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Sample records for locus conferring susceptibility

  1. The MTAP-CDKN2A Locus Confers Susceptibility to a Naturally Occurring Canine Cancer

    Science.gov (United States)

    Shearin, Abigail L.; Hedan, Benoit; Cadieu, Edouard; Erich, Suzanne A.; Schmidt, Emmett V.; Faden, Daniel L.; Cullen, John; Abadie, Jerome; Kwon, Erika M.; Gröne, Andrea; Devauchelle, Patrick; Rimbault, Maud; Karyadi, Danielle M.; Lynch, Mary; Galibert, Francis; Breen, Matthew; Rutteman, Gerard R.; André, Catherine; Parker, Heidi G.; Ostrander, Elaine A.

    2012-01-01

    Background Advantages offered by canine population substructure, combined with clinical presentations similar to human disorders, makes the dog an attractive system for studies of cancer genetics. Cancers that have been difficult to study in human families or populations are of particular interest. Histiocytic sarcoma is a rare and poorly understood neoplasm in humans that occurs in 15–25% of Bernese Mountain Dogs (BMD). Methods Genomic DNA was collected from affected and unaffected BMD in North America (NA) and Europe. Both independent and combined genome wide association studies (GWAS) were used to identify cancer-associated loci. Fine mapping and sequencing narrowed the primary locus to a single gene region. Results Both populations shared the same primary locus, which features a single haplotype spanning MTAP and part of CDKN2A and is present in 96% of affected BMD. The haplotype is within the region homologous to human chromosome 9p21, which has been implicated in several types of cancer. Conclusions We present the first GWAS for HS in any species. The data identify an associated haplotype in the highly cited tumor suppressor locus near CDKN2A. These data demonstrate the power of studying distinctive malignancies in highly predisposed dog breeds. Impact Here, we establish a naturally-occurring model of cancer susceptibility due to CDKN2 dysregulation, thus providing insight regarding this cancer-associated, complex, and poorly understood genomic region. PMID:22623710

  2. Analysis of human chromosome 21 for a locus conferring susceptibility to Hirschsprung Disease

    Energy Technology Data Exchange (ETDEWEB)

    Bolk, S.; Duggan, D.J.; Chakravarti, A. [Case Western Reserve Univ., Cleveland, OH (United States)

    1994-09-01

    It has been estimated that approximately 5% of patients diagnosed with Hirschsprung disease (HSCR), or aganglionic megacolon, have trisomy 21. Since the incidence of Hirschsprung disease is 1/5000 live births and the incidence of trisomy 21 is approximately 1/1000 live births, the observed occurrence of HSCR in trisomy 21 is fifty times higher than expected. We propose that at least one locus on chromosome 21 predisposes to HSCR. Although at fifty times elevated risk, only 1% of Down Syndrome cases have HSCR. Thus additional genes or genetic events are necessary for HSCR to manifest in patients with trisomy 21. Based on segregation analysis, Badner et al. postulated that recessive genes may be responsible for up to 80% of HSCR. We postulate that at least one such gene is on chromosome 21 and increased homozygosity for common recessive HSCR mutations may be one cause for the elevated risk of HSCR in cases of trisomy 21. To map such a chromosome 21 locus, we are searching for segments of human chromosome 21 which are identical by descent from the parent in whom non-disjunction occurred. These segments will arise either from meiosis I (followed by a crossover between the centromere and the locus) or from meiosis II (followed by no crossovers). Nine nuclear families with a proband diagnosed with HSCR and Down Syndrome have been genotyped for 18 microsatellite markers spanning human chromosome 21q. In all nine cases analyzed thus far, trisomy 21 resulted from maternal non-disjunction at meiosis I. At this point no single IBD region is apparent. Therefore, additional families are being ascertained and additional markers at high density are being genotyped to map the HSCR locus.

  3. A Locus at 5q33.3 Confers Resistance to Tuberculosis in Highly Susceptible Individuals

    Science.gov (United States)

    Sobota, Rafal S.; Stein, Catherine M.; Kodaman, Nuri; Scheinfeldt, Laura B.; Maro, Isaac; Wieland-Alter, Wendy; Igo, Robert P.; Magohe, Albert; Malone, LaShaunda L.; Chervenak, Keith; Hall, Noemi B.; Modongo, Chawangwa; Zetola, Nicola; Matee, Mecky; Joloba, Moses; Froment, Alain; Nyambo, Thomas B.; Moore, Jason H.; Scott, William K.; Lahey, Timothy; Boom, W. Henry; von Reyn, C. Fordham; Tishkoff, Sarah A.; Sirugo, Giorgio; Williams, Scott M.

    2016-01-01

    Immunosuppression resulting from HIV infection increases the risk of progression to active tuberculosis (TB) both in individuals newly exposed to Mycobacterium tuberculosis (MTB) and in those with latent infections. We hypothesized that HIV-positive individuals who do not develop TB, despite living in areas where it is hyperendemic, provide a model of natural resistance. We performed a genome-wide association study of TB resistance by using 581 HIV-positive Ugandans and Tanzanians enrolled in prospective cohort studies of TB; 267 of these individuals developed active TB, and 314 did not. A common variant, rs4921437 at 5q33.3, was significantly associated with TB (odds ratio = 0.37, p = 2.11 × 10−8). This variant lies within a genomic region that includes IL12B and is embedded in an H3K27Ac histone mark. The locus also displays consistent patterns of linkage disequilibrium across African populations and has signals of strong selection in populations from equatorial Africa. Along with prior studies demonstrating that therapy with IL-12 (the cytokine encoded in part by IL12B, associated with longer survival following MTB infection in mice deficient in CD4 T cells), our results suggest that this pathway might be an excellent target for the development of new modalities for treating TB, especially for HIV-positive individuals. Our results also indicate that studying extreme disease resistance in the face of extensive exposure can increase the power to detect associations in complex infectious disease. PMID:26942285

  4. Pasteurized whole milk confers reduced susceptibilities to the antimicrobial agents trimethoprim, gatifloxacin, cefotaxime and tetracycline via the marRAB locus in Escherichia coli.

    Science.gov (United States)

    Peng, Yang; Hernandez, Ricardo L; Crow, Robert R; Jones, Suzanna E; Mathews, Sara A; Arnold, Ayanna M; Castillo, Eliseo F; Moseley, Jennifer M; Varela, Manuel F

    2008-11-01

    We inoculated pasteurized whole milk with Escherichia coli strains GC4468 (intact marRAB locus), JHC1096 (Delta marRAB), or AG112 (Delta marR), and incubated each overnight at 37 degrees C. All strains were then recovered from the milk cultures, and susceptibilities to antimicrobial agents were determined by the E-test strip method (CLSI). Cells of strain GC4468, prior to culturing in milk, were susceptible to trimethoprim, gatifloxacin, cefotaxime and tetracycline. After culturing GC4468 in pasteurized milk, however, the minimal inhibitory concentrations (MICs) increased 1.4-fold for trimethoprim (P0.05), 1.5-fold for gatifloxacin (P0.05), 2.0-fold for cefotaxime (P=0.008), and 1.4-fold for tetracycline (P0.05). After culturing GC4468 on milk count agar the MICs were enhanced 3.4-fold for trimethoprim (P0.05), 10-fold for gatifloxacin (P=0.001), 7.1-fold for cefotaxime (P=0.011), and 40.5-fold for tetracycline (P=0.074), but exhibiting tetracycline resistance with a mean MIC of 74.7+/-18.47 microg/ml (CLSI). The MICs of the antimicrobial agents for JHC1096 cells after culturing in pasteurized whole milk were indistinguishable (P0.05) from baseline MICs measured before culturing in the same type of milk. Thus, Esch. coli cells harbouring the marRAB locus exhibit reduced susceptibilities to multiple antimicrobial agents after culturing in pasteurized whole milk.

  5. Polymorphisms at Locus 4p14 of Toll-Like Receptors TLR-1 and TLR-10 Confer Susceptibility to Gastric Carcinoma in Helicobacter pylori Infection.

    Directory of Open Access Journals (Sweden)

    M Ravishankar Ram

    Full Text Available Helicobacter pylori (H. pylori -induced gastric inflammation impacts the functions of leptin- and ghrelin-producing cells in the gastroduodenum. Inflammation resulting from H. pylori sensing via Toll-like receptors (TLRs and the associated downstream signaling largely remain ambiguous. Here, we investigated the role of gut hormones, pro-inflammatory cytokines and single nucleotide polymorphisms (SNPs associated with TLR 4p14 in H. pylori disease in 30 subjects with non-ulcer dyspepsia (NUD, 40 with peptic ulcer disease (PUD and 15 with gastric cancer (GC subjects positive and negative for H. pylori infection. The level of pro-inflammatory cytokines was directly proportional to the severity of gastritis, and disease status influenced the levels of gut hormones and pro-inflammatory cytokines. TLR-1 SNPs rs4833095 and TLR-10 SNPs rs10004195 and were directly associated with H. pylori disease, and were up-regulated in the presence of H. pylori in a genotype-independent manner. We concluded that TLR-1 rs4833095 and TLR10 rs10004195 confer susceptibility to development of gastroduodenal disease, especially GC in H.pylori disease.

  6. 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

    The study aimed to explore the role of ERBB3 in type 1 diabetes (T1D). We examined whether genetic variation of ERBB3 (rs2292239) affects residual β-cell function in T1D cases. Furthermore, we examined the expression of ERBB3 in human islets, the effect of ERBB3 knockdown on apoptosis in insulin......-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...... regulators in the β-cells and may constitute novel targets to prevent β-cell destruction in T1D....

  7. Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease.

    Science.gov (United States)

    Khor, Chiea Chuen; Davila, Sonia; Breunis, Willemijn B; Lee, Yi-Ching; Shimizu, Chisato; Wright, Victoria J; Yeung, Rae S M; Tan, Dennis E K; Sim, Kar Seng; Wang, Jie Jin; Wong, Tien Yin; Pang, Junxiong; Mitchell, Paul; Cimaz, Rolando; Dahdah, Nagib; Cheung, Yiu-Fai; Huang, Guo-Ying; Yang, Wanling; Park, In-Sook; Lee, Jong-Keuk; Wu, Jer-Yuarn; Levin, Michael; Burns, Jane C; Burgner, David; Kuijpers, Taco W; Hibberd, Martin L

    2011-11-13

    Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10(-11), odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10(-9), OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10(-12), OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings(1). The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.

  8. Male-pattern baldness susceptibility locus at 20p11.

    NARCIS (Netherlands)

    Richards, J.B.; Yuan, X.; Geller, F.; Waterworth, D.; Bataille, V.; Glass, D.; Song, K.; Waeber, G.; Vollenweider, P.; Aben, K.K.H.; Kiemeney, L.A.L.M.; Walters, B.; Soranzo, N.; Thorsteinsdottir, U.; Kong, A.; Rafnar, T.; Deloukas, P.; Sulem, P.; Stefansson, H.; Stefansson, K.; Spector, T.D.; Mooser, V.

    2008-01-01

    We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 x 10(-14) for rs1160312). The one man in seven who harbors risk alleles at both 20p1

  9. Male-pattern baldness susceptibility locus at 20p11.

    NARCIS (Netherlands)

    Richards, J.B.; Yuan, X.; Geller, F.; Waterworth, D.; Bataille, V.; Glass, D.; Song, K.; Waeber, G.; Vollenweider, P.; Aben, K.K.H.; Kiemeney, L.A.L.M.; Walters, B.; Soranzo, N.; Thorsteinsdottir, U.; Kong, A.; Rafnar, T.; Deloukas, P.; Sulem, P.; Stefansson, H.; Stefansson, K.; Spector, T.D.; Mooser, V.

    2008-01-01

    We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 x 10(-14) for rs1160312). The one man in seven who harbors risk alleles at both 20p1

  10. Multi-locus association study of schizophrenia susceptibility genes with a posterior probability method

    Institute of Scientific and Technical Information of China (English)

    SUN Xiangqing; JIA Yanbin; ZHANG Xuegong; XU Qi; SHEN Yan; LI Yanda

    2005-01-01

    Schizophrenia is a serious neuropsychiatric illness affecting about 1% of the world's population. It is considered a complex inheritance disorder. A number of genes are involved in combination in the etiology of the disorder. Evidence implicates the altered dopaminergic transmission in schizophrenia. In the present study, in order to identify susceptibility genes for schizophrenia in dopaminergic metabolism, we analyzed 59 single nucleotide polymorphisms (SNPs) in 24 genes of the dopaminergic pathway among 82 unrelated patients with schizophrenia and 108 matched normal controls. Considering that traditional single-locus association studies ignore the multigenic nature of complex diseases and do not take into account possible interactions between susceptibility genes, we proposed a multi-locus analysis method, using the posterior probability of morbidity as a measure of absolute disease risk for a multi-locus genotype combination, and developed an algorithm based on perturbation and average to detect the susceptibility multi-locus genotype combinations, as well as to repress noise and avoid false positive results at our best. A three-locus SNP genotype combination involved in the interactions of COMTand ALDH3B1 genes was detected to be significantly susceptible to schizophrenia.

  11. Contactin 4 as a Possible Autism Susceptibility Locus

    Science.gov (United States)

    2011-01-27

    3 yrs  Restricted interests and stereotypic and/or repetitive behaviors – Up to 90% of the risk is genetic, although underlying causes remain...Working Together, Achieving Success 1 2011 MHS Conference Autism Spectrum Disorder - ASD  Declared a national public health crisis – Nationwide 1 in...BACKGROUND – Autism is the most common neurodevelopmental disorder in the US  Deficits in communication and social interaction skills with onset

  12. Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus

    DEFF Research Database (Denmark)

    Horne, Hisani N; Chung, Charles C; Zhang, Han

    2016-01-01

    The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking...

  13. Fine-mapping of the 1p11.2 breast cancer susceptibility locus

    NARCIS (Netherlands)

    Horne, H.N. (Hisani N.); Chung, C.C. (Charles C.); Zhang, H. (Han); Yu, K. (Kai); Prokunina-Olsson, L. (Ludmila); K. Michailidou (Kyriaki); M.K. Bolla (Manjeet K.); Q. Wang (Qing); J. Dennis (Joe); J.L. Hopper (John); M.C. Southey (Melissa); M.K. Schmidt (Marjanka); A. Broeks (Annegien); K.R. Muir (K.); A. Lophatananon (Artitaya); P.A. Fasching (Peter); M.W. Beckmann (Matthias); O. Fletcher (Olivia); Johnson, N. (Nichola); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); Burwinkel, B. (Barbara); Marme, F. (Frederik); P. Guénel (Pascal); T. Truong (Thérèse); S.E. Bojesen (Stig); H. Flyger (Henrik); J. Benítez (Javier); A. González-Neira (Anna); H. Anton-Culver (Hoda); S.L. Neuhausen (Susan); Brenner, H. (Hermann); V. Arndt (Volker); A. Meindl (Alfons); R.K. Schmutzler (Rita); H. Brauch (Hiltrud); U. Hamann (Ute); H. Nevanlinna (Heli); S. Khan (Sofia); K. Matsuo (Keitaro); H. Iwata (Hiroji); T. Dörk (Thilo); N.V. Bogdanova (Natalia); A. Lindblom (Annika); S. Margolin (Sara); A. Mannermaa (Arto); V-M. Kosma (Veli-Matti); G. Chenevix-Trench (Georgia); A.H. Wu (Anna); Ven Den Berg, D. (David); A. Smeets (Ann); H. Zhao (Hui); J. Chang-Claude (Jenny); A. Rudolph (Anja); P. Radice (Paolo); M. Barile (Monica); F.J. Couch (Fergus); Vachon, C. (Celine); Giles, G.G. (Graham G.); R.L. Milne (Roger); C.A. Haiman (Christopher A.); L. Le Marchand (Loic); M.S. Goldberg (Mark); S.-H. Teo; N.A.M. Taib (Nur Aishah Mohd); V. Kristensen (Vessela); Borresen-Dale, A.-L. (Anne-Lise); W. Zheng (Wei); M. Shrubsole (Martha); R. Winqvist (Robert); A. Jukkola-Vuorinen (Arja); I.L. Andrulis (Irene); J.A. Knight (Julia); P. Devilee (Peter); C.M. Seynaeve (Caroline); M. García-Closas (Montserrat); K. Czene (Kamila); H. Darabi (Hatef); A. Hollestelle (Antoinette); J.W.M. Martens (John); J. Li (Jingmei); W. Lu (Wei); X.-O. Shu (Xiao-Ou); A. Cox (Angela); S.S. Cross (Simon); W.J. Blot (William); Q. Cai (Qiuyin); M. Shah (Mitul); C. Luccarini (Craig); Baynes, C. (Caroline); P. harrington (Patricia); D. Kang (Daehee); J.-Y. Choi (Ji-Yeob); J.M. Hartman (Joost); Chia, K.S. (Kee Seng); M. Kabisch (Maria); D. Torres (Diana); A. Jakubowska (Anna); J. Lubinski (Jan); S. Sangrajrang (Suleeporn); P. Brennan (Paul); S. Slager (Susan); D. Yannoukakos (Drakoulis); C.-Y. Shen (Chen-Yang); M.-F. Hou (Ming-Feng); A.J. Swerdlow (Anthony ); N. Orr (Nick); J. Simard (Jacques); P. Hall (Per); P.D.P. Pharoah (Paul); D.F. Easton (Douglas F.); Chanock, S.J. (Stephen J.); A.M. Dunning (Alison); J.D. Figueroa (Jonine)

    2016-01-01

    textabstractThe Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132)

  14. 19p13.1 Is a triple-negative-specific breast cancer susceptibility locus

    NARCIS (Netherlands)

    K. Stevens (Kristen); Z. Fredericksen (Zachary); C. Vachon (Celine); X. Wang (Xing); S. Margolin (Sara); A. Lindblom (Annika); H. Nevanlinna (Heli); D. Greco (Dario); K. Aittomäki (Kristiina); C. Blomqvist (Carl); J. Chang-Claude (Jenny); A. Vrieling (Alina); D. Flesch-Janys (Dieter); H.-P. Sinn (Hans-Peter); S. Wang-Gohrke (Shan); S. Nickels (Stefan); H. Brauch (Hiltrud); Y-D. Ko (Yon-Dschun); H.-P. Fischer; R.K. Schmutzler (Rita); A. Meindl (Alfons); C.R. Bartram (Claus); S. Schott (Sarah); C. Engel (Christoph); A.K. Godwin (Andrew); J. Weaver (JoEllen); S.S. Pathak; P. Sharma (Pankaj); H. Brenner (Hermann); H. Mul̈ler (Heiko); V. Arndt (Volker); C. Stegmaier (Christa); P. Miron (Penelope); D. Yannoukakos (Drakoulis); A. Stavropoulou (Alexandra); G. Fountzilas (George); H. Gogas (Helen); R. Swann (Ruth); M. Dwek (Miriam); A. Perkins (Annie); R.L. Milne (Roger); J. Benítez (Javier); M.P. Zamora (Pilar); J.I.A. Perez (Jose Ignacio Arias); S.E. Bojesen (Stig); S.F. Nielsen (Sune); B.G. Nordestgaard (Børge); H. Flyger (Henrik); P. Guénel (Pascal); T. Truong (Thérèse); F. Menegaux (Florence); E. Cordina-Duverger (Emilie); B. Burwinkel (Barbara); F. Marme (Federick); A. Schneeweiss (Andreas); C. Sohn (Christof); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); J. Peto (Julian); N. Johnson (Nichola); O. Fletcher (Olivia); I. dos Santos Silva (Isabel); P.A. Fasching (Peter); M.W. Beckmann (Matthias); A. Hartmann; A.B. Ekici (Arif); A. Lophatananon (Artitaya); K.R. Muir (Kenneth); P. Puttawibul (Puttisak); S. Wiangnon (Surapon); M.K. Schmidt (Marjanka); A. Broeks (Annegien); L.M. Braaf (Linde); E.H. Rosenberg (Efraim); J.L. Hopper (John); C. Apicella (Carmel); D.J. Park (Daniel); M.C. Southey (Melissa); A.J. Swerdlow (Anthony ); A. Ashworth (Alan); O. Nicholas (Orr); M. Schoemaker (Minouk); H. Anton-Culver (Hoda); A. Ziogas (Argyrios); L. Bernstein (Leslie); C.C. Dur (Christina Clarke); C-Y. Shen (Chen-Yang); J-C. Yu (Jyh-Cherng); H.-M. Hsu (Huan-Ming); C.-N. Hsiung (Chia-Ni); U. Hamann (Ute); T. Dun̈nebier (Thomas); T. Rud̈iger (Thomas); H.U. Ulmer (Hans); P.D.P. Pharoah (Paul); A.M. Dunning (Alison); M.K. Humphreys (Manjeet); Q. Wang (Qing); A. Cox (Angela); S.S. Cross (Simon); M.W.R. Reed (Malcolm); P. Hall (Per); K. Czene (Kamila); C.B. Ambrosone (Christine); F. Ademuyiwa (Foluso); H. Hwang (Helena); D. Eccles (Diana); M. García-Closas (Montserrat); J.D. Figueroa (Jonine); M.E. Sherman (Mark); J. Lissowska (Jolanta); P. Devilee (Peter); C.M. Seynaeve (Caroline); R.A.E.M. Tollenaar (Rob); M.J. Hooning (Maartje); I.L. Andrulis (Irene); J.A. Knight (Julia); G. Glendon (Gord); A.M. Mulligan (Anna Marie); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); E.M. John (Esther); A. Miron (Alexander); G.G. Alnæs (Grethe); V. Kristensen (Vessela); A.-L. Brøresen-Dale (Anne-Lise); G.G. Giles (Graham); L. Baglietto (Laura); C.A. McLean (Catriona Ann); G. Severi (Gianluca); M. Kosel (Matthew); V.S. Pankratz (Shane); S. Slager (Susan); J.E. Olson (Janet); P. Radice (Paolo); P. Peterlongo (Paolo); S. Manoukian (Siranoush); M. Barile (Monica); D. Lambrechts (Diether); S. Hatse (Sigrid); A.-S. Dieudonné (Anne-Sophie); M.R. Christiaens (Marie Rose); G. Chenevix-Trench (Georgia); J. Beesley (Jonathan); X. Chen (Xiaoqing); A. Mannermaa (Arto); V-M. Kosma (Veli-Matti); J. Hartikainen (Jaana); Y. Soini (Ylermi); D.F. Easton (Douglas); F.J. Couch (Fergus)

