support for genetic and clinical differences between DS-ALL and non-DS-ALL. PMID:24726034

Genetic susceptibility to type 2 diabetes and obesity

DEFF Research Database (Denmark)

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

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...... progress as regards the concepts, methodologies and derived outcomes of studies of the genetics of type 2 diabetes and obesity, and discuss avenues to be investigated in the future within this research field....

Genetic variants of STAT4 are associated with ankylosing spondylitis susceptibility and severity in a Chinese Han population

OpenAIRE

Liu, Zhixiang; Zhang, Peisen; Dong, Jie

2014-01-01

Objective: Genetic factors play an important role in ankylosing spondylitis (AS) etiology and signal transducer and activator of transcription 4 (STAT4) gene polymorphisms may be involved. The aim of this study was to test whether STAT4 variants were associated with susceptibility to AS in a Chinese population. Methods: A total of 175 subjects who were diagnosed as AS and 249 healthy age-matched controls were enrolled in the present study. The rs7574865 G/T SNP in STAT4 gene was genotyped in ...

The Role of Genetic, Dietary and Lifestyle Factors in Pediatric Metabolic Syndrome: A Review of the Literature from Prenatal to Adolescence

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Teresa Arora

2017-04-01

Full Text Available The metabolic syndrome (MetS is described as a cluster of health conditions that are associated with an increased risk of cardiovascular disease. The clinical diagnosis of MetS in pediatrics is challenging due to differing criteria, although the estimated prevalence continues to rise. The increased prevalence of childhood obesity and insulin resistance, in both developed and developing countries, is believed to be a major contributor to MetS diagnosis in children. We review the current literature surrounding genetic predisposition, maternal influence, epigenetics, environmental and lifestyle factors pertaining to pediatric MetS with a specific emphasis on obesity and insulin resistance. We highlight and discuss recent, key studies in prenatal through to adolescent populations and review evidence suggesting that children may be pre-disposed to obesity and insulin resistance, prenatally. We also discuss several key lifestyle drivers of these conditions including poor nutrition and dietary habits, insufficient physical activity, use of electronic devices, over-consumption of caffeinated and/or sugar-sweetened beverages, as well as the importance of sleep during childhood and adolescence in relation to metabolic health. We conclude with recommendations for preventable methods to tackle this growing pediatric public health issue, which, if current trends continue, will undoubtedly compromise the health and longevity of the next adult generation.

Problems and preferences in pediatric imaging

International Nuclear Information System (INIS)

Thukral, Brij Bhushan

2015-01-01

Radiological imaging is extremely valuable as a diagnostic tool in the pediatric population, but it comes with a number of distinct challenges as compared to the imaging of adults. This is because of the following: It requires dedicated imaging protocols to acquire the images, there is need for sedation or general anesthesia for longer procedures such as MRI, specific training is required for the healthcare personnel involved, thorough knowledge and expertise should be applied for evaluating the images, and most importantly, it requires consideration for radiation exposure if ionizing radiation is being used. One of the challenges for clinical care personnel is to gain the child's trust and co-operation before and throughout the duration of an examination, which can prove to be difficult in children who may be ill and have pain. This is important to acquire quality images and prevent repeat examinations. Even with a quality examination, the accurate interpretation of images requires a thorough knowledge of the intricate and dynamic face of anatomy and specific pathological presentations in children. The increased radiation sensitivity of growing organs and children's longer expected life spans make them more susceptible to the harmful effects of radiation. Imaging pediatric patients in a dedicated pediatric imaging department with dedicated pediatric CT technologists may result in greater compliance with pediatric protocols and significantly reduced patient dose. In order to prevent the harmful effects of ionizing radiation, As Low As Reasonably Achievable (ALARA) principle should be strictly followed. This article seeks to draw attention to various challenges of pediatric imaging and the ways to overcome them

[Profile and susceptibility to antibiotics in urinary tract infections in children and newborns from 2012 to 2013: Data from 1879 urine cultures].

Science.gov (United States)

Marzouk, M; Ferjani, A; Haj Ali, M; Boukadida, J

2015-05-01

We present recent data on the bacteriological profile and antibiotic susceptibility of uropathogenic bacteria isolated in children and newborns in our region over the past 2 years. A retrospective study on the positive urine cultures from pediatric and neonatal populations during 2012-2013. Bacteria were identified using conventional methods. Susceptibility testing was performed and interpreted as recommended by the committee of the susceptibility of the French Society of Microbiology (CA-SFM). We collected 1879 non-redundant bacteria with more than 73% Escherichia coli. Children and infants (mean age, 32 months [range, 1 month to 14 years]) accounted for 84% of the bacteria collected and newborns (mean age, 12 days [range, 1 day to 1 month]) 16%. A female predominance was observed in the pediatric population (M:F sex ratio, 3.2), whereas for the neonatal population, the proportions were almost identical in both sexes (M:F sex ratio, 1.1). Most of the positive urine cultures (n=1234) were from the community. Hospitalized patients (n=636) were divided into pediatric (60%) and neonatal units (40%). Five bacterial genera dominated the bacteriological profile: E. coli, Klebsiella sp., Proteus sp., Enterobacter sp., and Enterococcus. The susceptibility of the main BUP antibiotics used for treatment of frequent UTI showed the effectiveness of furadoine, imipenem, fosfomycin, and colistin. Amoxicillin kept constant activity against Enterococcus and Streptococcus agalactiae. The rates of resistance of Enterobacteriaceae to beta-lactam antibiotics were high, especially in the neonatal population. The production of extended-spectrum beta-lactamase (ESBL) was noted in 12.8% of pediatric Enterobacteria vs. 22.6% of the neonatal strains. For community Enterobacteriaceae, the activity of beta-lactam antibiotics was limited with 11.2% resistance to third-generation cephalosporins (C3G), including 8.6% ESBL production. The impact of widespread use of beta-lactam antibiotics in

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

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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 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.

Genetic Variation in the β2-Adrenocepter Gene Is Associated with Susceptibility to Bacterial Meningitis in Adults

Science.gov (United States)

Adriani, Kirsten S.; Brouwer, Matthijs C.; Baas, Frank; Zwinderman, Aeilko H.; van der Ende, Arie; van de Beek, Diederik

2012-01-01

Recently, the biased β2-adrenoceptor/β-arrestin pathway was shown to play a pivotal role in crossing of the blood brain barrier by Neisseria meningitidis. We hypothesized that genetic variation in the β2-adrenoceptor gene (ADRB2) may influence susceptibility to bacterial meningitis. In a prospective genetic association study we genotyped 542 patients with CSF culture proven community acquired bacterial meningitis and 376 matched controls for 2 functional single nucleotide polymorphisms in the β2-adrenoceptor gene (ADRB2). Furthermore, we analyzed if the use of non-selective beta-blockers, which bind to the β2-adrenoceptor, influenced the risk of bacterial meningitis. We identified a functional polymorphism in ADRB2 (rs1042714) to be associated with an increased risk for bacterial meningitis (Odds ratio [OR] 1.35, 95% confidence interval [CI] 1.04–1.76; p = 0.026). The association remained significant after correction for age and was more prominent in patients with pneumococcal meningitis (OR 1.52, 95% CI 1.12–2.07; p = 0.007). For meningococcal meningitis the difference in genotype frequencies between patients and controls was similar to that in pneumococcal meningitis, but this was not statistically significant (OR 1.43, 95% CI 0.60–3.38; p = 0.72). Patients with bacterial meningitis had a lower frequency of non-selective beta-blockers use compared to the age matched population (0.9% vs. 1.8%), although this did not reach statistical significance (OR 1.96 [95% CI 0.88–4.39]; p = 0.09). In conclusion, we identified an association between a genetic variant in the β2-adrenoceptor and increased susceptibility to bacterial meningitis. The potential benefit of pharmacological treatment targeting the β2-adrenoceptor to prevent bacterial meningitis in the general population or patients with bacteraemia should be further studied in both experimental studies and observational cohorts. PMID:22624056

Applications of Genomic Sequencing in Pediatric CNS Tumors.

Science.gov (United States)

Bavle, Abhishek A; Lin, Frank Y; Parsons, D Williams

2016-05-01

Recent advances in genome-scale sequencing methods have resulted in a significant increase in our understanding of the biology of human cancers. When applied to pediatric central nervous system (CNS) tumors, these remarkable technological breakthroughs have facilitated the molecular characterization of multiple tumor types, provided new insights into the genetic basis of these cancers, and prompted innovative strategies that are changing the management paradigm in pediatric neuro-oncology. Genomic tests have begun to affect medical decision making in a number of ways, from delineating histopathologically similar tumor types into distinct molecular subgroups that correlate with clinical characteristics, to guiding the addition of novel therapeutic agents for patients with high-risk or poor-prognosis tumors, or alternatively, reducing treatment intensity for those with a favorable prognosis. Genomic sequencing has also had a significant impact on translational research strategies in pediatric CNS tumors, resulting in wide-ranging applications that have the potential to direct the rational preclinical screening of novel therapeutic agents, shed light on tumor heterogeneity and evolution, and highlight differences (or similarities) between pediatric and adult CNS tumors. Finally, in addition to allowing the identification of somatic (tumor-specific) mutations, the analysis of patient-matched constitutional (germline) DNA has facilitated the detection of pathogenic germline alterations in cancer genes in patients with CNS tumors, with critical implications for genetic counseling and tumor surveillance strategies for children with familial predisposition syndromes. As our understanding of the molecular landscape of pediatric CNS tumors continues to advance, innovative applications of genomic sequencing hold significant promise for further improving the care of children with these cancers.

Pediatric - specific Antimicrobial Resistance Patterns of Urinary Tract Infections: A Single - Centre Experience from Turkey

OpenAIRE

Kandur, Yasar; Ozden, Sevinc; Buyukkaragoz, Bahar

2016-01-01

Objectives: Antimicrobial resistance of the causative microorganisms of pediatric urinary tract infection (UTI) is a growing problem. The aim of this study is to determine the changing pattern of antibiotic susceptibility in UTIs in an outpatient setting. Methods: We retrospectively reviewed the medical records of pediatric patients with UTI who were followed-up in our center between January-2014 and May-2015. Results: One hundred and seventy-one patients (M...

An in-depth characterization of the major psoriasis susceptibility locus identifies candidate susceptibility alleles within an HLA-C enhancer element.

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Alex Clop

Full Text Available Psoriasis is an immune-mediated skin disorder that is inherited as a complex genetic trait. Although genome-wide association scans (GWAS have identified 36 disease susceptibility regions, more than 50% of the genetic variance can be attributed to a single Major Histocompatibility Complex (MHC locus, known as PSORS1. Genetic studies indicate that HLA-C is the strongest PSORS1 candidate gene, since markers tagging HLA-Cw*0602 consistently generate the most significant association signals in GWAS. However, it is unclear whether HLA-Cw*0602 is itself the causal PSORS1 allele, especially as the role of SNPs that may affect its expression has not been investigated. Here, we have undertaken an in-depth molecular characterization of the PSORS1 interval, with a view to identifying regulatory variants that may contribute to disease susceptibility. By analysing high-density SNP data, we refined PSORS1 to a 179 kb region encompassing HLA-C and the neighbouring HCG27 pseudogene. We compared multiple MHC sequences spanning this refined locus and identified 144 candidate susceptibility variants, which are unique to chromosomes bearing HLA-Cw*0602. In parallel, we investigated the epigenetic profile of the critical PSORS1 interval and uncovered three enhancer elements likely to be active in T lymphocytes. Finally we showed that nine candidate susceptibility SNPs map within a HLA-C enhancer and that three of these variants co-localise with binding sites for immune-related transcription factors. These data indicate that SNPs affecting HLA-Cw*0602 expression are likely to contribute to psoriasis susceptibility and highlight the importance of integrating multiple experimental approaches in the investigation of complex genomic regions such as the MHC.

Evaluation of polymorphisms in pbp4 gene and genetic diversity in penicillin-resistant, ampicillin-susceptible Enterococcus faecalis from hospitals in different states in Brazil.

Science.gov (United States)

Infante, Victor Hugo Pacagnelli; Conceição, Natália; de Oliveira, Adriana Gonçalves; Darini, Ana Lúcia da Costa

2016-04-01

The aim of the present study was to verify whether penicillin-resistant, ampicillin-susceptible Enterococcus faecalis (PRASEF) occurred in Brazil prior to the beginning of the 21st century, and to verify whether ampicillin susceptibility can predict susceptibility to other β-lactams in E. faecalis with this inconsistent phenotype. The presence of polymorphisms in the pbp4 gene and genetic diversity among the isolates were investigated. Of 21 PRASEF analyzed, 5 (23.8%) and 4 (19.0%) were imipenem and piperacillin resistant simultaneously by disk diffusion and broth dilution respectively, contradicting the current internationally accepted standards of susceptibility testing. Sequencing of pbp4 gene revealed an amino acid substitution (Asp-573→Glu) in all PRASEF isolates but not in the penicillin-susceptible, ampicillin-susceptible E. faecalis. Most PRASEF (90.5%) had related pulsed-field gel electrophoresis profiles, but were different from other PRASEF described to date. Results demonstrate that penicillin-resistant, ampicillin-susceptible phenotype was already a reality in the 1990s in E. faecalis isolates in different Brazilian states, and some of these isolates were also imipenem- and piperacillin-resistant; therefore, internationally accepted susceptibility criteria cannot be applied to these isolates. According to pbp4 gene sequencing, this study suggests that a specific amino acid substitution in pbp4 gene found in all PRASEF analyzed is associated with penicillin resistance. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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.

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

An overview of posttraumatic stress disorder genetic studies by analyzing and integrating genetic data into genetic database PTSDgene

NARCIS (Netherlands)

Zhang, Kunlin; Qu, Susu; Chang, Suhua; Li, Gen; Cao, Chengqi; Fang, Kechi; Olff, Miranda; Wang, Li; Wang, Jing

2017-01-01

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric syndrome with complex etiology. Studies aiming to explore genetic susceptibility and environmental triggers of PTSD have been increasing. However, the results are limited and highly heterogeneous. To understand the genetic study

Murine adipose tissue-derived stromal cell apoptosis and susceptibility to oxidative stress in vitro are regulated by genetic background.

Directory of Open Access Journals (Sweden)

Robert Pazdro

Full Text Available Adipose tissue-derived stromal cells (ADSCs are of interest for regenerative medicine as they are isolated easily and can differentiate into multiple cell lineages. Studies of their in vitro proliferation, survival, and differentiation are common; however, genetic effects on these phenotypes remain unknown. To test if these phenotypes are genetically regulated, ADSCs were isolated from three genetically diverse inbred mouse strains--C57BL/6J (B6, BALB/cByJ (BALB, and DBA/2J (D2--in which genetic regulation of hematopoietic stem function is well known. ADSCs from all three strains differentiated into osteogenic and chondrogenic lineages in vitro. ADSCs from BALB grew least well in vitro, probably due to apoptotic cell death after several days in culture. BALB ADSCs were also the most susceptible to the free radical inducers menadione and H2O2. ADSCs from the three possible F1 hybrids were employed to further define genetic regulation of ADSC phenotypes. D2, but not B6, alleles stimulated ADSC expansion in BALB cells. In contrast, B6, but not D2, alleles rescued BALB H2O2 resistance. We conclude that low oxidative stress resistance does not limit BALB ADSC growth in vitro, as these phenotypes are genetically regulated independently. In addition, ADSCs from these strains are an appropriate model system to investigate genetic regulation of ADSC apoptosis and stress resistance in future studies. Such investigations are essential to optimize cell expansion and differentiation and thus, potential for regenerative medicine.

Allele-specific deletions in mouse tumors identify Fbxw7 as germline modifier of tumor susceptibility.

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Jesus Perez-Losada

Full Text Available Genome-wide association studies (GWAS have been successful in finding associations between specific genetic variants and cancer susceptibility in human populations. These studies have identified a range of highly statistically significant associations between single nucleotide polymorphisms (SNPs and susceptibility to development of a range of human tumors. However, the effect of each SNP in isolation is very small, and all of the SNPs combined only account for a relatively minor proportion of the total genetic risk (5-10%. There is therefore a major requirement for alternative routes to the discovery of genetic risk factors for cancer. We have previously shown using mouse models that chromosomal regions harboring susceptibility genes identified by linkage analysis frequently exhibit allele-specific genetic alterations in tumors. We demonstrate here that the Fbxw7 gene, a commonly mutated gene in a wide range of mouse and human cancers, shows allele-specific deletions in mouse lymphomas and skin tumors. Lymphomas from three different F1 hybrids show 100% allele-specificity in the patterns of allelic loss. Parental alleles from 129/Sv or Spretus/Gla mice are lost in tumors from F1 hybrids with C57BL/6 animals, due to the presence of a specific non-synonymous coding sequence polymorphism at the N-terminal portion of the gene. A specific genetic test of association between this SNP and lymphoma susceptibility in interspecific backcross mice showed a significant linkage (p = 0.001, but only in animals with a functional p53 gene. These data therefore identify Fbxw7 as a p53-dependent tumor susceptibility gene. Increased p53-dependent tumor susceptibility and allele-specific losses were also seen in a mouse skin model of skin tumor development. We propose that analysis of preferential allelic imbalances in tumors may provide an efficient means of uncovering genetic variants that affect mouse and human tumor susceptibility.

Genetics of osteoarthritis.

Science.gov (United States)

Rodriguez-Fontenla, Cristina; Gonzalez, Antonio

2015-01-01

Osteoarthritis (OA) is a complex disease caused by the interaction of multiple genetic and environmental factors. This review focuses on the studies that have contributed to the discovery of genetic susceptibility factors in OA. The most relevant associations discovered until now are discussed in detail: GDF-5, 7q22 locus, MCF2L, DOT1L, NCOA3 and also some important findings from the arcOGEN study. Moreover, the different approaches that can be used to minimize the specific problems of the study of OA genetics are discussed. These include the study of microsatellites, phenotype standardization and other methods such as meta-analysis of GWAS and gene-based analysis. It is expected that these new approaches contribute to finding new susceptibility genetic factors for OA. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Carriage, antimicrobial susceptibility profiles and genetic diversity of ...

African Journals Online (AJOL)

All isolates were susceptible to nitrofurantoin and linezolid and resistant in high numbers (194, 81.9%) to ampicillin. Resistances to amoxicillin-clavulanic acid, erythromycin, chloramphenicol, gentamicin, ciprofloxacin, norfloxacin and trimethoprimsulfamethoxazole were below 20%. The overall prevalence of MRSA among ...

Novel disease susceptibility factors for fungal necrotrophic pathogens in Arabidopsis.

Science.gov (United States)

Dobón, Albor; Canet, Juan Vicente; García-Andrade, Javier; Angulo, Carlos; Neumetzler, Lutz; Persson, Staffan; Vera, Pablo

2015-04-01

Host cells use an intricate signaling system to respond to invasions by pathogenic microorganisms. Although several signaling components of disease resistance against necrotrophic fungal pathogens have been identified, our understanding for how molecular components and host processes contribute to plant disease susceptibility is rather sparse. Here, we identified four transcription factors (TFs) from Arabidopsis that limit pathogen spread. Arabidopsis mutants defective in any of these TFs displayed increased disease susceptibility to Botrytis cinerea and Plectosphaerella cucumerina, and a general activation of non-immune host processes that contribute to plant disease susceptibility. Transcriptome analyses revealed that the mutants share a common transcriptional signature of 77 up-regulated genes. We characterized several of the up-regulated genes that encode peptides with a secretion signal, which we named PROVIR (for provirulence) factors. Forward and reverse genetic analyses revealed that many of the PROVIRs are important for disease susceptibility of the host to fungal necrotrophs. The TFs and PROVIRs identified in our work thus represent novel genetic determinants for plant disease susceptibility to necrotrophic fungal pathogens.

Novel disease susceptibility factors for fungal necrotrophic pathogens in Arabidopsis.

Directory of Open Access Journals (Sweden)

Albor Dobón

2015-04-01

Full Text Available Host cells use an intricate signaling system to respond to invasions by pathogenic microorganisms. Although several signaling components of disease resistance against necrotrophic fungal pathogens have been identified, our understanding for how molecular components and host processes contribute to plant disease susceptibility is rather sparse. Here, we identified four transcription factors (TFs from Arabidopsis that limit pathogen spread. Arabidopsis mutants defective in any of these TFs displayed increased disease susceptibility to Botrytis cinerea and Plectosphaerella cucumerina, and a general activation of non-immune host processes that contribute to plant disease susceptibility. Transcriptome analyses revealed that the mutants share a common transcriptional signature of 77 up-regulated genes. We characterized several of the up-regulated genes that encode peptides with a secretion signal, which we named PROVIR (for provirulence factors. Forward and reverse genetic analyses revealed that many of the PROVIRs are important for disease susceptibility of the host to fungal necrotrophs. The TFs and PROVIRs identified in our work thus represent novel genetic determinants for plant disease susceptibility to necrotrophic fungal pathogens.

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

Evaluation of antimicrobial susceptibilities and virulence factors of Staphylococcus aureus strains isolated from community-acquired and health-care associated pediatric infections.

Science.gov (United States)

Karbuz, Adem; Karahan, Zeynep Ceren; Aldemir-Kocabaş, Bilge; Tekeli, Alper; Özdemir, Halil; Güriz, Haluk; Gökdemir, Refik; İnce, Erdal; Çiftçi, Ergin

2017-01-01

Karbuz A, Karahan ZC, Aldemir-Kocabaş B, Tekeli A, Özdemir H, Güriz H, Gökdemir R, İnce E, Çiftçi E. Evaluation of antimicrobial susceptibilities and virulence factors of Staphylococcus aureus strains isolated from community-acquired and health-care associated pediatric infections. Turk J Pediatr 2017; 59: 395-403. The aim of this study was to investigate the enterotoxins and Panton-Valentine leukocidin (PVL) gene as virulence factor, identification if antimicrobial sensitivity patterns, agr (accessory gene regulator) types and sequence types and in resistant cases to obtain SCCmec (staphylococcal cassette chromosome mec) gene types which will be helpful to decide empirical therapy and future health politics for S. aureus species. Total of 150 isolates of S. aureus were isolated from the cultures of the child patients in January 2011 and December 2012. In this study, the penicillin resistance was observed as 93.8%. PVL and mecA was detected positive in 8.7% and in 6% of all S. aureus strains, respectively. Two MRSA (methicillin resistant S.aureus) strains were detected as SCCmec type III and SCCmec type V and five MRSA strains were detected as SCCmec type IV. SET-I and SET-G were the most common detected enterotoxins. In both community-associated and healthcare-associated MRSA strains, agr type 1 was detected most commonly. The most common sequence types were ST737 in 13 patients than ST22 in eight patients and ST121 in six patients. This study highlights a necessity to review the cause of small changes in the structural genes in order to determine whether it is a cause or outcome; community-acquired and healthcare associated strains overlap.

Pediatric chronic pancreatitis is associated with genetic risk factors and substantial disease burden.

Science.gov (United States)

Schwarzenberg, Sarah Jane; Bellin, Melena; Husain, Sohail Z; Ahuja, Monika; Barth, Bradley; Davis, Heather; Durie, Peter R; Fishman, Douglas S; Freedman, Steven D; Gariepy, Cheryl E; Giefer, Matthew J; Gonska, Tanja; Heyman, Melvin B; Himes, Ryan; Kumar, Soma; Morinville, Veronique D; Lowe, Mark E; Nuehring, Neil E; Ooi, Chee Y; Pohl, John F; Troendle, David; Werlin, Steven L; Wilschanski, Michael; Yen, Elizabeth; Uc, Aliye

2015-04-01

To determine the clinical presentation, diagnostic variables, risk factors, and disease burden in children with chronic pancreatitis. We performed a cross-sectional study of data from the International Study Group of Pediatric Pancreatitis: In Search for a Cure, a registry of children with acute recurrent pancreatitis and chronic pancreatitis. Between-group differences were compared using Wilcoxon rank-sum test. Among 170 subjects in the registry, 76 (45%) had chronic pancreatitis; 57% were female, 80% were white; median age at diagnosis was 9.9 years. Pancreatitis-predisposing genetic mutations were identified in 51 (67%) and obstructive risk factors in 25 (33%). Toxic/metabolic and autoimmune factors were uncommon. Imaging demonstrated ductal abnormalities and pancreatic atrophy more commonly than calcifications. Fifty-nine (77%) reported abdominal pain within the past year; pain was reported as constant and receiving narcotics in 28%. Children with chronic pancreatitis reported a median of 3 emergency department visits and 2 hospitalizations in the last year. Forty-seven subjects (70%) missed 1 day of school in the past month as the result of chronic pancreatitis; 26 (34%) missed 3 or more days. Children reporting constant pain were more likely to miss school (P = .002), visit the emergency department (P = .01), and experience hospitalizations (P = .03) compared with children with episodic pain. Thirty-three children (43%) underwent therapeutic endoscopic retrograde pancreatography; one or more pancreatic surgeries were performed in 30 (39%). Chronic pancreatitis occurs at a young age with distinct clinical features. Genetic and obstructive risk factors are common, and disease burden is substantial. Copyright © 2015 Elsevier Inc. All rights reserved.

Genetic testing in the epilepsies—Report of the ILAE Genetics Commission

OpenAIRE

Ottman, Ruth; Hirose, Shinichi; Jain, Satish; Lerche, Holger; Lopes-Cendes, Iscia; Noebels, Jeffrey L.; Serratosa, José; Zara, Federico; Scheffer, Ingrid E.

2010-01-01

In this report, the International League Against Epilepsy (ILAE) Genetics Commission discusses essential issues to be considered with regard to clinical genetic testing in the epilepsies. Genetic research on the epilepsies has led to the identification of more than 20 genes with a major effect on susceptibility to idiopathic epilepsies. The most important potential clinical application of these discoveries is genetic testing: the use of genetic information, either to clarify the diagnosis in ...

Journal of Genetics | Indian Academy of Sciences

Indian Academy of Sciences (India)

phenylketonuria; phenylalanine hydroxylase; gene mutation; human genetics. ... of Clinical Medical Research, Urumqi General Hospital of Lanzhou Command, PLA, Urumqi 830000, People's Republic of China; Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, People's Republic of China ...

Pediatric nephrology practice in Jordan

Directory of Open Access Journals (Sweden)

Kamal Akl

2017-01-01

Full Text Available The practice of pediatric nephrology in a developing country such as Jordan is governed by social, cultural, and economic issues. The prevalence of consanguinity contributes to the emergence of rare heredofamilial disorders and congenital anomalies of the kidneys and urinary tract. Epigenetic factors modify underlying genetic defect predisposing to symptomatic crystalluria. Future research should be directed at prevention.

Family-based exome-wide assessment of maternal genetic effects on susceptibility to childhood B-cell acute lymphoblastic leukemia in Hispanics

Science.gov (United States)

Archer, Natalie P.; Perez-Andreu, Virginia; Scheurer, Michael E.; Rabin, Karen R.; Peckham-Gregory, Erin C.; Plon, Sharon E.; Zabriskie, Ryan C.; De Alarcon, Pedro A.; Fernandez, Karen S.; Najera, Cesar R.; Yang, Jun J.; Antillon-Klussmann, Federico; Lupo, Philip J.

2016-01-01

Background Children of Hispanic ancestry have a higher incidence of acute lymphoblastic leukemia (ALL) than other ethnic groups, but the genetic basis for racial disparities remain incompletely understood. Genome-wide association studies (GWAS) of childhood ALL to date have focused on inherited genetic effects; however, maternal genetic effects (the role of maternal genotype on offspring phenotype development) may also play a role in ALL susceptibility. Methods We conducted a family-based exome-wide association study (EXWAS) of maternal genetic effects among Hispanics with childhood B-cell ALL (B-ALL) using the Illumina Human Exome BeadChip. We used a discovery cohort of 312 Guatemalan and Hispanic American families and an independent replication cohort of 152 Hispanic American families. Results Three maternal SNPs approached our threshold for significance, after correction for multiple testing (P<1.0×10−6): MTL5 rs12365708 (RR=2.62, 95% CI=1.61-4.27, P=1.8×10−5); ALKBH1 rs6494 (RR=3.77, 95% CI=1.84-7.74, P=3.7×10−5); NEUROG3 rs4536103 (RR=1.75, 95% CI=1.30-2.37, P=1.2×10−4). While effect sizes were similar, these SNPs were not nominally significant in our replication cohort. In a meta-analysis comprised of the discovery cohort and the replication cohort, these SNPs were still not statistically significant after correction for multiple comparisons (rs12365708: pooled RR=2.27, 95% CI=1.48-3.50, P=1.99×10−4; rs6494: pooled RR=2.31, 95% CI=1.38-3.85, P=0.001; rs4536103: pooled RR=1.67, 95% CI=1.29-2.16, P=9.23×10−5). Conclusions In the first family-based EXWAS to investigate maternal genotype effects associated with childhood ALL, our results did not implicate a strong role of maternal genotype on disease risk among Hispanics; however, we identified three maternal SNPs that may play a modest role in susceptibility. PMID:27529658

Genetic and molecular functional characterization of variants within TNFSF13B, a positional candidate preeclampsia susceptibility gene on 13q.

Directory of Open Access Journals (Sweden)

Mona H Fenstad

Full Text Available BACKGROUND: Preeclampsia is a serious pregnancy complication, demonstrating a complex pattern of inheritance. The elucidation of genetic liability to preeclampsia remains a major challenge in obstetric medicine. We have adopted a positional cloning approach to identify maternal genetic components, with linkages previously demonstrated to chromosomes 2q, 5q and 13q in an Australian/New Zealand familial cohort. The current study aimed to identify potential functional and structural variants in the positional candidate gene TNFSF13B under the 13q linkage peak and assess their association status with maternal preeclampsia genetic susceptibility. METHODOLOGY/PRINCIPAL FINDINGS: The proximal promoter and coding regions of the positional candidate gene TNFSF13B residing within the 13q linkage region was sequenced using 48 proband or founder individuals from Australian/New Zealand families. Ten sequence variants (nine SNPs and one single base insertion were identified and seven SNPs were successfully genotyped in the total Australian/New Zealand family cohort (74 families/480 individuals. Borderline association to preeclampsia (p = 0.0153 was observed for three rare SNPs (rs16972194, rs16972197 and rs56124946 in strong linkage disequilibrium with each other. Functional evaluation by electrophoretic mobility shift assays showed differential nuclear factor binding to the minor allele of the rs16972194 SNP, residing upstream of the translation start site, making this a putative functional variant. The observed genetic associations were not replicated in a Norwegian case/control cohort (The Nord-Trøndelag Health Study (HUNT2, 851 preeclamptic and 1,440 non-preeclamptic women. CONCLUSION/SIGNIFICANCE: TNFSF13B has previously been suggested to contribute to the normal immunological adaption crucial for a successful pregnancy. Our observations support TNFSF13B as a potential novel preeclampsia susceptibility gene. We discuss a possible role for TNFSF13B in

Susceptibility of Biomphalaria spp. to infection with Schistosoma mansoni in sympatric and allopatric combinations with observations on the genetic variability between snails.

Science.gov (United States)

Mostafa, Osama M S; El-Dafrawy, Shadia M

2011-08-25

This investigation was carried out to study the susceptibility of Saudi Biomphalaria arabica to Egyptian Schistosoma mansoni in comparison with the susceptibility of Egyptian Biomphalaria alexandrina to the same parasite. This was in order to know the possibility that the parasite might be able to spread into Saudi Arabia and to determine the genetic variability between Egyptian B. alexandrina and Saudi Biomphalaria arabica snails. Lab bred Egyptian B. alexandrina and Saudi B. arabica snails were exposed individually to 10 freshly hatched Egyptian S. mansoni miracidia/snail. The mortality rate, infection rate, prepatent period, duration of cercarial shedding and cercariae production per snail were recorded in both the sympatric couple (Egyptian B. alexandrina and Egyptian S. mansoni) and in the allopatric combination (Saudi B. arabica and Egyptian S. mansoni). The results revealed that, the survival rate of snails exposed to Egyptian S. mansoni miracidia at 34th day post-exposure (at first cercarial shedding) was higher in B. arabica than in B. alexandrina. After shedding, the mortality rate was higher in the B. arabica, compared to B. alexandrina. The infection rate was higher in B. arabica than B. alexandrina; the mean of prepatent period was shorter in the B. arabica than in the B. alexandrina. However, the duration of cercarial shedding was longer in the Egyptian snails and the cercarial production per snail was higher in B. alexandrina snails than in B. arabica. To study the genetic variability between B. alexandrina and B. arabica, RAPD-PCR on the genomic DNA of snails was done. RAPD-PCR revealed significant variation between the two snail species. In conclusion, the results suggest that B. arabica can play a role in the transmission of Egyptian S. mansoni in Saudi Arabia and therefore this parasite might be able to spread into the Kingdom. In addition, the RAPD-PCR results demonstrated genetic variability between the two species which may be related to the

Pediatrics in 21st Century and Beyond.

Science.gov (United States)

Singh, Meharban

2016-11-01

Pediatrics is a dynamic discipline and there is awareness and hope for actualizing outstanding achievements in the field of child health in 21 st century and beyond. Improved lifestyle and quality of children's health is likely to reduce the burden of adult diseases and enhance longevity because seeds of most adult diseases are sown in childhood. Identification and decoding of human genome is expected to revolutionize the practice of pediatrics. The day is not far off when a patient will walk into doctor's chamber with an electronic or digital health history on a CD or palmtop and a decoded genomic constitution. There will be reduced burden of genetic diseases because of selective abortions of "defective" fetuses and replacement of "bad" genes with "good" ones by genetic engineering. Availability of totipotent stem cells and developments in transplant technology are likely to revolutionize the management of a variety of hematologic cancers and life-threatening genetic disorders. The possibility of producing flawless designer babies by advances in assisted reproductive technologies (ARTs) is likely to be mired by several ethical and legal issues.The availability of newer vaccines by recombinant technology for emerging infective and for non-infective lifestyle diseases is likely to improve survival and quality of life. There is going to be a greater focus on the "patient" having the disease rather than "disease" per se by practicing holistic pediatrics by effective utilization of alternative or complementary strategies for health care. Due to advances in technology, pediatrics may get further dehumanized. A true healer cannot simply rely on technology; there must be a spiritual bond between the patient and the physician by exploiting the concept of psycho-neuro-immunology and body-mind interactions. In the years to come, physicians are likely to play "god" but medicine can't achieve immortality because anything born must die in accordance with nature's recycling

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

Genetic susceptibility of newborn daughters to oxidative stress

DEFF Research Database (Denmark)

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

2007-01-01

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 ...

Genetic risk profiles for a childhood with severe overweight.

Science.gov (United States)

González, J R; Estévez, M N; Giralt, P S; Cáceres, A; Pérez, L M L; González-Carpio, M; Ballester, F; Sunyer, J; Rodríguez-López, R

2014-08-01

The objective of this study was the description of a valid genetic risk score (GRS) to predict individuals with high susceptibility to childhood overweight by their genetic profiles. Case-control study including a group of children with high-risk familial predisposition to morbid obesity. Birth cohort from general population constituted the validation sample. For the discovery sample, 218 children with non-syndromic obesity and 190 control individuals were included. The validation sample was 653 children from two birth cohorts belonging to the INMA (Infancia y Medio Ambiente [Environment and Childhood] )project. 109 SNPs located in the genes FTO, SEC16B, BDNF, ETV5, SH2B1, GNPDA2, LYPLAL1, MSRA, TFAP2, KCTD15, MTCH2 and NEGR1, previously reported in association to body mass index (BMI) were analysed. For the validation sample, association between genome-wide data and BMI measurements between 3.5 and 5 years of age, were evaluated. The GRS includes six SNPs in the genes FTO, TFAP2B, SEC16B, ETV5 and SH2B1. The score distribution differs among cases and controls (P = 9.2 × 10(-14) ) showing a significant linear association with obesity (odds ratio [OR] per allele = 1.69; confidence interval [CI] 95% = 1.46-1.97; P = 4.3 × 10(-1) and area under the receiver operating characteristic curve [AUC] = 0.727; CI 95% = 0.676-0.778). The results were validated by the INMA cohort (OR per allele = 1.23 CI 95% = 1.03-1.48 and AUC = 0.601 CI 95% = 0.522-0.680). The use of our proposed genetic score provides useful information to determine those children who are susceptible to obesity. To improve the efficiency of clinical prevention and treatment of obesity, it is essential to design individualized based protocols in advance knowledge of the molecular basis of inherited susceptibility. © 2013 The Authors. Pediatric Obesity © 2013 International Association for the Study of Obesity.

[Genetics and epigenetics in autism].

Science.gov (United States)

Nakayama, Atsuo; Masaki, Shiego; Aoki, Eiko

2006-11-01

Autism is a behaviorally defined syndrome characterized by impaired social interaction and communication, and restricted, stereotyped interests and behaviors. Several lines of evidence support the contention that genetic factors are a large component to autism etiology. However, in spite of vigorous genetic studies, no single causative or susceptibility gene common in autism has been identified. Thus multiple susceptibility genes in interaction are considered to account for the disorder. Furthermore, environmental risk factors can accelerate the autism development of. Recent advances in understanding the epigenetic regulation may shed light on the interaction among multiple genetic factors and environmental factors.

India, Genomic diversity & Disease susceptibility

Indian Academy of Sciences (India)

Table of contents. India, Genomic diversity & Disease susceptibility · India, a paradise for Genetic Studies · Involved in earlier stages of Immune response protecting us from Diseases, Responsible for kidney and other transplant rejections Inherited from our parents · PowerPoint Presentation · Slide 5 · Slide 6 · Slide 7.

Genetics and epigenetics of rheumatoid arthritis

Science.gov (United States)

Viatte, Sebastien; Plant, Darren; Raychaudhuri, Soumya

2013-01-01

Investigators have made key advances in rheumatoid arthritis (RA) genetics in the past 10 years. Although genetic studies have had limited influence on clinical practice and drug discovery, they are currently generating testable hypotheses to explain disease pathogenesis. Firstly, we review here the major advances in identifying RA genetic susceptibility markers both within and outside of the MHC. Understanding how genetic variants translate into pathogenic mechanisms and ultimately into phenotypes remains a mystery for most of the polymorphisms that confer susceptibility to RA, but functional data are emerging. Interplay between environmental and genetic factors is poorly understood and in need of further investigation. Secondly, we review current knowledge of the role of epigenetics in RA susceptibility. Differences in the epigenome could represent one of the ways in which environmental exposures translate into phenotypic outcomes. The best understood epigenetic phenomena include post-translational histone modifications and DNA methylation events, both of which have critical roles in gene regulation. Epigenetic studies in RA represent a new area of research with the potential to answer unsolved questions. PMID:23381558

Association between two polymorphisms of the bone morpho-genetic protein-2 gene with genetic susceptibility to ossification of the posterior longitudinal ligament of the cervical spine and its severity

Institute of Scientific and Technical Information of China (English)

WANG Hao; YANG Zhao-hui; LIU Dong-mei; WANG Ling; MENG Xiang-long; TIAN Bao-peng

2008-01-01

Background Ossification of the posterior longitudinal ligament (OPLL) has a strong genetic background. Previous studies have shown that bone morphogenetic protein-2 (BMP2) and BMP2 mRNA are expressed in ossifying matrix and chondrocytes adjacent to cartilaginous areas of OPLL tissues and mesenchymal cells with fibroblastic features in the immediate vicinity of the cartilaginous areas. It is suggested that BMP2 plays different roles in the different stages of development of OPLL. However, it remains unknown which factors induce ligament cells to produce BMP2.Methods OPLL patients (n=192) and non-OPLL controls (n=304) were studied. Radiographs of the cervical spine were analyzed for extent of OPLL. We investigated whether single nucleotide polymorphisms of exons 3(-726) TIC and 3(-583) A/G in the BMP2 gene are statistically associated with genetic susceptibility to OPLL in Chinese Han subjects.Results There was no statistical difference between the occurrence of exons 3(-726) TIC and 3(-583) A/G and the occurrence of OPLL in the cervical spine. However, there was a significant association between occurrence of exon 3(-726) TIC polymorphism and occurrence of OPLL in males of cases and controls in the cervical spine. In addition, no significant association was found between the exons 3(-726) TIC and 3(-583) A/G with number of ossified cervical vertebrae in OPLL patients.Conclusions Exon 3(-583) A/G polymorphism in BMP2 gene is not associated with the occurrence and the extent of OPLL in the cervical spine. Chinese Han male patients with TC and CC genotypes in exon 3(-726) T/C have genetic susceptibility to OPLL but not to more extensive OPLL in the cervical spine.

Genetic and environmental contributions to hay fever among young adult twins

DEFF Research Database (Denmark)

Thomsen, Simon Francis; Suppli Ulrik, Charlotte; Kyvik, Kirsten Ohm

2006-01-01

environment, whereas the aetiology of 'sporadic' hay fever was mainly genetic. CONCLUSIONS: The susceptibility to develop hay fever is attributable to major genetic influences. However, effects of family environment and upbringing are also of importance in families where asthma is present. These results......BACKGROUND: The susceptibility to develop hay fever is putatively the result both of genetic and environmental causes. We estimated the significance and magnitude of genetic and environmental contributions to hay fever among young adult twins. METHODS: From the birth cohorts 1953-82 of The Danish...... effects accounted for 29% of the individual susceptibility to hay fever. The same genes contributed to the susceptibility to hay fever both in males and in females. In families with asthma, the susceptibility to develop hay fever was, in addition to genes, to a great extent ascribable to family...

A model to estimate effects of SNPs on host susceptibility and infectivity for an endemic infectious disease.

Science.gov (United States)

Biemans, Floor; de Jong, Mart C M; Bijma, Piter

2017-06-30

Infectious diseases in farm animals affect animal health, decrease animal welfare and can affect human health. Selection and breeding of host individuals with desirable traits regarding infectious diseases can help to fight disease transmission, which is affected by two types of (genetic) traits: host susceptibility and host infectivity. Quantitative genetic studies on infectious diseases generally connect an individual's disease status to its own genotype, and therefore capture genetic effects on susceptibility only. However, they usually ignore variation in exposure to infectious herd mates, which may limit the accuracy of estimates of genetic effects on susceptibility. Moreover, genetic effects on infectivity will exist as well. Thus, to design optimal breeding strategies, it is essential that genetic effects on infectivity are quantified. Given the potential importance of genetic effects on infectivity, we set out to develop a model to estimate the effect of single nucleotide polymorphisms (SNPs) on both host susceptibility and host infectivity. To evaluate the quality of the resulting SNP effect estimates, we simulated an endemic disease in 10 groups of 100 individuals, and recorded time-series data on individual disease status. We quantified bias and precision of the estimates for different sizes of SNP effects, and identified the optimum recording interval when the number of records is limited. We present a generalized linear mixed model to estimate the effect of SNPs on both host susceptibility and host infectivity. SNP effects were on average slightly underestimated, i.e. estimates were conservative. Estimates were less precise for infectivity than for susceptibility. Given our sample size, the power to estimate SNP effects for susceptibility was 100% for differences between genotypes of a factor 1.56 or more, and was higher than 60% for infectivity for differences between genotypes of a factor 4 or more. When disease status was recorded 11 times on each

Empiric Antibiotic Use and Susceptibility in Infants With Bacterial Infections: A Multicenter Retrospective Cohort Study.

Science.gov (United States)

Feldman, Elana A; McCulloh, Russell J; Myers, Angela L; Aronson, Paul L; Neuman, Mark I; Bradford, Miranda C; Alpern, Elizabeth R; Balamuth, Frances; Blackstone, Mercedes M; Browning, Whitney L; Hayes, Katie; Korman, Rosalynne; Leazer, Rianna C; Nigrovic, Lise E; Marble, Richard; Roben, Emily; Williams, Derek J; Tieder, Joel S

2017-07-20

To assess hospital differences in empirical antibiotic use, bacterial epidemiology, and antimicrobial susceptibility for common antibiotic regimens among young infants with urinary tract infection (UTI), bacteremia, or bacterial meningitis. We reviewed medical records from infants <90 days old presenting to 8 US children's hospitals with UTI, bacteremia, or meningitis. We used the Pediatric Health Information System database to identify cases and empirical antibiotic use and medical record review to determine infection, pathogen, and antimicrobial susceptibility patterns. We compared hospital-level differences in antimicrobial use, pathogen, infection site, and antimicrobial susceptibility. We identified 470 infants with bacterial infections: 362 (77%) with UTI alone and 108 (23%) with meningitis or bacteremia. Infection type did not differ across hospitals ( P = .85). Empirical antibiotic use varied across hospitals ( P < .01), although antimicrobial susceptibility patterns for common empirical regimens were similar. A third-generation cephalosporin would have empirically treated 90% of all ages, 89% in 7- to 28-day-olds, and 91% in 29- to 89-day-olds. The addition of ampicillin would have improved coverage in only 4 cases of bacteremia and meningitis. Ampicillin plus gentamicin would have treated 95%, 89%, and 97% in these age groups, respectively. Empirical antibiotic use differed across regionally diverse US children's hospitals in infants <90 days old with UTI, bacteremia, or meningitis. Antimicrobial susceptibility to common antibiotic regimens was similar across hospitals, and adding ampicillin to a third-generation cephalosporin minimally improves coverage. Our findings support incorporating empirical antibiotic recommendations into national guidelines for infants with suspected bacterial infection. Copyright © 2017 by the American Academy of Pediatrics.

Identification of genetic factors associated with susceptibility to angiotensin-converting enzyme inhibitors-induced cough.

Science.gov (United States)

Grilo, Antonio; Sáez-Rosas, María P; Santos-Morano, Juan; Sánchez, Elena; Moreno-Rey, Concha; Real, Luis M; Ramírez-Lorca, Reposo; Sáez, María E

2011-01-01

Angiotensin-converting enzyme inhibitors (ACEi) are the first selected drugs for hypertensive patients because of its protective properties against heart and kidney diseases. Persistent cough is a common adverse reaction associated with ACEi, which can bind to the treatment cessation, but its etiology remains an unresolved issue. The most accepted mechanism is that the inhibition of ACEi increases kinins levels, resulting in the activation of proinflammatory mechanisms and nitric oxide generation. However, relatively little is known about the genetic susceptibility to ACEi-induced cough in hypertensive patients. We carried out a monogenic association analysis of 39 polymorphisms and haplotypes in genes encoding key proteins related to ACEi activity with the occurrence of ACEi-induced cough. We also carried out a digenic association analysis and investigated the existence of epistatic interactions between the analyzed polymorphisms using a logistic regression procedure. Finally, we investigated the predictive value of the identified associations for ACEi-induced cough. We found that genetic polymorphisms in MME [rs2016848, P=0.002, odds ratio (OR)=1.795], BDKRB2 (rs8012552, P=0.012, OR=1.609), PTGER3 (rs11209716, P=0.002, OR=0.565), and ACE (rs4344) genes are associated with ACEi-related cough. For the latter, the effect is sex specific, having a protective effect in males (P=0.027, OR=0.560) and increasing the risk in females (P=0.031, OR=1.847). In addition, genetic interactions between peptidases involved in kinins levels (CPN1 and XPNPEP1) and proteins related to prostaglandin metabolism (PTGIS and PTGIR) strongly modify the risk of ACEi-induced cough presentation (0.102≤OR≤0.384 for protective combinations and 2.732≤OR≤7.216 for risk combinations). These results are consistent with the hypothesis that the mechanism of cough is related to the accumulation of bradykinin, substance P, and prostaglandins.

Alcohol Metabolizing Gene Polymorphisms as Genetic Biomarkers of Alcoholic Liver Disease Susceptibility and Severity: A Northeast India Patient Based Study

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Tarun K. Basumatary

2017-07-01

Full Text Available Background: Excessive alcohol consumption is associated with genetic predisposition to Alcoholic Liver Disease (ALD, but there is very limited data on both molecular and genetic aspects of ALD among the Northeast Indian (NEI population. Aim and Objectives: Screening the role of genetic alterations in alcohol metabolizing pathway genes in the pathogenesis of ALD which is prevalent in the ethnically NEI population. Material and Methods: Whole blood was collected from ALD patients (n=150 [alcoholic chronic liver disease (CLD, n=110 and alcoholic cirrhosis (Cirr/cirrhosis, n=40], Alcoholic Without Liver Disease (AWLD, n=93 and healthy controls (HC/controls, n=274 with informed consents along with Fibroscan based liver stiffness measurement (LSM score and clinical data. Alcohol Dehydrogenase 2 (ADH2 and Aldehyde Dehydrogenase 2 (ALDH2 genotyping was studied by Polymerase Chain Reaction with Confronting Two Pair Primers (PCR-CTPP; and Alcohol Dehydrogenase 3 (ADH3 by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP method. Results:ADH2*2 genotype was predominant and associated with increased risk of cirrhosis compared to healthy controls, AWLD and CLD cases; and CLD compared to AWLD cases. ADH3*1 genotype was associated with significantly increased risk of cirrhosis compared to healthy controls, AWLD and CLD cases (p<0.001. Variant ALDH2 genotype was rare and analysis of the joint effects of genotypes showed that higher variant genotype resulted increased risk of CLD and cirrhosis compared to AWLD, and cirrhosis compared to CLD; thereby confirming the association of the polymorphisms in key alcohol metabolizing genes in the predisposition to ALD susceptibility and severity. Presence of variant ADH2, ADH3 and ALDH2 genotypes correlated with higher LSM scores in ALD. Conclusion: Alterations in the alcohol metabolizing genes are critically associated with ALD susceptibility and severity.

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 multiple myeloma risk (P value range, 0.055-0.981), possibly with the exception of the SNP rs2227667 (SERPINE1) in women. CONCLUSIONS: We can exclude that the selected polymorphisms are major multiple myeloma risk factors. IMPACT: Independent validation studies are crucial to identify true genetic risk...

Prevalence, Virulence Genes, Antimicrobial Susceptibility, and Genetic Diversity of Bacillus cereus Isolated From Pasteurized Milk in China

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Tiantian Gao

2018-03-01

Full Text Available Bacillus cereus is a common and important food-borne pathogen that can be found in various food products. Due to low-temperature sterilization for a short period of time, pasteurization is not sufficient for complete elimination of B. cereus in milk, thereby cause severe economic loss and food safety problems. It is therefore of paramount importance to perform risk assessment of B. cereus in pasteurized milk. In this study, we isolated B. cereus from pasteurized milk samples in different regions of China, and evaluated the contamination situation, existence of virulence genes, antibiotic resistance profile and genetic polymorphism of B. cereus isolates. Intriguingly, 70 samples (27% were found to be contaminated by B. cereus and the average contamination level was 111 MPN/g. The distribution of virulence genes was assessed toward 10 enterotoxigenic genes (hblA, hblC, hblD, nheA, nheB, nheC, cytK, entFM, bceT, and hlyII and one emetic gene (cesB. Forty five percent strains harbored enterotoxigenic genes hblACD and 93% isolates contained nheABC gene cluster. The positive rate of cytK, entFM, bceT, hlyII, and cesB genes were 73, 96, 75, 54, and 5%, respectively. Antibiotic susceptibility assessment showed that most of the isolates were resistant to β-lactam antibiotics and rifampicin, but susceptible to other antibiotics such as ciprofloxacin, gentamicin and chloramphenicol. Total multidrug-resistant population was about 34%. In addition, B. cereus isolates in pasteurized milk showed a high genetic diversity. In conclusion, our findings provide the first reference on the prevalence, contamination level and characteristics of B. cereus isolated from pasteurized milk in China, suggesting a potential high risk of B. cereus to public health and dairy industry.

Exploration of genetic susceptibility factors for Parkinson's disease ...

Indian Academy of Sciences (India)

1Neurosciences Research Group, School of Medicine and Institute of Genetics, Universidad Nacional de Colombia, Bogotá ... factors for Parkinson's disease in a South American sample. J. Genet. 89, ... In the current work, we report the results of a system- ..... Synaptic dysfunction and oxidative stress in Alzheimer's disease:.

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

International Nuclear Information System (INIS)

Imai, Takashi

2003-01-01

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

Variegated colors of pediatric glioblastoma multiforme: what to expect?

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Vivek Immanuel

2017-08-01

Full Text Available Malignant gliomas account for 35-45% of primary brain tumors; among these glioblastoma multiforme (GBM is the most common adult brain tumor constituting approximately 85%. Its incidence is quite less in the pediatric population and treatment of these patients is particularly challenging. Exposure to ionizing radiation is the only environmental factor found to have any significant association with GBM. Several genetic alterations associated with GBM in adults have been well documented such as epidermal growth factor receptor amplification, overexpression of mouse double minute 2 homolog also known as E3 ubiquitin-protein ligase, Phosphatase and tensin homolog gene mutation, loss of heterozygosity of chromosome 10p and isocitrate dehydrogenase-1 mutation. However, data on genetic mutations in pediatric GBM is still lacking. Exophytic brain stem gliomas are rare tumors and are usually associated with a poor prognosis. The most effective treatment in achieving long-term survival in such patients, is surgical excision of the tumor and then chemoradiotherapy followed by adjuvant chemotherapy by temozolomide. This schedule is the standard treatment for GBM patients. In view of the rarity of pediatric GBM, we report here a case of pontine GBM in a 5-year-old girl.