    2012-01-01

    textabstractThe 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER),

  15. Fine-mapping of the 1p11.2 breast cancer susceptibility locus

    NARCIS (Netherlands)

    Horne, H.N. (Hisani N.); Chung, C.C. (Charles C.); Zhang, H. (Han); Yu, K. (Kai); Prokunina-Olsson, L. (Ludmila); K. Michailidou (Kyriaki); M.K. Bolla (Manjeet K.); Q. Wang (Qing); J. Dennis (Joe); J.L. Hopper (John); M.C. Southey (Melissa); M.K. Schmidt (Marjanka); A. Broeks (Annegien); K.R. Muir (K.); A. Lophatananon (Artitaya); P.A. Fasching (Peter); M.W. Beckmann (Matthias); O. Fletcher (Olivia); Johnson, N. (Nichola); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); Burwinkel, B. (Barbara); Marme, F. (Frederik); P. Guénel (Pascal); T. Truong (Thérèse); S.E. Bojesen (Stig); H. Flyger (Henrik); J. Benítez (Javier); A. González-Neira (Anna); H. Anton-Culver (Hoda); S.L. Neuhausen (Susan); Brenner, H. (Hermann); V. Arndt (Volker); A. Meindl (Alfons); R.K. Schmutzler (Rita); H. Brauch (Hiltrud); U. Hamann (Ute); H. Nevanlinna (Heli); S. Khan (Sofia); K. Matsuo (Keitaro); H. Iwata (Hiroji); T. Dörk (Thilo); N.V. Bogdanova (Natalia); A. Lindblom (Annika); S. Margolin (Sara); A. Mannermaa (Arto); V-M. Kosma (Veli-Matti); G. Chenevix-Trench (Georgia); A.H. Wu (Anna); Ven Den Berg, D. (David); A. Smeets (Ann); H. Zhao (Hui); J. Chang-Claude (Jenny); A. Rudolph (Anja); P. Radice (Paolo); M. Barile (Monica); F.J. Couch (Fergus); Vachon, C. (Celine); Giles, G.G. (Graham G.); R.L. Milne (Roger); C.A. Haiman (Christopher A.); L. Le Marchand (Loic); M.S. Goldberg (Mark); S.-H. Teo; N.A.M. Taib (Nur Aishah Mohd); V. Kristensen (Vessela); Borresen-Dale, A.-L. (Anne-Lise); W. Zheng (Wei); M. Shrubsole (Martha); R. Winqvist (Robert); A. Jukkola-Vuorinen (Arja); I.L. Andrulis (Irene); J.A. Knight (Julia); P. Devilee (Peter); C.M. Seynaeve (Caroline); M. García-Closas (Montserrat); K. Czene (Kamila); H. Darabi (Hatef); A. Hollestelle (Antoinette); J.W.M. Martens (John); J. Li (Jingmei); W. Lu (Wei); X.-O. Shu (Xiao-Ou); A. Cox (Angela); S.S. Cross (Simon); W.J. Blot (William); Q. Cai (Qiuyin); M. Shah (Mitul); C. Luccarini (Craig); Baynes, C. (Caroline); P. harrington (Patricia); D. Kang (Daehee); J.-Y. Choi (Ji-Yeob); J.M. Hartman (Joost); Chia, K.S. (Kee Seng); M. Kabisch (Maria); D. Torres (Diana); A. Jakubowska (Anna); J. Lubinski (Jan); S. Sangrajrang (Suleeporn); P. Brennan (Paul); S. Slager (Susan); D. Yannoukakos (Drakoulis); C.-Y. Shen (Chen-Yang); M.-F. Hou (Ming-Feng); A.J. Swerdlow (Anthony ); N. Orr (Nick); J. Simard (Jacques); P. Hall (Per); P.D.P. Pharoah (Paul); D.F. Easton (Douglas F.); Chanock, S.J. (Stephen J.); A.M. Dunning (Alison); J.D. Figueroa (Jonine)

    2016-01-01

    textabstractThe Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132)

  16. 9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer

    DEFF Research Database (Denmark)

    Warren, Helen; Dudbridge, Frank; Fletcher, Olivia

    2012-01-01

    Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).......Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686)....

  17. Linkage Analysis in Autoimmune Addison's Disease: NFATC1 as a Potential Novel Susceptibility Locus.

    Science.gov (United States)

    Mitchell, Anna L; Bøe Wolff, Anette; MacArthur, Katie; Weaver, Jolanta U; Vaidya, Bijay; Erichsen, Martina M; Darlay, Rebecca; Husebye, Eystein S; Cordell, Heather J; Pearce, Simon H S

    2015-01-01

    Autoimmune Addison's disease (AAD) is a rare, highly heritable autoimmune endocrinopathy. It is possible that there may be some highly penetrant variants which confer disease susceptibility that have yet to be discovered. DNA samples from 23 multiplex AAD pedigrees from the UK and Norway (50 cases, 67 controls) were genotyped on the Affymetrix SNP 6.0 array. Linkage analysis was performed using Merlin. EMMAX was used to carry out a genome-wide association analysis comparing the familial AAD cases to 2706 UK WTCCC controls. To explore some of the linkage findings further, a replication study was performed by genotyping 64 SNPs in two of the four linked regions (chromosomes 7 and 18), on the Sequenom iPlex platform in three European AAD case-control cohorts (1097 cases, 1117 controls). The data were analysed using a meta-analysis approach. In a parametric analysis, applying a rare dominant model, loci on chromosomes 7, 9 and 18 had LOD scores >2.8. In a non-parametric analysis, a locus corresponding to the HLA region on chromosome 6, known to be associated with AAD, had a LOD score >3.0. In the genome-wide association analysis, a SNP cluster on chromosome 2 and a pair of SNPs on chromosome 6 were associated with AAD (P <5x10-7). A meta-analysis of the replication study data demonstrated that three chromosome 18 SNPs were associated with AAD, including a non-synonymous variant in the NFATC1 gene. This linkage study has implicated a number of novel chromosomal regions in the pathogenesis of AAD in multiplex AAD families and adds further support to the role of HLA in AAD. The genome-wide association analysis has also identified a region of interest on chromosome 2. A replication study has demonstrated that the NFATC1 gene is worthy of future investigation, however each of the regions identified require further, systematic analysis.

  18. Linkage Analysis in Autoimmune Addison's Disease: NFATC1 as a Potential Novel Susceptibility Locus.

    Directory of Open Access Journals (Sweden)

    Anna L Mitchell

    Full Text Available Autoimmune Addison's disease (AAD is a rare, highly heritable autoimmune endocrinopathy. It is possible that there may be some highly penetrant variants which confer disease susceptibility that have yet to be discovered.DNA samples from 23 multiplex AAD pedigrees from the UK and Norway (50 cases, 67 controls were genotyped on the Affymetrix SNP 6.0 array. Linkage analysis was performed using Merlin. EMMAX was used to carry out a genome-wide association analysis comparing the familial AAD cases to 2706 UK WTCCC controls. To explore some of the linkage findings further, a replication study was performed by genotyping 64 SNPs in two of the four linked regions (chromosomes 7 and 18, on the Sequenom iPlex platform in three European AAD case-control cohorts (1097 cases, 1117 controls. The data were analysed using a meta-analysis approach.In a parametric analysis, applying a rare dominant model, loci on chromosomes 7, 9 and 18 had LOD scores >2.8. In a non-parametric analysis, a locus corresponding to the HLA region on chromosome 6, known to be associated with AAD, had a LOD score >3.0. In the genome-wide association analysis, a SNP cluster on chromosome 2 and a pair of SNPs on chromosome 6 were associated with AAD (P <5x10-7. A meta-analysis of the replication study data demonstrated that three chromosome 18 SNPs were associated with AAD, including a non-synonymous variant in the NFATC1 gene.This linkage study has implicated a number of novel chromosomal regions in the pathogenesis of AAD in multiplex AAD families and adds further support to the role of HLA in AAD. The genome-wide association analysis has also identified a region of interest on chromosome 2. A replication study has demonstrated that the NFATC1 gene is worthy of future investigation, however each of the regions identified require further, systematic analysis.

  19. Schizophrenia susceptibility gene locus at Xp22.3.

    Science.gov (United States)

    Milunsky, J; Huang, X L; Wyandt, H E; Milunsky, A

    1999-06-01

    Multiple genetic loci have been implicated in the search for schizophrenia susceptibility genes, none having been proven as causal. Genetic heterogeneity is probable in the polygenic etiology of schizophrenia. We report on two unrelated Caucasian women with paranoid schizophrenia (meeting Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria) who have an Xp22.3 overlapping deletion characterized by fluorescence in situ hybridization (FISH). Patient 1 was previously reported by us (Wyandt HE, Bugeau-Michaud L, Skare JC, Milunsky A. Partial duplication of Xp: a case report and review of previously reported cases. Amer J Med Genet 1991: 40: 280-283) to have a de novo partial duplication of Xp. At that time, she was a 24-year-old woman with short stature, irregular menses, other abnormalities suggestive of Turner syndrome, and paranoid schizophrenia. Recently, FISH analysis demonstrated that she has an inverted duplication (X)(p22.1p11.2) and a microscopic deletion (X)(p22.2p22.3) between DXS1233 and DXS7108 spanning approximately 16-18 cM. Patient 2 is a 14-year-old girl with short stature, learning disabilities, and paranoid schizophrenia. High-resolution chromosome analysis revealed a de novo deletion involving Xp22. FISH analysis showed that the deletion (X)(p22.2p22.3) spanned 10-12 cM between AFMB290XG5 and DXS1060. Given that deletions of Xp22 are not common events, the occurrence of two unrelated schizophrenia patients with an overlapping deletion of this region would be extraordinarily rare. Hence, the deletion within Xp22.3 almost certainly contains a gene involved in the pathogenesis of paranoid schizophrenia.

  20. Common variants in CASP3 confer susceptibility to Kawasaki disease.

    Science.gov (United States)

    Onouchi, Yoshihiro; Ozaki, Kouichi; Buns, Jane C; Shimizu, Chisato; Hamada, Hiromichi; Honda, Takafumi; Terai, Masaru; Honda, Akihito; Takeuchi, Takashi; Shibuta, Shoichi; Suenaga, Tomohiro; Suzuki, Hiroyuki; Higashi, Kouji; Yasukawa, Kumi; Suzuki, Yoichi; Sasago, Kumiko; Kemmotsu, Yasushi; Takatsuki, Shinichi; Saji, Tsutomu; Yoshikawa, Tetsushi; Nagai, Toshiro; Hamamoto, Kunihiro; Kishi, Fumio; Ouchi, Kazunobu; Sato, Yoshitake; Newburger, Jane W; Baker, Annette L; Shulman, Stanford T; Rowley, Anne H; Yashiro, Mayumi; Nakamura, Yoshikazu; Wakui, Keiko; Fukushima, Yoshimitsu; Fujino, Akihiro; Tsunoda, Tatsuhiko; Kawasaki, Tomisaku; Hata, Akira; Nakamura, Yusuke; Tanaka, Toshihiro

    2010-07-15

    Kawasaki disease (KD; OMIM 611775) is an acute vasculitis syndrome which predominantly affects small- and medium-sized arteries of infants and children. Epidemiological data suggest that host genetics underlie the disease pathogenesis. Here we report that multiple variants in the caspase-3 gene (CASP3) that are in linkage disequilibrium confer susceptibility to KD in both Japanese and US subjects of European ancestry. We found that a G to A substitution of one commonly associated SNP located in the 5' untranslated region of CASP3 (rs72689236; P = 4.2 x 10(-8) in the Japanese and P = 3.7 x 10(-3) in the European Americans) abolished binding of nuclear factor of activated T cells to the DNA sequence surrounding the SNP. Our findings suggest that altered CASP3 expression in immune effecter cells influences susceptibility to KD.

  1. Protection of Mycobacterium tuberculosis from reactive oxygen species conferred by the mel2 locus impacts persistence and dissemination.

    Science.gov (United States)

    Cirillo, Suat L G; Subbian, Selvakumar; Chen, Bing; Weisbrod, Torin R; Jacobs, William R; Cirillo, Jeffrey D

    2009-06-01

    Persistence of Mycobacterium tuberculosis in humans represents a major roadblock to elimination of tuberculosis. We describe identification of a locus in M. tuberculosis, mel2, that displays similarity to bacterial bioluminescent loci and plays an important role during persistence in mice. We constructed a deletion of the mel2 locus and found that the mutant displays increased susceptibility to reactive oxygen species (ROS). Upon infection of mice by aerosol the mutant grows normally until the persistent stage, where it does not persist as well as wild type. Histopathological analyses show that infection with the mel2 mutant results in reduced pathology and both CFU and histopathology indicate that dissemination of the mel2 mutant to the spleen is delayed. These data along with growth in activated macrophages and infection of Phox(-/-) and iNOS(-/-) mice and bone marrow-derived macrophages suggest that the primary mechanism by which mel2 affects pathogenesis is through its ability to confer resistance to ROS. These studies provide the first insight into the mechanism of action for this novel class of genes that are related to bioluminescence genes. The role of mel2 in resistance to ROS is important for persistence and dissemination of M. tuberculosis and suggests that homologues in other bacterial species are likely to play a role in pathogenesis.

  2. IDENTIFICATION OF A MAJOR QUANTITATIVE TRAIT LOCUS CONFERRING RICE BLAST RESISTANCE USING RECOMBINANT INBRED LINES

    Directory of Open Access Journals (Sweden)

    Sobrizal Sobrizal

    2013-05-01

    Full Text Available Blast disease caused by Pyricularia oryzae is one of the limiting factors for rice production world wide. The use of resistant varieties for managing blast disease is considered as the most eco-friendly approaches. However, their resistances may be broken down within a few years due to the appearance of new virulent blast races in the field. The objective of the present study was to identify the quantitative trait locus (QTL conferring resistance to blast disease using 126 recombinant inbred (RI lines originated from a crossing of a durably resistant upland rice genotype (Laka and a highly susceptible rice accession cultivar (Kencana Bali. The RI population was developed through a single seed descent method from 1997 to 2004. Resistance of the RI lines was evaluated for blast in an endemic area of Sukabumi, West Java, in 2005. Disease intensity of the blast was examined following the standard evaluation system developed by the International Rice Research Institute (IRRI. At the same year the RI lines were analyzed with 134 DNA markers. Results of the study showed that one major QTL was found to be associated with blast resistance, and this QTL was located near RM2136 marker on the long arm of chromosome 11. This QTL explained 87% of the phenotypic variation with 37% additive effect. The map position of this QTL differed from that of a partial resistant gene, Pi34, identified previously on chromosome 11 in the Japanese durably resistant variety, Chubu 32. The QTL, however, was almost at the same position as that of the multiple allele-resistant gene, Pik. Therefore, an allelic test should be conducted to clarify the allelic relationship between QTL identified in this study and the Pik. The RI lines are the permanent segregating population that could be very useful for analysing phenotypic variations of important agronomic traits possibly owned by the RI lines. The major QTL identified in this study could be used as a genetic resource in

  3. Transcription factor ICBP90 regulates the MIF promoter and immune susceptibility locus.

    Science.gov (United States)

    Yao, Jie; Leng, Lin; Sauler, Maor; Fu, Weiling; Zheng, Junsong; Zhang, Yi; Du, Xin; Yu, Xiaoqing; Lee, Patty; Bucala, Richard

    2016-02-01

    The immunoregulatory cytokine macrophage migration inhibitory factor (MIF) is encoded in a functionally polymorphic locus that is linked to the susceptibility of autoimmune and infectious diseases. The MIF promoter contains a 4-nucleotide microsatellite polymorphism (-794 CATT) that repeats 5 to 8 times in the locus, with greater numbers of repeats associated with higher mRNA levels. Because there is no information about the transcriptional regulation of these common alleles, we used oligonucleotide affinity chromatography and liquid chromatography-mass spectrometry to identify nuclear proteins that interact with the -794 CATT5-8 site. An analysis of monocyte nuclear lysates revealed that the transcription factor ICBP90 (also known as UHRF1) is the major protein interacting with the MIF microsatellite. We found that ICBP90 is essential for MIF transcription from monocytes/macrophages, B and T lymphocytes, and synovial fibroblasts, and TLR-induced MIF transcription is regulated in an ICBP90- and -794 CATT5-8 length-dependent manner. Whole-genome transcription analysis of ICBP90 shRNA-treated rheumatoid synoviocytes uncovered a subset of proinflammatory and immune response genes that overlapped with those regulated by MIF shRNA. In addition, the expression levels of ICBP90 and MIF were correlated in joint synovia from patients with rheumatoid arthritis. These findings identify ICBP90 as a key regulator of MIF transcription and provide functional insight into the regulation of the polymorphic MIF locus.

  4. A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females.

    Science.gov (United States)

    Sharma, Swarkar; Londono, Douglas; Eckalbar, Walter L; Gao, Xiaochong; Zhang, Dongping; Mauldin, Kristen; Kou, Ikuyo; Takahashi, Atsushi; Matsumoto, Morio; Kamiya, Nobuhiro; Murphy, Karl K; Cornelia, Reuel; Herring, John A; Burns, Dennis; Ahituv, Nadav; Ikegawa, Shiro; Gordon, Derek; Wise, Carol A

    2015-03-18

    Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.89 × 10(-9)) but not males (P=0.71). This association with IS is also found in independent female cohorts from the United States of America and Japan (overall P=2.15 × 10(-10), OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition. The 174-kb associated locus is distal to PAX1, which encodes paired box 1, a transcription factor involved in spine development. We identify a sequence in the associated locus with enhancer activity in zebrafish somitic muscle and spinal cord, an activity that is abolished by IS-associated SNPs. We thus identify a sexually dimorphic IS susceptibility locus, and propose the first functionally defined candidate mutations in an enhancer that may regulate expression in specific spinal cells.

  5. Multi-ethnic genome-wide association study identifies novel locus for type 2 diabetes susceptibility

    Science.gov (United States)

    Cook, James P; Morris, Andrew P

    2016-01-01

    Genome-wide association studies (GWAS) have traditionally been undertaken in homogeneous populations from the same ancestry group. However, with the increasing availability of GWAS in large-scale multi-ethnic cohorts, we have evaluated a framework for detecting association of genetic variants with complex traits, allowing for population structure, and developed a powerful test of heterogeneity in allelic effects between ancestry groups. We have applied the methodology to identify and characterise loci associated with susceptibility to type 2 diabetes (T2D) using GWAS data from the Resource for Genetic Epidemiology on Adult Health and Aging, a large multi-ethnic population-based cohort, created for investigating the genetic and environmental basis of age-related diseases. We identified a novel locus for T2D susceptibility at genome-wide significance (P<5 × 10−8) that maps to TOMM40-APOE, a region previously implicated in lipid metabolism and Alzheimer's disease. We have also confirmed previous reports that single-nucleotide polymorphisms at the TCF7L2 locus demonstrate the greatest extent of heterogeneity in allelic effects between ethnic groups, with the lowest risk observed in populations of East Asian ancestry. PMID:27189021

  6. Sequence divergence of Mus spretus and Mus musculus across a skin cancer susceptibility locus

    Directory of Open Access Journals (Sweden)

    Balmain Allan

    2008-12-01

    Full Text Available Abstract Background Mus spretus diverged from Mus musculus over one million years ago. These mice are genetically and phenotypically divergent. Despite the value of utilizing M. musculus and M. spretus for quantitative trait locus (QTL mapping, relatively little genomic information on M. spretus exists, and most of the available sequence and polymorphic data is for one strain of M. spretus, Spret/Ei. In previous work, we mapped fifteen loci for skin cancer susceptibility using four different M. spretus by M. musculus F1 backcrosses. One locus, skin tumor susceptibility 5 (Skts5 on chromosome 12, shows strong linkage in one cross. Results To identify potential candidate genes for Skts5, we sequenced 65 named and unnamed genes and coding elements mapping to the peak linkage area in outbred spretus, Spret/EiJ, FVB/NJ, and NIH/Ola. We identified polymorphisms in 62 of 65 genes including 122 amino acid substitutions. To look for polymorphisms consistent with the linkage data, we sequenced exons with amino acid polymorphisms in two additional M. spretus strains and one additional M. musculus strain generating 40.1 kb of sequence data. Eight candidate variants were identified that fit with the linkage data. To determine the degree of variation across M. spretus, we conducted phylogenetic analyses. The relatedness of the M. spretus strains at this locus is consistent with the proximity of region of ascertainment of the ancestral mice. Conclusion Our analyses suggest that, if Skts5 on chromosome 12 is representative of other regions in the genome, then published genomic data for Spret/EiJ are likely to be of high utility for genomic studies in other M. spretus strains.

  7. Loss of ATRX does not confer susceptibility to osteoarthritis.

    Directory of Open Access Journals (Sweden)

    Lauren A Solomon

    Full Text Available The chromatin remodelling protein ATRX is associated with the rare genetic disorder ATR-X syndrome. This syndrome includes developmental delay, cognitive impairment, and a variety of skeletal deformities. ATRX plays a role in several basic chromatin-mediated cellular events including DNA replication, telomere stability, gene transcription, and chromosome congression and cohesion during cell division. We have used a loss-of-function approach to directly investigate the role of Atrx in the adult skeleton in three different models of selective Atrx loss. We specifically targeted deletion of Atrx to the forelimb mesenchyme, to cartilage and to bone-forming osteoblasts. We previously demonstrated that loss of ATRX in forelimb mesenchyme causes brachydactyly while deletion in chondrocytes had minimal effects during development. We now show that targeted deletion of Atrx in osteoblasts causes minor dwarfism but does not recapitulate most of the skeletal phenotypes seen in ATR-X syndrome patients. In adult mice from all three models, we find that joints lacking Atrx are not more susceptible to osteoarthritis, as determined by OARSI scoring and immunohistochemistry. These results indicate that while ATRX plays limited roles during early stages of skeletal development, deficiency of the protein in adult tissues does not confer susceptibility to osteoarthritis.

  8. Loss of ATRX does not confer susceptibility to osteoarthritis.

    Science.gov (United States)

    Solomon, Lauren A; Russell, Bailey A; Makar, David; Bérubé, Nathalie G; Beier, Frank

    2013-01-01

    The chromatin remodelling protein ATRX is associated with the rare genetic disorder ATR-X syndrome. This syndrome includes developmental delay, cognitive impairment, and a variety of skeletal deformities. ATRX plays a role in several basic chromatin-mediated cellular events including DNA replication, telomere stability, gene transcription, and chromosome congression and cohesion during cell division. We have used a loss-of-function approach to directly investigate the role of Atrx in the adult skeleton in three different models of selective Atrx loss. We specifically targeted deletion of Atrx to the forelimb mesenchyme, to cartilage and to bone-forming osteoblasts. We previously demonstrated that loss of ATRX in forelimb mesenchyme causes brachydactyly while deletion in chondrocytes had minimal effects during development. We now show that targeted deletion of Atrx in osteoblasts causes minor dwarfism but does not recapitulate most of the skeletal phenotypes seen in ATR-X syndrome patients. In adult mice from all three models, we find that joints lacking Atrx are not more susceptible to osteoarthritis, as determined by OARSI scoring and immunohistochemistry. These results indicate that while ATRX plays limited roles during early stages of skeletal development, deficiency of the protein in adult tissues does not confer susceptibility to osteoarthritis.

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

    Directory of Open Access Journals (Sweden)

    Arne S Schaefer

    2009-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Arne S Schaefer

    2009-02-01

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

  11. Replication of GWAS Coding SNPs Implicates MMEL1 as a Potential Susceptibility Locus among Saudi Arabian Celiac Disease Patients

    Directory of Open Access Journals (Sweden)

    Omar I. Saadah

    2015-01-01

    Full Text Available Celiac disease (CD, a gluten intolerance disorder, was implicated to have 57 genetic susceptibility loci for Europeans but not for culturally and geographically distinct ethnic populations like Saudi Arabian CD patients. Therefore, we genotyped Saudi CD patients and healthy controls for three polymorphisms, that is, Phe196Ser in IRAK1, Trp262Arg in SH2B3, and Met518Thr in MMEL1 genes. Single locus analysis identified that carriers of the 518 Thr/Thr (MMEL1 genotype conferred a 1.6-fold increased disease risk compared to the noncarriers (OR = 2.6; 95% CI: 1.22–5.54; P<0.01. This significance persisted even under allelic (OR = 1.55; 95% CI: 1.05–2.28; P=0.02 and additive (OR = 0.35; 95% CI: 0.17–0.71; P=0.03 genetic models. However, frequencies for Trp262Arg (SH2B3 and Phe196Ser (IRAK1 polymorphisms were not significantly different between patients and controls. The overall best MDR model included Met518Thr and Trp262Arg polymorphisms, with a maximal testing accuracy of 64.1% and a maximal cross-validation consistency of 10 out of 10 (P=0.0156. Allelic distribution of the 518 Thr/Thr polymorphism in MMEL1 primarily suggests its independent and synergistic contribution towards CD susceptibility among Saudi patients. Lack of significant association of IRAK and SH2B3 gene polymorphisms in Saudi patients but their association in European groups suggests the genetic heterogeneity of CD.

  12. MAVS is not a Likely Susceptibility Locus for Addison's Disease and Type 1 Diabetes.

    Science.gov (United States)

    Zurawek, Magdalena; Fichna, Marta; Kazimierska, Marta; Fichna, Piotr; Dzikiewicz-Krawczyk, Agnieszka; Przybylski, Grzegorz; Ruchala, Marek; Nowak, Jerzy

    2017-06-01

    Mitochondrial antiviral signaling (MAVS) protein is an intracellular adaptor molecule, downstream of viral sensors, retinoid acid-inducible gene I (RIG-I)-like receptors (RLRs). Impaired antiviral cell signaling might contribute to autoimmunity. Studies have recently shown variations in genes encoding RLRs as risk factors for autoimmune diseases. We investigated whether MAVS coding polymorphisms are associated with Addison's disease (AD) and type 1 diabetes (T1D) in Polish population. We genotyped 140 AD, 532 T1D patients and 600 healthy controls for MAVS rs17857295, rs7262903, rs45437096 and rs7269320. Genotyping was performed by TaqMan assays. Distribution of the MAVS genotypes and alleles did not reveal significant differences between patients and controls (p > 0.05). This analysis did not indicate the association of the MAVS locus with susceptibility to AD and T1D.

  13. Evidence against an X-linked visual loss susceptibility locus in Leber hereditary optic neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Chalmers, R.M.; Davis, M.B.; Sweeney, M.G.; Wood, N.W.; Harding, A.E. [Inst. of Neurology, London (United Kingdom)

    1996-07-01

    Pedigree analysis of British families with Leber hereditary optic neuropathy (LHON) closely fits a model in which a pathogenic mtDNA mutation interacts with an X-linked visual loss susceptibility locus (VLSL). This model predicts that 60% of affected females will show marked skewing of X inactivation. Linkage analysis in British and Italian families with genetically proven LHON has excluded the presence of such a VLSL over 169 cM of the X chromosome both when all families were analyzed together and when only families with the bp 11778 mutation were studied. Further, there was no excess skewing of X inactivation in affected females. There was no evidence for close linkage to three markers in the pseudoautosomal region of the sex chromosomes. The mechanism of incomplete penetrance and male predominance in LHON remains unclear. 27 refs., 1 fig., 3 tabs.

  14. Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.

    Science.gov (United States)

    Horne, Hisani N; Chung, Charles C; Zhang, Han; Yu, Kai; Prokunina-Olsson, Ludmila; Michailidou, Kyriaki; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Hopper, John L; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A; Beckmann, Matthias W; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Iwata, Hiroji; Dörk, Thilo; Bogdanova, Natalia V; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Chenevix-Trench, Georgia; Wu, Anna H; Ven den Berg, David; Smeets, Ann; Zhao, Hui; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Barile, Monica; Couch, Fergus J; Vachon, Celine; Giles, Graham G; Milne, Roger L; Haiman, Christopher A; Marchand, Loic Le; Goldberg, Mark S; Teo, Soo H; Taib, Nur A M; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Shrubsole, Martha; Winqvist, Robert; Jukkola-Vuorinen, Arja; Andrulis, Irene L; Knight, Julia A; Devilee, Peter; Seynaeve, Caroline; García-Closas, Montserrat; Czene, Kamila; Darabi, Hatef; Hollestelle, Antoinette; Martens, John W M; Li, Jingmei; Lu, Wei; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S; Blot, William; Cai, Qiuyin; Shah, Mitul; Luccarini, Craig; Baynes, Caroline; Harrington, Patricia; Kang, Daehee; Choi, Ji-Yeob; Hartman, Mikael; Chia, Kee Seng; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; Brennan, Paul; Slager, Susan; Yannoukakos, Drakoulis; Shen, Chen-Yang; Hou, Ming-Feng; Swerdlow, Anthony; Orr, Nick; Simard, Jacques; Hall, Per; Pharoah, Paul D P; Easton, Douglas F; Chanock, Stephen J; Dunning, Alison M; Figueroa, Jonine D

    2016-01-01

    The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.

  15. Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus

    Science.gov (United States)

    Horne, Hisani N.; Chung, Charles C.; Zhang, Han; Yu, Kai; Prokunina-Olsson, Ludmila; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Hopper, John L.; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A.; Beckmann, Matthias W.; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E.; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Iwata, Hiroji; Dörk, Thilo; Bogdanova, Natalia V.; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Chenevix-Trench, Georgia; Wu, Anna H.; ven den Berg, David; Smeets, Ann; Zhao, Hui; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Barile, Monica; Couch, Fergus J.; Vachon, Celine; Giles, Graham G.; Milne, Roger L.; Haiman, Christopher A.; Marchand, Loic Le; Goldberg, Mark S.; Teo, Soo H.; Taib, Nur A. M.; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Shrubsole, Martha; Winqvist, Robert; Jukkola-Vuorinen, Arja; Andrulis, Irene L.; Knight, Julia A.; Devilee, Peter; Seynaeve, Caroline; García-Closas, Montserrat; Czene, Kamila; Darabi, Hatef; Hollestelle, Antoinette; Martens, John W. M.; Li, Jingmei; Lu, Wei; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S.; Blot, William; Cai, Qiuyin; Shah, Mitul; Luccarini, Craig; Baynes, Caroline; Harrington, Patricia; Kang, Daehee; Choi, Ji-Yeob; Hartman, Mikael; Chia, Kee Seng; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; Brennan, Paul; Slager, Susan; Yannoukakos, Drakoulis; Shen, Chen-Yang; Hou, Ming-Feng; Swerdlow, Anthony; Orr, Nick; Simard, Jacques; Hall, Per; Pharoah, Paul D. P.

    2016-01-01

    The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799–121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000–120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08–1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive. PMID:27556229

  16. Tandem amplification of a chromosomal segment harboring 5-enolpyruvylshikimate-3-phosphate synthase locus confers glyphosate resistance in Kochia scoparia.

    Science.gov (United States)

    Jugulam, Mithila; Niehues, Kindsey; Godar, Amar S; Koo, Dal-Hoe; Danilova, Tatiana; Friebe, Bernd; Sehgal, Sunish; Varanasi, Vijay K; Wiersma, Andrew; Westra, Philip; Stahlman, Phillip W; Gill, Bikram S

    2014-11-01

    Recent rapid evolution and spread of resistance to the most extensively used herbicide, glyphosate, is a major threat to global crop production. Genetic mechanisms by which weeds evolve resistance to herbicides largely determine the level of resistance and the rate of evolution of resistance. In a previous study, we determined that glyphosate resistance in Kochia scoparia is due to the amplification of the 5-Enolpyruvylshikimate-3-Phosphate Synthase (EPSPS) gene, the enzyme target of glyphosate. Here, we investigated the genomic organization of the amplified EPSPS copies using fluorescence in situ hybridization (FISH) and extended DNA fiber (Fiber FISH) on K. scoparia chromosomes. In both glyphosate-resistant K. scoparia populations tested (GR1 and GR2), FISH results displayed a single and prominent hybridization site of the EPSPS gene localized on the distal end of one pair of homologous metaphase chromosomes compared with a faint hybridization site in glyphosate-susceptible samples (GS1 and GS2). Fiber FISH displayed 10 copies of the EPSPS gene (approximately 5 kb) arranged in tandem configuration approximately 40 to 70 kb apart, with one copy in an inverted orientation in GR2. In agreement with FISH results, segregation of EPSPS copies followed single-locus inheritance in GR1 population. This is the first report of tandem target gene amplification conferring field-evolved herbicide resistance in weed populations.

  17. Identification of a novel susceptibility locus for juvenile idiopathic arthritis by genome-wide association analysis

    Science.gov (United States)

    Hinks, Anne; Barton, Anne; Shephard, Neil; Eyre, Steve; Bowes, John; Cargill, Michele; Wang, Eric; Ke, Xiayi; Kennedy, Giulia C; John, Sally; Worthington, Jane; Thomson, Wendy

    2009-01-01

    Objective Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease of childhood. Two well-established genetic factors known to contribute to JIA susceptibility, HLA and PTPN22, account for less than half of the genetic susceptibility to disease; therefore, additional genetic factors have yet to be identified. The purpose of this study was to perform a systematic search of the genome to identify novel susceptibility loci for JIA. Methods A genome-wide association study using Affymetrix GeneChip 100K arrays was performed in a discovery cohort (279 cases and 184 controls). Single-nucleotide polymorphisms (SNPs) showing the most significant differences between cases and controls were then genotyped in a validation sample of cases (n = 321) and controls, combined with control data from the 1958 UK birth cohort (n = 2,024). In one region in which association was confirmed, fine-mapping was performed (654 cases and 1,847 controls). Results Of the 112 SNPs that were significantly associated with JIA in the discovery cohort, 6 SNPs were associated with JIA in the independent validation cohort. The most strongly associated SNP mapped to the HLA region, while the second strongest association was with a SNP within the VTCN1 gene. Fine-mapping of that gene was performed, and 10 SNPs were found to be associated with JIA. Conclusion This study is the first to successfully apply a SNP-based genome-wide association approach to the investigation of JIA. The replicated association with markers in the VTCN1 gene defined an additional susceptibility locus for JIA and implicates a novel pathway in the pathogenesis of this chronic disease of childhood. PMID:19116933

  18. Four SNPs on chromosome 9p21 in a South Korean population implicate a genetic locus that confers high cross-race risk for development of coronary artery disease.

    Science.gov (United States)

    Shen, Gong-Qing; Li, Lin; Rao, Shaoqi; Abdullah, Kalil G; Ban, Ji Min; Lee, Bok-Soo; Park, Jeong Euy; Wang, Qing K

    2008-02-01

    Recent genome-wide association studies have identified 4 SNPs on chromosome 9p21 associated with CAD (rs10757274 and rs2383206) and myocardial infarction (MI: rs2383207 and rs10757278) in White populations in Northern Europe and North America. We aimed to determine whether this locus confers significant susceptibility to CAD in a South Korean population, and thus cross-race susceptibility to CAD. We performed a case-control association study with 611 unrelated CAD patients and 294 normal controls from South Korea. Allelic associations of SNPs and SNP haplotypes with CAD were evaluated. Multivariate logistic regression analysis was used to adjust effects of clinical covariates. We found that 4 SNPs on chromosome 9p21 were associated with susceptibility to CAD in a South Korean population. The association remained significant after adjusting for significant clinical covariates (P=0.001 to 0.024). We identified one risk haplotype (GGGG; P=0.017) and one protective haplotype (AAAA; P=0.007) for development of CAD. Further analysis suggested that the SNPs probably confer susceptibility to CAD in a dominance model (covariates-adjusted P=0.001 to 0.024; OR=2.37 to 1.54). This represents the first study that expands association of these 9p21 SNPs with CAD beyond White populations. Chromosome 9p21 is an important susceptibility locus that confers high cross-race risk for development of CAD.

  19. Mapping of a further malignant hyperthermia susceptibility locus to chromosome 3q13.1

    Energy Technology Data Exchange (ETDEWEB)

    Sudbrak, R.; Deufel, T. [Universitaet Muenster (Germany); Procaccio, V.; Lunardi, J.; Klausnitzer, M.; Mueller, C.R.; Hartung, E.J.; Curran, J.L.; Stewart, A.D. [and others

    1995-03-01

    Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic disease for which MH susceptibility (MHS) is transmitted as an autosomal dominant trait. A potentially life-threatening MH crisis is triggered by exposure to commonly used inhalational anesthetics and depolarizing muscle relaxants. The first malignant hyperthermia susceptibility locus (MHS1) was identified on human chromosome 19{sub q}13.1, and evidence has been obtained that defects in the gene for the calcium-release channel of skeletal muscle sarcoplasmic reticulum (ryanodine receptor; RYR1) can cause some forms of MH. However, MH has been shown to be genetically heterogeneous, and additional loci on chromosomes 17q and 7q have been suggested. In a collaborative search of the human genome with polymorphic microsatellite markers, we now found linkage of the MHS phenotype, as assessed by the European in vitro contracture test protocol, to markers defining a 1-cM interval on chromosome 3q13.1. A maximum multipoint lod score of 3.22 was obtained in a single German pedigree with classical MH, and none of the other pedigrees investigated in this study showed linkage to this region. Linkage to both MHS1/RYR1 and putative loci on chromosome 17q and 7q were excluded. This study supports the view that considerable genetic heterogeneity exists in MH. 47 refs., 2 figs., 3 tabs.

  20. Genome-wide association study of systemic sclerosis identifies CD247 as a novel susceptibility locus

    Science.gov (United States)

    Radstake, Timothy R.D.J.; Gorlova, Olga; Rueda, Blanca; Martin, Jose-Ezequiel; Alizadeh, Behrooz Z.; Palomino-Morales, Rogelio; Coenen, Marieke J.; Vonk, Madelon C.; Voskuyl, Alexandre E.; Scheurwegh, Annemie J.; Broen, Jasper C.; van Riel, Piet L.C.M.; van ‘t Slot, Ruben; Italiaander, Annet; Ophoff, Roel A.; Riemekasten, Gabriela; Hunzelmann, Nico; Simeon, Carmen P.; Ortego-Centeno, Norberto; González-Gay, Miguel A.; González-Escribano, María F.; Airo, Paolo; van Laar, Jaap; Herrick, Ariane; Worthington, Jane; Hesselstrand, Roger; Smith, Vanessa; de Keyser, Filip; Houssiau, Fredric; Chee, Meng May; Madhok, R; Shiels, Paul; Westhovens, Rene; Kreuter, Alexander; Kiener, Hans; de Baere, Elfride; Witte, Torsten; Padykov, Leonid; Klareskog, Lars; Beretta, Lorenzo; Scorza, Rafaella; Lie, Benedicte A.; Hoffman-Vold, Anna-Maria; Carreira, P; Varga, J.; Hinchcliff, M.; Gregersen, Peter; Lee, Annette T.; Ying, Jun; Han, Younghun; Weng, Shih-Feng; Amos, Christopher I.; Wigley, Fredrick M.; Hummers, Laura; Nelson, J. Lee; Agarwal, Sandeep K.; Assassi, Shervin; Gourh, Pravitt; Tan, Filemon K.; Koeleman, Bobby P.C.; Arnett, Frank C; Martin, Javier; Mayes, Maureen D.

    2010-01-01

    Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify novel SSc susceptibility loci we conducted the first genome wide association study (GWAS) in a population of Caucasian ancestry including a total of 2296 SSc patients and 5171 controls. Analysis of 279,621 autosomal single nucleotide polymorphisms (SNPs) followed by replication testing in an independent case-control set of European ancestry (2,753 SSc patients / 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23; rs2056626, P = 2.09 × 10−7 in the discovery samples, P = 3.39 × 10−9 in the combined analysis). Additionally, we confirm and firmly establish the role of MHC (2.31 × 10−18), IRF5 (P =1.86 × 10−13) and STAT4 (P =3.37 × 10−9) gene regions as SSc genetic risk factors. PMID:20383147

  1. Molecular genetic characterisation of the Asc locus of tomato conferring resistance to the fungal pathogen Alternaria alternata f. sp. lycopersici

    NARCIS (Netherlands)

    Biezen, E.A. van der; Overduin, B.; Kneppers, T.J.A.; Mesbah, L.A.; Nijkamp, H.J.J.; Hille, J.

    1994-01-01

    The Alternaria stem canker disease of tomato is caused by the fungal pathogen Alternaria alternata f. sp. lycopersici and its host-selective AAL-toxins. Resistance to the pathogen and insensitivity to the toxins are conferred by the Asc locus on chromosome 3L. Sensitivity to AAL-toxins is a relative

  2. Fine-mapping and phenotypic analysis of the Ity3 Salmonella susceptibility locus identify a complex genetic structure.

    Directory of Open Access Journals (Sweden)

    Rabia T Khan

    Full Text Available Experimental animal models of Salmonella infections have been widely used to identify genes important in the host immune response to infection. Using an F2 cross between the classical inbred strain C57BL/6J and the wild derived strain MOLF/Ei, we have previously identified Ity3 (Immunity to Typhimurium locus 3 as a locus contributing to the early susceptibility of MOLF/Ei mice to infection with Salmonella Typhimurium. We have also established a congenic strain (B6.MOLF-Ity/Ity3 with the MOLF/Ei Ity3 donor segment on a C57BL/6J background. The current study was designed to fine map and characterize functionally the Ity3 locus. We generated 12 recombinant sub-congenic strains that were characterized for susceptibility to infection, bacterial load in target organs, cytokine profile and anti-microbial mechanisms. These analyses showed that the impact of the Ity3 locus on survival and bacterial burden was stronger in male mice compared to female mice. Fine mapping of Ity3 indicated that two subloci contribute collectively to the susceptibility of B6.MOLF-Ity/Ity3 congenic mice to Salmonella infection. The Ity3.1 sublocus controls NADPH oxidase activity and is characterized by decreased ROS production, reduced inflammatory cytokine response and increased bacterial burden, thereby supporting a role for Ncf2 (neutrophil cytosolic factor 2 a subunit of NADPH oxidase as the gene underlying this sublocus. The Ity3.2 sub-locus is characterized by a hyperresponsive inflammatory cytokine phenotype after exposure to Salmonella. Overall, this research provides support to the combined action of hormonal influences and complex genetic factors within the Ity3 locus in the innate immune response to Salmonella infection in wild-derived MOLF/Ei mice.

  3. Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.

    Directory of Open Access Journals (Sweden)

    Simon N Stacey

    2010-07-01

    Full Text Available We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1 genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case:control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively. Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2 x 10(-3, African (OR = 1.35, P = 0.014, and Asian (OR = 1.23, P = 2.9 x 10(-4 population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9 x 10(-7, was without significant heterogeneity between ancestries (P(het = 0.36 and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268, which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.

  4. of the Locus Coeruleus Indicate Differing Susceptibility to Free Radical Content

    Directory of Open Access Journals (Sweden)

    Ramatis B. de Oliveira

    2012-01-01

    Full Text Available The present study investigated the effects of the antioxidants trolox and dithiothreitol (DTT on mouse Locus coeruleus (LC neurons. Electrophysiological measurement of action potential discharge and whole cell current responses in the presence of each antioxidant suggested that there are three neuronal subpopulations within the LC. In current clamp experiments, most neurons (55%; 6/11 did not respond to the antioxidants. The remaining neurons exhibited either hyperpolarization and decreased firing rate (27%; 3/11 or depolarization and increased firing rate (18%; 2/11. Calcium and JC-1 imaging demonstrated that these effects did not change intracellular Ca2+ concentration but may influence mitochondrial function as both antioxidant treatments modulated mitochondrial membrane potential. These suggest that the antioxidant-sensitive subpopulations of LC neurons may be more susceptible to oxidative stress (e.g., due to ATP depletion and/or overactivation of Ca2+-dependent pathways. Indeed it may be that this subpopulation of LC neurons is preferentially destroyed in neurological pathologies such as Parkinson’s disease. If this is the case, there may be a protective role for antioxidant therapies.