Absence of family history and phenotype-genotype correlation in pediatric Brugada syndrome: more burden to bear in clinical and genetic diagnosis.

Science.gov (United States)

Daimi, Houria; Khelil, Amel Haj; Ben Hamda, Khaldoun; Aranega, Amelia; Chibani, Jemni B E; Franco, Diego

2015-06-01

Brugada syndrome (BrS) is an autosomal-dominant genetic cardiac disorder caused in 18-30 % of the cases by SCN5A gene mutations and manifested by an atypical right bundle block pattern with ST segment elevation and T wave inversion in the right precordial leads. The syndrome is usually detected after puberty. The identification of BrS in pediatric patients is thus a rare occurrence, and most of the reported cases are unmasked after febrile episodes. Usually, having a family history of sudden death represents the first reason to perform an ECG in febrile children. However, this practice makes the sporadic cases of cardiac disease and specially the asymptomatic ones excluded from this diagnosis. Here, we report a sporadic case of a 2-month-old male patient presented with vaccination-related fever and ventricular tachycardia associated with short breathing, palpitation and cold sweating. ECG changes were consistent with type 1 BrS. SCN5A gene analysis of the proband and his family revealed a set of mutations and polymorphisms differentially distributed among family members, however, without any clear genotype-phenotype correlation. Based on our findings, we think that genetic testing should be pursued as a routine practice in symptomatic and asymptomatic pediatric cases of BrS, with or without family history of sudden cardiac death. Similarly, our study suggests that pediatrician should be encouraged to perform an ECG profiling in suspicious febrile children and quickly manage fever since it is the most important factor unmasking BrS in children.

The epidemiology of outpatient pain treatment in pediatrics

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Baldridge S

2018-05-01

Full Text Available Stacy Baldridge, Laura Wallace, Aditi Kadakia Purdue Pharma L.P., Stamford, CT, USA Background: There is limited real-world, population-level data on the prevalence and treatment of pain in children. An understanding of pediatric pain conditions and its management can help inform provider education, treatment guidelines, and design of pediatric pain studies. Therefore, in this study, we aimed to describe the prevalence of conditions associated with acute and chronic pain in pediatric patients and to characterize pediatric pain treatment with nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 (COX-2 inhibitors, opioids (immediate release or extended release, antidepressants, topical analgesics, anticonvulsants, and other therapies based on a large, real-world sample. Materials and methods: In this cohort study, we used administrative claims data from the Truven Health MarketScan® Research Databases, which contain data regarding demography, prescription, diagnosis, and procedure performed. Descriptive statistics were used to assess the prevalence of various conditions associated with pediatric pain and to estimate the proportion of patients who received various analgesic and nonanalgesic treatments. All analyses were stratified according to demographics. Results: This study included data on more than 30 million pediatric patients from throughout the US. Overall, among patients with commercial insurance, surgery was the most common pain-related diagnosis, followed by orthopedic conditions, malignancies, trauma, and genetic conditions. For patients with Medicaid, surgery was also the most common diagnosis, followed by traumatic injury, orthopedic conditions, malignancies, and genetic conditions. These diagnoses varied by age, with most showing higher prevalence in older children. Treatment varied substantially by condition, and many children (more than 50% for most of the conditions evaluated did not receive any prescription pain treatments

Quantitative genetics of Taura syndrome resistance in Pacific (Penaeus vannamei): A cure model approach

DEFF Research Database (Denmark)

Ødegård, Jørgen; Gitterle, Thomas; Madsen, Per

2011-01-01

cure survival model using Gibbs sampling, treating susceptibility and endurance as separate genetic traits. Results: Overall mortality at the end of test was 28%, while 38% of the population was considered susceptible to the disease. The estimated underlying heritability was high for susceptibility (0....... However, genetic evaluation of susceptibility based on the cure model showed clear associations with standard genetic evaluations that ignore the cure fraction for these data. Using the current testing design, genetic variation in observed survival time and absolute survival at the end of test were most...

Producing genetic knowledge and citizenship through the Internet: mothers, pediatric genetics, and cybermedicine.

Science.gov (United States)

Schaffer, Rebecca; Kuczynski, Kristine; Skinner, Debra

2008-01-01

This article analyses data from a longitudinal, ethnographic study conducted in the United States to examine how 100 mothers of children with genetic disorders used the Internet to interpret, produce, and circulate genetic knowledge pertaining to their child's condition. We describe how they came to value their own experiential knowledge, helped shift the boundaries of what counts as authoritative knowledge, and assumed the role of genetic citizen, fighting for specific rights while shouldering and contesting concomitant duties and obligations. This exploration of e-health use contributes to our understanding of the social practices and power relations that cut across online and off-line worlds to co-produce genetic knowledge and genetic citizenship in multiple contexts.

Antibiotic susceptibility of isolates from paediatric intensive care units in Zagreb.

Science.gov (United States)

Bedenić, Branka; Prahin, Esmina; Vranić-Ladavac, Mirna; Atalić, Vlasta; Sviben, Mario; Frančula-Zaninović, Sonja; Plečko, Vanda; Kalenić, Smilja

2014-02-01

Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program is a longitudinal global surveillance study to monitor in vitro data on microbial susceptibility in centers that prescribe meropenem. Results of the six years period (2002-2007) for the antimicrobial efficacy of meropenem compared to other broad-spectrum agents against Gram-negative and Gram-positive isolates collected at pediatric intensive care units of the University Hospital Center Zagreb in Croatia were reported. A total of 110 Gram-negative and 43 Gram-positive pathogens from pediatric specimens were tested. The minimum-inhibitory concentrations (MICs) were determined by broth microdilution method according to CLSI. There was no resistance to either imipenem or meropenem observed for Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis. High resistance rates of K. pneumoniae to ceftazidime and gentamicin (50%) are a raising concern. Pseudomonas aeruginosa was the most resistant Gram-negative species with two (12%) of the strains resistant to meropenem, three (18%) to imipenem, 10 (47%) to gentamicin and six (35%) to piperacillin/tazobactam and ciprofloxacin. According to our results meropenem remains an appropriate antibiotic for the treatment of severe infections caused by Gram-negative bacteria in pediatric population. The results indicate that meropenem has excellent potency and spectrum of activity despite being prescribed for a long time for the treatment of seriously ill patients, and still appears to be a reliable option for the initial empirical therapy of serious nosocomial infections in children. However, later studies have shown the emergence of carbapenem-resistant Gram-negative bacteria after 2008.

Comparison of individuals opting for BRCA1/2 or HNPCC genetic susceptibility testing with regard to coping, illness perceptions, illness experiences, family system characteristics and hereditary cancer distress

NARCIS (Netherlands)

van Oostrom, Iris; Meijers-Heijboer, Hanne; Duivenvoorden, Hugo J.; Brocker-Vriends, Annette H. J. T.; van Asperen, Christi J.; Sijmons, Rolf H.; Seynaeve, Caroline; Van Gool, Arthur R.; Klijn, Jan G. M.; Tibben, Aad

Objective: To study differences between individuals opting for genetic cancer susceptibility testing of a known familial BRCA1/2 and HNPCC related germline mutation. Methods: Coping, illness perceptions, experiences with cancer in relatives and family system characteristics were assessed in 271

Enterovirus-associated changes in blood transcriptomic profiles of children with genetic susceptibility to type 1 diabetes.

Science.gov (United States)

Lietzen, Niina; An, Le T T; Jaakkola, Maria K; Kallionpää, Henna; Oikarinen, Sami; Mykkänen, Juha; Knip, Mikael; Veijola, Riitta; Ilonen, Jorma; Toppari, Jorma; Hyöty, Heikki; Lahesmaa, Riitta; Elo, Laura L

2018-02-01

Enterovirus infections have been associated with the development of type 1 diabetes in multiple studies, but little is known about enterovirus-induced responses in children at risk for developing type 1 diabetes. Our aim was to use genome-wide transcriptomics data to characterise enterovirus-associated changes in whole-blood samples from children with genetic susceptibility to type 1 diabetes. Longitudinal whole-blood samples (356 samples in total) collected from 28 pairs of children at increased risk for developing type 1 diabetes were screened for the presence of enterovirus RNA. Seven of these samples were detected as enterovirus-positive, each of them collected from a different child, and transcriptomics data from these children were analysed to understand the individual-level responses associated with enterovirus infections. Transcript clusters with peaking or dropping expression at the time of enterovirus positivity were selected as the enterovirus-associated signals. Strong signs of activation of an interferon response were detected in four children at enterovirus positivity, while transcriptomic changes in the other three children indicated activation of adaptive immune responses. Additionally, a large proportion of the enterovirus-associated changes were specific to individuals. An enterovirus-induced signature was built using 339 genes peaking at enterovirus positivity in four of the children, and 77 of these genes were also upregulated in human peripheral blood mononuclear cells infected in vitro with different enteroviruses. These genes separated the four enterovirus-positive samples clearly from the remaining 352 blood samples analysed. We have, for the first time, identified enterovirus-associated transcriptomic profiles in whole-blood samples from children with genetic susceptibility to type 1 diabetes. Our results provide a starting point for understanding the individual responses to enterovirus infections in blood and their potential connection to

Pediatric glioma stem cells: biologic strategies for oncolytic HSV virotherapy

Directory of Open Access Journals (Sweden)

Gregory K Friedman

2013-02-01

Full Text Available While glioblastoma multiforme (GBM is the most common adult malignant brain tumor, GBMs in childhood represent less than 10% of pediatric malignant brain tumors and are phenotypically and molecularly distinct from adult GBMs. Similar to adult patients, outcomes for children with high-grade gliomas (HGGs remain poor. Furthermore, the significant morbidity and mortality yielded by pediatric GBM is compounded by neurotoxicity for the developing brain caused by current therapies. Poor outcomes have been attributed to a subpopulation of chemotherapy and radiotherapy resistant cells, termed ‘glioma stem cells’ (GSCs, ‘glioma progenitor cells’, or ‘glioma-initiating cells', which have the ability to initiate and maintain the tumor and to repopulate the recurring tumor after conventional therapy. Future innovative therapies for pediatric HGGs must be able to eradicate these therapy-resistant GSCs. Oncolytic herpes simplex viruses, genetically engineered to be safe for normal cells and to express diverse foreign anti-tumor therapeutic genes, have been demonstrated in preclinical studies to infect and kill GSCs and tumor cells equally while sparing normal brain cells. In this review, we discuss the unique aspects of pediatric GSCs, including markers to identify them, the microenvironment they reside in, signaling pathways that regulate them, mechanisms of cellular resistance, and approaches to target GSCs, with a focus on the promising therapeutic, genetically engineered oncolytic herpes simplex virus (HSV.

Genetic diversity and in vitro antibiotic susceptibility profile of ...

African Journals Online (AJOL)

STORAGESEVER

2009-04-06

Apr 6, 2009 ... and waste water sources in the Eastern Cape Province of South Africa using DNA fingerprinting and antibiotic susceptibility profile as test indices. Restriction digests ... fever they cause with human and animal excreta acting.

Ethical, social and counselling issues in hereditary cancer susceptibility.

Science.gov (United States)

Garber, J E; Patenaude, A F

1995-01-01

Genetic testing for hereditary susceptibility to disease is new. Much has been learned from experience with Huntington's disease and other non-malignant conditions. There are some differences in the case of predisposition testing for cancer: there is often the perception that cancer is preventable and sometimes curable, in contrast to other hereditary conditions. Testing raises many issues new to the medical community and to the public as well. There is great concern that the explosive technology be used responsibly, so that the potential benefits of genetic knowledge are not eclipsed by the risks to autonomy, privacy and justice. Practical concerns about insurability and discrimination may inhibit some at risk individuals from taking advantage of this powerful technology. There has been considerable effort already in the UK, Europe and the USA at the research and social levels to create protection for individuals found to carry genetic susceptibility to disease.

Clinical and Drug Resistance Characteristics of New Pediatric Tuberculosis Cases in Northern China.

Science.gov (United States)

Wang, Ting; Dong, Fang; Li, Qin-Jing; Yin, Qing-Qin; Song, Wen-Qi; Mokrousov, Igor; Jiao, Wei-Wei; Shen, A-Dong

2018-05-09

The aim of this study was to evaluate the clinical features and characteristics of drug resistance in newly diagnosed pediatric tuberculosis (TB) patients in northern China. Mycobacterium tuberculosis isolates were collected from September 2010 to October 2016 at the Beijing Children's Hospital. Patients were divided into two groups (resistant to at least one drug and pan-susceptible) according to drug susceptibility testing (DST) results. A total of 132 new cases, mainly from northern China (87.9%), were included in the study. The median age was 1.9 years (1 month-15 years). Resistance to at least one drug was detected in Mycobacterium tuberculosis isolates from 33 (25%) cases. Eight cases of multidrug-resistant TB (MDR-TB) (6.1%) were detected. The two groups did not differ in clinical presentations (disease site, fever >2 weeks, and cough >2 weeks) or in chest imaging (lesion location, lymphadenitis [mediastinal], and pleural effusion). The rate of Mycobacterium tuberculosis drug resistance in new pediatric TB cases was as high as in the new adult patients surveyed in the national drug resistance survey conducted in 2007. No significant difference was observed in clinical features between patients infected with drug-resistant and drug-susceptible strains. Routine DST is important for prescribing effective antituberculosis treatment regimens.

Pediatric High Grade Glioma: a Review and Update on Tumor Clinical Characteristics and Biology

Energy Technology Data Exchange (ETDEWEB)

Fangusaro, Jason, E-mail: jfangusaro@luriechildrens.org [Pediatric Neuro-Oncology, The Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, IL (United States)

2012-08-24

High grade gliomas (HGG) are one of the most common central nervous system (CNS) tumors encountered in adults, but they only represent approximately 8–12% of all pediatric CNS tumors. Historically, pediatric HGG were thought to be similar to adult HGG since they appear histologically identical; however, molecular, genetic, and biologic data reveal that they are distinct. Similar to adults, pediatric HGG are very aggressive and malignant lesions with few patients achieving long-term survival despite a variety of therapies. Initial treatment strategies typically consist of a gross total resection (GTR) when feasible followed by focal radiotherapy combined with chemotherapy. Over the last few decades, a wealth of data has emerged from basic science and pre-clinical animal models helping to better define the common biologic, genetic, and molecular make-up of these tumors. These data have not only provided a better understanding of tumor biology, but they have also provided new areas of research targeting molecular and genetic pathways with the potential for novel treatment strategies and improved patient outcomes. Here we provide a review of pediatric non-brainstem HGG, including epidemiology, presentation, histology, imaging characteristics, treatments, survival outcomes, and an overview of both basic and translational research. An understanding of all relevant pre-clinical tumor models, including their strengths and pitfalls is essential in realizing improved patient outcomes in this population.

Pediatric High Grade Glioma: a Review and Update on Tumor Clinical Characteristics and Biology

International Nuclear Information System (INIS)

Fangusaro, Jason

2012-01-01

High grade gliomas (HGG) are one of the most common central nervous system (CNS) tumors encountered in adults, but they only represent approximately 8–12% of all pediatric CNS tumors. Historically, pediatric HGG were thought to be similar to adult HGG since they appear histologically identical; however, molecular, genetic, and biologic data reveal that they are distinct. Similar to adults, pediatric HGG are very aggressive and malignant lesions with few patients achieving long-term survival despite a variety of therapies. Initial treatment strategies typically consist of a gross total resection (GTR) when feasible followed by focal radiotherapy combined with chemotherapy. Over the last few decades, a wealth of data has emerged from basic science and pre-clinical animal models helping to better define the common biologic, genetic, and molecular make-up of these tumors. These data have not only provided a better understanding of tumor biology, but they have also provided new areas of research targeting molecular and genetic pathways with the potential for novel treatment strategies and improved patient outcomes. Here we provide a review of pediatric non-brainstem HGG, including epidemiology, presentation, histology, imaging characteristics, treatments, survival outcomes, and an overview of both basic and translational research. An understanding of all relevant pre-clinical tumor models, including their strengths and pitfalls is essential in realizing improved patient outcomes in this population.

Pediatric MS

Science.gov (United States)

... Pediatric MS Share this page Facebook Twitter Email Pediatric MS Pediatric MS Pediatric MS Support Pediatric Providers ... system through the Pediatric MS Support Group . Treating pediatric MS In 2018 the U.S. Food and Drug ...

Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol.

Science.gov (United States)

Alvarez, Monica I; Glover, Luke C; Luo, Peter; Wang, Liuyang; Theusch, Elizabeth; Oehlers, Stefan H; Walton, Eric M; Tram, Trinh Thi Bich; Kuang, Yu-Lin; Rotter, Jerome I; McClean, Colleen M; Chinh, Nguyen Tran; Medina, Marisa W; Tobin, David M; Dunstan, Sarah J; Ko, Dennis C

2017-09-12

Risk, severity, and outcome of infection depend on the interplay of pathogen virulence and host susceptibility. Systematic identification of genetic susceptibility to infection is being undertaken through genome-wide association studies, but how to expeditiously move from genetic differences to functional mechanisms is unclear. Here, we use genetic association of molecular, cellular, and human disease traits and experimental validation to demonstrate that genetic variation affects expression of VAC14, a phosphoinositide-regulating protein, to influence susceptibility to Salmonella enterica serovar Typhi ( S Typhi) infection. Decreased VAC14 expression increased plasma membrane cholesterol, facilitating Salmonella docking and invasion. This increased susceptibility at the cellular level manifests as increased susceptibility to typhoid fever in a Vietnamese population. Furthermore, treating zebrafish with a cholesterol-lowering agent, ezetimibe, reduced susceptibility to S Typhi. Thus, coupling multiple genetic association studies with mechanistic dissection revealed how VAC14 regulates Salmonella invasion and typhoid fever susceptibility and may open doors to new prophylactic/therapeutic approaches.

Genetics of allergy and bronchial hyperresponsiveness

NARCIS (Netherlands)

Howard, TD; Wiesch, DG; Koppelman, GH; Postma, DS; Meyers, DA; Bleecker, ER

Allergy and asthma are closely related complex diseases caused by a combination of both genetic and environmental influences. Two common genetic approaches, candidate gene studies and genome-wide screens, have been used to localize and evaluate potential genetic factors that confer susceptibility or

[INTERNATIONAL COOPERATION IN PEDIATRIC RHEUMATOLOGY: THE SHARE PROJECT].

Science.gov (United States)

Uziel, Yosef

2017-07-01

The SHARE initiative is a project initiated by the European Society of Pediatric Rheumatology for the purpose of improving clinical care in the field of pediatric rheumatology. Towards this goal numerous working plans and surveys were conducted. All pediatric rheumatology centers were mapped in terms of staff members, quality and types of treatments in each country, in order to improve and plan the best way for the diagnosis and treatment of rheumatic disease in children. After termination of the optimal clinical approach and care, position papers were written including all recommendations based on the scientific literature in the field. In addition, recommendations were set regarding the encouragement of international research, especially in light of the major advances achieved in the genetic aspects of pediatric rheumatology diseases, and the need for sharing biological samples between researchers from different countries and continents. Information for patients became more available regarding the diseases and the medical centers in each country. Futhermore, educational programs for interns and young fellows were written for the promotion of higher and identical academic levels in different countries.

Influence of the A3669G Glucocorticoid Receptor Gene Polymorphism on the Metabolic Profile of Pediatric Patients with Congenital Adrenal Hyperplasia

Directory of Open Access Journals (Sweden)

Ricardo P. P. Moreira

2014-01-01

Full Text Available Background. Pediatric CAH patients have an increased risk of cardiovascular disease, and it remains unknown if genetic predisposition is a contributing factor. Glucocorticoid receptor gene (NR3C1 polymorphisms are associated with an adverse metabolic profile. Our aim was to analyze the association between the NR3C1 polymorphisms and the metabolic profile of pediatric CAH patients. Methods. Forty-one patients (26SW/15SV received glucocorticoid (GC replacement therapy to achieve normal androgen levels. Obesity was defined by BMI≥95th percentile. NR3C1 alleles were genotyped, and association analyses with phenotype were done with Chi-square, t-test, and multivariate and regression analysis. Results. Obesity was observed in 31.7% of patients and was not correlated with GC doses and treatment duration. Z-score BMI was positively correlated with blood pressure, triglycerides, LDL-c levels, and HOMA-IR. NR3C1 polymorphisms, BclI and A3669G, were found in 23.1% and 9.7% of alleles, respectively. A3669G carriers presented higher LDL-c levels compared to wild-type subjects. BclI-carriers and noncarriers did not differ. Conclusion. Our results suggest that A3669G-polymorphism could be involved with a susceptibility to adverse lipid profile in pediatric CAH patients. This study provides new insight into the GR screening during CAH treatment, which could help to identify the subgroup of at-risk patients who would most benefit from preventive therapeutic action.

Comparison of Two Different Disk Diffusion Agar Tests in Determination of Antibiotic Susceptibility for E-Coli Isolated from Urinary Tract Infection in Pediatrics

Directory of Open Access Journals (Sweden)

I. Sedighi

2010-04-01

Full Text Available Introduction & Objective: Urinary Tract Infection (UTI is one of the most common infections during childhood and E-Coli is the more predominant pathogen recovered in UTI. Disk Diffusion agar test is a method of choice because it is cost effective, simple, and now routinely used for detection of antibiotic susceptibility. A rapid increase in antibiotic resistance in our region made the authors to design a study to compare this traditional method with two different disk diffusion agar tests.Materials & Methods: Our study was conducted between 2009 and 2010 in Be’sat teaching hospital on 100 pediatric patients ranged 15 days to 13 years old with positive urine culture for E-coli. Antibiogram detection was performed by disk diffusion agar test with two different kits as Padtan-Teb (made in Iran and Mast (made in the U.K. for Co-trimoxazol, Amikacin, Ceftriaxone, Nalidixic Acid, Cefixime, and Nitrofurantoin. At last the data was analyzed by McNemar test.Results: Co-trimoxazol obtained the lowest (23% Padtan-Teb and 26% Mast and Nitrofurantoin had the highest (86% Padtan-Teb and 97% Mast sensitivity in the two methods which were used in our study. The results were statistically significant for Amikacin, Ceftriaxone, Cefixime, and Nitrofurantoin. The data was analyzed by Mc Memar test.Conclusion: According to our study the results of antibiotic susceptibility were more compatible with other non national Disk diffusion agar test and thus we recommend that our manufactures in Iran should increase the quality of their products.

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

International Nuclear Information System (INIS)

Habib, E.E.; Aziz, M.; Kotb, M.

2005-01-01

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

Application Form for NCI Cancer Genetics Services Directory

Science.gov (United States)

Professionals who provide services related to cancer genetics (cancer risk assessment, genetic counseling, genetic susceptibility testing, and others) may fill out this application form to be listed in the National Cancer Institute's Cancer Genetics Services Directory.

Inclusion Criteria for NCI Cancer Genetics Services Directory

Science.gov (United States)

Professionals who provide services related to cancer genetics (cancer risk assessment, genetic counseling, genetic susceptibility testing, and others) must meet these criteria before applying to be listed in the National Cancer Institute's Cancer Genetics Services Directory.

Extended biofilm susceptibility assay for Staphylococcus aureus bovine mastitis isolates: evidence for association between genetic makeup and biofilm susceptibility.

Science.gov (United States)

Melchior, M B; van Osch, M H J; Lam, T J G M; Vernooij, J C M; Gaastra, W; Fink-Gremmels, J

2011-12-01

Staphylococcus aureus is one of the most prevalent causes of bovine mastitis. The antimicrobial treatment of this disease is currently based on antimicrobial susceptibility tests according to Clinical and Laboratory Standards Institute standards. However, various authors have shown a discrepancy between the results of this standard susceptibility test and the actual cure rate of the applied antimicrobial treatment. Increasing evidence suggests that in vivo biofilm formation by Staph. aureus, which is not assessed in the antimicrobial susceptibility tests, is associated with this problem, resulting in disappointing cure rates, especially for infections of longer duration. Previous data obtained with a limited number of strains showed that the extended biofilm antimicrobial susceptibility (EBS) assay reveals differences between strains, which cannot be derived from a standard susceptibility test or from a 24-h biofilm susceptibility test. The objective of this study was to test a collection of Staph. aureus bovine mastitis strains in the EBS assay and to model the effect of antimicrobial exposure, duration of antimicrobial exposure, and genotype profile of the strains on antimicrobial susceptibility. With the results from a previous study with the same collection of strains, the effect of genotype represented by accessory gene regulator gene (agr-type), the presence of insertional sequence 257 (IS257), intercellular adhesion (ica), and the β-lactamase (blaZ) gene were entered as explanatory factors in a logistic regression model. The agr locus of Staph. aureus controls the expression of most of the virulence factors, represses the transcription of several cell wall-associated proteins, and activates several exoproteins during the post-exponential phase. The IS257 gene has been related to biofilm formation in vitro and was found earlier in 50% of the agr-type 2 strains. The ica gene cluster encodes for the production of an extracellular polysaccharide adhesin, termed

acetyltransferases: Influence on Lung Cancer Susceptibility

African Journals Online (AJOL)

Lung cancer remains a major health challenge in the world. It is the commonest cause of cancer mortality in men, it has been suggested that genetic susceptibility may contribute to the major risk factor, with increasing prevalence of smoking. Lung cancer has reached epidemic proportions in India. Recently indoor air ...

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 ...

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 genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine and quinine are described. METHODS: Pfcrt K76T, pfmdr1 gene copy numbers, N86Y, Y184F and 1034-1246 sequences were determined using PCR-based methods. Blood samples came from virtually all (n=1806) children aged.......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....

The Identification of Fatigue Resistant and Fatigue Susceptible Individuals

National Research Council Canada - National Science Library

Harrison, Richard; Chaiken, Scott; Harville, Donald; Fischer, Joseph; Fisher, Dion; Whitmore, Jeff

2008-01-01

The present study was designed to target two specific areas regarding fatigue. The primary purpose was to begin investigations into possible genetic markers linked to fatigue resistance and fatigue susceptibility...

Introducing medical genetics services in Ethiopia using the MiGene Family History App.