  5. Association of Five SNPs at the PARK16 locus as a Susceptibility Locus with Parkinson's Disease for Forensic Application

    Institute of Scientific and Technical Information of China (English)

    CUI Hong-gang; TIAN Xiao-fei; LUO Xiao-guang; LI Feng-rui; ZHU Lan-hui; ZHOU Yi-shu; REN Yan

    2013-01-01

    To investigate the association of five SNPs (rs823083,rs708723,rs4951261,rs823076 and rs16856110) at the PARK16 locus with Parkinson's disease (PD),and to potentiate its forensic application.The genomic DNAs of 215 PD patients and 212 matched controls from the northern Han Chinese population were amplified in two independent PCR systems and subsequently genotyped by digestion with the three endonucleases (Hinf Ⅰ,Nco Ⅰ and Msp Ⅰ).The genetic parameters and association studies were carried out with SPSS 13.0,Haploview version 4.2 and PLINK 1.07 sofiwares.We detected accurately all genotypes in the five SNPs with multiplex PCR-RFLP and mismatched multiplex PCR-RFLP techniques.The genotypes of four SNPs,except for rs823083,were in Hardy-Weinberg equilibrium.The four SNPs,rs16856110,rs4951261,rs708723 and rs823076,which were in linkage equilibrium,should not be associated with PD (P-values ranging from 0.077 to 0.544).The SNPs investigated at the PARK16 locus were not found to be involved in PD-associated blocks in the northern Han Chinese population.The allele distributions of rs708723,rs4951261,rs823076 and rs16856110 in the northern Han Chinese population can be highly polymorphic,which can be applied to genetic analvsis and forensic practices.

  6. Development of a sequence characteristic amplified region marker linked to the L4 locus conferring broad spectrum resistance to tobamoviruses in pepper plants.

    Science.gov (United States)

    Kim, Hyun Jung; Han, Jung-Heon; Yoo, Jae Hyoung; Cho, Hwa Jin; Kim, Byung-Dong

    2008-04-30

    To develop molecular markers linked to the L4 locus conferring resistance to tobamovirus pathotypes in pepper plants, we performed AFLP with 512 primer combinations for susceptible (S pool) and resistant (R pool) DNA bulks against pathotype 1.2 of pepper mild mottle virus. Each bulk was made by pooling the DNA of five homozygous individuals from a T10 population, which was a near-isogenic BC4F2 generation for the L4 locus. A total of 19 primer pairs produced scorable bands in the R pool. Further screening with these primer pairs was done on DNA bulks from T102, a BC10F2 derived from T10 by back crossing. Three AFLP markers were finally selected and designated L4-a, L4-b and L4-c. L4-a and L4-c each underwent one recombination event, whereas no recombination for L4-b was seen in 20 individuals of each DNA bulk. Linkage analysis of these markers in 112 F2 T102 individuals showed that they were each within 2.5 cM of the L4 locus. L4-b was successfully converted into a simple 340-bp SCAR marker, designated L4SC340, which mapped 1.8 cM from the L4 locus in T102 and 0.9 cM in another BC10F2 population, T101. We believe that this newly characterized marker will improve selection of tobamovirus resistance in pepper plants by reducing breeding cost and time.

  7. Mutations in the Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL Confer Multidrug Resistance

    Directory of Open Access Journals (Sweden)

    Gregory LaMonte

    2016-07-01

    Full Text Available Mutations in the Plasmodium falciparum cyclic amine resistance locus (PfCARL are associated with parasite resistance to the imidazolopiperazines, a potent class of novel antimalarial compounds that display both prophylactic and transmission-blocking activity, in addition to activity against blood-stage parasites. Here, we show that pfcarl encodes a protein, with a predicted molecular weight of 153 kDa, that localizes to the cis-Golgi apparatus of the parasite in both asexual and sexual blood stages. Utilizing clustered regularly interspaced short palindromic repeat (CRISPR-mediated gene introduction of 5 variants (L830V, S1076N/I, V1103L, and I1139K, we demonstrate that mutations in pfcarl are sufficient to generate resistance against the imidazolopiperazines in both asexual and sexual blood-stage parasites. We further determined that the mutant PfCARL protein confers resistance to several structurally unrelated compounds. These data suggest that PfCARL modulates the levels of small-molecule inhibitors that affect Golgi-related processes, such as protein sorting or membrane trafficking, and is therefore an important mechanism of resistance in malaria parasites.

  8. A discrete genetic locus confers xyloglucan metabolism in select human gut Bacteroidetes.

    Science.gov (United States)

    Larsbrink, Johan; Rogers, Theresa E; Hemsworth, Glyn R; McKee, Lauren S; Tauzin, Alexandra S; Spadiut, Oliver; Klinter, Stefan; Pudlo, Nicholas A; Urs, Karthik; Koropatkin, Nicole M; Creagh, A Louise; Haynes, Charles A; Kelly, Amelia G; Cederholm, Stefan Nilsson; Davies, Gideon J; Martens, Eric C; Brumer, Harry

    2014-02-27

    A well-balanced human diet includes a significant intake of non-starch polysaccharides, collectively termed 'dietary fibre', from the cell walls of diverse fruits and vegetables. Owing to the paucity of alimentary enzymes encoded by the human genome, our ability to derive energy from dietary fibre depends on the saccharification and fermentation of complex carbohydrates by the massive microbial community residing in our distal gut. The xyloglucans (XyGs) are a ubiquitous family of highly branched plant cell wall polysaccharides whose mechanism(s) of degradation in the human gut and consequent importance in nutrition have been unclear. Here we demonstrate that a single, complex gene locus in Bacteroides ovatus confers XyG catabolism in this common colonic symbiont. Through targeted gene disruption, biochemical analysis of all predicted glycoside hydrolases and carbohydrate-binding proteins, and three-dimensional structural determination of the vanguard endo-xyloglucanase, we reveal the molecular mechanisms through which XyGs are hydrolysed to component monosaccharides for further metabolism. We also observe that orthologous XyG utilization loci (XyGULs) serve as genetic markers of XyG catabolism in Bacteroidetes, that XyGULs are restricted to a limited number of phylogenetically diverse strains, and that XyGULs are ubiquitous in surveyed human metagenomes. Our findings reveal that the metabolism of even highly abundant components of dietary fibre may be mediated by niche species, which has immediate fundamental and practical implications for gut symbiont population ecology in the context of human diet, nutrition and health.

  9. Analysis of positional candidate genes in the AAA1 susceptibility locus for abdominal aortic aneurysms on chromosome 19

    Directory of Open Access Journals (Sweden)

    Ferrell Robert E

    2011-01-01

    Full Text Available Abstract Background Abdominal aortic aneurysm (AAA is a complex disorder with multiple genetic risk factors. Using affected relative pair linkage analysis, we previously identified an AAA susceptibility locus on chromosome 19q13. This locus has been designated as the AAA1 susceptibility locus in the Online Mendelian Inheritance in Man (OMIM database. Methods Nine candidate genes were selected from the AAA1 locus based on their function, as well as mRNA expression levels in the aorta. A sample of 394 cases and 419 controls was genotyped for 41 SNPs located in or around the selected nine candidate genes using the Illumina GoldenGate platform. Single marker and haplotype analyses were performed. Three genes (CEBPG, PEPD and CD22 were selected for DNA sequencing based on the association study results, and exonic regions were analyzed. Immunohistochemical staining of aortic tissue sections from AAA and control individuals was carried out for the CD22 and PEPD proteins with specific antibodies. Results Several SNPs were nominally associated with AAA (p CEBPG, peptidase D (PEPD, and CD22. Haplotype analysis found a nominally associated 5-SNP haplotype in the CEBPG/PEPD locus, as well as a nominally associated 2-SNP haplotype in the CD22 locus. DNA sequencing of the coding regions revealed no variation in CEBPG. Seven sequence variants were identified in PEPD, including three not present in the NCBI SNP (dbSNP database. Sequencing of all 14 exons of CD22 identified 20 sequence variants, five of which were in the coding region and six were in the 3'-untranslated region. Five variants were not present in dbSNP. Immunohistochemical staining for CD22 revealed protein expression in lymphocytes present in the aneurysmal aortic wall only and no detectable expression in control aorta. PEPD protein was expressed in fibroblasts and myofibroblasts in the media-adventitia border in both aneurysmal and non-aneurysmal tissue samples. Conclusions Association testing

  10. A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults

    Directory of Open Access Journals (Sweden)

    Granger Donald L

    2010-10-01

    Full Text Available Abstract Background Severe malaria (SM syndromes caused by Plasmodium falciparum infection result in major morbidity and mortality each year. However, only a fraction of P. falciparum infections develop into SM, implicating host genetic factors as important determinants of disease outcome. Previous studies indicate that tumour necrosis factor (TNF and lymphotoxin alpha (LTα may be important for the development of cerebral malaria (CM and other SM syndromes. Methods An extensive analysis was conducted of single nucleotide polymorphisms (SNPs in the TNF, LTA and LTB genes in highland Papuan children and adults, a population historically unexposed to malaria that has migrated to a malaria endemic region. Generated P-values for SNPs spanning the LTA/TNF/LTB locus were corrected for multiple testing of all the SNPs and haplotype blocks within the region tested through 10,000 permutations. A global P-value of Results No associations between SNPs in the TNF/LTA/LTB locus and susceptibility to SM in highland Papuan children and adults were found. Conclusions These results support the notion that unique selective pressure on the TNF/LTA/LTB locus in different populations has influenced the contribution of the gene products from this region to SM susceptibility.

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Identification of the tyrosine-protein phosphatase non-receptor type 2 as a rheumatoid arthritis susceptibility locus in europeans.

    Directory of Open Access Journals (Sweden)

    Joanna E Cobb

    Full Text Available OBJECTIVES: Genome-wide association studies have facilitated the identification of over 30 susceptibility loci for rheumatoid arthritis (RA. However, evidence for a number of potential susceptibility genes have not so far reached genome-wide significance in studies of Caucasian RA. METHODS: A cohort of 4286 RA patients from across Europe and 5642 population matched controls were genotyped for 25 SNPs, then combined in a meta-analysis with previously published data. RESULTS: Significant evidence of association was detected for nine SNPs within the European samples. When meta-analysed with previously published data, 21 SNPs were associated with RA susceptibility. Although SNPs in the PTPN2 gene were previously reported to be associated with RA in both Japanese and European populations, we show genome-wide evidence for a different SNP within this gene associated with RA susceptibility in an independent European population (rs7234029, P = 4.4×10(-9. CONCLUSIONS: This study provides further genome-wide evidence for the association of the PTPN2 locus (encoding the T cell protein tyrosine phosphastase with Caucasian RA susceptibility. This finding adds to the growing evidence for PTPN2 being a pan-autoimmune susceptibility gene.

  13. Identification of the Tyrosine-Protein Phosphatase Non-Receptor Type 2 as a Rheumatoid Arthritis Susceptibility Locus in Europeans

    Science.gov (United States)

    Cobb, Joanna E.; Plant, Darren; Flynn, Edward; Tadjeddine, Meriem; Dieudé, Philippe; Cornélis, François; Ärlestig, Lisbeth; Dahlqvist, Solbritt Rantapää; Goulielmos, George; Boumpas, Dimitrios T.; Sidiropoulos, Prodromos; Krintel, Sophine B.; Ørnbjerg, Lykke M.; Hetland, Merete L.; Klareskog, Lars; Haeupl, Thomas; Filer, Andrew; Buckley, Christopher D.; Raza, Karim; Witte, Torsten; Schmidt, Reinhold E.; FitzGerald, Oliver; Veale, Douglas; Eyre, Stephen; Worthington, Jane

    2013-01-01

    Objectives Genome-wide association studies have facilitated the identification of over 30 susceptibility loci for rheumatoid arthritis (RA). However, evidence for a number of potential susceptibility genes have not so far reached genome-wide significance in studies of Caucasian RA. Methods A cohort of 4286 RA patients from across Europe and 5642 population matched controls were genotyped for 25 SNPs, then combined in a meta-analysis with previously published data. Results Significant evidence of association was detected for nine SNPs within the European samples. When meta-analysed with previously published data, 21 SNPs were associated with RA susceptibility. Although SNPs in the PTPN2 gene were previously reported to be associated with RA in both Japanese and European populations, we show genome-wide evidence for a different SNP within this gene associated with RA susceptibility in an independent European population (rs7234029, P = 4.4×10−9). Conclusions This study provides further genome-wide evidence for the association of the PTPN2 locus (encoding the T cell protein tyrosine phosphastase) with Caucasian RA susceptibility. This finding adds to the growing evidence for PTPN2 being a pan-autoimmune susceptibility gene. PMID:23840476

  14. A copy number variant at the KITLG locus likely confers risk for canine squamous cell carcinoma of the digit.

    Science.gov (United States)

    Karyadi, Danielle M; Karlins, Eric; Decker, Brennan; vonHoldt, Bridgett M; Carpintero-Ramirez, Gretchen; Parker, Heidi G; Wayne, Robert K; Ostrander, Elaine A

    2013-03-01

    The domestic dog is a robust model for studying the genetics of complex disease susceptibility. The strategies used to develop and propagate modern breeds have resulted in an elevated risk for specific diseases in particular breeds. One example is that of Standard Poodles (STPOs), who have increased risk for squamous cell carcinoma of the digit (SCCD), a locally aggressive cancer that causes lytic bone lesions, sometimes with multiple toe recurrence. However, only STPOs of dark coat color are at high risk; light colored STPOs are almost entirely unaffected, suggesting that interactions between multiple pathways are necessary for oncogenesis. We performed a genome-wide association study (GWAS) on STPOs, comparing 31 SCCD cases to 34 unrelated black STPO controls. The peak SNP on canine chromosome 15 was statistically significant at the genome-wide level (P(raw) = 1.60 × 10(-7); P(genome) = 0.0066). Additional mapping resolved the region to the KIT Ligand (KITLG) locus. Comparison of STPO cases to other at-risk breeds narrowed the locus to a 144.9-Kb region. Haplotype mapping among 84 STPO cases identified a minimal region of 28.3 Kb. A copy number variant (CNV) containing predicted enhancer elements was found to be strongly associated with SCCD in STPOs (P = 1.72 × 10(-8)). Light colored STPOs carry the CNV risk alleles at the same frequency as black STPOs, but are not susceptible to SCCD. A GWAS comparing 24 black and 24 light colored STPOs highlighted only the MC1R locus as significantly different between the two datasets, suggesting that a compensatory mutation within the MC1R locus likely protects light colored STPOs from disease. Our findings highlight a role for KITLG in SCCD susceptibility, as well as demonstrate that interactions between the KITLG and MC1R loci are potentially required for SCCD oncogenesis. These findings highlight how studies of breed-limited diseases are useful for disentangling multigene disorders.

  15. Common variants of the PINK1 and PARL genes do not confer genetic susceptibility to schizophrenia in Han Chinese.

    Science.gov (United States)

    Li, Xiao; Zhang, Wen; Zhang, Chen; Yi, Zhenghui; Zhang, Deng-Feng; Gong, Wei; Tang, Jinsong; Wang, Dong; Lu, Weihong; Chen, Xiaogang; Fang, Yiru; Yao, Yong-Gang

    2015-04-01

    Schizophrenia is a prevalent psychiatric disorder with a complex etiology. Mitochondrial dysfunction has been frequently reported in schizophrenia. Phosphatase and tension homologue-induced kinase 1 (PINK1) and presenilin-associated rhomboid-like protease (PARL) are mitochondrial proteins, and genetic variants of these two genes may confer genetic susceptibility to schizophrenia by influencing mitochondrial function. In this study, we conducted a two-stage genetic association study to test this hypothesis. We genotyped 4 PINK1 and 5 PARL genetic variants and evaluated the potential association of the 9 SNPs with schizophrenia in two independent case-control cohorts of 2510 Han Chinese individuals. No positive association of common genetic variants of the PINK1 and PARL genes with schizophrenia was identified in our samples after Bonferroni correction. Re-analysis of the newly updated Psychiatric Genetics Consortium (PGC) data sets confirmed our negative result. Intriguingly, one PINK1 SNP (rs10916832), which showed a marginally significant association in only Hunan samples (P = 0.032), is associated with the expression of a schizophrenia susceptible gene KIF17 according to the expression quantitative trait locus (eQTL) analysis. Our study indicated that common genetic variants of the PINK1 and PARL genes are unlikely to be involved in schizophrenia. Further studies are essential to characterize the role of the PINK1 and PARL genes in schizophrenia.

  16. Immunochip SNP array identifies novel genetic variants conferring susceptibility to candidaemia

    NARCIS (Netherlands)

    Kumar, Vinod; Cheng, Shih-Chin; Johnson, Melissa D.; Smeekens, Sanne P.; Wojtowicz, Agnieszka; Giamarellos-Bourboulis, Evangelos; Karjalainen, Juha; Franke, Lude; Withoff, Sebo; Plantinga, Theo S.; de Veerdonk, Frank L. van; van der Meer, Jos W. M.; Joosten, Leo A. B.; Sokol, Harry; Bauer, Hermann; Herrmann, Bernhard G.; Bochud, Pierre-Yves; Marchetti, Oscar; Perfect, John R.; Xavier, Ramnik J.; Kullberg, Bart Jan; Wijmenga, Cisca; Netea, Mihai G.

    2014-01-01

    Candidaemia is the fourth most common cause of bloodstream infection, with a high mortality rate of up to 40%. Identification of host genetic factors that confer susceptibility to candidaemia may aid in designing adjunctive immunotherapeutic strategies. Here we hypothesize that variation in immune g

  17. Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children

    DEFF Research Database (Denmark)

    Xu, Heng; Zhang, Hui; Yang, Wenjian;

    2015-01-01

    There is increasing evidence from genome-wide association studies for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children, yet the effects of protein-coding variants on ALL risk have not been systematically evaluated. Here we show a missense variant...... of haematopoietic progenitor cells, and is preferentially retained in ALL tumour cells. Resequencing the CDKN2A-CDKN2B locus in 2,407 childhood ALL cases reveals 19 additional putative functional germline variants. These results provide direct functional evidence for the influence of inherited genetic variation...

  18. Murine lupus susceptibility locus Sle1a requires the expression of two sub-loci to induce inflammatory T cells.

    Science.gov (United States)

    Cuda, C M; Zeumer, L; Sobel, E S; Croker, B P; Morel, L

    2010-10-01

    The NZM2410-derived Sle1a lupus susceptibility locus induces activated autoreactive CD4(+) T cells and reduces the number and function of Foxp3(+) regulatory T cells (Tregs). In this study, we first showed that Sle1a contributes to autoimmunity by increasing antinuclear antibody production when expressed on either NZB or NZW heterozygous genomes, and by enhancing the chronic graft versus host disease response indicating an expansion of the autoreactive B-cell pool. Screening two non-overlapping recombinants, the Sle1a.1 and Sle1a.2 intervals that cover the entire Sle1a locus, revealed that both Sle1a.1 and Sle1a.2 were necessary for the full Sle1a phenotype. Sle1a.1, and to a lesser extent Sle1a.2, significantly affected CD4(+) T-cell activation as well as Treg differentiation and function. Sle1a.2 also increased the production of autoreactive B cells. As the Sle1a.1 and Sle1a.2 intervals contain only 1 and 15 known genes, respectively, this study considerably reduces the number of candidate genes responsible for the production of autoreactive T cells. These results also show that the Sle1 locus is an excellent model for the genetic architecture of lupus, in which a major obligate phenotype results from the coexpression of multiple genetic variants with individual weak effects.

  19. Novel susceptibility locus at 22q11 for diabetic nephropathy in type 1 diabetes

    DEFF Research Database (Denmark)

    Wessman, Maija; Forsblom, Carol; Kaunisto, Mari A

    2011-01-01

    Diabetic nephropathy (DN) affects about 30% of patients with type 1 diabetes (T1D) and contributes to serious morbidity and mortality. So far only the 3q21-q25 region has repeatedly been indicated as a susceptibility region for DN. The aim of this study was to search for new DN susceptibility loci...

  20. Caspase 9 promoter polymorphisms confer increased susceptibility to breast cancer.

    Science.gov (United States)

    Theodoropoulos, George E; Michalopoulos, Nikolaos V; Pantou, Malena P; Kontogianni, Panagiota; Gazouli, Maria; Karantanos, Theodoros; Lymperi, Maria; Zografos, George C

    2012-10-01

    Caspases (CASPs), play a crucial role in the development and progression of cancer. We evaluated the association between two polymorphisms (rs4645978 and rs4645981) of the CASP9 gene and the risk of breast cancer (BC). Genotypes and allelic frequencies for the two polymorphisms were determined in 261 patients with breast cancer and 480 healthy controls. Polymerase chain reaction-restriction fragment length polymorphisms were used, and statistical significance was determined by the χ(2) test. Carriers of the rs4645978G allele (AG and GG genotypes) were at higher risk for BC than individuals with other genotypes (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.07-2.37, P = 0.022). The rs4645978GG genotype, in particular, was associated with the highest risk for BC development (OR 2.25, 95% CI 1.45-3.49, P = 0.0003). Similarly, individuals with at least one rs4645981T allele were at a significantly increased risk of developing BC compared with those harboring the CC genotype (OR 2.75, 95% CI 1.99-3.78, P < 0.0001), and the risk of BC increased with increasing numbers of rs4645981T alleles (OR 2.66, 95% CI 1.91-3.69, P < 0.0001 for the CT genotype; OR 3.95, 95% CI 1.58-9.88, P = 0.004 for the TT genotype). The CASP9 promoter polymorphisms rs4645978 and rs4645981 are associated with BC susceptibility and suggest that CASP9 transcriptional regulation is an important factor during BC development.