Science.gov (United States)

Quinonez, Shane C; Yeshidinber, Abate; Lourie, Michael A; Bekele, Delayehu; Mekonnen, Yemisrach; Nigatu, Balkachew; Metaferia, Gesit; Jebessa, Solomie

2018-06-11

Almost all low-income countries and many middle-income countries lack the capacity to deliver medical genetics services. We developed the MiGene Family History App (MFHA), which assists doctors with family history collection and population-level epidemiologic analysis. The MFHA was studied at St. Paul's Hospital in Addis Ababa, Ethiopia. A needs assessment was used to assess Ethiopian physicians' experience with genetics services. The MFHA then collected patient data over a 6-month period. The majority of doctors provide genetics services, with only 16% reporting their genetics knowledge is sufficient. A total of 1699 patients from the pediatric ward (n = 367), neonatal intensive care unit (NICU) (n = 477), and antenatal clinic (n = 855) were collected using the MFHA with a 4% incidence of a MFHA-screened condition present. The incidence was 11.7% in the pediatric ward, 3% in the NICU, and 0.5% in the antenatal clinic. Heart malformations (5.5% of patients) and trisomy 21 (4.4% of patients) were the most common conditions in the pediatric ward. Medical genetics services are needed in Ethiopia. As other countries increase their genetics capacity, the MFHA can provide fundamental genetics services and collect necessary epidemiologic data.

Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes.

Science.gov (United States)

Dobbins, Sara E; Broderick, Peter; Chubb, Daniel; Kinnersley, Ben; Sherborne, Amy L; Houlston, Richard S

2016-10-01

Although family history is a major risk factor for colorectal cancer (CRC) a genetic diagnosis cannot be obtained in over 50 % of familial cases when screened for known CRC cancer susceptibility genes. The genetics of undefined-familial CRC is complex and recent studies have implied additional clinically actionable mutations for CRC in susceptibility genes for other cancers. To clarify the contribution of non-CRC susceptibility genes to undefined-familial CRC we conducted a mutational screen of 114 cancer susceptibility genes in 847 patients with early-onset undefined-familial CRC and 1609 controls by analysing high-coverage exome sequencing data. We implemented American College of Medical Genetics and Genomics standards and guidelines for assigning pathogenicity to variants. Globally across all 114 cancer susceptibility genes no statistically significant enrichment of likely pathogenic variants was shown (6.7 % cases 57/847, 5.3 % controls 85/1609; P = 0.15). Moreover there was no significant enrichment of mutations in genes such as TP53 or BRCA2 which have been proposed for clinical testing in CRC. In conclusion, while we identified genes that may be considered interesting candidates as determinants of CRC risk warranting further research, there is currently scant evidence to support a role for genes other than those responsible for established CRC syndromes in the clinical management of familial CRC.

Influence of the IL6 Gene in Susceptibility to Systemic Sclerosis

NARCIS (Netherlands)

Cenit, M.C.; Simeon, C.P.; Vonk, M.C.; Callejas-Rubio, J.L.; Espinosa, G.; Carreira, P.; Blanco, F.J.; Narvaez, J.; Tolosa, C.; Roman-Ivorra, J.A.; Gomez-Garcia, I.; Garcia-Hernandez, F.J.; Gallego, M.; Garcia-Portales, R.; Egurbide, M.V.; Fonollosa, V.; Garcia de la Pena, P.; Lopez-Longo, F.J.; Gonzalez-Gay, M.A.; The Spanish Scleroderma, G.; Hesselstrand, R.; Riemekasten, G.; Witte, T.J.M. de; Voskuyl, A.E.; Schuerwegh, A.J.; Madhok, R.; Fonseca, C.; Denton, C.; Nordin, A.; Palm, O.; Laar, J.M. van; Hunzelmann, N.; Distler, J.H.; Kreuter, A.; Herrick, A.; Worthington, J.; Koeleman, B.P.; Radstake, T.R.D.J.; Martin, J.

2012-01-01

OBJECTIVE: Systemic sclerosis (SSc) is a genetically complex autoimmune disease; the genetic component has not been fully defined. Interleukin 6 (IL-6) plays a crucial role in immunity and fibrosis, both key aspects of SSc. We investigated the influence of IL6 gene in the susceptibility and

The genetics of radiation-induced osteosarcoma

International Nuclear Information System (INIS)

Rosemann, M.; Kuosaite, V.; Nathrath, M.; Atkinson, M.J.

2002-01-01

Individual genetic variation can influence susceptibility to the carcinogenic effects of many environmental carcinogens. In radiation-exposed populations those individuals with a greater genetically determined susceptibility would be at greater risk of developing cancer. To include this modification of risk into radiation protection schemes it is necessary to identify the genes responsible for determining individual sensitivity. Alpha-particle-induced osteosarcoma in the mouse has been adopted as a model of human radiation carcinogenesis, and genome-wide screens have been conducted for allelic imbalance and genetic linkage. These studies have revealed a series of genes involved in determining the sensitivity to radiogenic osteosarcoma formation. (author)

Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients

Science.gov (United States)

Keel, Siobán B.; Scott, Angela; Sanchez-Bonilla, Marilyn; Ho, Phoenix A.; Gulsuner, Suleyman; Pritchard, Colin C.; Abkowitz, Janis L.; King, Mary-Claire; Walsh, Tom; Shimamura, Akiko

2016-01-01

The clinical and histopathological distinctions between inherited versus acquired bone marrow failure and myelodysplastic syndromes are challenging. The identification of inherited bone marrow failure/myelodysplastic syndromes is critical to inform appropriate clinical management. To investigate whether a subset of pediatric and young adults undergoing transplant for aplastic anemia or myelodysplastic syndrome have germline mutations in bone marrow failure/myelodysplastic syndrome genes, we performed a targeted genetic screen of samples obtained between 1990–2012 from children and young adults with aplastic anemia or myelodysplastic syndrome transplanted at the Fred Hutchinson Cancer Research Center. Mutations in inherited bone marrow failure/myelodysplastic syndrome genes were found in 5.1% (5/98) of aplastic anemia patients and 13.6% (15/110) of myelodysplastic syndrome patients. While the majority of mutations were constitutional, a RUNX1 mutation present in the peripheral blood at a 51% variant allele fraction was confirmed to be somatically acquired in one myelodysplastic syndrome patient. This highlights the importance of distinguishing germline versus somatic mutations by sequencing DNA from a second tissue or from parents. Pathological mutations were present in DKC1, MPL, and TP53 among the aplastic anemia cohort, and in FANCA, GATA2, MPL, RTEL1, RUNX1, SBDS, TERT, TINF2, and TP53 among the myelodysplastic syndrome cohort. Family history or physical examination failed to reliably predict the presence of germline mutations. This study shows that while any single specific bone marrow failure/myelodysplastic syndrome genetic disorder is rare, screening for these disorders in aggregate identifies a significant subset of patients with inherited bone marrow failure/myelodysplastic syndrome. PMID:27418648

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.

Speech and language pathology & pediatric HIV.

Science.gov (United States)

Retzlaff, C

1999-12-01

Children with HIV have critical speech and language issues because the virus manifests itself primarily in the developing central nervous system, sometimes causing speech, motor control, and language disabilities. Language impediments that develop during the second year of life seem to be especially severe. HIV-infected children are also susceptible to recurrent ear infections, which can damage hearing. Developmental issues must be addressed for these children to reach their full potential. A decline in language skills may coincide with or precede other losses in cognitive ability. A speech pathologist can play an important role on a pediatric HIV team. References are included.

Genome-wide association study identifies novel breast cancer susceptibility loci

Science.gov (United States)

Easton, Douglas F.; Pooley, Karen A.; Dunning, Alison M.; Pharoah, Paul D. P.; Thompson, Deborah; Ballinger, Dennis G.; Struewing, Jeffery P.; Morrison, Jonathan; Field, Helen; Luben, Robert; Wareham, Nicholas; Ahmed, Shahana; Healey, Catherine S.; Bowman, Richard; Meyer, Kerstin B.; Haiman, Christopher A.; Kolonel, Laurence K.; Henderson, Brian E.; Marchand, Loic Le; Brennan, Paul; Sangrajrang, Suleeporn; Gaborieau, Valerie; Odefrey, Fabrice; Shen, Chen-Yang; Wu, Pei-Ei; Wang, Hui-Chun; Eccles, Diana; Evans, D. Gareth; Peto, Julian; Fletcher, Olivia; Johnson, Nichola; Seal, Sheila; Stratton, Michael R.; Rahman, Nazneen; Chenevix-Trench, Georgia; Bojesen, Stig E.; Nordestgaard, Børge G.; Axelsson, Christen K.; Garcia-Closas, Montserrat; Brinton, Louise; Chanock, Stephen; Lissowska, Jolanta; Peplonska, Beata; Nevanlinna, Heli; Fagerholm, Rainer; Eerola, Hannaleena; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Ahn, Sei-Hyun; Hunter, David J.; Hankinson, Susan E.; Cox, David G.; Hall, Per; Wedren, Sara; Liu, Jianjun; Low, Yen-Ling; Bogdanova, Natalia; Schürmann, Peter; Dörk, Thilo; Tollenaar, Rob A. E. M.; Jacobi, Catharina E.; Devilee, Peter; Klijn, Jan G. M.; Sigurdson, Alice J.; Doody, Michele M.; Alexander, Bruce H.; Zhang, Jinghui; Cox, Angela; Brock, Ian W.; MacPherson, Gordon; Reed, Malcolm W. R.; Couch, Fergus J.; Goode, Ellen L.; Olson, Janet E.; Meijers-Heijboer, Hanne; van den Ouweland, Ans; Uitterlinden, André; Rivadeneira, Fernando; Milne, Roger L.; Ribas, Gloria; Gonzalez-Neira, Anna; Benitez, Javier; Hopper, John L.; McCredie, Margaret; Southey, Melissa; Giles, Graham G.; Schroen, Chris; Justenhoven, Christina; Brauch, Hiltrud; Hamann, Ute; Ko, Yon-Dschun; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana; Day, Nicholas E.; Cox, David R.; Ponder, Bruce A. J.; Luccarini, Craig; Conroy, Don; Shah, Mitul; Munday, Hannah; Jordan, Clare; Perkins, Barbara; West, Judy; Redman, Karen; Driver, Kristy; Aghmesheh, Morteza; Amor, David; Andrews, Lesley; Antill, Yoland; Armes, Jane; Armitage, Shane; Arnold, Leanne; Balleine, Rosemary; Begley, Glenn; Beilby, John; Bennett, Ian; Bennett, Barbara; Berry, Geoffrey; Blackburn, Anneke; Brennan, Meagan; Brown, Melissa; Buckley, Michael; Burke, Jo; Butow, Phyllis; Byron, Keith; Callen, David; Campbell, Ian; Chenevix-Trench, Georgia; Clarke, Christine; Colley, Alison; Cotton, Dick; Cui, Jisheng; Culling, Bronwyn; Cummings, Margaret; Dawson, Sarah-Jane; Dixon, Joanne; Dobrovic, Alexander; Dudding, Tracy; Edkins, Ted; Eisenbruch, Maurice; Farshid, Gelareh; Fawcett, Susan; Field, Michael; Firgaira, Frank; Fleming, Jean; Forbes, John; Friedlander, Michael; Gaff, Clara; Gardner, Mac; Gattas, Mike; George, Peter; Giles, Graham; Gill, Grantley; Goldblatt, Jack; Greening, Sian; Grist, Scott; Haan, Eric; Harris, Marion; Hart, Stewart; Hayward, Nick; Hopper, John; Humphrey, Evelyn; Jenkins, Mark; Jones, Alison; Kefford, Rick; Kirk, Judy; Kollias, James; Kovalenko, Sergey; Lakhani, Sunil; Leary, Jennifer; Lim, Jacqueline; Lindeman, Geoff; Lipton, Lara; Lobb, Liz; Maclurcan, Mariette; Mann, Graham; Marsh, Deborah; McCredie, Margaret; McKay, Michael; McLachlan, Sue Anne; Meiser, Bettina; Milne, Roger; Mitchell, Gillian; Newman, Beth; O'Loughlin, Imelda; Osborne, Richard; Peters, Lester; Phillips, Kelly; Price, Melanie; Reeve, Jeanne; Reeve, Tony; Richards, Robert; Rinehart, Gina; Robinson, Bridget; Rudzki, Barney; Salisbury, Elizabeth; Sambrook, Joe; Saunders, Christobel; Scott, Clare; Scott, Elizabeth; Scott, Rodney; Seshadri, Ram; Shelling, Andrew; Southey, Melissa; Spurdle, Amanda; Suthers, Graeme; Taylor, Donna; Tennant, Christopher; Thorne, Heather; Townshend, Sharron; Tucker, Kathy; Tyler, Janet; Venter, Deon; Visvader, Jane; Walpole, Ian; Ward, Robin; Waring, Paul; Warner, Bev; Warren, Graham; Watson, Elizabeth; Williams, Rachael; Wilson, Judy; Winship, Ingrid; Young, Mary Ann; Bowtell, David; Green, Adele; deFazio, Anna; Chenevix-Trench, Georgia; Gertig, Dorota; Webb, Penny

2009-01-01

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2>0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P<10−7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P<0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach. PMID:17529967

Age at Development of Type 1 Diabetes– and Celiac Disease–Associated Antibodies and Clinical Disease in Genetically Susceptible Children Observed From Birth

OpenAIRE

Simell, Satu; Hoppu, Sanna; Simell, Tuu; Ståhlberg, Marja-Riitta; Viander, Markku; Routi, Taina; Simell, Ville; Veijola, Riitta; Ilonen, Jorma; Hyöty, Heikki; Knip, Mikael; Simell, Olli

2010-01-01

OBJECTIVE To compare the ages and sequence in which antibodies associated with type 1 diabetes and celiac disease appear and overt diseases develop in children with an HLA-conferred susceptibility to both diseases. RESEARCH DESIGN AND METHODS We observed 2,052 children carrying genetic risks for both type 1 diabetes and celiac disease from birth until the median age of 5.7 years and analyzed diabetes- and celiac disease–associated antibodies in serum samples collected at 3- to 12-month interv...

Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease

NARCIS (Netherlands)

van der Harst, Pim; Verweij, Niek

2018-01-01

Rationale: Coronary artery disease (CAD) is a complex phenotype driven by genetic and environmental factors. Ninety-seven genetic risk loci have been identified to date, but the identification of additional susceptibility loci might be important to enhance our understanding of the genetic

A strabismus susceptibility locus on chromosome 7p

Science.gov (United States)

Parikh, Vaishali; Shugart, Yin Yao; Doheny, Kimberly F.; Zhang, Jie; Li, Lan; Williams, John; Hayden, David; Craig, Brian; Capo, Hilda; Chamblee, Denise; Chen, Cathy; Collins, Mary; Dankner, Stuart; Fiergang, Dean; Guyton, David; Hunter, David; Hutcheon, Marcia; Keys, Marshall; Morrison, Nancy; Munoz, Michelle; Parks, Marshall; Plotsky, David; Protzko, Eugene; Repka, Michael X.; Sarubbi, Maria; Schnall, Bruce; Siatkowski, R. Michael; Traboulsi, Elias; Waeltermann, Joanne; Nathans, Jeremy

2003-01-01

Strabismus has been known to have a significant genetic component, but the mode of inheritance and the identity of the relevant genes have been enigmatic. This paper reports linkage analysis of nonsyndromic strabismus. The principal results of this study are: (i) the demonstrated feasibility of identifying and recruiting large families in which multiple members have (or had) strabismus; (ii) the linkage in one large family of a presumptive strabismus susceptibility locus to 7p22.1 with a multipoint logarithm of odds score of 4.51 under a model of recessive inheritance; and (iii) the failure to observe significant linkage to 7p in six other multiplex families, consistent with genetic heterogeneity among families. These findings suggest that it will be possible to localize and ultimately identify strabismus susceptibility genes by linkage analysis and mutation screening of candidate genes. PMID:14519848

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

Immune and biochemical responses in skin differ between bovine hosts genetically susceptible and resistant to the cattle tick Rhipicephalus microplus.

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Franzin, Alessandra Mara; Maruyama, Sandra Regina; Garcia, Gustavo Rocha; Oliveira, Rosane Pereira; Ribeiro, José Marcos Chaves; Bishop, Richard; Maia, Antônio Augusto Mendes; Moré, Daniela Dantas; Ferreira, Beatriz Rossetti; Santos, Isabel Kinney Ferreira de Miranda

2017-01-31

Ticks attach to and penetrate their hosts' skin and inactivate multiple components of host responses in order to acquire a blood meal. Infestation loads with the cattle tick, Rhipicephalus microplus, are heritable: some breeds carry high loads of reproductively successful ticks, whereas in others, few ticks feed and reproduce efficiently. In order to elucidate the mechanisms that result in the different outcomes of infestations with cattle ticks, we examined global gene expression and inflammation induced by tick bites in skins from one resistant and one susceptible breed of cattle that underwent primary infestations with larvae and nymphs of R. microplus. We also examined the expression profiles of genes encoding secreted tick proteins that mediate parasitism in larvae and nymphs feeding on these breeds. Functional analyses of differentially expressed genes in the skin suggest that allergic contact-like dermatitis develops with ensuing production of IL-6, CXCL-8 and CCL-2 and is sustained by HMGB1, ISG15 and PKR, leading to expression of pro-inflammatory chemokines and cytokines that recruit granulocytes and T lymphocytes. Importantly, this response is delayed in susceptible hosts. Histopathological analyses of infested skins showed inflammatory reactions surrounding tick cement cones that enable attachment in both breeds, but in genetically tick-resistant bovines they destabilized the cone. The transcription data provided insights into tick-mediated activation of basophils, which have previously been shown to be a key to host resistance in model systems. Skin from tick-susceptible bovines expressed more transcripts encoding enzymes that detoxify tissues. Interestingly, these enzymes also produce volatile odoriferous compounds and, accordingly, skin rubbings from tick-susceptible bovines attracted significantly more tick larvae than rubbings from resistant hosts. Moreover, transcripts encoding secreted modulatory molecules by the tick were significantly more

CNS autoimmune disease after Streptococcus pyogenes infections: animal models, cellular mechanisms and genetic factors

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Cutforth, Tyler; DeMille, Mellissa MC; Agalliu, Ilir; Agalliu, Dritan

2016-01-01

Streptococcus pyogenes infections have been associated with two autoimmune diseases of the CNS: Sydenham’s chorea (SC) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus infections (PANDAS). Despite the high frequency of pharyngeal streptococcus infections among children, only a small fraction develops SC or PANDAS. This suggests that several factors in combination are necessary to trigger autoimmune complications: specific S. pyogenes strains that induce a strong immune response toward the host nervous system; genetic susceptibility that predispose children toward an autoimmune response involving movement or tic symptoms; and multiple infections of the throat or tonsils that lead to a robust Th17 cellular and humoral immune response when untreated. In this review, we summarize the evidence for each factor and propose that all must be met for the requisite neurovascular pathology and behavioral deficits found in SC/PANDAS. PMID:27110222

Importance of genetic factors in the etiology of atopic dermatitis: a twin study

DEFF Research Database (Denmark)

Thomsen, Simon F; Ulrik, Charlotte S; Kyvik, Kirsten O

2007-01-01

The susceptibility to develop atopic dermatitis can be attributed both to genetic and environmental causes. We estimated the relative impact of genetic and environmental factors in the etiology of atopic dermatitis in a population-based sample of twins. From the birth cohorts of 1953-1982 who wer...... dermatitis both in male and female patients (p = 0.98). The estimates were adjusted for age. The susceptibility to develop atopic dermatitis is attributable to mainly genetic differences between people. However, differences in environmental exposures also are of importance......The susceptibility to develop atopic dermatitis can be attributed both to genetic and environmental causes. We estimated the relative impact of genetic and environmental factors in the etiology of atopic dermatitis in a population-based sample of twins. From the birth cohorts of 1953-1982 who were...... with a threefold increased risk among cotwins of an affected fraternal twin, relative to the general population. Genes accounted for 82% and nonshared environmental factors accounted for 18% of the individual susceptibility to develop atopic dermatitis. The same genes contributed to the susceptibility to atopic...

Wild rodents as a model to discover genes and pathways underlying natural variation in infectious disease susceptibility.

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Turner, A K; Paterson, S

2013-11-01

Individuals vary in their susceptibility to infectious disease, and it is now well established that host genetic factors form a major component of this variation. The discovery of genes underlying susceptibility has the potential to lead to improved disease control, through the identification and management of vulnerable individuals and the discovery of novel therapeutic targets. Laboratory rodents have proved invaluable for ascertaining the function of genes involved in immunity to infection. However, these captive animals experience conditions very different to the natural environment, lacking the genetic diversity and environmental pressures characteristic of natural populations, including those of humans. It has therefore often proved difficult to translate basic laboratory research to the real world. In order to further our understanding of the genetic basis of infectious disease resistance, and the evolutionary forces that drive variation in susceptibility, we propose that genetic research traditionally conducted on laboratory animals is expanded to the more ecologically valid arena of natural populations. In this article, we highlight the potential of using wild rodents as a new resource for biomedical research, to link the functional genetic knowledge gained from laboratory rodents with the variation in infectious disease susceptibility observed in humans and other natural populations. © 2013 John Wiley & Sons Ltd.

Identification of shared genetic susceptibility locus for coronary artery disease, type 2 diabetes and obesity: a meta-analysis of genome-wide studies

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Wu Chaoneng

2012-06-01

Full Text Available Abstract Type 2 diabetes (2DM, obesity, and coronary artery disease (CAD are frequently coexisted being as key components of metabolic syndrome. Whether there is shared genetic background underlying these diseases remained unclear. We performed a meta-analysis of 35 genome screens for 2DM, 36 for obesity or body mass index (BMI-defined obesity, and 21 for CAD using genome search meta-analysis (GSMA, which combines linkage results to identify regions with only weak evidence and provide genetic interactions among different diseases. For each study, 120 genomic bins of approximately 30 cM were defined and ranked according to the best linkage evidence within each bin. For each disease, bin 6.2 achieved genomic significanct evidence, and bin 9.3, 10.5, 16.3 reached suggestive level for 2DM. Bin 11.2 and 16.3, and bin 10.5 and 9.3, reached suggestive evidence for obesity and CAD respectively. In pooled all three diseases, bin 9.3 and 6.5 reached genomic significant and suggestive evidence respectively, being relatively much weaker for 2DM/CAD or 2DM/obesity or CAD/obesity. Further, genomewide significant evidence was observed of bin 16.3 and 4.5 for 2DM/obesity, which is decreased when CAD was added. These findings indicated that bin 9.3 and 6.5 are most likely to be shared by 2DM, obesity and CAD. And bin 16.3 and 4.5 are potentially common regions to 2DM and obesity only. The observed shared susceptibility regions imply a partly overlapping genetic aspects of disease development. Fine scanning of these regions will definitely identify more susceptibility genes and causal variants.

Genetic susceptibility to bilateral tinnitus in a Swedish twin cohort.

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Maas, Iris Lianne; Brüggemann, Petra; Requena, Teresa; Bulla, Jan; Edvall, Niklas K; Hjelmborg, Jacob V B; Szczepek, Agnieszka J; Canlon, Barbara; Mazurek, Birgit; Lopez-Escamez, Jose A; Cederroth, Christopher R

2017-09-01

Genetic contributions to tinnitus have been difficult to determine due to the heterogeneity of the condition and its broad etiology. Here, we evaluated the genetic and nongenetic influences on self-reported tinnitus from the Swedish Twin Registry (STR). Cross-sectional data from the STR was obtained. Casewise concordance rates (the risk of one twin being affected given that his/her twin partner has tinnitus) were compared for monozygotic (MZ) and dizygotic (DZ) twin pairs (N = 10,464 concordant and discordant twin pairs) and heritability coefficients (the proportion of the total variance attributable to genetic factors) were calculated using biometrical model fitting procedures. Stratification of tinnitus cases into subtypes according to laterality (unilateral versus bilateral) revealed that heritability of bilateral tinnitus was 0.56; however, it was 0.27 for unilateral tinnitus. Heritability was greater in men (0.68) than in women (0.41). However, when female pairs younger than 40 years of age were selected, heritability of 0.62 was achieved with negligible effects of shared environment. Unlike unilateral tinnitus, bilateral tinnitus is influenced by genetic factors and might constitute a genetic subtype. Overall, our study provides the initial evidence for a tinnitus phenotype with a genetic influence.Genet Med advance online publication 23 March 2017.

Journal of Genetics | Indian Academy of Sciences

Indian Academy of Sciences (India)

Home; Journals; Journal of Genetics. Vasanth Konda Mohan. Articles written in Journal of Genetics. Volume 93 Issue 2 August 2014 pp 597-605 Review Article. Association of susceptible genetic markers and autoantibodies in rheumatoid arthritis · Vasanth Konda Mohan Nalini Ganesan Rajasekhar Gopalakrishnan.

STAT4 gene polymorphisms are associated with susceptibility and ANA status in primary biliary cirrhosis.

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Joshita, Satoru; Umemura, Takeji; Nakamura, Minoru; Katsuyama, Yoshihiko; Shibata, Soichiro; Kimura, Takefumi; Morita, Susumu; Komatsu, Michiharu; Matsumoto, Akihiro; Yoshizawa, Kaname; Ishibashi, Hiromi; Tanaka, Eiji; Ota, Masao

2014-01-01

Recent genome-wide association studies suggest that genetic factors contribute to primary biliary cirrhosis (PBC) susceptibility. Although several reports have demonstrated that the interleukin (IL) 12 signaling pathway is involved in PBC pathogenesis, its precise genetic factors have not been fully clarified. Here, we performed an association analysis between IL12A, IL12RB, and signal transducer and activator of transcription 4 (STAT4) genetic variations and susceptibility to PBC. Single nucleotide polymorphisms (SNPs) were genotyped in 395 PBC patients and 458 healthy subjects of Japanese ethnicity and evaluated for associations with PBC susceptibility, anti-nuclear antibody (ANA) status, and anti-mitochondrial antibody (AMA) status. We detected significant associations with PBC susceptibility for several STAT4 SNPs (rs10168266; P = 9.4 × 10(-3), rs11889341; P = 1.2 × 10(-3), rs7574865; P = 4.0 × 10(-4), rs8179673; P = 2.0 × 10(-4), and rs10181656; P = 4.2 × 10(-5)). Three risk alleles (rs7574865; P = 0.040, rs8179673; P = 0.032, and rs10181656; P = 0.031) were associated with ANA status, but not with AMA positivity. Our findings confirm that STAT4 is involved in PBC susceptibility and may play a role in ANA status in the Japanese population.