  1. NBS Proifling Identiifes Potential Novel Locus from Solanum demissum That Confers Broad-Spectrum Resistance to Phytophthora infestans

    Institute of Scientific and Technical Information of China (English)

    ZHANG Kun; XU Jian-fei; DUAN Shao-guang; PANG Wan-fu; BIAN Chun-song; LIU Jie; JIN Li-ping

    2014-01-01

    Potato late blight, caused by the oomycete pathogen Phytophthora infestans, is the most serious disease of potato worldwide. The adoption of varieties with resistance genes, especially broad-spectrum resistance genes, is the most efifcient approach to control late blight. Solanum demissum is a well-known wild potato species from which 11 race-speciifc resistance genes have been identiifed, however, no broad-spectrum resistance genes like RB have been reported in this species. Here, we report a novel reisistance locus from S. demissum that potentially confer broad-spectrum resistance to late blight. A small segregating population of S. demissum were assessed for resistance to aggressive P. infestans isolates (race 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11). This coupled with nucleotide binding site (NBS) proifling analyses, led to the identiifcation of three fragments that linked to the potential candidate resistance gene(s). Cloning and sequence analysis of these fragments suggested that the identiifed resistance gene locus is located in the region containing R2 resistance gene at chromosome 4. Based on the sequences of the cloned fragments, a co-segregating sequence characterized ampliifed region (SCAR) marker, RDSP, was developed. The newly identiifed marker RDSP will be useful for marker assisted breeding and further cloning of this potential resistance gene locus.

  2. Novel Rheumatoid Arthritis Susceptibility Locus at 22q12 Identified in an Extended UK Genome-Wide Association Study

    Science.gov (United States)

    Orozco, Gisela; Viatte, Sebastien; Bowes, John; Martin, Paul; Wilson, Anthony G; Morgan, Ann W; Steer, Sophia; Wordsworth, Paul; Hocking, Lynne J; Barton, Anne; Worthington, Jane; Eyre, Stephen

    2014-01-01

    Objective The number of confirmed rheumatoid arthritis (RA) loci currently stands at 32, but many lines of evidence indicate that expansion of existing genome-wide association studies (GWAS) enhances the power to detect additional loci. This study was undertaken to extend our previous RA GWAS in a UK cohort, adding more independent RA cases and healthy controls, with the aim of detecting novel association signals for susceptibility to RA in a homogeneous UK cohort. Methods A total of 3,223 UK RA cases and 5,272 UK controls were available for association analyses, with the extension adding 1,361 cases and 2,334 controls to the original GWAS data set. The genotype data for all RA cases were imputed using the Impute program version 2. After stringent quality control thresholds were applied, 3,034 cases and 5,271 controls (1,831,729 single-nucleotide polymorphisms [SNPs]) were available for analysis. Association testing was performed using Plink software. Results The analyses indicated a suggestive association with susceptibility to RA (P < 0.0001) for 6 novel RA loci that have been previously found to be associated with other autoimmune diseases; these 6 SNPs were genotyped in independent samples. Two of the associated loci were validated, one of which was associated with RA at genome-wide levels of significance in the combined analysis, identifying a novel RA locus at 22q12 (P = 6.9 × 10−9). In addition, most of the previously known RA susceptibility loci were confirmed to be associated with RA, and for 16 of the loci, the strength of the association was increased. Conclusion This study identified a new RA locus mapping to 22q12. These results support the notion that increasing the power of GWAS enhances novel gene discovery. PMID:24449572

  3. A copy number variant at the KITLG locus likely confers risk for canine squamous cell carcinoma of the digit.

    Directory of Open Access Journals (Sweden)

    Danielle M Karyadi

    2013-03-01

    Full Text Available The domestic dog is a robust model for studying the genetics of complex disease susceptibility. The strategies used to develop and propagate modern breeds have resulted in an elevated risk for specific diseases in particular breeds. One example is that of Standard Poodles (STPOs, who have increased risk for squamous cell carcinoma of the digit (SCCD, a locally aggressive cancer that causes lytic bone lesions, sometimes with multiple toe recurrence. However, only STPOs of dark coat color are at high risk; light colored STPOs are almost entirely unaffected, suggesting that interactions between multiple pathways are necessary for oncogenesis. We performed a genome-wide association study (GWAS on STPOs, comparing 31 SCCD cases to 34 unrelated black STPO controls. The peak SNP on canine chromosome 15 was statistically significant at the genome-wide level (P(raw = 1.60 × 10(-7; P(genome = 0.0066. Additional mapping resolved the region to the KIT Ligand (KITLG locus. Comparison of STPO cases to other at-risk breeds narrowed the locus to a 144.9-Kb region. Haplotype mapping among 84 STPO cases identified a minimal region of 28.3 Kb. A copy number variant (CNV containing predicted enhancer elements was found to be strongly associated with SCCD in STPOs (P = 1.72 × 10(-8. Light colored STPOs carry the CNV risk alleles at the same frequency as black STPOs, but are not susceptible to SCCD. A GWAS comparing 24 black and 24 light colored STPOs highlighted only the MC1R locus as significantly different between the two datasets, suggesting that a compensatory mutation within the MC1R locus likely protects light colored STPOs from disease. Our findings highlight a role for KITLG in SCCD susceptibility, as well as demonstrate that interactions between the KITLG and MC1R loci are potentially required for SCCD oncogenesis. These findings highlight how studies of breed-limited diseases are useful for disentangling multigene disorders.

  4. Allele variations in the OCA2 gene (pink-eyed-dilution locus) are associated with genetic susceptibility to melanoma.

    Science.gov (United States)

    Jannot, Anne-Sophie; Meziani, Roubila; Bertrand, Guylene; Gérard, Benedicte; Descamps, Vincent; Archimbaud, Alain; Picard, Catherine; Ollivaud, Laurence; Basset-Seguin, Nicole; Kerob, Delphine; Lanternier, Guy; Lebbe, Celeste; Saiag, P; Crickx, Beatrice; Clerget-Darpoux, Françoise; Grandchamp, Bernard; Soufir, Nadem; Melan-Cohort

    2005-08-01

    The occuloalbinism 2 (OCA2) gene, localized at 15q11, encodes a melanosomal transmembrane protein that is involved in the most common form of human occulo-cutaneous albinism, a human genetic disorder characterized by fair pigmentation and susceptibility to skin cancer. We wondered whether allele variations at this locus could influence susceptibility to malignant melanoma (MM). In all, 10 intragenic single-nucleotide polymorphisms (SNPs) were genotyped in 113 patients with melanomas and in 105 Caucasian control subjects with no personal or family history of skin cancer. By comparing allelic distribution between cases and controls, we show that MM and OCA2 are associated (p value=0.030 after correction for multiple testing). Then, a recently developed strategy, the 'combination test' enabled us to show that a combination formed by two SNPs was most strongly associated to MM, suggesting a possible interaction between intragenic SNPs. In addition, the role of OCA2 on MM risk was also detected using a logistic model taking into account the presence of variants of the melanocortin 1 receptor gene (MC1R, a key pigmentation gene) and all pigmentation characteristics as melanoma risk factors. Our data demonstrate that a second pigmentation gene, in addition to MC1R, is involved in genetic susceptibility to melanoma.

  5. Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21.

    Science.gov (United States)

    Tabassum, Rubina; Chauhan, Ganesh; Dwivedi, Om Prakash; Mahajan, Anubha; Jaiswal, Alok; Kaur, Ismeet; Bandesh, Khushdeep; Singh, Tejbir; Mathai, Benan John; Pandey, Yogesh; Chidambaram, Manickam; Sharma, Amitabh; Chavali, Sreenivas; Sengupta, Shantanu; Ramakrishnan, Lakshmi; Venkatesh, Pradeep; Aggarwal, Sanjay K; Ghosh, Saurabh; Prabhakaran, Dorairaj; Srinath, Reddy K; Saxena, Madhukar; Banerjee, Monisha; Mathur, Sandeep; Bhansali, Anil; Shah, Viral N; Madhu, Sri Venkata; Marwaha, Raman K; Basu, Analabha; Scaria, Vinod; McCarthy, Mark I; Venkatesan, Radha; Mohan, Viswanathan; Tandon, Nikhil; Bharadwaj, Dwaipayan

    2013-03-01

    Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10⁻⁹). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10⁻¹²) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D.

  6. 19p13.1 is a triple-negative-specific breast cancer susceptibility locus

    DEFF Research Database (Denmark)

    Stevens, Kristen N; Fredericksen, Zachary; Vachon, Celine M

    2012-01-01

    associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER......-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170...... and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 × 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence...

  7. The 12p13.33/RAD52 locus and genetic susceptibility to squamous cell cancers of upper aerodigestive tract.

    Directory of Open Access Journals (Sweden)

    Manon Delahaye-Sourdeix

    Full Text Available Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC. Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10(-4. We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10(-3 and LUSC (p = 9x10(-4 tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075 and LUSC (n = 464, q-value = 0.007 tumors and correlated with higher RAD52 tumor expression levels (p = 6x10(-48 and p = 3x10(-29 in UADT and LUSC, respectively. In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors.

  8. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus

    NARCIS (Netherlands)

    Radstake, Timothy R D J; Gorlova, Olga; Rueda, Blanca; Martin, Jose-Ezequiel; Alizadeh, Behrooz Z; Palomino-Morales, Rogelio; Coenen, Marieke J; Vonk, Madelon C; Voskuyl, Alexandre E; Schuerwegh, Annemie J; Broen, Jasper C; van Riel, Piet L C M; van 't Slot, Ruben; Italiaander, Annet; Ophoff, Roel A; Riemekasten, Gabriela; Hunzelmann, Nico; Simeon, Carmen P; Ortego-Centeno, Norberto; González-Gay, Miguel A; González-Escribano, María F; Airo, Paolo; van Laar, Jaap; Herrick, Ariane; Worthington, Jane; Hesselstrand, Roger; Smith, Vanessa; de Keyser, Filip; Houssiau, Fredric; Chee, Meng May; Madhok, Rajan; Shiels, Paul; Westhovens, Rene; Kreuter, Alexander; Kiener, Hans; de Baere, Elfride; Witte, Torsten; Padykov, Leonid; Klareskog, Lars; Beretta, Lorenzo; Scorza, Rafaella; Lie, Benedicte A; Hoffmann-Vold, Anna-Maria; Carreira, Patricia; Varga, John; Hinchcliff, Monique; Gregersen, Peter K; Lee, Annette T; Ying, Jun; Han, Younghun; Weng, Shih-Feng; Amos, Christopher I; Wigley, Fredrick M; Hummers, Laura; Nelson, J Lee; Agarwal, Sandeep K; Assassi, Shervin; Gourh, Pravitt; Tan, Filemon K; Koeleman, Bobby P C; Arnett, Frank C; Martin, Javier; Mayes, Maureen D

    2010-01-01

    Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry includ

  9. Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus.

    Science.gov (United States)

    Demirci, F Yesim; Wang, Xingbin; Morris, David L; Feingold, Eleanor; Bernatsky, Sasha; Pineau, Christian; Clarke, Ann; Ramsey-Goldman, Rosalind; Manzi, Susan; Vyse, Timothy J; Kamboh, M I

    2017-06-01

    A major systemic lupus erythematosus (SLE) susceptibility locus lies within a common inversion polymorphism region (encompassing 3.8 - 4.5  Mb) located at 8p23. Initially implicated genes included FAM167A-BLK and XKR6, of which BLK received major attention due to its known role in B-cell biology. Recently, additional SLE risk carried in non-inverted background was also reported. In this case -control study, we further investigated the 'extended' 8p23 locus (~ 4  Mb) where we observed multiple SLE signals and assessed these signals for their relation to the inversion affecting this region. The study involved a North American discovery data set (~ 1200  subjects) and a replication data set (> 10 000  subjects) comprising European-descent individuals. Meta-analysis of 8p23 SNPs, with p signals (XKR6-FAM167A-BLK subregion), our results also revealed two 'new' SLE signals, including SGK223-CLDN23-MFHAS1 (6.06 × 10(-9) ≤ meta p ≤ 4.88 × 10(-8)) and CTSB (meta p = 4.87 × 10(-8)) subregions that are located > 2 Mb upstream and ~ 0.3  Mb downstream from previously reported signals. Functional assessment of relevant SNPs indicated putative cis-effects on the expression of various genes at 8p23. Additional analyses in discovery sample, where the inversion genotypes were inferred, replicated the association of non-inverted status with SLE risk and suggested that a number of SLE risk alleles are predominantly carried in non-inverted background. Our results implicate multiple (known+novel) SLE signals/genes at the extended 8p23 locus, beyond previously reported signals/genes, and suggest that this broad locus contributes to SLE risk through the effects of multiple genes/pathways. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  10. A second gene at the tomato Cf-4 locus confers resistance to Cladosporium fulvum through recognition of a novel avirulence determinant

    NARCIS (Netherlands)

    Nijkamp, HJJ; Takken, Frank L.W.; Thomas, Colwyn M.; Joosten, Matthieu H.A.J.; Golstein, Catherine; Westerink, Nienke; Hille, Jacques; Nijkamp, H. John J.; Wit, Pierre J.G.M. de; Jones, Jonathan D.G.

    1999-01-01

    The tomato Cf-4 and Cf-9 genes confer resistance to the leaf mould pathogen Cladosporium fulvum and map at a complex locus on the short arm of chromosome 1. It was previously shown that the gene encoding Cf-4, which recognizes the Avr4 avirulence determinant, is one of five tandemly duplicated homol

  11. Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility

    DEFF Research Database (Denmark)

    Guigas, B; de Leeuw van Weenen, J E; van Leeuwen, N

    2014-01-01

    AIMS: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic β-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to Type 2 diabetes in humans. METHODS: Four potentially...

  12. 9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: Evidence from the Breast Cancer Association Consortium

    NARCIS (Netherlands)

    H. Warren (Helen); F. Dudbridge (Frank); O. Fletcher (Olivia); N. Orr (Nick); N. Johnson (Nichola); J.L. Hopper (John); C. Apicella (Carmel); M.C. Southey (Melissa); M. Mahmoodi (Maryam); M.K. Schmidt (Marjanka); A. Broeks (Annegien); S. Cornelissen (Sten); L.M. Braaf (Linde); K.R. Muir (Kenneth); A. Lophatananon (Artitaya); A. Chaiwerawattana (Arkom); S. Wiangnon (Surapon); P.A. Fasching (Peter); M.W. Beckmann (Matthias); A.B. Ekici (Arif); R. Schulz-Wendtland (Rüdiger); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); B. Burwinkel (Barbara); F. Marme (Federick); A. Schneeweiss (Andreas); C. Sohn (Christof); P. Guénel (Pascal); T. Truong (Thérèse); P. Laurent-Puig (Pierre); C. Mulot (Claire); S.E. Bojesen (Stig); S.F. Nielsen (Sune); H. Flyger (Henrik); B.G. Nordestgaard (Børge); R.L. Milne (Roger); J. Benítez (Javier); J.I. Arias Pérez (José Ignacio); M.P. Zamora (Pilar); H. Anton-Culver (Hoda); A. Ziogas (Argyrios); L. Bernstein (Leslie); C.C. Dur (Christina Clarke); H. Brenner (Hermann); H. Müller (Heike); V. Arndt (Volker); A. Langheinz (Anne); A. Meindl (Alfons); M. Golatta (Michael); C.R. Bartram (Claus); R.K. Schmutzler (Rita); H. Brauch (Hiltrud); C. Justenhoven (Christina); T. Brüning (Thomas); J. Chang-Claude (Jenny); S. Wang-Gohrke (Shan); U. Eilber (Ursula); T. Dörk (Thilo); P. Schürmann (Peter); M. Bremer (Michael); P. Hillemanns (Peter); H. Nevanlinna (Heli); T.A. Muranen (Taru); K. Aittomäki (Kristiina); C. Blomqvist (Carl); N.V. Bogdanova (Natalia); N.N. Antonenkova (Natalia); Y.I. Rogov (Yuri); M. Bermisheva (Marina); D. Prokofyeva (Darya); G. Zinnatullina (Guzel); E.K. Khusnutdinova (Elza); A. Lindblom (Annika); S. Margolin (Sara); A. Mannermaa (Arto); V-M. Kosma (Veli-Matti); J. Hartikainen (Jaana); V. Kataja (Vesa); G. Chenevix-Trench (Georgia); J. Beesley (Jonathan); X. Chen (Xiaoqing); D. Lambrechts (Diether); A. Smeets (Ann); R. Paridaens (Robert); C. Weltens (Caroline); D. Flesch-Janys (Dieter); K. Buck (Katharina); T.W. Behrens (Timothy); P. Peterlongo (Paolo); L. Bernard (Loris); S. Manoukian (Siranoush); P. Radice (Paolo); F.J. Couch (Fergus); C. Vachon (Celine); X. Wang (Xing); J.E. Olson (Janet); G.G. Giles (Graham); L. Baglietto (Laura); C.A. McLean (Cariona); G. Severi (Gianluca); E.M. John (Esther); A. Miron (Alexander); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); I.L. Andrulis (Irene); J.A. Knight (Julia); A.M. Mulligan (Anna Marie); N. Weerasooriya (Nayana); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); J.W.M. Martens (John); C.M. Seynaeve (Caroline); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); A. Jager (Agnes); M.M.A. Tilanus-Linthorst (Madeleine); P. Hall (Per); K. Czene (Kamila); J. Liu (Jianjun); J. Li (Jingmei); A. Cox (Angela); S.S. Cross (Simon); I.W. Brock (Ian); M.W.R. Reed (Malcolm); P.D.P. Pharoah (Paul); F. Blows (Fiona); A.M. Dunning (Alison); M. Ghoussaini (Maya); A. Ashworth (Alan); A.J. Swerdlow (Anthony ); M. Jones (Marta); M. Schoemaker (Minouk); D.F. Easton (Douglas); M.K. Humphreys (Manjeet); Q. Wang (Qing); J. Peto (Julian); I. dos Santos Silva (Isabel)

    2012-01-01

    textabstractBackground: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). Methods: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which

  13. 9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: Evidence from the Breast Cancer Association Consortium

    NARCIS (Netherlands)

    H. Warren (Helen); F. Dudbridge (Frank); O. Fletcher (Olivia); N. Orr (Nick); N. Johnson (Nichola); J.L. Hopper (John); C. Apicella (Carmel); M.C. Southey (Melissa); M. Mahmoodi (Maryam); M.K. Schmidt (Marjanka); A. Broeks (Annegien); S. Cornelissen (Sten); L.M. Braaf (Linde); K.R. Muir (Kenneth); A. Lophatananon (Artitaya); A. Chaiwerawattana (Arkom); S. Wiangnon (Surapon); P.A. Fasching (Peter); M.W. Beckmann (Matthias); A.B. Ekici (Arif); R. Schulz-Wendtland (Rüdiger); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); B. Burwinkel (Barbara); F. Marme (Federick); A. Schneeweiss (Andreas); C. Sohn (Christof); P. Guénel (Pascal); T. Truong (Thérèse); P. Laurent-Puig (Pierre); C. Mulot (Claire); S.E. Bojesen (Stig); S.F. Nielsen (Sune); H. Flyger (Henrik); B.G. Nordestgaard (Børge); R.L. Milne (Roger); J. Benítez (Javier); J.I. Arias Pérez (José Ignacio); M.P. Zamora (Pilar); H. Anton-Culver (Hoda); A. Ziogas (Argyrios); L. Bernstein (Leslie); C.C. Dur (Christina Clarke); H. Brenner (Hermann); H. Müller (Heike); V. Arndt (Volker); A. Langheinz (Anne); A. Meindl (Alfons); M. Golatta (Michael); C.R. Bartram (Claus); R.K. Schmutzler (Rita); H. Brauch (Hiltrud); C. Justenhoven (Christina); T. Brüning (Thomas); J. Chang-Claude (Jenny); S. Wang-Gohrke (Shan); U. Eilber (Ursula); T. Dörk (Thilo); P. Schürmann (Peter); M. Bremer (Michael); P. Hillemanns (Peter); H. Nevanlinna (Heli); T.A. Muranen (Taru); K. Aittomäki (Kristiina); C. Blomqvist (Carl); N.V. Bogdanova (Natalia); N.N. Antonenkova (Natalia); Y.I. Rogov (Yuri); M. Bermisheva (Marina); D. Prokofyeva (Darya); G. Zinnatullina (Guzel); E.K. Khusnutdinova (Elza); A. Lindblom (Annika); S. Margolin (Sara); A. Mannermaa (Arto); V-M. Kosma (Veli-Matti); J. Hartikainen (Jaana); V. Kataja (Vesa); G. Chenevix-Trench (Georgia); J. Beesley (Jonathan); X. Chen (Xiaoqing); D. Lambrechts (Diether); A. Smeets (Ann); R. Paridaens (Robert); C. Weltens (Caroline); D. Flesch-Janys (Dieter); K. Buck (Katharina); T.W. Behrens (Timothy); P. Peterlongo (Paolo); L. Bernard (Loris); S. Manoukian (Siranoush); P. Radice (Paolo); F.J. Couch (Fergus); C. Vachon (Celine); X. Wang (Xing); J.E. Olson (Janet); G.G. Giles (Graham); L. Baglietto (Laura); C.A. McLean (Cariona); G. Severi (Gianluca); E.M. John (Esther); A. Miron (Alexander); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); I.L. Andrulis (Irene); J.A. Knight (Julia); A.M. Mulligan (Anna Marie); N. Weerasooriya (Nayana); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); J.W.M. Martens (John); C.M. Seynaeve (Caroline); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); A. Jager (Agnes); M.M.A. Tilanus-Linthorst (Madeleine); P. Hall (Per); K. Czene (Kamila); J. Liu (Jianjun); J. Li (Jingmei); A. Cox (Angela); S.S. Cross (Simon); I.W. Brock (Ian); M.W.R. Reed (Malcolm); P.D.P. Pharoah (Paul); F. Blows (Fiona); A.M. Dunning (Alison); M. Ghoussaini (Maya); A. Ashworth (Alan); A.J. Swerdlow (Anthony ); M. Jones (Marta); M. Schoemaker (Minouk); D.F. Easton (Douglas); M.K. Humphreys (Manjeet); Q. Wang (Qing); J. Peto (Julian); I. dos Santos Silva (Isabel)

    2012-01-01

    textabstractBackground: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). Methods: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which

  14. An S-locus independent pollen factor confers self-compatibility in 'Katy' apricot.

    Directory of Open Access Journals (Sweden)

    Elena Zuriaga

    Full Text Available Loss of pollen-S function in Prunus self-compatible cultivars has been mostly associated with deletions or insertions in the S-haplotype-specific F-box (SFB genes. However, self-compatible pollen-part mutants defective for non-S-locus factors have also been found, for instance, in the apricot (Prunus armeniaca cv. 'Canino'. In the present study, we report the genetic and molecular analysis of another self-compatible apricot cv. termed 'Katy'. S-genotype of 'Katy' was determined as S(1S(2 and S-RNase PCR-typing of selfing and outcrossing populations from 'Katy' showed that pollen gametes bearing either the S(1- or the S(2-haplotype were able to overcome self-incompatibility (SI barriers. Sequence analyses showed no SNP or indel affecting the SFB(1 and SFB(2 alleles from 'Katy' and, moreover, no evidence of pollen-S duplication was found. As a whole, the obtained results are compatible with the hypothesis that the loss-of-function of a S-locus unlinked factor gametophytically expressed in pollen (M'-locus leads to SI breakdown in 'Katy'. A mapping strategy based on segregation distortion loci mapped the M'-locus within an interval of 9.4 cM at the distal end of chr.3 corresponding to ∼1.29 Mb in the peach (Prunus persica genome. Interestingly, pollen-part mutations (PPMs causing self-compatibility (SC in the apricot cvs. 'Canino' and 'Katy' are located within an overlapping region of ∼273 Kb in chr.3. No evidence is yet available to discern if they affect the same gene or not, but molecular markers seem to indicate that both cultivars are genetically unrelated suggesting that every PPM may have arisen independently. Further research will be necessary to reveal the precise nature of 'Katy' PPM, but fine-mapping already enables SC marker-assisted selection and paves the way for future positional cloning of the underlying gene.

  15. An S-locus independent pollen factor confers self-compatibility in 'Katy' apricot.

    Science.gov (United States)

    Zuriaga, Elena; Muñoz-Sanz, Juan V; Molina, Laura; Gisbert, Ana D; Badenes, María L; Romero, Carlos

    2013-01-01

    Loss of pollen-S function in Prunus self-compatible cultivars has been mostly associated with deletions or insertions in the S-haplotype-specific F-box (SFB) genes. However, self-compatible pollen-part mutants defective for non-S-locus factors have also been found, for instance, in the apricot (Prunus armeniaca) cv. 'Canino'. In the present study, we report the genetic and molecular analysis of another self-compatible apricot cv. termed 'Katy'. S-genotype of 'Katy' was determined as S(1)S(2) and S-RNase PCR-typing of selfing and outcrossing populations from 'Katy' showed that pollen gametes bearing either the S(1)- or the S(2)-haplotype were able to overcome self-incompatibility (SI) barriers. Sequence analyses showed no SNP or indel affecting the SFB(1) and SFB(2) alleles from 'Katy' and, moreover, no evidence of pollen-S duplication was found. As a whole, the obtained results are compatible with the hypothesis that the loss-of-function of a S-locus unlinked factor gametophytically expressed in pollen (M'-locus) leads to SI breakdown in 'Katy'. A mapping strategy based on segregation distortion loci mapped the M'-locus within an interval of 9.4 cM at the distal end of chr.3 corresponding to ∼1.29 Mb in the peach (Prunus persica) genome. Interestingly, pollen-part mutations (PPMs) causing self-compatibility (SC) in the apricot cvs. 'Canino' and 'Katy' are located within an overlapping region of ∼273 Kb in chr.3. No evidence is yet available to discern if they affect the same gene or not, but molecular markers seem to indicate that both cultivars are genetically unrelated suggesting that every PPM may have arisen independently. Further research will be necessary to reveal the precise nature of 'Katy' PPM, but fine-mapping already enables SC marker-assisted selection and paves the way for future positional cloning of the underlying gene.

  16. Physical Confirmation and Comparative Genomics of the Rat Mammary carcinoma susceptibility 3 Quantitative Trait Locus

    Directory of Open Access Journals (Sweden)

    Saasha Le

    2017-06-01

    Full Text Available Human breast and rat mammary cancer susceptibility are complex phenotypes where complete sets of risk associated loci remain to be identified for both species. We tested multiple congenic rat strains to physically confirm and positionally map rat Mammary carcinoma susceptibility 3 (Mcs3—a mammary cancer resistance allele previously predicted at Rattus norvegicus chromosome 1 (RNO1. The mammary cancer susceptible Wistar Furth (WF strain was the recipient, and the mammary cancer resistant Copenhagen (Cop strain was the RNO1-segment donor for congenics. Inbred WF females averaged 6.3 carcinogen-induced mammary carcinomas per rat. Two WF.Cop congenic strains averaged 2.8 and 3.4 mammary carcinomas per rat, which confirmed Mcs3 as an independently acting allele. Two other WF.Cop congenic strains averaged 6.6 and 8.1 mammary carcinomas per rat, and, thus, did not contain Mcs3. Rat Mcs3 was delimited to 27.8 Mb of RNO1 from rs8149408 to rs105131702 (RNO1:143700228-171517317 of RGSC 6.0/rn6. Human genetic variants with p values for association to breast cancer risk below 10−7 had not been reported for Mcs3 orthologous loci; however, human variants located in Mcs3-orthologous regions with potential association to risk (10−7 < p < 10−3 were listed in some population-based studies. Further, rat Mcs3 contains sequence orthologous to human 11q13/14—a region frequently amplified in female breast cancer. We conclude that Mcs3 is an independently acting mammary carcinoma resistance allele. Human population-based, genome-targeted association studies interrogating Mcs3 orthologous loci may yield novel breast cancer risk associated variants and genes.

  17. Physical Confirmation and Comparative Genomics of the Rat Mammary carcinoma susceptibility 3 Quantitative Trait Locus.

    Science.gov (United States)

    Le, Saasha; Martin, Zachary C; Samuelson, David J

    2017-06-07

    Human breast and rat mammary cancer susceptibility are complex phenotypes where complete sets of risk associated loci remain to be identified for both species. We tested multiple congenic rat strains to physically confirm and positionally map rat Mammary carcinoma susceptibility 3 (Mcs3)-a mammary cancer resistance allele previously predicted at Rattus norvegicus chromosome 1 (RNO1). The mammary cancer susceptible Wistar Furth (WF) strain was the recipient, and the mammary cancer resistant Copenhagen (Cop) strain was the RNO1-segment donor for congenics. Inbred WF females averaged 6.3 carcinogen-induced mammary carcinomas per rat. Two WF.Cop congenic strains averaged 2.8 and 3.4 mammary carcinomas per rat, which confirmed Mcs3 as an independently acting allele. Two other WF.Cop congenic strains averaged 6.6 and 8.1 mammary carcinomas per rat, and, thus, did not contain Mcs3 Rat Mcs3 was delimited to 27.8 Mb of RNO1 from rs8149408 to rs105131702 (RNO1:143700228-171517317 of RGSC 6.0/rn6). Human genetic variants with p values for association to breast cancer risk below 10(-7) had not been reported for Mcs3 orthologous loci; however, human variants located in Mcs3-orthologous regions with potential association to risk (10(-7) < p < 10(-3)) were listed in some population-based studies. Further, rat Mcs3 contains sequence orthologous to human 11q13/14-a region frequently amplified in female breast cancer. We conclude that Mcs3 is an independently acting mammary carcinoma resistance allele. Human population-based, genome-targeted association studies interrogating Mcs3 orthologous loci may yield novel breast cancer risk associated variants and genes. Copyright © 2017 Le et al.

  18. Characterization and mapping of LanrBo: a locus conferring anthracnose resistance in narrow-leafed lupin (Lupinus angustifolius L.).

    Science.gov (United States)

    Fischer, Kristin; Dieterich, Regine; Nelson, Matthew N; Kamphuis, Lars G; Singh, Karam B; Rotter, Björn; Krezdorn, Nicolas; Winter, Peter; Wehling, Peter; Ruge-Wehling, Brigitte

    2015-10-01

    A novel and highly effective source of anthracnose resistance in narrow-leafed lupin was identified. Resistance was shown to be governed by a single dominant locus. Molecular markers have been developed, which can be used for selecting resistant genotypes in lupin breeding. A screening for anthracnose resistance of a set of plant genetic resources of narrow-leafed lupin (Lupinus angustifolius L.) identified the breeding line Bo7212 as being highly resistant to anthracnose (Colletotrichum lupini). Segregation analysis indicated that the resistance of Bo7212 is inherited by a single dominant locus. The corresponding resistance gene was given the designation LanrBo. Previously published molecular anchor markers allowed us to locate LanrBo on linkage group NLL-11 of narrow-leafed lupin. Using information from RNAseq data obtained with inoculated resistant vs. susceptible lupin entries as well as EST-sequence information from the model genome Lotus japonicus, additional SNP and EST markers linked to LanrBo were derived. A bracket of two LanrBo-flanking markers allows for precise marker-assisted selection of the novel resistance gene in narrow-leafed lupin breeding programs.

  19. PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance.

    Directory of Open Access Journals (Sweden)

    Soto Romuald Kiando

    2016-10-01

    Full Text Available Fibromuscular dysplasia (FMD is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80% but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05 generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10-4 in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1. Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10-10, 1,154 cases and 3,895 controls. The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10-4 and wall to lumen ratio (P = 0.002 in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003. Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development. We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.

  20. 11q13 is a Susceptibility Locus for Hormone Receptor Positive Breast Cancer

    DEFF Research Database (Denmark)

    Lambrechts, Diether; Truong, Therese; Justenhoven, Christina

    2012-01-01

    A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10 and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we...... genotyped the variants rs2380205, rs1011970, rs704010, rs614367, rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P = 3 × 10-9) and weak...... evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10-39). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR...

  1. Rare variation at the TNFAIP3 locus and susceptibility to rheumatoid arthritis

    Science.gov (United States)

    Bowes, John; Lawrence, Robert; Eyre, Stephen; Panoutsopoulou, Kalliope; Orozco, Gisela; Elliott, Katherine S.; Ke, Xiayi; Morris, Andrew P.; Thomson, Wendy; Worthington, Jane; Barton, Anne

    2010-01-01

    Genome-wide association studies (GWAS) conducted using commercial single nucleotide polymorphisms (SNP) arrays have proven to be a powerful tool for the detection of common disease susceptibility variants. However, their utility for the detection of lower frequency variants is yet to be practically investigated. Here we describe the application of a rare variant collapsing method to a large genome-wide SNP dataset, the Wellcome Trust Case Control Consortium rheumatoid arthritis (RA) GWAS. We partitioned the data into gene-centric bins and collapsed genotypes of low frequency variants (defined here as MAF ≤0.05) into a single count coupled with univariate analysis. We then prioritised gene regions for further investigation in an independent cohort of 3,355 cases and 2,427 controls based on rare variant signal p value and prior evidence to support involvement in RA. A total of 14,536 gene bins were investigated in the primary analysis and signals mapping to the TNFAIP3 and chr17q24 loci were selected for further investigation. We detected replicating association to low frequency variants in the TNFAIP3 gene (combined p = 6.6 × 10−6). Even though rare variants are not well-represented and can be difficult to genotype in GWAS, our study supports the application of low frequency variant collapsing methods to genome-wide SNP datasets as a means of exploiting data that are routinely ignored. Electronic supplementary material The online version of this article (doi:10.1007/s00439-010-0889-1) contains supplementary material, which is available to authorized users. PMID:20852893

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

    Directory of Open Access Journals (Sweden)

    Bridget H Maher

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

  3. Heterogeneous Responses to Antioxidants in Noradrenergic Neurons of the Locus Coeruleus Indicate Differing Susceptibility to Free Radical Content

    Science.gov (United States)

    de Oliveira, Ramatis B.; Gravina, Fernanda S.; Lim, Rebecca; Brichta, Alan M.; Callister, Robert J.; van Helden, Dirk F.

    2012-01-01

    The present study investigated the effects of the antioxidants trolox and dithiothreitol (DTT) on mouse Locus coeruleus (LC) neurons. Electrophysiological measurement of action potential discharge and whole cell current responses in the presence of each antioxidant suggested that there are three neuronal subpopulations within the LC. In current clamp experiments, most neurons (55%; 6/11) did not respond to the antioxidants. The remaining neurons exhibited either hyperpolarization and decreased firing rate (27%; 3/11) or depolarization and increased firing rate (18%; 2/11). Calcium and JC-1 imaging demonstrated that these effects did not change intracellular Ca2+ concentration but may influence mitochondrial function as both antioxidant treatments modulated mitochondrial membrane potential. These suggest that the antioxidant-sensitive subpopulations of LC neurons may be more susceptible to oxidative stress (e.g., due to ATP depletion and/or overactivation of Ca2+-dependent pathways). Indeed it may be that this subpopulation of LC neurons is preferentially destroyed in neurological pathologies such as Parkinson's disease. If this is the case, there may be a protective role for antioxidant therapies. PMID:22577493

  4. A genome-wide association analysis identified a novel susceptible locus for pathological myopia at 11q24.1.

    Directory of Open Access Journals (Sweden)

    Hideo Nakanishi

    2009-09-01

    Full Text Available Myopia is one of the most common ocular disorders worldwide. Pathological myopia, also called high myopia, comprises 1% to 5% of the general population and is one of the leading causes of legal blindness in developed countries. To identify genetic determinants associated with pathological myopia in Japanese, we conducted a genome-wide association study, analyzing 411,777 SNPs with 830 cases and 1,911 general population controls in a two-stage design (297 cases and 934 controls in the first stage and 533 cases and 977 controls in the second stage. We selected 22 SNPs that showed P-values smaller than 10(-4 in the first stage and tested them for association in the second stage. The meta-analysis combining the first and second stages identified an SNP, rs577948, at chromosome 11q24.1, which was associated with the disease (P = 2.22x10(-7 and OR of 1.37 with 95% confidence interval: 1.21-1.54. Two genes, BLID and LOC399959, were identified within a 200-kb DNA encompassing rs577948. RT-PCR analysis demonstrated that both genes were expressed in human retinal tissue. Our results strongly suggest that the region at 11q24.1 is a novel susceptibility locus for pathological myopia in Japanese.

  5. Linkage and comparative mapping of the locus controlling susceptibility towards E. COLI F4ab/ac diarrhoea in pigs.

    Science.gov (United States)

    Jørgensen, C B; Cirera, S; Anderson, S I; Archibald, A L; Raudsepp, T; Chowdhary, B; Edfors-Lilja, I; Andersson, L; Fredholm, M

    2003-01-01

    In 1995, Edfors-Lilja and coworkers mapped the locus for the E. COLI K88ab (F4ab) and K88ac (F4ac) intestinal receptor to pig chromosome 13 (SSC13). Using the same family material we have refined the map position to a region between the microsatellite markers Sw207 and Sw225. Primers from these markers were used to screen a pig BAC library and the positive clones were used for fluorescent in situ hybridization (FISH) analysis. The results of the FISH analysis helped to propose a candidate gene region in the SSC13q41-->q44 interval. Shotgun sequencing of the FISH-mapped BAC clones revealed that the candidate region contains an evolutionary breakpoint between human and pig. In order to further characterise the rearrangements between SSC13 and human chromosome 3 (HSA3), detailed gene mapping of SSC13 was carried out. Based on this mapping data we have constructed a detailed comparative map between SSC13 and HSA3. Two candidate regions on human chromosome 3 have been identified that are likely to harbour the human homologue of the gene responsible for susceptibility towards E. COLI F4ab/ac diarrhoea in pigs.

  6. Functional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41.

    Science.gov (United States)

    Bigot, Pierre; Colli, Leandro M; Machiela, Mitchell J; Jessop, Lea; Myers, Timothy A; Carrouget, Julie; Wagner, Sarah; Roberson, David; Eymerit, Caroline; Henrion, Daniel; Chanock, Stephen J

    2016-07-07

    Genome-wide association studies have identified multiple renal cell carcinoma (RCC) susceptibility loci. Here, we use regional imputation and bioinformatics analysis of the 12p12.1 locus to identify the single-nucleotide polymorphism (SNP) rs7132434 as a potential functional variant. Luciferase assays demonstrate allele-specific regulatory activity and, together with data from electromobility shift assays, suggest allele-specific differences at rs7132434 for AP-1 transcription factor binding. In an analysis of The Cancer Genome Atlas data, SNPs highly correlated with rs7132434 show allele-specific differences in BHLHE41 expression (trend P value=6.3 × 10(-7)). Cells overexpressing BHLHE41 produce larger mouse xenograft tumours, while RNA-seq analysis reveals that constitutively increased BHLHE41 induces expression of IL-11. We conclude that the RCC risk allele at 12p12.1 maps to rs7132434, a functional variant in an enhancer that upregulates BHLHE41 expression which, in turn, induces IL-11, a member of the IL-6 cytokine family.

  7. Genetic dissection of a TIR-NB-LRR locus from the wild North American grapevine species Muscadinia rotundifolia identifies paralogous genes conferring resistance to major fungal and oomycete pathogens in cultivated grapevine.

    Science.gov (United States)

    Feechan, Angela; Anderson, Claire; Torregrosa, Laurent; Jermakow, Angelica; Mestre, Pere; Wiedemann-Merdinoglu, Sabine; Merdinoglu, Didier; Walker, Amanda R; Cadle-Davidson, Lance; Reisch, Bruce; Aubourg, Sebastien; Bentahar, Nadia; Shrestha, Bipna; Bouquet, Alain; Adam-Blondon, Anne-Françoise; Thomas, Mark R; Dry, Ian B

    2013-11-01

    The most economically important diseases of grapevine cultivation worldwide are caused by the fungal pathogen powdery mildew (Erysiphe necator syn. Uncinula necator) and the oomycete pathogen downy mildew (Plasmopara viticola). Currently, grapegrowers rely heavily on the use of agrochemicals to minimize the potentially devastating impact of these pathogens on grape yield and quality. The wild North American grapevine species Muscadinia rotundifolia was recognized as early as 1889 to be resistant to both powdery and downy mildew. We have now mapped resistance to these two mildew pathogens in M. rotundifolia to a single locus on chromosome 12 that contains a family of seven TIR-NB-LRR genes. We further demonstrate that two highly homologous (86% amino acid identity) members of this gene family confer strong resistance to these unrelated pathogens following genetic transformation into susceptible Vitis vinifera winegrape cultivars. These two genes, designated resistance to Uncinula necator (MrRUN1) and resistance to Plasmopara viticola (MrRPV1) are the first resistance genes to be cloned from a grapevine species. Both MrRUN1 and MrRPV1 were found to confer resistance to multiple powdery and downy mildew isolates from France, North America and Australia; however, a single powdery mildew isolate collected from the south-eastern region of North America, to which M. rotundifolia is native, was capable of breaking MrRUN1-mediated resistance. Comparisons of gene organization and coding sequences between M. rotundifolia and the cultivated grapevine V. vinifera at the MrRUN1/MrRPV1 locus revealed a high level of synteny, suggesting that the TIR-NB-LRR genes at this locus share a common ancestor. © 2013 The Authors The Plant Journal © 2013 John Wiley & Sons Ltd.

  8. Additive susceptibility to insulin-dependent diabetes conferred by HLA-DQB1 and insulin genes.

    Science.gov (United States)

    She, J X; Bui, M M; Tian, X H; Muir, A; Wakeland, E K; Zorovich, B; Zhang, L P; Liu, M C; Thomson, G; Maclaren, N K

    1994-01-01

    Several genomic polymorphisms at the insulin (INS) gene and its flanking regions were analyzed in 197 unrelated Caucasian patients affected by insulin-dependent diabetes (IDDM) and 159 ethnically matched, normal controls ascertained from the South-Eastern United States. We found that the frequency of homozygotes for the common variant at the insulin gene was significantly increased in the diabetic population (RR = 2.0, p INS gene. We determined the HLA-DQB1 genotypes by denaturing gradient gel electrophoresis (DGGE) and/or sequence-specific primers (SSP) techniques to assess the possible interactions between INS and HLA. DQB1*0302 had the strongest predisposing effect on IDDM susceptibility (RR = 9.3) and DQB1*0602 the strongest protective effect (RR = 0.02). However, a significant predisposing effect of DQB1*0201 could be demonstrated only after removal of the effects of DQB1*0302 and DQB1*0602. Analyses of the genotypes revealed that all genotypes containing 0602 were protective and that the heterozygous genotype 0201/0302 and homozygous genotype 0302/0302 confer the highest risk (RR = 20.9 and 12.9 respectively). However, heterozygous genotypes 0302/X (X excludes 0201, 0302 and 0602) have a significantly lower predisposing risk. Similarly, there is heterogeneity in risk between predisposing 0201/0201 homozygous individuals and protective 0201/X individuals. When subjects were stratified by HLA genotypes, the relative risks conferred by INS did not vary, thus suggesting that the susceptibility effects conferred by HLA and INS are additive rather than interactive.