STAT4 Gene Polymorphisms Are Associated with Susceptibility and ANA Status in Primary Biliary Cirrhosis

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Satoru Joshita

2014-01-01

Full Text Available Recent genome-wide association studies suggest that genetic factors contribute to primary biliary cirrhosis (PBC susceptibility. Although several reports have demonstrated that the interleukin (IL 12 signaling pathway is involved in PBC pathogenesis, its precise genetic factors have not been fully clarified. Here, we performed an association analysis between IL12A, IL12RB, and signal transducer and activator of transcription 4 (STAT4 genetic variations and susceptibility to PBC. Single nucleotide polymorphisms (SNPs were genotyped in 395 PBC patients and 458 healthy subjects of Japanese ethnicity and evaluated for associations with PBC susceptibility, anti-nuclear antibody (ANA status, and anti-mitochondrial antibody (AMA status. We detected significant associations with PBC susceptibility for several STAT4 SNPs (rs10168266; P=9.4×10-3, rs11889341; P=1.2×10-3, rs7574865; P=4.0×10-4, rs8179673; P=2.0×10-4, and rs10181656; P=4.2×10-5. Three risk alleles (rs7574865; P=0.040, rs8179673; P=0.032, and rs10181656; P=0.031 were associated with ANA status, but not with AMA positivity. Our findings confirm that STAT4 is involved in PBC susceptibility and may play a role in ANA status in the Japanese population.

Pediatric melioidosis in Sarawak, Malaysia: Epidemiological, clinical and microbiological characteristics.

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Mohan, Anand; Podin, Yuwana; Tai, Nickson; Chieng, Chae-Hee; Rigas, Vanessa; Machunter, Barbara; Mayo, Mark; Wong, Desiree; Chien, Su-Lin; Tan, Lee-See; Goh, Charles; Bantin, Reginal; Mijen, Alexander; Chua, Wen-Yi; Hii, King-Ching; Wong, See-Chang; Ngian, Hie-Ung; Wong, Jin-Shyan; Hashim, Jamilah; Currie, Bart J; Ooi, Mong-How

2017-06-01

Melioidosis is a serious, and potentially fatal community-acquired infection endemic to northern Australia and Southeast Asia, including Sarawak, Malaysia. The disease, caused by the usually intrinsically aminoglycoside-resistant Burkholderia pseudomallei, most commonly affects adults with predisposing risk factors. There are limited data on pediatric melioidosis in Sarawak. A part prospective, part retrospective study of children aged Sarawak between 2009 and 2014. We examined epidemiological, clinical and microbiological characteristics. Forty-two patients were recruited during the 6-year study period. The overall annual incidence was estimated to be 4.1 per 100,000 children Sarawak has a very high incidence of pediatric melioidosis, caused predominantly by gentamicin-susceptible B. pseudomallei strains. Children frequently presented with disseminated disease and had an alarmingly high death rate, despite the absence of any apparent predisposing risk factor.

In vitro antimicrobial susceptibility and genetic resistance determinants of Streptococcus agalactiae isolated from mastitic cows in Brazilian dairy herds

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Juliana Rosa da Silva

2017-08-01

Full Text Available Streptococcus agalactiae is one of the main causative agents of bovine mastitis and is associated with several economic losses for producers. Few studies have evaluated antimicrobial susceptibility and the prevalence of genetic resistance determinants among isolates of this bacterium from Brazilian dairy cattle. This work aimed to evaluate the frequency of the antimicrobial resistance genes ermA, ermB, mefA, tetO, tetM, aphA3, and aad-6, and in vitro susceptibility to the antimicrobials amikacin, erythromycin, clindamycin, tetracycline, gentamicin, penicillin, ceftiofur, and cefalotin, and the associations between resistance genotypes and phenotypes among 118 S. agalactiae isolates obtained from mastitic cows in Brazilian dairy herds. Of the resistance genes examined, ermB was found in 19 isolates (16.1%, tetO in 23 (19.5%, and tetM in 24 (20.3%. The genes ermA, mefA, aphA3, and aad-6 were not identified. There was an association between the presence of genes ermB, tetM, and tetO and phenotypic resistance to erythromycin, clindamycin, and tetracycline. Rates of resistance to the tested antibiotics varied, as follows: erythromycin (19.5%, tetracycline (35.6%, gentamicin (9.3%, clindamycin (20.3%, penicillin (3.4%, and amikacin (38.1%; conversely, all isolates were susceptible to ceftiofur and cefalotin. Antimicrobial resistance testing facilitates the treatment decision process, allowing the most judicious choice of antibiotics. Moreover, it enables regional and temporal monitoring of the resistance dynamics of this pathogen of high importance to human and animal health.

Genetic changes associated with testicular cancer susceptibility.

Science.gov (United States)

Pyle, Louise C; Nathanson, Katherine L

2016-10-01

Testicular germ cell tumor (TGCT) is a highly heritable cancer primarily affecting young white men. Genome-wide association studies (GWAS) have been particularly effective in identifying multiple common variants with strong contribution to TGCT risk. These loci identified through association studies have implicated multiple genes as associated with TGCT predisposition, many of which are unique among cancer types, and regulate processes such as pluripotency, sex specification, and microtubule assembly. Together these biologically plausible genes converge on pathways involved in male germ cell development and maturation, and suggest that perturbation of them confers susceptibility to TGCT, as a developmental defect of germ cell differentiation. Copyright © 2016 Elsevier Inc. All rights reserved.

Key Challenges in the Search for Innovative Drug Treatments for Special Populations. Converging Needs in Neonatology, Pediatrics, and Medical Genetics.

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MacLeod, Stuart

2017-08-04

The explosion of knowledge concerning the interplay of genetic and environmental factors determining pathophysiology and guiding therapeutic choice has altered the landscape in pediatric clinical pharmacology and pharmacy. The need for innovative research methods and design expertise for small clinical trials to be undertaken in sparse populations has been accentuated. At the same time, shortfalls in critical human resources represent a key challenge, especially in low- and middle-income countries where the need for new research and education directions is greatest. Unless a specific action plan is urgently developed, there will be a continuing gap in availability of the essential expertise needed to address treatment challenges in special patient populations such as neonates, patients suffering from rare or neglected diseases, and children of all ages.

Role of T cell receptor delta gene in susceptibility to celiac disease.

Science.gov (United States)

Roschmann, E; Wienker, T F; Volk, B A

1996-02-01

There is a strong genetic influence on the susceptibility to celiac disease. Although in the vast majority of patients with celiac disease, the HLA-DQ(alpha1*0501, beta1*0201) heterodimer encoded by the alleles HLA-DQA1*0501 and HLA-DQB1*0201 seems to confer the primary disease susceptibility, it cannot be excluded that other genes contribute to disease susceptibility, as indicated by the difference in concordance rates between monozygotic twins and HLA identical siblings (70% vs. 30%). Obviously other genes involved in the genetic control of T cell mediated immune response could potentially influence susceptibility to celiac disease. The density of T cells using the gammadelta T cell receptor (TCR) is considerably increased in the jejunal epithelium of patients with celiac disease, an abnormality considered to be specific for celiac disease. This suggests an involvement of gammadelta T cells in the pathogenesis of the disease. To ascertain whether the TCR delta (TCRD) gene contributes to celiac disease susceptibility we carried out an association study and genetic linkage analysis using a highly polymorphic microsatellite marker at the TCRD locus on chromosome 14q11.2. The association study demonstrated no significant difference in allele frequencies of the TCRD gene marker between celiac disease patients and controls; accordingly, the relative risk estimates did not reach the level of statistical significance. In the linkage analysis, performed in 23 families, the logarithm of the odds (LOD) scores calculated for celiac disease versus the TCRD gene marker excluded linkage, suggesting that there is no determinant contributing to celiac disease status at or 5 cM distant to the analyzed TCRD gene marker. In conclusion, the results of the present study provide no evidence that the analyzed TCRD gene contributes substantially to celiac disease susceptibility.

Genetic Susceptibility and Neurotransmitters in Tourette Syndrome

NARCIS (Netherlands)

Paschou, Peristera; Fernandez, Thomas V.; Sharp, Frank; Heiman, Gary A.; Hoekstra, Pieter J.; Martino, D; Cavanna, AE

2013-01-01

Family studies have consistently shown that Tourette syndrome (TS) is a familial disorder and twin studies have clearly indicated a genetic contribution in the etiology of TS. Whereas early segregation studies of TS suggested a single-gene autosomal dominant disorder, later studies have pointed to

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

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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.

Genetics of Vitiligo

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Spritz, Richard; Andersen, Genevieve

2016-01-01

Synopsis Vitiligo is “complex disorder” (also termed polygenic and multifactorial), reflecting simultaneous contributions of multiple genetic risk factors and environmental triggers. Large-scale genome-wide association studies, principally in European-derived whites and in Chinese, have discovered approximately 50 different genetic loci that contribute to vitiligo risk, some of which also contribute to other autoimmune diseases that are epidemiologically associated with vitiligo. At many of these vitiligo susceptibility loci the corresponding relevant genes have now been identified, and for some of these genes the specific DNA sequence variants that contribute to vitiligo risk are also now known. A large fraction of these genes encode proteins involved in immune regulation, a number of others play roles in cellular apoptosis, and still others are involved in regulating functions of melanocytes. For this last group, there appears to be an opposite relationship between susceptibility to vitiligo and susceptibility to melanoma, suggesting that vitiligo may engage a normal mechanism of immune surveillance for melanoma. While many of the specific biologic mechanisms through which these genetic factors operate to cause vitiligo remain to be elucidated, it is now clear that vitiligo is an autoimmune disease involving a complex relationship between programming and function of the immune system, aspects of the melanocyte autoimmune target, and dysregulation of the immune response. PMID:28317533

Pediatric obesity: Causes, symptoms, prevention and treatment.

Science.gov (United States)

Xu, Shumei; Xue, Ying

2016-01-01

Pediatric or childhood obesity is the most prevalent nutritional disorder among children and adolescents worldwide. Approximately 43 million individuals are obese, 21-24% children and adolescents are overweight, and 16-18% of individuals have abdominal obesity. The prevalence of obesity is highest among specific ethnic groups. Obesity increases the risk of heart diseases in children and adults. Childhood obesity predisposes the individual to insulin resistance and type 2 diabetes, hypertension, hyperlipidemia, liver and kidney diseases and causes reproductive dysfunction in adults. Obesity in children is a major health concern of the developed world. The National Health and Nutrition Examination Survey has reported that the prevalence of obesity is on the increase in all the pediatric age groups, in males and females, and in various ethnic and racial groups. Factors, such as eating habits, genetics, environment, metabolism, and lifestyle play an important role in the development of obesity. Over 90% of obesity cases are idiopathic and less than 10% are associated with genetic and hormonal causes. Obesity occurs when the body consumes more calories than it burns, through overeating and underexercising. The symptoms of obesity include breathing disorders, sleep apnea, chronic obstructive pulmonary disease, certain types of cancer such as prostate, bowel, breast and uterine, coronary heart disease, diabetes (type 2 in children), depression, liver and gallbladder problems, gastro-esophageal reflux disease, high blood pressure, high cholesterol, stroke, and joint diseases such as osteoarthritis, pain in knees and lower back. Environmental, behavioral such as consumption of convenience foods, genetic, and family factors contribute to pediatric obesity. Obesity can be countered through lower calorie consumption, weight loss and diet programs, as well as increased physical activity. A number of endogenous molecules including leptin, hypothalamic melanocortin 4 receptor

Serotyping and Antimicrobial Susceptibility Pattern of Escherichia coli Isolates from Urinary Tract Infections in Pediatric Population in a Tertiary Care Hospital

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Shweta Sharma

2016-01-01

Full Text Available Urinary tract infections (UTIs in pediatric population are associated with high morbidity and long term complications. In recent years, there is increased prevalence of Escherichia coli (E. coli strains producing extended spectrum β-lactamase, Amp C, and Metallo β-lactamase, making the clinical management even more difficult. This study was aimed to detect the serotypes and to determine antimicrobial susceptibility profile of E. coli isolates from urine samples of children <10 yrs old. A total of 75 pure E. coli strains isolated from patients with symptoms of UTI and colony count ≥105 organisms/mL were included in the study. Antibiotic sensitivity pattern showed maximum resistance to nalidixic acid (98.7%, followed by ampicillin (97.3%, amoxi-clavulanate (96%, and fluoroquinolones (92% while most of the isolates were found sensitive to piperacillin-tazobactam (13.3%, nitrofurantoin (5.3%, and meropenem (1.3%. 48% of the strains were ESBL producer (extended spectrum beta lactamase. 44% strains were typable withantisera used in our study and the most common serogroup was O6 (33.3% followed by O1 (15.1% and O15 (15.1%. To conclude, judicious use of antibiotics according to hospital antibiotic policy and infection control measures should be implemented to prevent spread of multidrug resistant organisms.

Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload.

Science.gov (United States)

Fetterman, Jessica L; Zelickson, Blake R; Johnson, Larry W; Moellering, Douglas R; Westbrook, David G; Pompilius, Melissa; Sammy, Melissa J; Johnson, Michelle; Dunham-Snary, Kimberly J; Cao, Xuemei; Bradley, Wayne E; Zhang, Jinju; Wei, Chih-Chang; Chacko, Balu; Schurr, Theodore G; Kesterson, Robert A; Dell'italia, Louis J; Darley-Usmar, Victor M; Welch, Danny R; Ballinger, Scott W

2013-10-15

Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mtDNA sequence variation contributes to disease susceptibility. In the present study we show a novel animal model of mtDNA polymorphisms, the MNX (mitochondrial-nuclear exchange) mouse, in which the mtDNA from the C3H/HeN mouse has been inserted on to the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harbouring the C57/BL6J mtDNA generate more ROS (reactive oxygen species) and have a higher mitochondrial membrane potential relative to those with C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the 'mitochondrial paradigm' for the development of disease susceptibility, and show that the mtDNA modulates cellular bioenergetics, mitochondrial ROS generation and susceptibility to cardiac stress.

Degree of Tissue Differentiation Dictates Susceptibility to BRAF-Driven Colorectal Cancer

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Kevin Tong

2017-12-01

Full Text Available Oncogenic mutations in BRAF are believed to initiate serrated colorectal cancers; however, the mechanisms of BRAF-driven colon cancer are unclear. We find that oncogenic BRAF paradoxically suppresses stem cell renewal and instead promotes differentiation. Correspondingly, tumor formation is inefficient in BRAF-driven mouse models of colon cancer. By reducing levels of differentiation via genetic manipulation of either of two distinct differentiation-promoting factors (Smad4 or Cdx2, stem cell activity is restored in BRAFV600E intestines, and the oncogenic capacity of BRAFV600E is amplified. In human patients, we observe that reduced levels of differentiation in normal tissue is associated with increased susceptibility to serrated colon tumors. Together, these findings help resolve the conditions necessary for BRAF-driven colon cancer initiation. Additionally, our results predict that genetic and/or environmental factors that reduce tissue differentiation will increase susceptibility to serrated colon cancer. These findings offer an opportunity to identify susceptible individuals by assessing their tissue-differentiation status.

Detection and Characterization of Infections and Infection Susceptibility

Science.gov (United States)

2018-03-27

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)

Virtual Pediatric Hospital

Science.gov (United States)

... Thoracopaedia - An Imaging Encyclopedia of Pediatric Thoracic Disease Virtual Pediatric Hospital is the Apprentice's Assistant™ Last revised ... pediatric resources: GeneralPediatrics.com | PediatricEducation.org | SearchingPediatrics.com Virtual Pediatric Hospital is curated by Donna M. D' ...

Clinical and diagnostic pathways in pediatric fungal infections

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Elio Castagnola

2013-07-01

Full Text Available Generally speaking, in pediatrics the patients mostly affected by fungal infections are hematological patients, followed by those with solid tumors, and transplant recipients. Candida infections generally occur just after birth, whereas Aspergillus infections are age-related, and increase their incidence with age. However, among infections, the incidence of bacteremias are still greater than that of mycoses. In pediatrics, in Italy the immunocompromised patients – thus particularly susceptible to fungal infections – are mainly those with severe combined immunodeficiency, chronic mucocutaneous candidiasis, and chronic granulomatous disease. Particular Aspergillus or Scedosporium infections should be considered in peculiar kinds of patients, such as those affected by cystic fibrosis. Finally, different kinds of fungi should be considered in those who come from or spend a lot time in specific areas, such as South America (e.g. coccidioidomycoses, for which differential diagnosis is with tuberculosis.http://dx.doi.org/10.7175/rhc.v4i1S.859

Genetic risks and healthy choices: creating citizen-consumers of genetic services through empowerment and facilitation.

Science.gov (United States)

Harvey, Alison

2010-03-01

Genetic testing to identify susceptibility to a variety of common complex diseases is increasingly becoming available. In this article, focusing on the development of genetic susceptibility testing for diet-related disease, I examine the emergence of direct-to-the-consumer genetic testing services and the (re)configuration of healthcare provision, both within and outside the specialist genetics service, in the UK. I identify two key techniques within these practices: empowerment and facilitation. Using Foucauldian social theory, I show that empowerment and facilitation are being positioned as tools for the creation of citizen-consumers who will make appropriate dietary choices, based on the results of their genetic analysis. Through these techniques, individuals are transformed into properly entrepreneurial citizens who will, through judicious choices, act to maximise their 'vital capital' (their health) and the capital of the social body. I argue that the user of these services is not purely an economic figure, making rational choices as a consumer, but that her configuration as a citizen-consumer who avails herself of genetic information and services in a proper manner ensures that she is fit to contribute to the economic life of our present.

Influence of Factor V Leiden on susceptibility to and outcome from critical illness: a genetic association study

DEFF Research Database (Denmark)

Benfield, Thomas; Ejrnæs, Karen; Juul, Klaus

2010-01-01

ABSTRACT: INTRODUCTION: Disturbance of the pro-coagulatant and anti-coagulant balance is associated with a poor outcome from critical illness. The objective of this study is to determine whether the Factor V Leiden (FVL) mutation is associated with susceptibility to or death from critical illness....... METHODS: A genetic association study involving four case cohorts comprising two Gram negative sepsis, one invasive pneumococcal disease and one intensive care unit cohort with a total of 1,249 patients. Controls were derived from a population-based cohort study (N = 8,147). DNA from patients and controls...... not appear to increase the risk of admission due to severe invasive infections. Nevertheless, in the subgroup of patients admitted to intensive care an increased risk and a poorer long-term outcome for individuals with critical illness were observed for FVL mutation carriers....

Pediatric Specialists

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... Healthy Children > Family Life > Medical Home > Pediatric Specialists Pediatric Specialists Article Body ​Your pediatrician may refer your child to a pediatric specialist for further evaluation and treatment. Pediatric specialists ...

Identification of a herpes simplex labialis susceptibility region on human chromosome 21.

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Hobbs, Maurine R; Jones, Brandt B; Otterud, Brith E; Leppert, Mark; Kriesel, John D

2008-02-01

Most of the United States population is infected with either herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2, or both. Reactivations of HSV-1 infection cause herpes simplex labialis (HSL; cold sores or fever blisters), which is the most common recurring viral infection in humans. To investigate the possibility of a human genetic component conferring resistance or susceptibility to cold sores (i.e., a HSL susceptibility gene), we conducted a genetic linkage analysis that included serotyping and phenotyping 421 individuals from 39 families enrolled in the Utah Genetic Reference Project. Linkage analysis identified a 2.5-Mb nonrecombinant region of interest on the long arm of human chromosome 21, with a multipoint logarithm of odds score of 3.9 noted near marker abmc65 (D21S409). Nonparametric linkage analysis of the data also provided strong evidence for linkage (P = .0005). This region of human chromosome 21 contains 6 candidate genes for herpes susceptibility. The development of frequent cold sores is associated with a region on the long arm of human chromosome 21. This region contains several candidate genes that could influence the frequency of outbreaks of HSL.

[Issues on business of genetic testing in near future].

Science.gov (United States)

Takada, Fumio

2009-06-01

Since 1990's, a business condition that company sells genetic testing services directly to consumers without through medical facility, so called "direct-to-consumers (DTC) genetic testing", has risen. They provide genetic testing for obesity, disease susceptibility or paternity, etc. There are serious problems in this kind of business. Most of the providers do not make sales with face-to-face selling, and do through internet instead. They do not provide genetic counseling by certified genetic counselor or clinical geneticist. Most DTC genetic testing services for disease susceptibility or predispositions including obesity, lack scientific validity, clinical validity and clinical utility. And also including paternity genetic testing, they all have risks of ethical legal and social issues (ELSI) in genetic discrimination and/or eugenics. The specific problem in Japan is that the healthcare section of the government still has not paid attention and not taken seriously the requirement to deploy safety net.

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...

Allele-specific DNA methylation of disease susceptibility genes in Japanese patients with inflammatory bowel disease.

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Chiba, Hirofumi; Kakuta, Yoichi; Kinouchi, Yoshitaka; Kawai, Yosuke; Watanabe, Kazuhiro; Nagao, Munenori; Naito, Takeo; Onodera, Motoyuki; Moroi, Rintaro; Kuroha, Masatake; Kanazawa, Yoshitake; Kimura, Tomoya; Shiga, Hisashi; Endo, Katsuya; Negoro, Kenichi; Nagasaki, Masao; Unno, Michiaki; Shimosegawa, Tooru

2018-01-01

Inflammatory bowel disease (IBD) has an unknown etiology; however, accumulating evidence suggests that IBD is a multifactorial disease influenced by a combination of genetic and environmental factors. The influence of genetic variants on DNA methylation in cis and cis effects on expression have been demonstrated. We hypothesized that IBD susceptibility single-nucleotide polymorphisms (SNPs) regulate susceptibility gene expressions in cis by regulating DNA methylation around SNPs. For this, we determined cis-regulated allele-specific DNA methylation (ASM) around IBD susceptibility genes in CD4+ effector/memory T cells (Tem) in lamina propria mononuclear cells (LPMCs) in patients with IBD and examined the association between the ASM SNP genotype and neighboring susceptibility gene expressions. CD4+ effector/memory T cells (Tem) were isolated from LPMCs in 15 Japanese IBD patients (ten Crohn's disease [CD] and five ulcerative colitis [UC] patients). ASM analysis was performed by methylation-sensitive SNP array analysis. We defined ASM as a changing average relative allele score ([Formula: see text]) >0.1 after digestion by methylation-sensitive restriction enzymes. Among SNPs showing [Formula: see text] >0.1, we extracted the probes located on tag-SNPs of 200 IBD susceptibility loci and around IBD susceptibility genes as candidate ASM SNPs. To validate ASM, bisulfite-pyrosequencing was performed. Transcriptome analysis was examined in 11 IBD patients (seven CD and four UC patients). The relation between rs36221701 genotype and neighboring gene expressions were analyzed. We extracted six candidate ASM SNPs around IBD susceptibility genes. The top of [Formula: see text] (0.23) was rs1130368 located on HLA-DQB1. ASM around rs36221701 ([Formula: see text] = 0.14) located near SMAD3 was validated using bisulfite pyrosequencing. The SMAD3 expression was significantly associated with the rs36221701 genotype (p = 0.016). We confirmed the existence of cis-regulated ASM around

Allele-specific DNA methylation of disease susceptibility genes in Japanese patients with inflammatory bowel disease

Science.gov (United States)

Chiba, Hirofumi; Kakuta, Yoichi; Kinouchi, Yoshitaka; Kawai, Yosuke; Watanabe, Kazuhiro; Nagao, Munenori; Naito, Takeo; Onodera, Motoyuki; Moroi, Rintaro; Kuroha, Masatake; Kanazawa, Yoshitake; Kimura, Tomoya; Shiga, Hisashi; Endo, Katsuya; Negoro, Kenichi; Nagasaki, Masao; Unno, Michiaki; Shimosegawa, Tooru

2018-01-01

Background Inflammatory bowel disease (IBD) has an unknown etiology; however, accumulating evidence suggests that IBD is a multifactorial disease influenced by a combination of genetic and environmental factors. The influence of genetic variants on DNA methylation in cis and cis effects on expression have been demonstrated. We hypothesized that IBD susceptibility single-nucleotide polymorphisms (SNPs) regulate susceptibility gene expressions in cis by regulating DNA methylation around SNPs. For this, we determined cis-regulated allele-specific DNA methylation (ASM) around IBD susceptibility genes in CD4+ effector/memory T cells (Tem) in lamina propria mononuclear cells (LPMCs) in patients with IBD and examined the association between the ASM SNP genotype and neighboring susceptibility gene expressions. Methods CD4+ effector/memory T cells (Tem) were isolated from LPMCs in 15 Japanese IBD patients (ten Crohn's disease [CD] and five ulcerative colitis [UC] patients). ASM analysis was performed by methylation-sensitive SNP array analysis. We defined ASM as a changing average relative allele score (ΔRAS¯) >0.1 after digestion by methylation-sensitive restriction enzymes. Among SNPs showing ΔRAS¯ >0.1, we extracted the probes located on tag-SNPs of 200 IBD susceptibility loci and around IBD susceptibility genes as candidate ASM SNPs. To validate ASM, bisulfite-pyrosequencing was performed. Transcriptome analysis was examined in 11 IBD patients (seven CD and four UC patients). The relation between rs36221701 genotype and neighboring gene expressions were analyzed. Results We extracted six candidate ASM SNPs around IBD susceptibility genes. The top of ΔRAS¯ (0.23) was rs1130368 located on HLA-DQB1. ASM around rs36221701 (ΔRAS¯ = 0.14) located near SMAD3 was validated using bisulfite pyrosequencing. The SMAD3 expression was significantly associated with the rs36221701 genotype (p = 0.016). Conclusions We confirmed the existence of cis-regulated ASM around IBD

Pediatric DXA: clinical applications

International Nuclear Information System (INIS)

Binkovitz, Larry A.; Sparke, Paul; Henwood, Maria J.

2007-01-01

Normal bone mineral accrual requires adequate dietary intake of calcium, vitamin D and other nutrients; hepatic and renal activation of vitamin D; normal hormone levels (thyroid, parathyroid, reproductive and growth hormones); and neuromuscular functioning with sufficient stress upon the skeleton to induce bone deposition. The presence of genetic or acquired diseases and the therapies that are used to treat them can also impact bone health. Since the introduction of clinical DXA in pediatrics in the early 1990s, there has been considerable investigation into the causes of low bone mineral density (BMD) in children. Pediatricians have also become aware of the role adequate bone mass accrual in childhood has in preventing osteoporotic fractures in late adulthood. Additionally, the availability of medications to improve BMD has increased with the development of bisphosphonates. These factors have led to the increased utilization of DXA in pediatrics. This review summarizes much of the previous research regarding BMD in children and is meant to assist radiologists and clinicians with DXA utilization and interpretation. (orig.)