  9. Evidence against an X-linked locus close to DXS7 determining visual loss susceptibility in British and Italian families with Leber hereditary optic neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Sweeney, M.G.; Davis, M.B.; Lashwood, A.; Brockington, M.; Harding, A.E. (Institute of Neurology, Queen Square, London (United Kingdom)); Toscano, A. (Clinica Neurologica, Messina (Italy))

    1992-10-01

    Leber hereditary optic neuropathy (LHON) is associated with mutations of mtDNA, but two features of LHON pedigrees are not explicable solely on the basis of mitochondrial inheritance. There is a large excess of affected males, and not all males at risk develop the disease. These observations could be explained by the existence of an X-linked visual loss susceptibility gene. This hypothesis was supported by linkage studies in Finland, placing the susceptibility locus at DXS7, with a maximum lod score of 2.48 at a recombination fraction of 0. Linkage studies in 1 Italian and 12 British families with LHON, analyzed either together or separately depending on the associated mtDNA mutation, have excluded the presence of such a locus from an interval of about 30 cM around DXS7 in these kindreds, with a total lod score of -26.51 at a recombination fraction of 0. 17 refs., 2 figs., 1 tab.

  10. Susceptibility to insulin-dependent diabetes mellitus maps to a locus (IDDM11) on human chromosome 14q24.3-q31

    Energy Technology Data Exchange (ETDEWEB)

    Field, L.L.; Tobias, R. [Univ. of Calgary, Alberta (Canada); Thomson, G. [Univ. of California, Berkeley, CA (United States)] [and others

    1996-04-01

    To locate genes predisposing to insulin-dependent diabetes mellitus (IDDM), an autoimmune disorder resulting from destruction of the insulin-producing pancreatic cells, we are testing linkage of IDDM susceptibility to polymorphic markers across the genome using families with two or more IDDM children. A new susceptibility locus (IDDM11) has been localized to chromosome 14q24.3-q31 by detection of significant linkage to microsatellite D14S67, using both maximum likelihood methods D14S67, using both maximum likelihood methods (LOD{sub max} = 4.0 at {theta} = 0.20) and affected sib pair (ASP) methods (P = 1 x 10{sup -5}). This represents the strongest reported evidence for linkage to any IDDM locus outside the HLA region. The subset of families in which affected children did not show increased sharing of HLA genes (HLA sharing {le}50%) provided most of the support for D14S67 linkage (LOD{sub max}4.6 at {theta} = 0.12;ASP P < 5 x 10{sup -6}). There was significant linkage heterogeneity between the HLA-defined subsets of families (P = 0.009), suggesting that IDDM11 may be an important susceptibility locus in families lacking strong HLA region predisposition. 52 refs., 2 figs., 3 tabs.

  11. Association analysis revealed one susceptibility locus for vitiligo with immune-related diseases in the Chinese Han population.

    Science.gov (United States)

    Li, Shu; Yao, Weiyi; Pan, Qian; Tang, Xianfa; Zhao, Suli; Wang, Wenjun; Zhu, Zhengwei; Gao, Jinping; Sheng, Yujun; Zhou, Fusheng; Zheng, Xiaodong; Zuo, Xianbo; Sun, Liangdan; Zhang, Anping

    2015-07-01

    Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other immune-related diseases. However, there is no reported study on the associations between immune susceptibility polymorphisms and the risk of vitiligo with immune-related diseases. The aim of this study was to evaluate the potential influence of 10 single-nucleotide polymorphisms (SNPs) at 18q21.31 (rs10503019), 4p16.1 (rs11940117), 3q28 (rs1464510), 14q12 (rs2273844), 12q13.2 (rs2456973), 16q12.2 (rs3213758), 10q25.3 (rs4353229), 3q13.33 (rs59374417), and 10p15.1 (rs706779 and rs7090530) on vitiligo with immune-related diseases in the Chinese Han population. All SNPs were genotyped in 552 patients with vitiligo-associated immune-related diseases and 1656 controls using the Sequenom MassArray system. Data were analyzed with PLINK 1.07 software. The C allele of rs2456973 at 12q13.2 was observed to be significantly associated with vitiligo-associated immune-related diseases (autoimmune diseases and allergic diseases) (P = 0.0028, odds ratio (OR) = 1.27). In subphenotype analysis, the rs2456973 C allele was also significantly associated with early-onset vitiligo by comparing with controls (P = 0.0001) and in the case-only analysis (P = 0.0114). We confirmed that 12q13.2 was an important candidate locus for vitiligo with immune-related diseases (autoimmune diseases and allergic diseases) and affected disease phenotypes with early onset.

  12. Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations

    NARCIS (Netherlands)

    Einarsdottir, Elisabet; Bevova, Marianna R.; Zhernakova, Alexandra; Monsuur, Alienke; Koskinen, Lotta L. E.; van't Slot, Ruben; Mulder, Chris; Mearin, M. Luisa; Korponay-Szabo, Ilma R.; Kaukinen, Katri; Kurppa, Kalle; Kere, Juha; Maki, Markku; Wijmenga, Cisca; Saavalainen, Paivi

    Celiac disease is an inflammatory enteropathy caused by intolerance to gluten. Previous linkage studies in the Dutch, Finnish and Hungarian populations have revealed a locus on chromosome 6q21-22 conferring susceptibility to celiac disease. This locus has previously been implicated in susceptibility

  13. Toll-like receptors gene polymorphisms may confer increased susceptibility to breast cancer development.

    Science.gov (United States)

    Theodoropoulos, George E; Saridakis, Vasilios; Karantanos, Theodoros; Michalopoulos, Nikolaos V; Zagouri, Flora; Kontogianni, Panagiota; Lymperi, Maria; Gazouli, Maria; Zografos, George C

    2012-08-01

    Toll-like receptor (TLR) activation may be an important event in tumor cell immune evasion. TLR2 and TLR4 gene polymorphisms have been related to increased susceptibility to cancer development in various organs. 261 patients and 480 health individuals were investigated for genotype and allelic frequencies of a 22-bp nucleotide deletion (-196 to -174del) in the promoter of TLR2 gene as well as two polymorphisms causing amino acid substitutions (Asp299Gly and Thr399Ile) in TLR4 gene. As far as (-196 to -174del) in TLR2 gene is concerned ins/del and del/del genotypes and del allele were significantly more frequent in breast cancer patients compared to healthy controls. Considering Asp299Gly replacement of TLR4 gene, Gly carriers (Asp/Gly & Gly/Gly genotype) and Gly allele were overrepresented among the breast cancer cases. The -174 to -196del of TLR2 gene and Asp299Gly of TLR4 gene polymorphisms may confer an increased susceptibility to breast cancer development.

  14. The lupus susceptibility locus Sle1 facilitates the peripheral development and selection of anti-DNA B cells through impaired receptor editing.

    Science.gov (United States)

    Chang, Soog-Hee; Kim, Tae-Joo; Kim, Young-Joo; Liu, Yang; Min, So-Youn; Park, Min-Jung; Park, Hyun-Sil; Lee, Sun-Kyung; Nam, Ki-Hoan; Kim, Ho-Youn; Mohan, Chandra; Kim, Hang-Rae

    2014-06-15

    Systemic lupus erythematosus is characterized by the spontaneous production of IgG autoantibodies in patients and lupus-prone mice. In this study, we investigated the effect of the Sle1 lupus susceptibility locus on the peripheral development of 56R(+) anti-DNA transgenic B cells by tracking 56R(+) B cells in mice without (B6.56R) or with (B6.Sle1.56R) the Sle1 locus. Compared with B6.56R mice, B6.Sle1.56R mice exhibited increased class-switched IgG2a anti-DNA Abs in their serum, encoded by the transgene. Interestingly, within the spleen, Sle1 facilitated the development of these cells into clusters of IgG2a class-switched B cells juxtaposed to CD4(+) T cells within extrafollicular sites. Through sequence analysis of B cell hybridomas, we also found that B cells from B6.Sle1.56R mice are inefficient at Ig H and L chain editing. Thus, the Ig H chains in Sle1.56R(+) B cells are partnered more often with cationic L chains that facilitate DNA binding. Taken together, these findings indicate that the Sle1 lupus-susceptibility locus may facilitate the emergence of anti-DNA B cells by subduing BCR revision and possibly by shaping the extrafollicular development of effector B cells, although the precise molecular mechanisms await further study.

  15. Role of a genetic variant on the 15q25.1 lung cancer susceptibility locus in smoking-associated nasopharyngeal carcinoma.

    Science.gov (United States)

    Ji, Xuemei; Zhang, Weidong; Gui, Jiang; Fan, Xia; Zhang, Weiwei; Li, Yafang; An, Guangyu; Zhu, Dakai; Hu, Qiang

    2014-01-01

    The 15q25.1 lung cancer susceptibility locus, containing CHRNA5, could modify lung cancer susceptibility and multiple smoking related phenotypes. However, no studies have investigated the association between CHRNA5 rs3841324, which has been proven to have the highest association with CHRNA5 mRNA expression, and the risk of other smoking-associated cancers, except lung cancer. In the current study we examined the association between rs3841324 and susceptibility to smoking-associated nasopharyngeal carcinoma (NPC). In this case-control study we genotyped the CHRNA5 rs3841324 polymorphism with 400 NPC cases and 491 healthy controls who were Han Chinese and frequency-matched by age (±5 years), gender, and alcohol consumption. Univariate and multivariate logistic regression analyses were used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI). We found that individuals with CHRNA5 rs3841324 combined variant genotypes (ins/del+del/del) had a >1.5-fold elevated risk for NPC than those with the ins/ins genotype (adjusted OR = 1.52; 95% CI, 1.16-2.00), especially among ever smokers (adjusted OR = 2.07; 95% CI, 1.23-3.48). The combined variant genotypes acted jointly with cigarette smoking to contribute to a 4.35-fold increased NPC risk (adjusted OR = 4.35; 95% CI, 2.57-7.38). There was a dose-response relationship between deletion alleles and NPC susceptibility (trend test, P = 0.011). Our results suggest that genetic variants on the 15q25.1 lung cancer susceptibility locus may influence susceptibility to NPC, particularly for smoking-associated NPC. Such work may be helpful to facilitate an understanding of the etiology of smoking-associated cancers and improve prevention efforts.

  16. Genetic and physical fine-mapping of the Sc locus conferring indica-japonica hybrid sterility in rice (Oryza sativa L.)

    Institute of Scientific and Technical Information of China (English)

    YANG Cunyi; CHEN Zhongzheng; ZHUANG Chuxiong; MEI Mantong; LIU Yaoguang

    2004-01-01

    Hybrid sterility is a major hindrance to utilizing the heterosis in indica-japonica hybrids. To isolate a gene Sc conferring the hybrid sterility, the locus was mapped using molecular markers and an F2 population derived from a cross between near isogenic lines. A primary linkage analysis showed that Sc was linked closely with 4 markers on chromosome 3, on which the genetic distance between a marker RG227 and Sc was 0.07 cM. Chromosome walking with a rice TAC genomic library was carried out using RG227 as a starting probe, and a contig of ca. 320 kb covering the Sc locus was constructed. Two TAC clones, M45E14 and M90J01 that might cover the Sc locus, were partially sequenced. By searching the rice sequence databases with sequences of the TACs and RG227 a japonica rice BAC sequence, OSJNBb0078P24 was identified. By comparing the TAC and BAC sequences, six new PCR-based markers were developed. With these markers the Sc locus was further mapped to a region of 46 kb. The results suggest that the BAC OSJNBb0078P24 and TAC M45E14 contain the Sc gene. Six ORFs were predicted in the focused 46-kb region.

  17. Different KIRs confer susceptibility and protection to adults with latent autoimmune diabetes in Latvian and Asian Indian populations.

    Science.gov (United States)

    Shastry, Arun; Sedimbi, Saikiran K; Rajalingam, Raja; Rumba, Ingrida; Kanungo, Alok; Sanjeevi, C B

    2008-12-01

    KIRs (killer Ig-like receptors) expressed on natural killer (NK) cells are an important component of innate (and adaptive) immunity. They are either activatory or inhibitory, and certain KIRs are known to interact with specific motifs of HLA Class I molecules, which is very crucial in determining whether a cell is targeted to lysis or otherwise. Latent autoimmune diabetes in adults (LADA) is a slowly progressive form of autoimmune diabetes, with an adult onset (>30 years). Because autoantibodies and autoimmunity involved are involved in the etiology of LADA, KIRs might play an important role in conferring susceptibility to or protection against the disease. The purpose of this study was to identify killer immunoglobulin-like receptor (KIR) genes, which are associated with susceptibility to and protection against type 1 diabetes in Latvian and Asian Indian patients with LADA. KIR and HLA-C ligand genotyping was performed using PCR-SSP in LADA patients from Latvia (n= 45) with age- and sex-matched controls (n= 92) and from India (n= 86) with controls (n= 98). Results showed that in Latvian patients with LADA, KIRs 2DL1, 2DS2, and 2DS4 were associated with susceptibility and KIR 2DS5 with protection. In Asian Indian LADA patients, KIRs 2DL5 and 3DL1 were associated with susceptibility and KIRs 2DS1 and 2DS3 with protection. Stratification analyses for KIRs that bind to HLA-C1 and C2 were performed. We concluded that KIRs are important in conferring susceptibility (or protection) to adult patients with LADA in both our study populations. However the KIR genes (and their HLA-C ligands) conferring susceptibility or protection in these two populations differ, showing a role of ethnicity in disease susceptibility.

  18. Immunochip SNP array identifies novel genetic variants conferring susceptibility to candidemia

    Science.gov (United States)

    Smeekens, Sanne P.; Wojtowicz, Agnieszka; Giamarellos-Bourboulis, Evangelos; Karjalainen, Juha; Franke, Lude; Withoff, Sebo; Plantinga, Theo S.; van de Veerdonk, Frank L.; van der Meer, Jos W.M.; Joosten, Leo A.B.; Bochud, Pierre-Yves; Marchetti, Oscar; Perfect, John R.; Xavier, Ramnik; Kullberg, Bart Jan; Wijmenga, Cisca; Netea, Mihai G.

    2016-01-01

    Candidemia is the fourth most common cause of bloodstream infection, with a high mortality rate of up to 40%. Identification of host genetic factors that confer susceptibility to candidemia may aid in designing adjunctive immunotherapeutic strategies. We hypothesized that variation in immune genes may predispose to candidemia. We analyzed 118,989 SNPs across 186 loci known to be associated with immune-mediated diseases in the largest candidemia cohort to date of 217 patients of European ancestry and a group of 11,920 controls. The significant associations were validated by comparison with a disease-matched control group. We observed significant association between candidemia and SNPs in the CD58 (P = 1.97×10−11; OR = 4.68), LCE4A-C1orf68 (P = 1.98×10−10; OR = 4.25) and TAGAP (P = 1.84×10−8; OR = 2.96) loci. Individuals carrying two or more risk alleles had an increased risk for candidemia of 19.4-fold compared to individuals carrying no risk allele. While latent cornified envelope (LCE) genes contribute to mucosal integrity, the role of CD58 and TAGAP in host defense is unknown. Studies using transcriptomics, pathway analysis, and immunological validation showed that CD58 plays a role in the recognition and phagocytosis of Candida by macrophages, while TAGAP was involved in Candida-induced cytokine production. TAGAP-deficient mice were more susceptible to systemic Candida infection. We identified three novel genetic risk factors for candidemia, which we subsequently validated for their role in antifungal host defense. PMID:25197941

  19. Linkage Analyses of Chromosome 18 Markers Do Not Identify a Major Susceptibility Locus for Bipolar Affective Disorder in the Old Order Amish

    Science.gov (United States)

    Pauls, David L.; Ott, Jurg; Paul, Steven M.; Allen, Cleona R.; Fann, Cathy S. J.; Carulli, John P.; Falls, Kathleen M.; Bouthillier, Christine A.; Gravius, Thomas C.; Keith, Tim P.; Egeland, Janice A.; Ginns, Edward I.

    1995-01-01

    Previously reported linkage of bipolar affective disorder to DNA markers in the pericentromeric region of chromosome 18 was reexamined in a larger homogeneous sample of Old Order Amish families. Four markers (D18S21, D18S53, D18S44, and D18S40) were examined in three kindreds containing 31 bipolar I (BP I) individuals. Although linkage findings were replicated in the one previously studied Amish pedigree containing four BP I individuals, linkage to this region was excluded in the larger sample. If a susceptibility locus for bipolar disorder is located in this region of chromosome 18, it is of minor significance in this population. PMID:7668292

  20. A Genome-Wide SNP Linkage Analysis Suggests a Susceptibility Locus on 6p21 for Ankylosing Spondylitis and Inflammatory Back Pain Trait

    Science.gov (United States)

    Zhang, Yanli; Liao, Zetao; Wei, Qiujing; Pan, Yunfeng; Wang, Xinwei; Cao, Shuangyan; Guo, Zishi; Wu, Yuqiong; Rong, Ju; Jin, Ou; Xu, Manlong; Gu, Jieruo

    2016-01-01

    Objectives To screen susceptibility loci for ankylosing spondylitis (AS) using an affected-only linkage analysis based on high-density single nucleotide polymorphisms (SNPs) in a genome-wide manner. Patients and Methods AS patients from ten families with Cantonese origin of China were enrolled in the study. Blood samples were genotyped using genomic DNA derived from peripheral blood leukocytes by Illumina HumanHap 610-Quad SNP Chip. Genotype data were generated using the Illumina BeadStudio 3.2 software. PLINK package was used to remove non-autosomal SNPs and to further eliminate markers of typing errors. An affected-only linkage analysis was carried out using both non-parametric and parametric linkage analyses, as implemented in MERLIN. Result Seventy-eight AS patients (48 males and 30 females, mean age: 39±16 years) were enrolled in the study. The mean age of onset was 23±10 years and mean duration of disease was 16.7±12.2 years. Iritis (2/76, 2.86%), dactylitis (5/78, 6.41%), hip joint involvement (9/78, 11.54%), peripheral arthritis (22/78, 28.21%), inflammatory back pain (IBP) (69/78, 88.46%) and HLA-B27 positivity (70/78, 89.74%) were observed in these patients. Using non-parameter linkage analysis, we found one susceptibility locus for AS, IBP and HLA-B27 in 6p21 respectively, spanning about 13.5Mb, 20.9Mb and 21.2Mb, respectively No significant results were found in the other clinical trait groups including dactylitis, hip involved and arthritis. The identical susceptibility locus region spanning above 9.44Mb was detected in AS IBP and HLA-B27 by the parametric linkage analysis. Conclusion Our genome-wide SNP linkage analysis in ten families with ankylosing spondylitis suggests a susceptibility locus on 6p21 in AS, which is a risk locus for IBP in AS patients. PMID:27973620

  1. Serum proteomes distinguish children developing type 1 diabetes in a cohort with HLA-conferred susceptibility.

    Science.gov (United States)

    Moulder, Robert; Bhosale, Santosh D; Erkkilä, Timo; Laajala, Essi; Salmi, Jussi; Nguyen, Elizabeth V; Kallionpää, Henna; Mykkänen, Juha; Vähä-Mäkilä, Mari; Hyöty, Heikki; Veijola, Riitta; Ilonen, Jorma; Simell, Tuula; Toppari, Jorma; Knip, Mikael; Goodlett, David R; Lähdesmäki, Harri; Simell, Olli; Lahesmaa, Riitta

    2015-06-01

    We determined longitudinal serum proteomics profiles from children with HLA-conferred diabetes susceptibility to identify changes that could be detected before seroconversion and positivity for disease-associated autoantibodies. Comparisons were made between children who seroconverted and progressed to type 1 diabetes (progressors) and those who remained autoantibody negative, matched by age, sex, sample periodicity, and risk group. The samples represented the prediabetic period and ranged from the age of 3 months to 12 years. After immunoaffinity depletion of the most abundant serum proteins, isobaric tags for relative and absolute quantification were used for sample labeling. Quantitative proteomic profiles were then measured for 13 case-control pairs by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Additionally, a label-free LC-MS/MS approach was used to analyze depleted sera from six case-control pairs. Importantly, differences in abundance of a set of proteins were consistently detected before the appearance of autoantibodies in the progressors. Based on top-scoring pairs analysis, classification of such progressors was observed with a high success rate. Overall, the data provide a reference of temporal changes in the serum proteome in healthy children and children progressing to type 1 diabetes, including new protein candidates, the levels of which change before clinical diagnosis.

  2. Common variants in the TPH2 promoter confer susceptibility to paranoid schizophrenia.

    Science.gov (United States)

    Yi, Zhenghui; Zhang, Chen; Lu, Weihong; Song, Lisheng; Liu, Dentang; Xu, Yifeng; Fang, Yiru

    2012-07-01

    Serotonergic system-related genes may be good candidates in investigating the genetic basis of schizophrenia. Our previous study suggested that promoter region of tryptophan hydroxylase 2 gene (TPH2) may confer the susceptibility to paranoid schizophrenia. In this study, we investigated whether common variants within TPH2 promoter may predispose to paranoid schizophrenia in Han Chinese. A total of 509 patients who met DSM-IV criteria for paranoid schizophrenia and 510 matched healthy controls were recruited for this study. Five polymorphisms within TPH2 promoter region were tested. No statistically significant differences were found in allele or genotype frequencies between schizophrenic patients and healthy controls. The frequency of the rs4448731T-rs6582071A-rs7963803A-rs4570625T-rs11178997A haplotype was significantly higher in cases compared to the controls (P = 0.003; OR = 1.49; 95% CI, 1.15-1.95). Our results suggest that the common variants within TPH2 promoter are associated with paranoid schizophrenia in Han Chinese. Further studies in larger samples are warranted to elucidate the role of TPH2 in the etiology of paranoid schizophrenia.

  3. Exome and Transcriptome Sequencing of Aedes aegypti Identifies a Locus That Confers Resistance to Brugia malayi and Alters the Immune Response

    KAUST Repository

    Juneja, Punita

    2015-03-27

    Many mosquito species are naturally polymorphic for their abilities to transmit parasites, a feature which is of great interest for controlling vector-borne disease. Aedes aegypti, the primary vector of dengue and yellow fever and a laboratory model for studying lymphatic filariasis, is genetically variable for its capacity to harbor the filarial nematode Brugia malayi. The genome of Ae. aegypti is large and repetitive, making genome resequencing difficult and expensive. We designed exome captures to target protein-coding regions of the genome, and used association mapping in a wild Kenyan population to identify a single, dominant, sex-linked locus underlying resistance. This falls in a region of the genome where a resistance locus was previously mapped in a line established in 1936, suggesting that this polymorphism has been maintained in the wild for the at least 80 years. We then crossed resistant and susceptible mosquitoes to place both alleles of the gene into a common genetic background, and used RNA-seq to measure the effect of this locus on gene expression. We found evidence for Toll, IMD, and JAK-STAT pathway activity in response to early stages of B. malayi infection when the parasites are beginning to die in the resistant genotype. We also found that resistant mosquitoes express anti-microbial peptides at the time of parasite-killing, and that this expression is suppressed in susceptible mosquitoes. Together, we have found that a single resistance locus leads to a higher immune response in resistant mosquitoes, and we identify genes in this region that may be responsible for this trait.