Depression from childhood into late adolescence: Influence of gender, development, genetic susceptibility, and peer stress.

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Hankin, Benjamin L; Young, Jami F; Abela, John R Z; Smolen, Andrew; Jenness, Jessica L; Gulley, Lauren D; Technow, Jessica R; Gottlieb, Andrea Barrocas; Cohen, Joseph R; Oppenheimer, Caroline W

2015-11-01

Depression is a debilitating mental illness with clear developmental patterns from childhood through late adolescence. Here, we present data from the Gene Environment Mood (GEM) study, which used an accelerated longitudinal cohort design with youth (N = 665) starting in 3rd, 6th, and 9th grades, and a caretaker, who were recruited from the general community, and were then assessed repeatedly through semistructured diagnostic interviews every 6 months over 3 years (7 waves of data) to establish and then predict trajectories of depression from age 8 to 18. First, we demonstrated that overall prevalence rates of depression over time, by age, gender, and pubertal status, in the GEM study closely match those trajectories previously obtained in past developmental epidemiological research. Second, we tested whether a genetic vulnerability-stress model involving 5-HTTLPR and chronic peer stress was moderated by developmental factors. Results showed that older aged adolescents with SS/SL genotype, who experienced higher peer chronic stress over 3 years, were the most likely to be diagnosed with a depressive episode over time. Girls experiencing greater peer chronic stress were the most likely to develop depression. This study used repeated assessments of diagnostic interviewing in a moderately large sample of youth over 3 years to show that depression rates increase in middle to late adolescence, or postpubertally, and that the gender difference in depression emerges earlier in adolescence (age 12.5), or postpubertally. Additionally, genetically susceptible older adolescents who experience chronic peer stress were the most likely to become depressed over time. (c) 2015 APA, all rights reserved).

Regulatory network of GATA3 in pediatric acute lymphoblastic leukemia

OpenAIRE

Hou, Qianqian; Liao, Fei; Zhang, Shouyue; Zhang, Duyu; Zhang, Yan; Zhou, Xueyan; Xia, Xuyang; Ye, Yuanxin; Yang, Hanshuo; Li, Zhaozhi; Wang, Leiming; Wang, Xi; Ma, Zhigui; Zhu, Yiping; Ouyang, Liang

2017-01-01

GATA3 polymorphisms were reported to be significantly associated with susceptibility of pediatric B-lineage acute lymphoblastic leukemia (ALL), by impacting on GATA3 expression. We noticed that ALL-related GATA3 polymorphism located around in the tissue-specific enhancer, and significantly associated with GATA3 expression. Although the regulatory network of GATA3 has been well reported in T cells, the functional status of GATA3 is poorly understood in B-ALL. We thus conducted genome-wide gene...

An evolving scientific basis for the prevention and treatment of pediatric obesity.

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Katzmarzyk, P T; Barlow, S; Bouchard, C; Catalano, P M; Hsia, D S; Inge, T H; Lovelady, C; Raynor, H; Redman, L M; Staiano, A E; Spruijt-Metz, D; Symonds, M E; Vickers, M; Wilfley, D; Yanovski, J A

2014-07-01

The 2013 Pennington Biomedical Research Center's Scientific Symposium focused on the treatment and management of pediatric obesity and was designed to (i) review recent scientific advances in the prevention, clinical treatment and management of pediatric obesity, (ii) integrate the latest published and unpublished findings and (iii) explore how these advances can be integrated into clinical and public health approaches. The symposium provided an overview of important new advances in the field, which led to several recommendations for incorporating the scientific evidence into practice. The science presented covered a range of topics related to pediatric obesity, including the role of genetic differences, epigenetic events influenced by in utero development, pre-pregnancy maternal obesity status, maternal nutrition and maternal weight gain on developmental programming of adiposity in offspring. Finally, the relative merits of a range of various behavioral approaches targeted at pediatric obesity were covered, together with the specific roles of pharmacotherapy and bariatric surgery in pediatric populations. In summary, pediatric obesity is a very challenging problem that is unprecedented in evolutionary terms; one which has the capacity to negate many of the health benefits that have contributed to the increased longevity observed in the developed world.

Prevalence and spectrum of large deletions or duplications in the major long QT syndrome-susceptibility genes and implications for long QT syndrome genetic testing.

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Tester, David J; Benton, Amber J; Train, Laura; Deal, Barbara; Baudhuin, Linnea M; Ackerman, Michael J

2010-10-15

Long QT syndrome (LQTS) is a cardiac channelopathy associated with syncope, seizures, and sudden death. Approximately 75% of LQTS is due to mutations in genes encoding for 3 cardiac ion channel α-subunits (LQT1 to LQT3). However, traditional mutational analyses have limited detection capabilities for atypical mutations such as large gene rearrangements. We set out to determine the prevalence and spectrum of large deletions/duplications in the major LQTS-susceptibility genes in unrelated patients who were mutation negative after point mutation analysis of LQT1- to LQT12-susceptibility genes. Forty-two unrelated, clinically strong LQTS patients were analyzed using multiplex ligation-dependent probe amplification, a quantitative fluorescent technique for detecting multiple exon deletions and duplications. The SALSA multiplex ligation-dependent probe amplification LQTS kit from MRC-Holland was used to analyze the 3 major LQTS-associated genes, KCNQ1, KCNH2, and SCN5A, and the 2 minor genes, KCNE1 and KCNE2. Overall, 2 gene rearrangements were found in 2 of 42 unrelated patients (4.8%, confidence interval 1.7 to 11). A deletion of KCNQ1 exon 3 was identified in a 10-year-old Caucasian boy with a corrected QT duration of 660 ms, a personal history of exercise-induced syncope, and a family history of syncope. A deletion of KCNQ1 exon 7 was identified in a 17-year-old Caucasian girl with a corrected QT duration of 480 ms, a personal history of exercise-induced syncope, and a family history of sudden cardiac death. In conclusion, because nearly 5% of patients with genetically elusive LQTS had large genomic rearrangements involving the canonical LQTS-susceptibility genes, reflex genetic testing to investigate genomic rearrangements may be of clinical value. Copyright © 2010 Elsevier Inc. All rights reserved.

An Evolutionary Perspective on Family Studies: Differential Susceptibility to Environmental Influences.

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Hartman, Sarah; Belsky, Jay

2016-12-01

An evolutionary perspective of human development provides the basis for the differential-susceptibility hypothesis which stipulates that individuals should differ in their susceptibility to environmental influences, with some being more affected than others by both positive and negative developmental experiences and environmental exposures. This paper reviews evidence consistent with this claim while revealing that temperamental and genetic characteristics play a role in distinguishing more and less susceptible individuals. The differential-susceptibility framework under consideration is contrasted to the traditional diathesis-stress view that "vulnerability" traits predispose some to being disproportionately affected by (only) adverse experiences. We raise several issues stimulated by the literature that need to be clarified in further research. Lastly, we suggest that therapy may differ in its effects depending on an individual's susceptibility. © 2015 Family Process Institute.

Genetics of infectious diseases: hidden etiologies and common pathways.

Science.gov (United States)

Orlova, Marianna; Di Pietrantonio, Tania; Schurr, Erwin

2011-09-01

Since the completion of the human genome sequence, the study of common genetic polymorphisms in complex human diseases has become a main activity of human genetics. Employing genome-wide association studies, hundreds of modest genetic risk factors have been identified. In infectious diseases the identification of common risk factors has been varied and as in other common diseases it seems likely that important genetic risk factors remain to be discovered. Nevertheless, the identification of disease-specific genetic risk factors revealed an unexpected overlap in susceptibility genes of diverse inflammatory and infectious diseases. Analysis of the multi-disease susceptibility genes has allowed the definition of shared key pathways of inflammatory dysregulation and suggested unexpected infectious etiologies for other "non-infectious" common diseases.

Overlap of disease susceptibility loci for rheumatoid arthritis and juvenile idiopathic arthritis

Science.gov (United States)

Hinks, Anne; Eyre, Steve; Ke, Xiayi; Barton, Anne; Martin, Paul; Flynn, Edward; Packham, Jon; Worthington, Jane; Thomson, Wendy

2010-01-01

Background Genome-wide association studies (GWAS) have been extremely successful in the search for susceptibility risk factors for complex genetic autoimmune diseases. As more studies are published, evidence is emerging of considerable overlap of loci between these diseases. In juvenile idiopathic arthritis (JIA), another complex genetic autoimmune disease, the strategy of using information from autoimmune disease GWAS or candidate gene studies to help in the search for novel JIA susceptibility loci has been successful, with confirmed association with two genes, PTPN22 and IL2RA. Rheumatoid arthritis (RA) is an autoimmune disease that shares similar clinical and pathological features with JIA and, therefore, recently identified confirmed RA susceptibility loci are also excellent JIA candidate loci. Objective To determine the overlap of disease susceptibility loci for RA and JIA. Methods Fifteen single nucleotide polymorphisms (SNPs) at nine RA-associated loci were genotyped in Caucasian patients with JIA (n=1054) and controls (n=3531) and tested for association with JIA. Allele and genotype frequencies were compared between cases and controls using the genetic analysis software, PLINK. Results Two JIA susceptibility loci were identified, one of which was a novel JIA association (STAT4) and the second confirmed previously published associations of the TRAF1/C5 locus with JIA. Weak evidence of association of JIA with three additional loci (Chr6q23, KIF5A and PRKCQ) was also obtained, which warrants further investigation. Conclusion All these loci are good candidates in view of the known pathogenesis of JIA, as genes within these regions (TRAF1, STAT4, TNFAIP3, PRKCQ) are known to be involved in T-cell receptor signalling or activation pathways. PMID:19674979

Genetic variations in MTHFR and esophageal squamous cell carcinoma susceptibility in Chinese Han population.

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Tang, Weifeng; Zhang, Sheng; Qiu, Hao; Wang, Lixin; Sun, Bin; Yin, Jun; Gu, Haiyong

2014-05-01

Esophageal cancer is the sixth most common cancer worldwide. Esophageal squamous cell carcinoma (ESCC) is a fatal malignancy associated with low 5-year survival rate. The aim of this study was to assess the association between methylenetetrahydrofolate reductase (MTHFR) tagging single nucleotide polymorphisms (SNPs) rs1801133 C>T, rs3753584 A>G, rs4845882 G>A, rs4846048 A>G and rs9651118 T>C genotypes and ESCC susceptibility in a hospital-based case-control study. We conducted genotyping analyses for these five SNPs with 629 ESCC cases and 686 controls in a Chinese Han population. Ligation detection reaction method was used to identify genotypes of these MTHFR SNPs. Our results demonstrated that MTHFR rs1801133 C>T was associated with the risk of ESCC; however, MTHFR rs4845882 G>A and rs4846048 A>G SNPs were associated with the decreased risk of ESCC, and MTHFR rs3753584 A>G and rs9651118 T>C SNPs were not associated with ESCC risk. Our findings suggests that MTHFR rs1801133 C>T, rs4845882 G>A and rs4846048 A>G SNPs may be genetic modifiers for developing ESCC in Chinese Han population.

An update on Cushing syndrome in pediatrics.

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Stratakis, Constantine A

2018-04-09

Cushing syndrome (CS) in childhood results mostly from the exogenous administration of glucocorticoids; endogenous CS is a rare disease. The latter is the main reason pediatric patients with CS escape diagnosis for too long. Other barriers to optimal care of a pediatric patient with CS include improper following of the proper sequence of testing for diagnosing CS, which stems from lack of understanding of pathophysiology of the hypothalamic-pituitary-adrenal axis; lack of access to proper (i.e., experienced, state-of-the-art) surgical treatment; and unavailability of well-tolerated and effective medications to control hypercortisolemia. This report reviews the state-of-the-art in diagnosing CS and provides an update on the most recent discoveries in its genetics and treatment. Copyright © 2018. Published by Elsevier Masson SAS.

Biomarkers, Trauma, and Sepsis in Pediatrics: A Review

Directory of Open Access Journals (Sweden)

Marianne Frieri

2016-01-01

Full Text Available Context: There is a logical connection with biomarkers, trauma, and sepsis. This review paper provides new information and clinical practice implications. Biomarkers are very important especially in pediatrics. Procalcitonin and other biomarkers are helpful in identifying neonatal sepsis, defense mechanisms of the immune system. Pediatric trauma and sepsis is very important both in infants and in children. Stress management both in trauma is based upon the notion that stress causes an immune imbalance in susceptible individuals. Evidence Acquisition: Data sources included studies indexed in PubMed, a meta- analysis, predictive values, research strategies, and quality assessments. A recent paper by one of the authors stated marked increase in serum procalcitonin during the course of a septic process often indicates an exacerbation of the illness, and a decreasing level is a sign of improvement. A review of epidemiologic studies on pediatric soccer patients was also addressed. Keywords for searching included biomarkers, immunity, trauma, and sepsis. Results: Of 50 reviewed articles, 34 eligible articles were selected including biomarkers, predictive values for procalcitonin, identifying children at risk for intra-abdominal injuries, blunt trauma, and epidemiology, a meta-analysis. Of neonatal associated sepsis, the NF-kappa B pathway by inflammatory stimuli in human neutrophils, predictive value of gelsolin for the outcomes of preterm neonates, a meta-analysis interleukin-8 for neonatal sepsis diagnosis. Conclusions: Biomarkers are very important especially in pediatrics. Procalcitonin and other biomarkers are helpful in identifying neonatal sepsis, defense mechanisms, and physiological functions of the immune system. Pediatric trauma and sepsis is very important both in infants and in children. Various topics were covered such as biomarkers, trauma, sepsis, inflammation, innate immunity, role of neutrophils and IL-8, reactive oxygen species

Social pediatrics: weaving horizontal and vertical threads through pediatric residency.

Science.gov (United States)

van den Heuvel, Meta; Martimianakis, Maria Athina Tina; Levy, Rebecca; Atkinson, Adelle; Ford-Jones, Elizabeth; Shouldice, Michelle

2017-01-13

Social pediatrics teaches pediatric residents how to understand disease within their patients' social, environmental and political contexts. It's an essential component of pediatric residency training; however there is very little literature that addresses how such a broad-ranging topic can be taught effectively. The aim of this study was to determine and characterize social pediatric education in our pediatric residency training in order to identify strengths and gaps. A social pediatrics curriculum map was developed, attending to 3 different dimensions: (1) the intended curriculum as prescribed by the Objectives of Training for Pediatrics of the Royal College of Physicians and Surgeons of Canada (RCPSC), (2) the formal curriculum defined by rotation-specific learning objectives, and (3) the informal/hidden curriculum as reflected in resident and teacher experiences and perceptions. Forty-one social pediatric learning objectives were extracted from the RCPSC Objectives of Training for Pediatrics, most were listed in the Medical Expert (51%) and Health Advocate competencies (24%). Almost all RCPSC social pediatric learning objectives were identified in more than one rotation and/or seminar. Adolescent Medicine (29.2%), Pediatric Ambulatory Medicine (26.2%) and Developmental Pediatrics (25%) listed the highest proportion of social pediatric learning objectives. Four (10%) RCPSC social pediatric objectives were not explicitly named within learning objectives of the formal curriculum. The informal curriculum revealed that both teachers and residents viewed social pediatrics as integral to all clinical encounters. Perceived barriers to teaching and learning of social pediatrics included time constraints, particularly in a tertiary care environment, and the value of social pediatrics relative to medical expert knowledge. Despite the lack of an explicit thematic presentation of social pediatric learning objectives by the Royal College and residency training program

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...

Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus.

Directory of Open Access Journals (Sweden)

Christopher G Bell

2010-11-01

Full Text Available Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D, focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip and absolute methylation values were estimated using a Bayesian algorithm (BATMAN. Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p = 9.40×10(-4, permutation p = 1.0×10(-3. Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p = 1.13×10(-7. Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM, encapsulates a Highly Conserved Non-Coding Element (HCNE that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases.

Is early-onset microsatellite and chromosomally stable colorectal cancer a hallmark of a genetic susceptibility syndrome?

Science.gov (United States)

Kets, C M; van Krieken, J H J M; van Erp, P E J; Feuth, T; Jacobs, Y H A; Brunner, H G; Ligtenberg, M J L; Hoogerbrugge, N

2008-02-15

Most colorectal cancers show either microsatellite or chromosomal instability. A subset of colorectal cancers, especially those diagnosed at young age, is known to show neither of these forms of genetic instability and thus might have a distinct pathogenesis. Colorectal cancers diagnosed at young age are suggestive for hereditary predisposition. We investigate whether such early-onset microsatellite and chromosomally stable colorectal cancers are a hallmark of a genetic susceptibility syndrome. The ploidy status of microsatellite stable (familial) colorectal cancers of patients diagnosed before age 50 (n = 127) was analyzed in relation to the histopathological characteristics and family history. As a control the ploidy status of sporadic colorectal cancer, with normal staining of mismatch repair proteins, diagnosed at the age of 69 years or above (n = 70) was determined. A diploid DNA content was used as a marker for chromosomal stability. Within the group of patients with (familial) early onset microsatellite stable colorectal cancer the chromosomally stable tumors did not differ from chromosomally unstable tumors with respect to mean age at diagnosis, fulfillment of Amsterdam criteria or pathological characteristics. Segregation analysis did not reveal any family with microsatellite and chromosomally stable colorectal cancer in 2 relatives. The prevalence of microsatellite and chromosomally stable colorectal cancer was not significantly different for the early and late onset group (28 and 21%, respectively). We find no evidence that early-onset microsatellite and chromosomally stable colorectal cancer is a hallmark of a hereditary colorectal cancer syndrome. (c) 2007 Wiley-Liss, Inc.

KCNA5 gene is not confirmed as a systemic sclerosis-related pulmonary arterial hypertension genetic susceptibility factor

Science.gov (United States)

2012-01-01

Introduction Potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) is implicated in vascular tone regulation, and its inhibition during hypoxia produces pulmonary vasoconstriction. Recently, a protective association of the KCNA5 locus with systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) was reported. Hence, the aim of this study was to replicate these findings in an independent multicenter Caucasian SSc cohort. Methods The 2,343 SSc cases (179 PAH positive, confirmed by right-heart catheterization) and 2,690 matched healthy controls from five European countries were included in this study. Rs10744676 single-nucleotide polymorphism (SNP) was genotyped by using a TaqMan SNP genotyping assay. Results Individual population analyses of the selected KCNA5 genetic variant did not show significant association with SSc or any of the defined subsets (for example, limited cutaneous SSc, diffuse cutaneous SSc, anti-centromere autoantibody positive and anti-topoisomerase autoantibody positive). Furthermore, pooled analyses revealed no significant evidence of association with the disease or any of the subsets, not even the PAH-positive group. The comparison of PAH-positive patients with PAH-negative patients showed no significant differences among patients. Conclusions Our data do not support an important role of KCNA5 as an SSc-susceptibility factor or as a PAH-development genetic marker for SSc patients. PMID:23270786

Genetic variation in the extended major histocompatibility complex and susceptibility to childhood acute lymphoblastic leukemia: a review of the evidence

Directory of Open Access Journals (Sweden)

Kevin Y Urayama

2013-12-01

Full Text Available The enduring suspicion that infections and immunologic response may play a role in the etiology of childhood leukemia, particularly acute lymphoblastic leukemia (ALL, is now supported, albeit still indirectly, by numerous epidemiological studies. The cumulative evidence includes, for example, descriptive observations of a peculiar peak incidence at age 2-5 years for ALL in economically developed countries, clustering of cases in situations of population mixing associated with unusual patterns of personal contacts, associations with various proxy measures for immune modulatory exposures early in life, and genetic susceptibility conferred by variation in genes involved in the immune system. In this review, our focus is the extended major histocompatibility complex (xMHC, an approximately 7.6 megabase region that is well-known for its high density of expressed genes, extensive polymorphisms exhibiting complex linkage disequilibrium patterns, and its disproportionately large number of immune-related genes, including human leukocyte antigen (HLA. First discovered through the role they play in transplant rejection, the classical HLA class I (HLA-A, -B, and -C and class II (HLA-DR, HLA-DQ, and HLA-DP molecules reside at the epicenter of the immune response pathways and are now the targets of many disease susceptibility studies, including those for childhood leukemia. The genes encoding the HLA molecules are only a minority of the over 250 expressed genes in the xMHC, and a growing number of studies are beginning to evaluate other loci through targeted investigations or utilizing a mapping approach with a comprehensive screen of the entire region. Here, we review the current epidemiologic evidence available to date regarding genetic variation contained within this highly unique region of the genome and its relationship with childhood ALL risk.

Modulation of the Genome and Epigenome of Individuals Susceptible to Autism by Environmental Risk Factors

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Costas Koufaris

2015-04-01

Full Text Available Diverse environmental factors have been implicated with the development of autism spectrum disorders (ASD. Genetic factors also underlie the differential vulnerability to environmental risk factors of susceptible individuals. Currently the way in which environmental risk factors interact with genetic factors to increase the incidence of ASD is not well understood. A greater understanding of the metabolic, cellular, and biochemical events involved in gene x environment interactions in ASD would have important implications for the prevention and possible treatment of the disorder. In this review we discuss various established and more alternative processes through which environmental factors implicated in ASD can modulate the genome and epigenome of genetically-susceptible individuals.

Strain, Sex, and Open-Field Behavior: Factors Underlying the Genetic Susceptibility to Helplessness

Science.gov (United States)

Padilla, Eimeira; Barrett, Douglas W.; Shumake, Jason D.; Gonzalez-Lima, F.

2009-01-01

Learned helplessness represents a failure to escape after exposure to inescapable stress and may model human psychiatric disorders related to stress. Previous work has demonstrated individual differences in susceptibility to learned helplessness. In this study, we assessed different factors associated with this susceptibility, including strain, sex, and open-field behavior. Testing of three rat strains (Holtzman, Long-Evans, and Sprague-Dawley) revealed that Holtzman rats were the most susceptible to helplessness. Holtzman rats not only had the longest escape latencies following inescapable shock, but also showed spontaneous escape deficits in the absence of prior shock when tested with a fixed-ratio 2 (FR2) running response. Moreover, when tested with fixed-ratio 1 (FR1) running—an easy response normally unaffected by helplessness training in rats—inescapable shock significantly increased the escape latencies of Holtzman rats. Within the Holtzman strain, we confirmed recent findings that females showed superior escape performance and therefore appeared more resistant to helplessness than males. However, regression and covariance analyses suggest that this sex difference may be explained by more baseline ambulatory activity among females. In addition, some indices of novelty reactivity (greater exploration of novel vs. familiar open-field) predicted subsequent helpless behavior. In conclusion, Holtzman rats, and especially male Holtzman rats, have a strong predisposition to become immobile when stressed which interferes with their ability to learn active escape responses. The Holtzman strain therefore appears to be a commercially available model for studying susceptibility to helplessness in males, and novelty-seeking may be a marker of this susceptibility. PMID:19428642

[EXOME ANALYSIS - A GAME CHANGER IN PEDIATRICS].

Science.gov (United States)

Ta-Shma, Asaf; Edvardson, Simon; Elpeleg, Orly; Stepensky, Polina

2018-03-01

Thirteen years after the completion of the human genome project, the determination of the genomic sequence of the coding parts of the DNA (the exones, hence the exome), has turned into a primary diagnostic tool in daily use in clinical practice. The Department of Genetics at Hadassah was the first in Israel to introduce exome analysis as a robust diagnostic tool into the pediatric departments. Till now 2600 exomes were analyzed at Hadassah, 850 of them in 2016 alone. Exome analysis is cheap and fast, enabling precise and non-invasive diagnosis for a vast array of genetic disorders and congenital malformations. The unique composition of the population which the hospital serves (marked by a high rate of consanguinity) enabled reaching diagnosis in 65% of the cases, twice the rate in medical centers worldwide. The results of this analysis enable genetic counseling to patients' families and prevention of serious disorders. Moreover, the results contribute to the understanding of the biological basis of newly identified disorders and in certain cases assist in the management of the patients. The major limitation of exome analysis is the multitude of identified variants which exist in any individual and which challenge our ability to pick the disease-causing variant. In the case of a disease-causing variant in a new gene, experimental proof is required to validate the causality of the variant; occasionally, an incidental finding with possible clinical significance is identified, raising serious ethical concerns. In this article, we will review the use of this technology through the experience of three pediatric departments at Hadassah.

Pediatric neurocritical care.

Science.gov (United States)

Murphy, Sarah

2012-01-01

Pediatric neurocritical care is an emerging multidisciplinary field of medicine and a new frontier in pediatric critical care and pediatric neurology. Central to pediatric neurocritical care is the goal of improving outcomes in critically ill pediatric patients with neurological illness or injury and limiting secondary brain injury through optimal critical care delivery and the support of brain function. There is a pressing need for evidence based guidelines in pediatric neurocritical care, notably in pediatric traumatic brain injury and pediatric stroke. These diseases have distinct clinical and pathophysiological features that distinguish them from their adult counterparts and prevent the direct translation of the adult experience to pediatric patients. Increased attention is also being paid to the broader application of neuromonitoring and neuroprotective strategies in the pediatric intensive care unit, in both primary neurological and primary non-neurological disease states. Although much can be learned from the adult experience, there are important differences in the critically ill pediatric population and in the circumstances that surround the emergence of neurocritical care in pediatrics.

Network Analysis of Human Genes Influencing Susceptibility to Mycobacterial Infections

Science.gov (United States)

Lipner, Ettie M.; Garcia, Benjamin J.; Strong, Michael

2016-01-01

Tuberculosis and nontuberculous mycobacterial infections constitute a high burden of pulmonary disease in humans, resulting in over 1.5 million deaths per year. Building on the premise that genetic factors influence the instance, progression, and defense of infectious disease, we undertook a systems biology approach to investigate relationships among genetic factors that may play a role in increased susceptibility or control of mycobacterial infections. We combined literature and database mining with network analysis and pathway enrichment analysis to examine genes, pathways, and networks, involved in the human response to Mycobacterium tuberculosis and nontuberculous mycobacterial infections. This approach allowed us to examine functional relationships among reported genes, and to identify novel genes and enriched pathways that may play a role in mycobacterial susceptibility or control. Our findings suggest that the primary pathways and genes influencing mycobacterial infection control involve an interplay between innate and adaptive immune proteins and pathways. Signaling pathways involved in autoimmune disease were significantly enriched as revealed in our networks. Mycobacterial disease susceptibility networks were also examined within the context of gene-chemical relationships, in order to identify putative drugs and nutrients with potential beneficial immunomodulatory or anti-mycobacterial effects. PMID:26751573

Chronicle of pediatric radiology

International Nuclear Information System (INIS)

Benz-Bohm, Gabriele; Richter, Ernst

2012-01-01

The chronicle of pediatric radiology covers the following issues: Development of pediatric radiology in Germany (BRD, DDR, pediatric radiological accommodations); development of pediatric radiology in the Netherlands (chronology and pediatric radiological accommodations); development of pediatric radiology in Austria (chronology and pediatric radiological accommodations); development of pediatric radiology in Switzerland (chronology and pediatric radiological accommodations).

Pediatric uroradiology. 2nd rev. ed.

International Nuclear Information System (INIS)

Fotter, Richard

2008-01-01

Since the first edition of Pediatric Uroradiology, very significant advances have been made in the imaging and treatment of common and important pediatric urologic disorders such as vesicoureteric reflux, urinary tract infection, and upper urinary tract dilatation. This revised and extended version takes full account of the sometimes dramatic changes. Where appropriate, new contents have been included, e.g., on genetics, while other information that continues to be pertinent has been retained. This book describes in detail all aspects of pediatric uroradiology. While it is written primarily from the point of view of the radiologist, it includes essential information for the pediatrician, pediatric surgeon, and urologist. It is specifically designed to aid the clinician in decisions on imaging management. The newest techniques and the changing relevance of imaging and interventional procedures are presented, and the diverse problems associated with the changing anatomy, physiology, and pathophysiology from the newborn period to adulthood are explained. The whole spectrum of imaging features of agenesis, anomalies, dysplasia, parenchymal diseases, neoplastic diseases, stone disease, renal vascular hypertension, renal failure, renal transplantation, and genitourinary trauma is covered. Individual chapters are devoted to vesicoureteric reflux, urinary tract infection, upper urinary tract dilatation, voiding dysfunction, and neurogenic bladder. A new chapter on the clinical management of common nephrourologic disorders, with the subtitle ''guidelines and beyond,'' explains how imaging is embedded in the whole process of clinical management today. Short conclusions are included at the end of chapters and sections to provide the reader with the key information on the specific topic under consideration. (orig.)

Pediatric uroradiology. 2nd rev. ed.

Energy Technology Data Exchange (ETDEWEB)

Fotter, Richard (ed.) [Univ. Hospital Medical Univ. Graz (Austria). Div. of Pediatric Radiology

2008-07-01

Since the first edition of Pediatric Uroradiology, very significant advances have been made in the imaging and treatment of common and important pediatric urologic disorders such as vesicoureteric reflux, urinary tract infection, and upper urinary tract dilatation. This revised and extended version takes full account of the sometimes dramatic changes. Where appropriate, new contents have been included, e.g., on genetics, while other information that continues to be pertinent has been retained. This book describes in detail all aspects of pediatric uroradiology. While it is written primarily from the point of view of the radiologist, it includes essential information for the pediatrician, pediatric surgeon, and urologist. It is specifically designed to aid the clinician in decisions on imaging management. The newest techniques and the changing relevance of imaging and interventional procedures are presented, and the diverse problems associated with the changing anatomy, physiology, and pathophysiology from the newborn period to adulthood are explained. The whole spectrum of imaging features of agenesis, anomalies, dysplasia, parenchymal diseases, neoplastic diseases, stone disease, renal vascular hypertension, renal failure, renal transplantation, and genitourinary trauma is covered. Individual chapters are devoted to vesicoureteric reflux, urinary tract infection, upper urinary tract dilatation, voiding dysfunction, and neurogenic bladder. A new chapter on the clinical management of common nephrourologic disorders, with the subtitle 'guidelines and beyond,' explains how imaging is embedded in the whole process of clinical management today. Short conclusions are included at the end of chapters and sections to provide the reader with the key information on the specific topic under consideration. (orig.)

The presence of urinary nitrites is a significant predictor of pediatric urinary tract infection susceptibility to first- and third-generation cephalosporins.

Science.gov (United States)

Weisz, Dany; Seabrook, Jamie A; Lim, Rodrick K

2010-07-01

Previous studies in adults have refuted the use of nitrites as a predictor of bacterial resistance to both trimethoprim-sulfamethoxazole and cephalosporins. Some centers now consider first-line outpatient therapy with an oral third-generation cephalosporin appropriate for young children. The objective of this study was to determine if nitrite-negative pediatric urinary tract infections (UTIs) were more likely than nitrite-positive UTIs to be resistant to cephalosporins. This may enable physicians to adjust antimicrobial therapy before patients leave the Emergency Department (ED) to avoid the complications of ineffectively treated pediatric UTIs. A retrospective chart review examined, over a 9-month period, 173 pediatric patients who were diagnosed with a clinical UTI in the ED and who also had a positive urine culture and a recorded dipstick at the time of visit. The chi-squared test and Fisher's exact test were used to compare nitrite-negative vs. nitrite-positive UTIs for resistance to third-generation cephalosporins and other empiric antimicrobials. For third-generation cephalosporins, 1.4% of nitrite-positive UTIs were resistant, whereas 14.4% of nitrite-negative UTIs were resistant (95% confidence interval [CI] -0.22 to -0.05). For first-generation cephalosporins, 8.4% were resistant in the nitrite-positive group, compared to 22.2% in the nitrite-negative group (95% CI -0.24 to -0.03). The absence of urinary nitrites is a significant indicator for potential resistance to cephalosporins in pediatric UTIs. Due to low levels of pediatric UTI resistance, cephalosporins continue to represent useful empiric therapy in the general pediatric population. However, in high-risk patients, physicians may opt to alter their empiric choice of antibiotic based on the presence of urinary nitrites. Copyright 2010 Elsevier Inc. All rights reserved.

Understanding the relative roles of pharmacogenetics and ontogeny in pediatric drug development and regulatory science.

Science.gov (United States)

Leeder, J Steven; Kearns, Gregory L; Spielberg, Stephen P; van den Anker, John

2010-12-01

Understanding the dose-exposure-response relationship across the pediatric age spectrum from preterm and term newborns to infants, children, adolescents, and adults is a major challenge for clinicians, pharmaceutical companies, and regulatory agencies. Over the past 3 decades, clinical investigations of many drugs commonly used in pediatric therapeutics have provided valuable insights into age-associated differences in drug disposition and action. However, our understanding of the contribution of genetic variation to variability in drug disposition and response in children generally has lagged behind that of adults. This article proposes a systematic approach that can be used to assess the relative contributions of ontogeny and genetic variation for a given compound. Application of the strategy is illustrated using the current regulatory dilemma posed by the safety and effectiveness of over-the-counter cough and cold remedies as an example. The results of the analysis can be used to aid in the design of studies to yield maximally informative data in pediatric populations of different ages and developmental stages and thereby improve the efficiency of study design.

Underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis

NARCIS (Netherlands)

N. Bomer (Nils); W. den Hollander (Wouter); Y.F.M. Ramos (Yolande); S.D. Bos (Steffan); R. van der Breggen (Ruud); N. Lakenberg (Nico); B.A. Pepers (Barry); A.E. van Eeden (Annelies); A. Darvishan (Arash); E.W. Tobi (Elmar); B.J. Duijnisveld (Bouke); E.B. van den Akker (Erik); B.T. Heijmans (Bastiaan); W.M.C. van Roon-Mom (Willeke); F.J. Verbeek (Fons); G.J.V.M. van Osch (Gerjo); R.G.H.H. Nelissen (Rob); P.E. Slagboom (Eline); I. Meulenbelt (Ingrid)

2014-01-01

textabstractObjectives: To investigate how the genetic susceptibility gene DIO2 confers risk to osteoarthritis (OA) onset in humans and to explore whether counteracting the deleterious effect could contribute to novel therapeutic approaches. Methods: Epigenetically regulated expression of DIO2 was

Genome-wide association studies on HIV susceptibility, pathogenesis and pharmacogenomics

NARCIS (Netherlands)

van Manen, Daniëlle; van 't Wout, Angélique B.; Schuitemaker, Hanneke

2012-01-01

Susceptibility to HIV-1 and the clinical course after infection show a substantial heterogeneity between individuals. Part of this variability can be attributed to host genetic variation. Initial candidate gene studies have revealed interesting host factors that influence HIV infection, replication

Biomarkers of susceptibility: State of the art and implications for occupational exposure to engineered nanomaterials

International Nuclear Information System (INIS)

Iavicoli, Ivo; Leso, Veruscka; Schulte, Paul A.

2016-01-01

Rapid advances and applications in nanotechnology are expected to result in increasing occupational exposure to nano-sized materials whose health impacts are still not completely understood. Scientific efforts are required to identify hazards from nanomaterials and define risks and precautionary management strategies for exposed workers. In this scenario, the definition of susceptible populations, which may be at increased risk of adverse effects may be important for risk assessment and management. The aim of this review is to critically examine available literature to provide a comprehensive overview on susceptibility aspects potentially affecting heterogeneous responses to nanomaterials workplace exposure. Genetic, genotoxic and epigenetic alterations induced by nanomaterials in experimental studies were assessed with respect to their possible function as determinants of susceptibility. Additionally, the role of host factors, i.e. age, gender, and pathological conditions, potentially affecting nanomaterial toxicokinetic and health impacts, were also analysed. Overall, this review provides useful information to obtain insights into the nanomaterial mode of action in order to identify potentially sensitive, specific susceptibility biomarkers to be validated in occupational settings and addressed in risk assessment processes. The findings of this review are also important to guide future research into a deeper characterization of nanomaterial susceptibility in order to define adequate risk communication strategies. Ultimately, identification and use of susceptibility factors in workplace settings has both scientific and ethical issues that need addressing. - Highlights: • To define susceptible populations is important for risk assessment and management; • Genetic susceptibility may influence the individual response to nanomaterial exposure; • Susceptibility factors in workplace settings have both scientific and ethical issues.

Biomarkers of susceptibility: State of the art and implications for occupational exposure to engineered nanomaterials

Energy Technology Data Exchange (ETDEWEB)

Iavicoli, Ivo, E-mail: ivo.iavicoli@unina.it [Department of Public Health, Division of Occupational Medicine, University of Naples Federico II, Via S. Pansini 5, 80131 Naples (Italy); Leso, Veruscka, E-mail: veruscka@email.it [Institute of Public Health, Section of Occupational Medicine, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome (Italy); Schulte, Paul A., E-mail: pas4@cdc.gov [National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, 4676 Columbia Parkway, MS C-14, Cincinnati, OH 45226 (United States)

2016-05-15

Rapid advances and applications in nanotechnology are expected to result in increasing occupational exposure to nano-sized materials whose health impacts are still not completely understood. Scientific efforts are required to identify hazards from nanomaterials and define risks and precautionary management strategies for exposed workers. In this scenario, the definition of susceptible populations, which may be at increased risk of adverse effects may be important for risk assessment and management. The aim of this review is to critically examine available literature to provide a comprehensive overview on susceptibility aspects potentially affecting heterogeneous responses to nanomaterials workplace exposure. Genetic, genotoxic and epigenetic alterations induced by nanomaterials in experimental studies were assessed with respect to their possible function as determinants of susceptibility. Additionally, the role of host factors, i.e. age, gender, and pathological conditions, potentially affecting nanomaterial toxicokinetic and health impacts, were also analysed. Overall, this review provides useful information to obtain insights into the nanomaterial mode of action in order to identify potentially sensitive, specific susceptibility biomarkers to be validated in occupational settings and addressed in risk assessment processes. The findings of this review are also important to guide future research into a deeper characterization of nanomaterial susceptibility in order to define adequate risk communication strategies. Ultimately, identification and use of susceptibility factors in workplace settings has both scientific and ethical issues that need addressing. - Highlights: • To define susceptible populations is important for risk assessment and management; • Genetic susceptibility may influence the individual response to nanomaterial exposure; • Susceptibility factors in workplace settings have both scientific and ethical issues.

Bezoar in a Pediatric Oncology Patient Treated with Coca-Cola.

Science.gov (United States)

Naramore, Sara; Virojanapa, Amy; Bell, Moshe; Jhaveri, Punit N

2015-01-01

A bezoar is a mass of indigestible material. Bezoars can present with a gradual onset of non-specific gastrointestinal symptoms including abdominal pain, nausea and vomiting. However, bezoars can result in more serious conditions such as intestinal bleeding or obstruction. Without quick recognition, particularly in susceptible individuals, the diagnosis and treatment can be delayed. Currently resolution is achieved with enzymatic dissolution, endoscopic fragmentation or surgery. We describe, to our knowledge, the first pediatric patient with lymphoma to have had a bezoar treated with Coca-Cola.

Gene expression profiling of the local cecal response of genetic chicken lines that differ in their susceptibility to Campylobacter jejuni colonization.

Directory of Open Access Journals (Sweden)

Xianyao Li

Full Text Available Campylobacter jejuni (C. jejuni is one of the most common causes of human bacterial enteritis worldwide primarily due to contaminated poultry products. Previously, we found a significant difference in C. jejuni colonization in the ceca between two genetically distinct broiler lines (Line A (resistant has less colony than line B (susceptible on day 7 post inoculation. We hypothesize that different mechanisms between these two genetic lines may affect their ability to resist C. jejuni colonization in chickens. The molecular mechanisms of the local host response to C. jejuni colonization in chickens have not been well understood. In the present study, to profile the cecal gene expression in the response to C. jejuni colonization and to compare differences between two lines at the molecular level, RNA of ceca from two genetic lines of chickens (A and B were applied to a chicken whole genome microarray for a pair-comparison between inoculated (I and non-inoculated (N chickens within each line and between lines. Our results demonstrated that metabolism process and insulin receptor signaling pathways are key contributors to the different response to C. jejuni colonization between lines A and B. With C. jejuni inoculation, lymphocyte activation and lymphoid organ development functions are important for line A host defenses, while cell differentiation, communication and signaling pathways are important for line B. Interestingly, circadian rhythm appears play a critical role in host response of the more resistant A line to C. jejuni colonization. A dramatic differential host response was observed between these two lines of chickens. The more susceptible line B chickens responded to C. jejuni inoculation with a dramatic up-regulation in lipid, glucose, and amino acid metabolism, which is undoubtedly for use in the response to the colonization with little or no change in immune host defenses. However, in more resistant line A birds the host defense

Assessment of relatedness between neurocan gene as bipolar disorder susceptibility locus and schizophrenia

Directory of Open Access Journals (Sweden)

Lilijana Oruč

2012-11-01

Full Text Available Large scale genetic association meta-analyses showed that neurocan (NCAN gene polymorphism rs1064395 is susceptibility locus for bipolar disorder. These studies also included patients with bipolar disorder originated from Bosnia and Herzegovina. Followed by theory of shared genetic elements between bipolar disorder and schizophrenia susceptibility, other studies explored several genetic factors with schizophrenia vulnerability as well. In this work, authors investigated the association between previously confirmed bipolar disorder genetic risk factor-neurocan with schizophrenia in a population sample of Bosnia and Herzegovina.Ethical aspects of this research were assessed by Ethics Committee of Clinical Center University of Sarajevo. Blood samples for DNA extraction were taken from the total of 86 patients and healthy individuals who previously signed informed consent. Genotyping for rs 1064395 was done using direct sequencing method. A case-control analysis of common genetic polymorphism within neurocan gene and schizophrenia status in a consecutively sampled patient cohort have been done using Fisher-exact test with odds-ratio calculation. No statistically significant allele and genotype association with disease status was found (p>0.05.Our finding supports the fact that large-scale genetic association studies approach need to be employed when detecting the variants with small additive effect in phenotypes with complex ethiology.

Tissue quantification for development of pediatric phantom

International Nuclear Information System (INIS)

Alves, A.F.F.; Miranda, J.R.A.; Pina, D.R.

2013-01-01

The optimization of the risk- benefit ratio is a major concern in the pediatric radiology, due to the greater vulnerability of children to the late somatic effects and genetic effects of exposure to radiation compared to adults. In Brazil, it is estimated that the causes of death from head trauma are 18 % for the age group between 1-5 years and the radiograph is the primary diagnostic test for the detection of skull fracture . Knowing that the image quality is essential to ensure the identification of structures anatomical and minimizing errors diagnostic interpretation, this paper proposed the development and construction of homogeneous phantoms skull, for the age group 1-5 years. The construction of the phantoms homogeneous was performed using the classification and quantification of tissue present in the skull of pediatric patients. In this procedure computational algorithms were used, using Matlab, to quantify distinct biological tissues present in the anatomical regions studied , using pictures retrospective CT scans. Preliminary data obtained from measurements show that between the ages of 1-5 years, assuming an average anteroposterior diameter of the pediatric skull region of the 145.73 ± 2.97 mm, can be represented by 92.34 mm ± 5.22 of lucite and 1.75 ± 0:21 mm of aluminum plates of a provision of PEP (Pacient equivalent phantom). After its construction, the phantoms will be used for image and dose optimization in pediatric protocols process to examinations of computerized radiography

Optimization of exposure parameters for pediatric chest x-ray imaging

Science.gov (United States)

Park, Hye-Suk; Kim, Ye-Seul; Kim, Hee-Joung

2012-03-01

The pediatric patients are more susceptible to the effects of ionizing radiation than adults. Pediatric patients are smaller, more radiosensitive than adult patients and many cannot stand unassisted. Their characteristics affect the method of imaging projection and how dose is optimized. The purpose of this study was to investigate the effect of various technical parameters for the dose optimization in pediatric chest radiological examinations by evaluating effective dose and effective detective quantum efficiency (eDQE) including the scatter radiation from the object, the blur caused by the focal spot, geometric magnification and detector characteristics. For the tube voltages ranging from 40 to 90 kV in 10 kV increments at the focus-to-detector distance of 100, 110, 120, 150, 180 cm, the eDQE was evaluated at same effective dose. The results showed that the eDQE was largest at 60 kVp without and with an anti-scatter grid. Especially, the eDQE was considerably higher without the use of an anti-scatter grid on equivalent effective dose. This indicates that the reducing the scatter radiation did not compensate for the loss of absorbed effective photons in the grid. When the grid is not used the eDQE increased with increasing focus-to-detector distance because of the greater effective modulation transfer function (eMTF) with the lower focal spot blurring. In conclusion, for pediatric patients, the amount of scattered radiation is less, and the amount of grid attenuation increased unnecessary radiation dose.

Trichoscopy in pediatric age group

Directory of Open Access Journals (Sweden)

Subrata Malakar

2018-01-01

Full Text Available Approach to trichology in the pediatric age group is based on the clinical expertise of the dermatologist and investigative techniques. Currently, the trichoscope is an indispensible, noninvasive tool in the diagnosis of trichological disorders. It not only highlights the subtle tricoscopic points invisible to the naked eye but also serves as a prognostic and monitoring tool in therapeutic management. Trichoscopy goes a long way in improving the diagnostic and clinical acumen of the physician. In the pediatric age group, trichoscopy deals with pattern analysis ranging from hair shaft patterns to follicular, perifollicular, and interfollicular patterns. It not only describes the key trichoscopic features of noncicatricial alopecias, cicatricial alopecias, and genetic hair shaft defects but also helps to delineate various trichological mimics from each other. For compiling data, all trichology cases presenting to a tertiary care center were examined and photographed with a Fotofinder, DermLite Foto II Pro, and DermLite DL 3N. All trichological data were analyzed, and interpretations were based on the literature available.

Genetic contribution of CISH promoter polymorphisms to susceptibility to tuberculosis in Chinese children.

Directory of Open Access Journals (Sweden)

Lin Sun

Full Text Available Tuberculosis (TB is the leading cause of death due to an infectious disease worldwide, particularly in developing countries. A series of candidate genes have been suggested to be associated with development of TB disease. Among them, the human Cytokine-inducible Src homology 2(SH2 domain protein (CISH gene has been very recently reported to be involved in T cell activation and differentiation in response to Mycobacterium tuberculosis infection. Here, we studied the association between CISH promoter polymorphisms and pediatric TB. A case-control study enrolled 352 TB patients and 527 healthy controls, who were of Han Chinese ethnicity and aged from 0.2 to 18 years. CISH gene promoter SNPs rs414171, rs622502 and rs809451 were genotyped in all subjects and transcriptional activity, mRNA level, and plasma cytokine level of subjects with different genotypes were further examined. Carriers with rs414171TT homozygotes and rs809451GC heterozygotes had a 1.78-fold (95% CI,1.16-2.74 and 1.86-fold (95% CI, 1.26-2.74 excess risk of developing TB compared to those with wild-type genotypes. A greater risk of TB disease was observed in population carrying C(-809451-T(-414171-C(-622502 haplotype (OR 3.66, 95% CI:2.12-6.32. The G(-809451-A(-414171-C(-622502-containing CISH promoter drove a 5.43-fold increased reporter expression compared to the C(-809451-T(-414171-C(-622502-containing counterpart in Hela cell lines (P = 0.0009. PBMCs carrying rs414171TT homozygotes and rs809451GC heterozygotes showed a reduced CISH mRNA level compared to cells carrying wild type genotypes. Individuals with the rs414171TT genotype had significantly increased IL-12p40 and IL-10 production. In conclusion, CISH promoter rs414171 and rs809451 polymorphisms may play a vital role in mediating individual susceptibility to tuberculosis.

Genetic contribution of CISH promoter polymorphisms to susceptibility to tuberculosis in Chinese children.

Science.gov (United States)

Sun, Lin; Jin, Ya-qiong; Shen, Chen; Qi, Hui; Chu, Ping; Yin, Qing-qin; Li, Jie-qiong; Tian, Jian-ling; Jiao, Wei-wei; Xiao, Jing; Shen, A-dong

2014-01-01

Tuberculosis (TB) is the leading cause of death due to an infectious disease worldwide, particularly in developing countries. A series of candidate genes have been suggested to be associated with development of TB disease. Among them, the human Cytokine-inducible Src homology 2(SH2) domain protein (CISH) gene has been very recently reported to be involved in T cell activation and differentiation in response to Mycobacterium tuberculosis infection. Here, we studied the association between CISH promoter polymorphisms and pediatric TB. A case-control study enrolled 352 TB patients and 527 healthy controls, who were of Han Chinese ethnicity and aged from 0.2 to 18 years. CISH gene promoter SNPs rs414171, rs622502 and rs809451 were genotyped in all subjects and transcriptional activity, mRNA level, and plasma cytokine level of subjects with different genotypes were further examined. Carriers with rs414171TT homozygotes and rs809451GC heterozygotes had a 1.78-fold (95% CI,1.16-2.74) and 1.86-fold (95% CI, 1.26-2.74) excess risk of developing TB compared to those with wild-type genotypes. A greater risk of TB disease was observed in population carrying C(-809451)-T(-414171)-C(-622502) haplotype (OR 3.66, 95% CI:2.12-6.32). The G(-809451)-A(-414171)-C(-622502)-containing CISH promoter drove a 5.43-fold increased reporter expression compared to the C(-809451)-T(-414171)-C(-622502)-containing counterpart in Hela cell lines (P = 0.0009). PBMCs carrying rs414171TT homozygotes and rs809451GC heterozygotes showed a reduced CISH mRNA level compared to cells carrying wild type genotypes. Individuals with the rs414171TT genotype had significantly increased IL-12p40 and IL-10 production. In conclusion, CISH promoter rs414171 and rs809451 polymorphisms may play a vital role in mediating individual susceptibility to tuberculosis.

Background differences in baseline and stimulated MMP levels influence abdominal aortic aneurysm susceptibility

Science.gov (United States)

Dale, Matthew A.; Ruhlman, Melissa K.; Zhao, Shijia; Meisinger, Trevor; Gu, Linxia; Swier, Vicki J.; Agrawal, Devendra K.; Greiner, Timothy C.; Carson, Jeffrey S.; Baxter, B. Timothy; Xiong, Wanfen

2015-01-01

Objective Evidence has demonstrated profound influence of genetic background on cardiovascular phenotypes. Murine models in Marfan syndrome (MFS) have shown that genetic background-related variations affect thoracic aortic aneurysm formation, rupture, and lifespan of mice. MFS mice with C57Bl/6 genetic background are less susceptible to aneurysm formation compared to the 129/SvEv genetic background. In this study, we hypothesize that susceptibility to abdominal aortic aneurysm (AAA) will be increased in 129/SvEv mice versus C57Bl/6 mice. We tested this hypothesis by assessing differences in aneurysm size, tissue properties, immune response, and MMP expression. Methods Mice of C57Bl/6 or 129/SvEv background underwent AAA induction by periaortic application of CaCl2. Baseline aortic diameters, tissue properties and MMP levels were measured. After aneurysm induction, diameters, MMP expression, and immune response (macrophage infiltration and bone marrow transplantation) were measured. Results Aneurysms were larger in 129/SvEv mice than C57Bl/6 mice (83.0% ± 13.6 increase compared to 57.8% ± 6.4). The aorta was stiffer in the 129/SvEv mice compared to C57Bl/6 mice (952.5 kPa ± 93.6 versus 621.4 kPa ± 84.2). Baseline MMP-2 and post-aneurysm MMP-2 and -9 levels were higher in 129/SvEv aortas compared to C57Bl/6 aortas. Elastic lamella disruption/fragmentation and macrophage infiltration were increased in 129/SvEv mice. Myelogenous cell reversal by bone marrow transplantation did not affect aneurysm size. Conclusions These data demonstrate that 129/SvEv mice are more susceptible to AAA compared to C57Bl/6 mice. Intrinsic properties of the aorta between the two strains of mice, including baseline expression of MMP-2, influence susceptibility to AAA. PMID:26546710

Profile of genetic disorders prevalent in northeast region of Cairo ...

African Journals Online (AJOL)

As clinical geneticists, we recently reviewed our 43 years experience in an attempt to represent the frequency of genetic disorders in the Division of Genetics at Pediatric Hospital, Faculty of Medicine, Ain-Shams University, Cairo, Egypt, during the period from 1966 to 2009. All patients (from birth up to 18 years) suspected of ...

Genetic selection for coping style predicts stressor susceptibility

NARCIS (Netherlands)

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

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

Association of susceptible genetic markers and autoantibodies in ...

Indian Academy of Sciences (India)

antigen (HLA) locus accounting for at least 30% of overall genetic risk. Non-HLA genes, i.e. ..... to specific regions of DNA and helps control the activity of certain genes. Encodes a transcription factor ..... The cost of such an extensive panel may ...

Genetic variants in pachyonychia congenita-associated keratins increase susceptibility to tooth decay.

Science.gov (United States)

Duverger, Olivier; Carlson, Jenna C; Karacz, Chelsea M; Schwartz, Mary E; Cross, Michael A; Marazita, Mary L; Shaffer, John R; Morasso, Maria I

2018-01-01

Pachyonychia congenita (PC) is a cutaneous disorder primarily characterized by nail dystrophy and painful palmoplantar keratoderma. PC is caused by mutations in KRT6A, KRT6B, KRT6C, KRT16, and KRT17, a set of keratin genes expressed in the nail bed, palmoplantar epidermis, oral mucosal epithelium, hair follicle and sweat gland. RNA-seq analysis revealed that all PC-associated keratins (except for Krt6c that does exist in the mouse genome) are expressed in the mouse enamel organ. We further demonstrated that these keratins are produced by ameloblasts and are incorporated into mature human enamel. Using genetic and intraoral examination data from 573 adults and 449 children, we identified several missense polymorphisms in KRT6A, KRT6B and KRT6C that lead to a higher risk for dental caries. Structural analysis of teeth from a PC patient carrying a p.Asn171Lys substitution in keratin-6a (K6a) revealed disruption of enamel rod sheaths resulting in altered rod shape and distribution. Finally, this PC-associated substitution as well as more frequent caries-associated SNPs, found in two of the KRT6 genes, that result in p.Ser143Asn substitution (rs28538343 in KRT6B and rs151117600 in KRT6C), alter the assembly of K6 filaments in ameloblast-like cells. These results identify a new set of keratins involved in tooth enamel formation, distinguish novel susceptibility loci for tooth decay and reveal additional clinical features of pachyonychia congenita.

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

NARCIS (Netherlands)

Mckay, James D.; Hung, Rayjean J; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C.; Caporaso, Neil E.; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A.; Qian, David C.; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N.; Bojesen, Stig E.; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeboeller, Heike; Aldrich, Melinda C.; Bush, William S.; Tardon, Adonina; Rennert, Gad; Teare, M. Dawn; Field, John K.; Kiemeney, Lambertus A.; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B.; Andrew, Angeline S.; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C.; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S.; Mellemgaard, Anders; Saliba, Walid; Marcus, Michael W.; Timens, Wim

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association

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

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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.

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

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Li Yang

Full Text Available 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 < 0.0001. Classification and regression tree (CART demonstrated that women carrying both the genotypes of TGFBR1 rs6478974 TT and rs10512263 TC/CC had the highest risk of EC (aOR = 7.86, 95% CI = 3.42-18.07, P<0.0001. Multifactor dimensionality reduction (MDR revealed that TGFB1 rs1800469 plus TGFBR1 rs6478974 was the best interactional model to detect EC risk. LR, CART and MDR all revealed that TGFBR1 rs6478974 was the most important protective locus for EC. In haplotype association study, TGFBR1 haplotype CACGA carrier showed the lowest EC risk among women with longer menarche-first full term 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.

Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity

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Bustamante, Jacinta; Boisson-Dupuis, Stéphanie; Abel, Laurent; Casanova, Jean-Laurent

2014-01-01

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare condition characterized by predisposition to clinical disease caused by weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria, in otherwise healthy individuals with no overt abnormalities in routine hematological and immunological tests. MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis, and more rarely to infections with other intramacrophagic bacteria, fungi, or parasites, and even, perhaps, a few viruses. Since 1996, nine MSMD-causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, CYBB) genes have been discovered. The high level of allelic heterogeneity has already led to the definition of 18 different disorders. The nine gene products are physiologically related, as all are involved in IFN-γ-dependent immunity. These disorders impair the production of (IL12B, IL12RB1, IRF8, ISG15, NEMO) or the response to (IFNGR1, IFNGR2, STAT1, IRF8, CYBB) IFN-γ. These defects account for only about half the known MSMD cases. Patients with MSMD-causing genetic defects may display other infectious diseases, or even remain asymptomatic. Most of these inborn errors do not show complete clinical penetrance for the case-definition phenotype of MSMD. We review here the genetic, immunological, and clinical features of patients with inborn errors of IFN-γ-dependent immunity. PMID:25453225

A preliminary study of genetic factors that influence susceptibility to bovine tuberculosis in the British cattle herd.

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Erin E Driscoll

2011-04-01

Full Text Available Associations between specific host genes and susceptibility to Mycobacterial infections such as tuberculosis have been reported in several species. Bovine tuberculosis (bTB impacts greatly the UK cattle industry, yet genetic predispositions have yet to be identified. We therefore used a candidate gene approach to study 384 cattle of which 160 had reacted positively to an antigenic skin test ('reactors'. Our approach was unusual in that it used microsatellite markers, embraced high breed diversity and focused particularly on detecting genes showing heterozygote advantage, a mode of action often overlooked in SNP-based studies. A panel of neutral markers was used to control for population substructure and using a general linear model-based approach we were also able to control for age. We found that substructure was surprisingly weak and identified two genomic regions that were strongly associated with reactor status, identified by markers INRA111 and BMS2753. In general the strength of association detected tended to vary depending on whether age was included in the model. At INRA111 a single genotype appears strongly protective with an overall odds ratio of 2.2, the effect being consistent across nine diverse breeds. Our results suggest that breeding strategies could be devised that would appreciably increase genetic resistance of cattle to bTB (strictly, reduce the frequency of incidence of reactors with implications for the current debate concerning badger-culling.

Pediatric Asthma

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... Science Education & Training Home Conditions Asthma (Pediatric) Asthma (Pediatric) Make an Appointment Refer a Patient Ask a ... meet the rising demand for asthma care. Our pediatric asthma team brings together physicians, nurses, dietitians, physical ...

Clinical negligence claims in pediatric surgery in England: pattern and trends.

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Thyoka, Mandela

2015-02-01

We hypothesized that there has been an increase in the number of successful litigation claims in pediatric surgery in England. Our aim was to report the incidence, causes, and costs of clinical negligence claims against the National Health Service (NHS) in relation to pediatric surgery. We queried the NHS Litigation Authority (NHSLA) on litigation claims among children undergoing pediatric surgery in England (2004-2012). We decided a priori to only examine closed cases (decision and payment made). Data included year of claim, year of payment of claim, payment per claim, paid-to-closed ratio, and severity of outcome of clinical incident. Out of 112 clinical negligence claims in pediatric surgery, 93 (83%) were finalized-73 (65%) were settled and damages paid to the claimant and 20 (18%) were closed with no payment, and 19 (17%) remain open. The median payment was £13,537 (600-500,000) and median total cost borne by NHSLA was £31,445 (600-730,202). Claims were lodged at a median interval of 2 (0-13) years from time of occurrence with 55 (75%) cases being settled within the 3 years of being received. The commonest reasons for claims were postoperative complications (n=20, 28%), delayed treatment (n=16, 22%), and/or diagnosis (n=14, 19%). Out of 73, 17 (23%) closed claims resulted in case fatality. Conclusion: Two-thirds of all claims in pediatric surgery resulted in payment to claimant, and the commonest reasons for claims were postoperative complications, delayed treatment, and/or diagnosis. Nearly a quarter of successful claims were in cases where negligence resulted in case fatality. Pediatric surgeons should be aware of common diagnostic and treatment shortfalls as high-risk areas of increased susceptibility to clinical negligence claims. Georg Thieme Verlag KG Stuttgart · New York.

Pediatric sleep apnea

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Sleep apnea - pediatric; Apnea - pediatric sleep apnea syndrome; Sleep-disordered breathing - pediatric ... Untreated pediatric sleep apnea may lead to: High blood pressure Heart or lung problems Slow growth and development

Human genetics of infectious diseases: a unified theory

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Casanova, Jean-Laurent; Abel, Laurent

2007-01-01

Since the early 1950s, the dominant paradigm in the human genetics of infectious diseases postulates that rare monogenic immunodeficiencies confer vulnerability to multiple infectious diseases (one gene, multiple infections), whereas common infections are associated with the polygenic inheritance of multiple susceptibility genes (one infection, multiple genes). Recent studies, since 1996 in particular, have challenged this view. A newly recognised group of primary immunodeficiencies predisposing the individual to a principal or single type of infection is emerging. In parallel, several common infections have been shown to reflect the inheritance of one major susceptibility gene, at least in some populations. This novel causal relationship (one gene, one infection) blurs the distinction between patient-based Mendelian genetics and population-based complex genetics, and provides a unified conceptual frame for exploring the molecular genetic basis of infectious diseases in humans. PMID:17255931

Evaluating the Trends of Bloodstream Infections among Pediatric and Adult Patients at a Teaching Hospital of Kathmandu, Nepal: Role of Drug Resistant Pathogens

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Narayan Prasad Parajuli

2017-01-01

Full Text Available Bloodstream infections (BSIs are among the significant causes of morbidity and mortality for patients of all age groups. However, very little is known about the trends of bacterial bloodstream infections and antimicrobial susceptibilities among pediatric and adult population from Nepal. In this study, we have investigated the different etiological agents responsible for bloodstream infections among pediatric and adult patients and the role of drug resistant organisms in these infections at a tertiary care teaching hospital of Kathmandu, Nepal. A total of 3,088 blood culture specimens obtained from pediatric and adult patients suspected to have bloodstream infections were processed by standard microbiological methods. Significant bacterial pathogens were identified by morphological, biochemical, and serological methods as suggested by American Society for Microbiology. In vitro antimicrobial susceptibility testing was performed by Kirby-Bauer disk diffusion method and interpreted according to the guidelines of Clinical and Laboratory Standards Institute. Overall, incidence of bloodstream infections among the suspected patients was 7.48%. Pediatric patients (n=90, 9.37% were the significant subgroup of patients affected with bloodstream infections compared to adults (p<0.05, CI-95%. Gram positive (n=49, 54.4% bacteria in pediatric and gram negative bacteria (n=141, 78.7% in adult patients were the most common isolates for BSI. Staphylococcus aureus (n=41, 45.6% in pediatric patients and Salmonella enterica (n=40, 28.3% in adult patients were the leading pathogens. Trends of antimicrobial resistance among isolated bacterial strains were significantly high in adults compared to pediatric patients. Methicillin resistant Staphylococcus aureus (MRSA (31.4%, extended spectrum beta-lactamase (ESBL (12.5%, and metallo-beta-lactamase (MBL (3.9% producing gram negatives were major resistant strains. Our study shows higher rates of bloodstream infections in

Ethical principles and pitfalls of genetic testing for dementia.

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Hedera, P

2001-01-01

Progress in the genetics of dementing disorders and the availability of clinical tests for practicing physicians increase the need for a better understanding of multifaceted issues associated with genetic testing. The genetics of dementia is complex, and genetic testing is fraught with many ethical concerns. Genetic testing can be considered for patients with a family history suggestive of a single gene disorder as a cause of dementia. Testing of affected patients should be accompanied by competent genetic counseling that focuses on probabilistic implications for at-risk first-degree relatives. Predictive testing of at-risk asymptomatic patients should be modeled after presymptomatic testing for Huntington's disease. Testing using susceptibility genes has only a limited diagnostic value at present because potential improvement in diagnostic accuracy does not justify potentially negative consequences for first-degree relatives. Predictive testing of unaffected subjects using susceptibility genes is currently not recommended because individual risk cannot be quantified and there are no therapeutic interventions for dementia in presymptomatic patients.

Underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis

NARCIS (Netherlands)

Bomer, N.; Den Hollander, W.T.H.F.; Ramos, Y.F.M.; Bos, S.D.; Van der Breggen, R.; Lakenberg, N.; Pepers, B.A.; Van Eeden, A.E.; Darvishan, A.; Tobi, E.W.; Duijnisveld, B.J.; Van den Akker, E.B.; Heijmans, B.T.; Van Roon-Mom, W.M.C.; Verbeek, F.J.; Osch, G.J.V.M.; Nelissen, R.G.H.H.; Slagboom, P.E.; Meulenbelt, I.

2015-01-01

Objectives: To investigate how the genetic susceptibility gene DIO2 confers risk to osteoarthritis (OA) onset in humans and to explore whether counteracting the deleterious effect could contribute to novel therapeutic approaches. Methods: Epigenetically regulated expression of DIO2 was explored by

Gene-environment interaction involving recently identified colorectal cancer susceptibility loci

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Kantor, Elizabeth D.; Hutter, Carolyn M.; Minnier, Jessica; Berndt, Sonja I.; Brenner, Hermann; Caan, Bette J.; Campbell, Peter T.; Carlson, Christopher S.; Casey, Graham; Chan, Andrew T.; Chang-Claude, Jenny; Chanock, Stephen J.; Cotterchio, Michelle; Du, Mengmeng; Duggan, David; Fuchs, Charles S.; Giovannucci, Edward L.; Gong, Jian; Harrison, Tabitha A.; Hayes, Richard B.; Henderson, Brian E.; Hoffmeister, Michael; Hopper, John L.; Jenkins, Mark A.; Jiao, Shuo; Kolonel, Laurence N.; Le Marchand, Loic; Lemire, Mathieu; Ma, Jing; Newcomb, Polly A.; Ochs-Balcom, Heather M.; Pflugeisen, Bethann M.; Potter, John D.; Rudolph, Anja; Schoen, Robert E.; Seminara, Daniela; Slattery, Martha L.; Stelling, Deanna L.; Thomas, Fridtjof; Thornquist, Mark; Ulrich, Cornelia M.; Warnick, Greg S.; Zanke, Brent W.; Peters, Ulrike; Hsu, Li; White, Emily

2014-01-01

BACKGROUND Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) that are associated with risk of colorectal cancer (CRC). Prior research has evaluated the presence of gene-environment interaction involving the first 10 identified susceptibility loci, but little work has been conducted on interaction involving SNPs at recently identified susceptibility loci, including: rs10911251, rs6691170, rs6687758, rs11903757, rs10936599, rs647161, rs1321311, rs719725, rs1665650, rs3824999, rs7136702, rs11169552, rs59336, rs3217810, rs4925386, and rs2423279. METHODS Data on 9160 cases and 9280 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR) were used to evaluate the presence of interaction involving the above-listed SNPs and sex, body mass index (BMI), alcohol consumption, smoking, aspirin use, post-menopausal hormone (PMH) use, as well as intake of dietary calcium, dietary fiber, dietary folate, red meat, processed meat, fruit, and vegetables. Interaction was evaluated using a fixed-effects meta-analysis of an efficient Empirical Bayes estimator, and permutation was used to account for multiple comparisons. RESULTS None of the permutation-adjusted p-values reached statistical significance. CONCLUSIONS The associations between recently identified genetic susceptibility loci and CRC are not strongly modified by sex, BMI, alcohol, smoking, aspirin, PMH use, and various dietary factors. IMPACT Results suggest no evidence of strong gene-environment interactions involving the recently identified 16 susceptibility loci for CRC taken one at a time. PMID:24994789

Pediatric Sinusitis

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... ENTCareers Marketplace Find an ENT Doctor Near You Pediatric Sinusitis Pediatric Sinusitis Patient Health Information News media interested in ... sinuses are present at birth. Unlike in adults, pediatric sinusitis is difficult to diagnose because symptoms of ...

Mitochondrial Genetic Background Modulates Bioenergetics and Susceptibility to Acute Cardiac Volume – Overload

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Fetterman, Jessica L.; Zelickson, Blake R.; Johnson, Larry W.; Moellering, Douglas R.; Westbrook, David G.; Pompilius, Melissa; Sammy, Melissa J.; Johnson, Michelle; Dunham-Snary, Kimberly J.; Cao, Xuemei; Bradley, Wayne E.; Zhang, Jinju; Wei, Chih-Chang; Chacko, Balu; Schurr, Theodore G.; Kesterson, Robert A.; Dell’Italia, Louis J.; Darley-Usmar, Victor M.; Welch, Danny R.; Ballinger, Scott W.

2013-01-01

Synopsis Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mitochondrial DNA (mtDNA) sequence variation contributes to disease susceptibility. In this study we present a novel animal model of mtDNA polymorphisms, the mitochondrial nuclear exchange mouse (MNX), in which the mtDNA from C3H/HeN mouse has been inserted onto the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harboring the C57/BL6J mtDNA generate more reactive oxygen species (ROS) and have a higher mitochondrial membrane potential relative to those having the C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the “mitochondrial paradigm” for the development of disease susceptibility, and show that the mtDNA modulates, cellular bioenergetics, mitochondrial reactive oxygen species generation and susceptibility to cardiac stress. PMID:23924350

Human genetic factors in tuberculosis: an update.

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van Tong, Hoang; Velavan, Thirumalaisamy P; Thye, Thorsten; Meyer, Christian G

2017-09-01

Tuberculosis (TB) is a major threat to human health, especially in many developing countries. Human genetic variability has been recognised to be of great relevance in host responses to Mycobacterium tuberculosis infection and in regulating both the establishment and the progression of the disease. An increasing number of candidate gene and genome-wide association studies (GWAS) have focused on human genetic factors contributing to susceptibility or resistance to TB. To update previous reviews on human genetic factors in TB we searched the MEDLINE database and PubMed for articles from 1 January 2014 through 31 March 2017 and reviewed the role of human genetic variability in TB. Search terms applied in various combinations were 'tuberculosis', 'human genetics', 'candidate gene studies', 'genome-wide association studies' and 'Mycobacterium tuberculosis'. Articles in English retrieved and relevant references cited in these articles were reviewed. Abstracts and reports from meetings were also included. This review provides a recent summary of associations of polymorphisms of human genes with susceptibility/resistance to TB. © 2017 John Wiley & Sons Ltd.

Isolation and antimicrobial drug susceptibility pattern of bacterial pathogens from pediatric patients with otitis media in selected health institutions, Addis Ababa, Ethiopia: a prospective cross-sectional study.

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Hailegiyorgis, Tewodros Tesfa; Sarhie, Wondemagegn Demsiss; Workie, Hailemariam Mekonnen

2018-01-01

Otitis media is inflammation of the middle ear and tympanic membrane, which often occurs after an acute upper respiratory tract infection. It is the most common episode of infection in children and the second most important cause of hearing loss affecting 1.23 billion people, thus ranked fifth global burden of disease with a higher incidence in sub-Saharan Africa. Thus, the aim of this study was to determine the isolation rate of bacterial pathogens from pediatric patients with otitis media. Institutional based cross-sectional study was conducted from January 2013-June 2014 in Addis Ababa among 210 pediatrics patients. Demographic, clinical and associated factors data was obtained in face to face interview with guardians/parents by 5 trained nurse data collectors using structured questionnaire. Middle ear drainage swab was collected following all aseptic procedures and transported to the microbiology laboratory. Culture and Antimicrobial sensitivity test were performed according to the standards. The data quality was assured by questionnaire translation, retranslation and pretesting. Reference strains were used as a positive and negative control for biochemical tests, and culture results were cross checked. Data was checked for completeness, consistency and then entered into Epi Info v3.5.1 and analyzed by SPSS v20. Data interpretation was made using graphs, tables, and result statements. A total of 196 middle ear drainage swab samples were analyzed from pediatric patients and of those 95 (48.5%) samples were positive for pathogenic organisms. The major isolate was S. aureus (15.8%) followed by P. aeruginosa (10.9%), Viridians streptococcus (9.9%), S. pneumoniae (8.9%) and S. pyogenes (7.9%). Upper respiratory tract infection history and living in the rural area have shown significant association with the isolation of pathogenic organism, ( p-value = 0.035) and ( p-value = 0.003) respectively. Most of the isolates show a high level of resistance to

Adaptive major histocompatibility complex (MHC) and neutral genetic variation in two native Baltic Sea fishes (perch Perca fluviatilis and zander Sander lucioperca) with comparisons to an introduced and disease susceptible population in Australia (P. fluviatilis): assessing the risk of disease epidemics.

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Faulks, L K; Östman, Ö

2016-04-01

This study assessed the major histocompatibility complex (MHC) and neutral genetic variation and structure in two percid species, perch Perca fluviatilis and zander Sander lucioperca, in a unique brackish ecosystem, the Baltic Sea. In addition, to assess the importance of MHC diversity to disease susceptibility in these populations, comparisons were made to an introduced, disease susceptible, P. fluviatilis population in Australia. Eighty-three MHC class II B exon 2 variants were amplified: 71 variants from 92 P. fluviatilis samples, and 12 variants from 82 S. lucioperca samples. Microsatellite and MHC data revealed strong spatial genetic structure in S. lucioperca, but not P. fluviatilis, across the Baltic Sea. Both microsatellite and MHC data showed higher levels of genetic diversity in P. fluviatilis from the Baltic Sea compared to Australia, which may have facilitated the spread of an endemic virus, EHNV in the Australian population. The relatively high levels of genetic variation in the Baltic Sea populations, together with spatial genetic structure, however, suggest that there currently seems to be little risk of disease epidemics in this system. To ensure this remains the case in the face of ongoing environmental changes, fisheries and habitat disturbance, the conservation of local-scale genetic variation is recommended. © 2016 The Fisheries Society of the British Isles.

Journal of Genetics | Indian Academy of Sciences

Indian Academy of Sciences (India)

Home; Journals; Journal of Genetics. STEFANOS BONOVAS. Articles written in Journal of Genetics. Volume 97 Issue 1 March 2018 pp 235-251 RESEARCH ARTICLE. Interleukin gene polymorphisms and susceptibility to HIV-1 infection: a meta-analysis · CHRISSA G TSIARA GEORGIOS K. NIKOLOPOULOS NIKI L. DIMOU ...

Role of genetics in the etiopathogenesis of genetic generalized epilepsy: A review of current literature

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S A Balarabe

2016-01-01

Full Text Available Until recently, genetic generalized epilepsy (GGE was believed to be of presumed genetic etiology with no identifiable genetic mutation or demonstrable epigenetic abnormality. A wide range of epileptic disorders has clue for an inherited susceptibility. Monogenic disorders associated with epilepsy mental retardation and structural brain lesion typified by heterotopias, tuberous sclerosis, and progressive myoclonus epilepsies account for about 1% of epilepsies. This review focuses on the role of genetic mutations and epigenetic rearrangements in the pathophysiologic mechanism of GGE. To achieve this; PubMed, EMBASE, and Google Scholar were systematically and comprehensively searched using keywords (“epilepsy” “juvenile myoclonic epilepsy (JME,” “typical absences,” “idiopathic generalized epilepsy,” “JME,” “juvenile absence epilepsy,” “childhood absence epilepsy” “generalized tonic-clonic seizure” “GTCS”. Most GGE has evidence of underlying genetic inheritance. Recent animal studies have shown that early detection and treatment of genetic generalized epilepsies can alter the phenotypic presentation in rodents. These findings suggest a critical period in epileptogenesis, during which spike-and-wave seizures can be suppressed, leading to chronic changes in the brain (epileptogenesis and the preceding dysfunctions may, therefore, be targeted using therapeutic approaches that may either delay or inhibit the transition to active epileptic attack. The interplay between genetic mutations and epigenetic rearrangements play important roles in the development of GCE and that this process, especially at crucial developmental periods, is very susceptible to environmental modulations.

Gabriella Miller Kids First (GMKF/Kids First) Pediatric Research Program | Office of Cancer Genomics

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The Gabriella Miller Kids First initiative is a trans-NIH effort to increase understanding of genetic changes associated with certain devastating pediatric conditions. The initiative will develop a centralized database of well-curated clinical and genetic sequence data from childhood cancer and structural birth defects cohorts comprising thousands of patients and their families. To learn more about the initiative and the data available, please visit https://commonfund.nih.gov/kidsfirst

Role of genetics in infection-associated arthritis.

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Benham, Helen; Robinson, Philip C; Baillet, Athan C; Rehaume, Linda M; Thomas, Ranjeny

2015-04-01

Genetic discoveries in arthritis and their associated biological pathways spanning the innate and adaptive immune system demonstrate the strong association between susceptibility to arthritis and control of exogenous organisms. The canonical theory of the aetiology of immune-mediated arthritis and other immune-mediated diseases is that the introduction of exogenous antigenic stimuli to a genetically susceptible host sets up the environment for an abnormal immune response manifesting as disease. A disruption in host-microbe homeostasis driven by disease-associated genetic variants could ultimately provide the source of exogenous antigen triggering disease development. We discuss genetic variants impacting the innate and adaptive arms of the immune system and their relationship to microbial control and arthritic disease. We go on to consider the evidence for a relationship between HLA-B27, infection and arthritis, and then emerging evidence for an interaction between microbiota and rheumatoid arthritis. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

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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

Association of STAT4 gene polymorphism with increased susceptibility of rheumatoid arthritis in a northern Chinese Han subpopulation.

Science.gov (United States)

Zhao, Yi; Liu, Xu; Liu, Xia; Su, Yin; Li, Yanmei; Zhang, Xiaoping; Zhu, Lei; Wang, Shiyao; Wang, Tian; Jiang, Quan; Liu, Xiangyuan; Li, Xiaoxia; Huang, Cibo; Jia, Rulin; Lu, Xiaolan; Guo, Jianping; Li, Zhanguo

2013-04-01

Several studies have reported STAT4 polymorphism is strongly associated with increased susceptibility to rheumatoid arthritis (RA). However, a study from China showed no association between STAT4 and RA susceptibility in a Chinese Han subpopulation. Since the northern Hans are known to be genetically different from the southern Hans, the aim of this study was to investigate the association of STAT4 polymorphism with RA in a large cohort of a northern Chinese Han subpopulation. 640 RA patients and 662 healthy controls were enrolled. DNA samples were genotyped for STAT4 rs7574865 by direct sequencing. The association of single nucleotide polymorphism (SNP) rs7574865 with RA susceptibility was calculated and the relationship between rs7574865 polymorphism and RA subgroups stratified by clinical features was estimated. We confirmed a significant association of STAT4 rs7574865 polymorphism with RA susceptibility in northern Chinese Han population. The frequency of the minor T allele in RA was significantly higher than in healthy controls (35.2% vs. 31.1%; P = 0.029, OR 1.2 [95% CI 1.02-1.41]). There was also a significant difference in the distribution of the genotypes of SNP rs7574865 between RA patients and healthy controls (P = 0.02). Stratification analyses showed no associations between the genetic risk and clinical/serologic features, but a potential high frequency of TT genotype in a rheumatoid factor-negative subgroup, although it did not reach statistical significance (P = 0.084, OR 2.01 [95% CI 0.91-4.45]). STAT4 rs7574865 is significantly associated with RA susceptibility in northern Chinese Han subpopulations. The genetic differences of Han subpopulations should be considered when genetic susceptibility for diseases is studied. © 2013 The Authors International Journal of Rheumatic Diseases © 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.