  4. Exome and Transcriptome Sequencing of Aedes aegypti Identifies a Locus That Confers Resistance to Brugia malayi and Alters the Immune Response

    Science.gov (United States)

    Juneja, Punita; Ariani, Cristina V.; Ho, Yung Shwen; Akorli, Jewelna; Palmer, William J.; Pain, Arnab; Jiggins, Francis M.

    2015-01-01

    Many mosquito species are naturally polymorphic for their abilities to transmit parasites, a feature which is of great interest for controlling vector-borne disease. Aedes aegypti, the primary vector of dengue and yellow fever and a laboratory model for studying lymphatic filariasis, is genetically variable for its capacity to harbor the filarial nematode Brugia malayi. The genome of Ae. aegypti is large and repetitive, making genome resequencing difficult and expensive. We designed exome captures to target protein-coding regions of the genome, and used association mapping in a wild Kenyan population to identify a single, dominant, sex-linked locus underlying resistance. This falls in a region of the genome where a resistance locus was previously mapped in a line established in 1936, suggesting that this polymorphism has been maintained in the wild for the at least 80 years. We then crossed resistant and susceptible mosquitoes to place both alleles of the gene into a common genetic background, and used RNA-seq to measure the effect of this locus on gene expression. We found evidence for Toll, IMD, and JAK-STAT pathway activity in response to early stages of B. malayi infection when the parasites are beginning to die in the resistant genotype. We also found that resistant mosquitoes express anti-microbial peptides at the time of parasite-killing, and that this expression is suppressed in susceptible mosquitoes. Together, we have found that a single resistance locus leads to a higher immune response in resistant mosquitoes, and we identify genes in this region that may be responsible for this trait. PMID:25815506

  5. Genotyping of TRIM5 locus in northern pig-tailed macaques (Macaca leonina, a primate species susceptible to Human Immunodeficiency Virus type 1 infection

    Directory of Open Access Journals (Sweden)

    Jiang Xue-Long

    2009-06-01

    Full Text Available Abstract Background The pig-tailed macaques are the only Old World monkeys known to be susceptible to human immunodeficiency virus type 1 (HIV-1 infection. We have previously reported that the TRIM5-Cyclophilin A (TRIMCyp fusion in pig-tailed macaques (Macaca nemestrina is dysfunctional in restricting HIV-1, which may explain why pig-tailed macaques are susceptible to HIV-1 infection. Similar results have also been reported by other groups. However, according to the current primate taxonomy, the previously reported M. nemestrina are further classified into three species, which all belong to the Macaca spp. This calls for the need to look into the previous studies in more details. Results The local species Northern pig-tailed macaque (M. leonina was analyzed for the correlation of TRIM5 structure and HIV-1 infection. Eleven M. leonina animals were analyzed, and all of them were found to possess TRIM5-CypA fusion at the TRIM5 locus. The transcripts encoding the dysfunctional TRIM5-CypA should result from the G-to-T mutation in the 3'-splicing site of intron 6. Polymorphism in the putative TRIMCyp recognition domain was observed. The peripheral blood mononuclear cells (PBMCs of M. leonina were susceptible to HIV-1 infection. Consistent with the previous results, expression of the M. leonina TRIMCyp in HeLa-T4 cells rendered the cells resistant to HIV-2ROD but not to SIVmac239 infection. Conclusion The susceptibility of M. leonina to HIV-1 infection is due to the dysfunctional TRIM5-CypA fusion in the TRIM5 locus. This finding should broaden our perspective in developing better HIV/AIDS non-human primate animal models.

  6. Polymorphisms and haplotypes of the chromosome locus 17q12-17q21.1 contribute to adult asthma susceptibility in Slovenian patients.

    Science.gov (United States)

    Žavbi, Mateja; Korošec, Peter; Fležar, Matjaž; Škrgat Kristan, Sabina; Marc Malovrh, Mateja; Rijavec, Matija

    2016-06-01

    One of the major asthma susceptibility loci is 17q12-17q21.1, but the relationship between this locus and adult asthma is unclear. Association analysis of 13 single nucleotide polymorphisms (SNPs) and haplotypes from 17q12-17q21.1 was performed in 418 adult patients with asthma and 288 controls from Slovenia. Single SNP analysis revealed only marginal associations with adult asthma for SNPs located in GSDMA, GSDMB, ORMDL3 and ZPBP2 genes, and rs7219080 was the most highly associated. Analyses of asthma phenotypes found no association with atopy or lung function, but rs2305480 and rs8066582 were associated with childhood asthma and rs9916279 was associated with asthma in smokers. Notably, haplotypes consisting of rs9916279, rs8066582, rs1042658, and rs2302777 harbouring PSMD3, CSF3 and MED24 genes were highly associated with asthma. The four most common haplotypes, TCCG, TTTA, CCCA and TTCA, were more frequent in patients with asthma, whereas TTCG, TCCA, TCTA and TTTG were more frequent in controls. Only 3% of asthma patients belonged to haplotypes TTCG, TCCA, TCTA and TTTG compared with nearly one-third (31%) of controls. Associations confirmed that the 17q12-17q21.1 locus harbours a genetic determinant for asthma risk in adults and suggest that in addition to the previously known ORMDL3-GSDM locus, CSF3-PSMD3-MED24 also plays a role in asthma pathogenesis.

  7. Locus-Specific Databases and Recommendations to Strengthen Their Contribution to the Classification of Variants in Cancer Susceptibility Genes

    NARCIS (Netherlands)

    Greenblatt, Marc S.; Brody, Lawrence C.; Foulkes, William D.; Genuardi, Maurizio; Hofstra, Robert M. W.; Olivier, Magali; Plon, Sharon E.; Sijmons, Rolf H.; Sinilnikova, Olga; Spurdle, Amanda B.

    2008-01-01

    Locus-specific databases (LSDBs) are curated collections of sequence variants in genes associated with disease. LSDBs of cancer-related genes often serve as a critical resource to researchers, diagnostic laboratories, clinicians, and others in the cancer genetics community. LSDBs are poised to play

  8. Familial migraine: Exclusion of the susceptibility gene from the reported locus of familial hemiplegic migraine on 19p

    Energy Technology Data Exchange (ETDEWEB)

    Hovatta, I.; Peltonen, L. [National Public Health Institute, Helsinki (Finland); Kallela, M.; Faerkkilae, M. [Helsinki Univ. Central Hospital (Finland)

    1994-10-01

    Genetic isolates are highly useful in analyses of the molecular background of complex diseases since the enrichment of a limited number of predisposing genes can be predicted in representative families or in specific geographical regions. It has been suggested that the pathophysiology and etiology of familial hemiplegic migraine (FHM) and typical migraine with aura are most probably the same. Recent assignment of FHM locus to chromosome 19p in two French families makes it now possible to test this hypothesis. We report here linkage data on four families with multiple cases of migraine disorder originating from the genetically isolated population of Finland. We were interested to discover whether the migraine in these families would also show linkage to the markers on 19p. We could exclude a region of 50 cM, flanking the reported FHM locus, as a site of migraine locus in our four families. It seems evident that locus heterogeneity exists between different diagnostic classes of migraine spectrum of diseases and also between different ethnic groups. 10 refs., 2 figs., 1 tab.

  9. Susceptibility to anthrax lethal toxin-induced rat death is controlled by a single chromosome 10 locus that includes rNlrp1.

    Directory of Open Access Journals (Sweden)

    Zachary L Newman

    2010-05-01

    Full Text Available Anthrax lethal toxin (LT is a bipartite protease-containing toxin and a key virulence determinant of Bacillus anthracis. In mice, LT causes the rapid lysis of macrophages isolated from certain inbred strains, but the correlation between murine macrophage sensitivity and mouse strain susceptibility to toxin challenge is poor. In rats, LT induces a rapid death in as little as 37 minutes through unknown mechanisms. We used a recombinant inbred (RI rat panel of 19 strains generated from LT-sensitive and LT-resistant progenitors to map LT sensitivity in rats to a locus on chromosome 10 that includes the inflammasome NOD-like receptor (NLR sensor, Nlrp1. This gene is the closest rat homolog of mouse Nlrp1b, which was previously shown to control murine macrophage sensitivity to LT. An absolute correlation between in vitro macrophage sensitivity to LT-induced lysis and animal susceptibility to the toxin was found for the 19 RI strains and 12 additional rat strains. Sequencing Nlrp1 from these strains identified five polymorphic alleles. Polymorphisms within the N-terminal 100 amino acids of the Nlrp1 protein were perfectly correlated with LT sensitivity. These data suggest that toxin-mediated lethality in rats as well as macrophage sensitivity in this animal model are controlled by a single locus on chromosome 10 that is likely to be the inflammasome NLR sensor, Nlrp1.

  10. Identification of the tyrosine-protein phosphatase non-receptor type 2 as a rheumatoid arthritis susceptibility locus in europeans

    DEFF Research Database (Denmark)

    Cobb, Joanna E; Plant, Darren; Flynn, Edward;

    2013-01-01

    Genome-wide association studies have facilitated the identification of over 30 susceptibility loci for rheumatoid arthritis (RA). However, evidence for a number of potential susceptibility genes have not so far reached genome-wide significance in studies of Caucasian RA....

  11. Understanding of HLA-conferred susceptibility to chronic hepatitis B infection requires HLA genotyping-based association analysis

    Science.gov (United States)

    Nishida, Nao; Ohashi, Jun; Khor, Seik-Soon; Sugiyama, Masaya; Tsuchiura, Takayo; Sawai, Hiromi; Hino, Keisuke; Honda, Masao; Kaneko, Shuichi; Yatsuhashi, Hiroshi; Yokosuka, Osamu; Koike, Kazuhiko; Kurosaki, Masayuki; Izumi, Namiki; Korenaga, Masaaki; Kang, Jong-Hon; Tanaka, Eiji; Taketomi, Akinobu; Eguchi, Yuichiro; Sakamoto, Naoya; Yamamoto, Kazuhide; Tamori, Akihiro; Sakaida, Isao; Hige, Shuhei; Itoh, Yoshito; Mochida, Satoshi; Mita, Eiji; Takikawa, Yasuhiro; Ide, Tatsuya; Hiasa, Yoichi; Kojima, Hiroto; Yamamoto, Ken; Nakamura, Minoru; Saji, Hiroh; Sasazuki, Takehiko; Kanto, Tatsuya; Tokunaga, Katsushi; Mizokami, Masashi

    2016-01-01

    Associations of variants located in the HLA class II region with chronic hepatitis B (CHB) infection have been identified in Asian populations. Here, HLA imputation method was applied to determine HLA alleles using genome-wide SNP typing data of 1,975 Japanese individuals (1,033 HBV patients and 942 healthy controls). Together with data of an additional 1,481 Japanese healthy controls, association tests of six HLA loci including HLA-A, C, B, DRB1, DQB1, and DPB1, were performed. Although the strongest association was detected at a SNP located in the HLA-DP locus in a SNP-based GWAS using data from the 1,975 Japanese individuals, HLA genotyping-based analysis identified DQB1*06:01 as having the strongest association, showing a greater association with CHB susceptibility (OR = 1.76, P = 6.57 × 10−18) than any one of five HLA-DPB1 alleles that were previously reported as CHB susceptibility alleles. Moreover, HLA haplotype analysis showed that, among the five previously reported HLA-DPB1 susceptibility and protective alleles, the association of two DPB1 alleles (DPB1*09:01, and *04:01) had come from linkage disequilibrium with HLA-DR-DQ haplotypes, DRB1*15:02-DQB1*06:01 and DRB1*13:02-DQB1*06:04, respectively. The present study showed an example that SNP-based GWAS does not necessarily detect the primary susceptibility locus in the HLA region. PMID:27091392

  12. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

    DEFF Research Database (Denmark)

    Lawrenson, Kate; Kar, Siddhartha; McCue, Karen

    2016-01-01

    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-n...

  13. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

    NARCIS (Netherlands)

    K. Lawrenson (Kate); S. Kar (Siddhartha); K. McCue (Karen); Kuchenbaeker, K. (Karoline); K. Michailidou (Kyriaki); J.P. Tyrer (Jonathan); J. Beesley (Jonathan); S.J. Ramus (Susan); Li, Q. (Qiyuan); Delgado, M.K. (Melissa K.); J.M. Lee (Janet M.); K. Aittomäki (Kristiina); I.L. Andrulis (Irene); H. Anton-Culver (Hoda); Arndt, V. (Volker); B.K. Arun (Banu); B. Arver (Brita Wasteson); E.V. Bandera (Elisa); M. Barile (Monica); Barkardottir, R.B. (Rosa B.); D. Barrowdale (Daniel); M.W. Beckmann (Matthias); J. Benítez (Javier); A. Berchuck (Andrew); M. Bisogna (Maria); L. Bjorge (Line); C. Blomqvist (Carl); W.J. Blot (William); N.V. Bogdanova (Natalia); Bojesen, A. (Anders); S.E. Bojesen (Stig); M.K. Bolla (Manjeet K.); B. Bonnani (Bernardo); A.-L. Borresen-Dale (Anne-Lise); H. Brauch (Hiltrud); P. Brennan (Paul); H. Brenner (Hermann); F. Bruinsma (Fiona); J. Brunet (Joan); S.A.B.S. Buhari (Shaik Ahmad Bin Syed); B. Burwinkel (Barbara); R. Butzow (Ralf); S.S. Buys (Saundra); Q. Cai (Qiuyin); T. Caldes (Trinidad); I. Campbell (Ian); Canniotto, R. (Rikki); J. Chang-Claude (Jenny); Chiquette, J. (Jocelyne); Choi, J.-Y. (Ji-Yeob); K.B.M. Claes (Kathleen B.M.); L.S. Cook (Linda S.); A. Cox (Angela); D.W. Cramer (Daniel); S.S. Cross (Simon); C. Cybulski (Cezary); K. Czene (Kamila); M.B. Daly (Mary B.); F. Damiola (Francesca); A. Dansonka-Mieszkowska (Agnieszka); H. Darabi (Hatef); J. Dennis (Joe); P. Devilee (Peter); O. Díez (Orland); J.A. Doherty (Jennifer A.); S.M. Domchek (Susan); C.M. Dorfling (Cecilia); T. Dörk (Thilo); M. Dumont (Martine); H. Ehrencrona (Hans); B. Ejlertsen (Bent); S.D. Ellis (Steve); C. Engel (Christoph); E. Lee (Eunjung); Evans, D.G. (D. Gareth); P.A. Fasching (Peter); L. Feliubadaló (L.); J.D. Figueroa (Jonine); D. Flesch-Janys (Dieter); O. Fletcher (Olivia); H. Flyger (Henrik); L. Foretova (Lenka); F. Fostira (Florentia); W.D. Foulkes (William); B.L. Fridley (Brooke); E. Friedman (Eitan); D. Frost (Debra); Gambino, G. (Gaetana); P.A. Ganz (Patricia A.); J. Garber (Judy); M. García-Closas (Montserrat); A. Gentry-Maharaj (Aleksandra); M. Ghoussaini (Maya); G.G. Giles (Graham); R. Glasspool (Rosalind); A.K. Godwin (Andrew K.); M.S. Goldberg (Mark); D. Goldgar (David); A. González-Neira (Anna); E.L. Goode (Ellen); M.T. Goodman (Marc); M.H. Greene (Mark H.); J. Gronwald (Jacek); P. Guénel (Pascal); C.A. Haiman (Christopher A.); P. Hall (Per); Hallberg, E. (Emily); U. Hamann (Ute); T.V.O. Hansen (Thomas); P. harrington (Patricia); J.M. Hartman (Joost); N. Hassan (Norhashimah); S. Healey (Sue); P.U. Heitz; J. Herzog (Josef); E. Høgdall (Estrid); C.K. Høgdall (Claus); F.B.L. Hogervorst (Frans); A. Hollestelle (Antoinette); J.L. Hopper (John); P.J. Hulick (Peter); T. Huzarski (Tomasz); E.N. Imyanitov (Evgeny); C. Isaacs (Claudine); H. Ito (Hidemi); A. Jakubowska (Anna); R. Janavicius (Ramunas); A. Jensen (Allan); E.M. John (Esther); Johnson, N. (Nichola); M. Kabisch (Maria); D. Kang (Daehee); M.K. Kapuscinski (Miroslav K.); Karlan, B.Y. (Beth Y.); S. Khan (Sofia); L.A.L.M. Kiemeney (Bart); M. Kjaer (Michael); J.A. Knight (Julia); I. Konstantopoulou (I.); V-M. Kosma (Veli-Matti); V. Kristensen (Vessela); J. Kupryjanczyk (Jolanta); A. Kwong (Ava); M. de La Hoya (Miguel); Y. Laitman (Yael); Lambrechts, D. (Diether); N.D. Le (Nhu D.); K. De Leeneer (Kim); K.J. Lester (Kathryn); D.A. Levine (Douglas); J. Li (Jingmei); A. Lindblom (Annika); J. Long (Jirong); A. Lophatananon (Artitaya); J.T. Loud (Jennifer); K.H. Lu (Karen); J. Lubinski (Jan); A. Mannermaa (Arto); S. Manoukian (Siranoush); L. Le Marchand (Loic); S. Margolin (Sara); F. Marme (Frederick); L.F. Massuger (Leon); K. Matsuo (Keitaro); S. Mazoyer (Sylvie); L. McGuffog (Lesley); C.A. McLean (Catriona Ann); I. McNeish (Iain); A. Meindl (Alfons); U. Menon (Usha); Mensenkamp, A.R. (Arjen R.); R.L. Milne (Roger); M. Montagna (Marco); K.B. Moysich (Kirsten); K.R. Muir (K.); A.-M. Mulligan (Anna-Marie); K.L. Nathanson (Katherine); R.B. Ness (Roberta); S.L. Neuhausen (Susan); H. Nevanlinna (Heli); S. Nord (Silje); R.L. Nussbaum (Robert L.); K. Odunsi (Kunle); K. Offit (Kenneth); E. Olah; O.I. Olopade (Olufunmilayo I.); J.E. Olson (Janet); C. Olswold (Curtis); D.M. O'Malley (David M.); I. Orlow (Irene); N. Orr (Nick); A. Osorio (Ana); Park, S.K. (Sue Kyung); C.L. Pearce (Celeste); T. Pejovic (Tanja); P. Peterlongo (Paolo); G. Pfeiler (Georg); C. Phelan (Catherine); E.M. Poole (Elizabeth); K. Pykäs (Katri); P. Radice (Paolo); J. Rantala (Johanna)

    2016-01-01

    textabstractA locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 ×

  14. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

    NARCIS (Netherlands)

    K. Lawrenson (Kate); S. Kar (Siddhartha); K. McCue (Karen); Kuchenbaeker, K. (Karoline); K. Michailidou (Kyriaki); J.P. Tyrer (Jonathan); J. Beesley (Jonathan); S.J. Ramus (Susan); Li, Q. (Qiyuan); Delgado, M.K. (Melissa K.); J.M. Lee (Janet M.); K. Aittomäki (Kristiina); I.L. Andrulis (Irene); H. Anton-Culver (Hoda); Arndt, V. (Volker); B.K. Arun (Banu); B. Arver (Brita Wasteson); E.V. Bandera (Elisa); M. Barile (Monica); Barkardottir, R.B. (Rosa B.); D. Barrowdale (Daniel); M.W. Beckmann (Matthias); J. Benítez (Javier); A. Berchuck (Andrew); M. Bisogna (Maria); L. Bjorge (Line); C. Blomqvist (Carl); W.J. Blot (William); N.V. Bogdanova (Natalia); Bojesen, A. (Anders); S.E. Bojesen (Stig); M.K. Bolla (Manjeet K.); B. Bonnani (Bernardo); A.-L. Borresen-Dale (Anne-Lise); H. Brauch (Hiltrud); P. Brennan (Paul); H. Brenner (Hermann); F. Bruinsma (Fiona); J. Brunet (Joan); S.A.B.S. Buhari (Shaik Ahmad Bin Syed); B. Burwinkel (Barbara); R. Butzow (Ralf); S.S. Buys (Saundra); Q. Cai (Qiuyin); T. Caldes (Trinidad); I. Campbell (Ian); Canniotto, R. (Rikki); J. Chang-Claude (Jenny); Chiquette, J. (Jocelyne); Choi, J.-Y. (Ji-Yeob); K.B.M. Claes (Kathleen B.M.); L.S. Cook (Linda S.); A. Cox (Angela); D.W. Cramer (Daniel); S.S. Cross (Simon); C. Cybulski (Cezary); K. Czene (Kamila); M.B. Daly (Mary B.); F. Damiola (Francesca); A. Dansonka-Mieszkowska (Agnieszka); H. Darabi (Hatef); J. Dennis (Joe); P. Devilee (Peter); O. Díez (Orland); J.A. Doherty (Jennifer A.); S.M. Domchek (Susan); C.M. Dorfling (Cecilia); T. Dörk (Thilo); M. Dumont (Martine); H. Ehrencrona (Hans); B. Ejlertsen (Bent); S.D. Ellis (Steve); C. Engel (Christoph); E. Lee (Eunjung); Evans, D.G. (D. Gareth); P.A. Fasching (Peter); L. Feliubadaló (L.); J.D. Figueroa (Jonine); D. Flesch-Janys (Dieter); O. Fletcher (Olivia); H. Flyger (Henrik); L. Foretova (Lenka); F. Fostira (Florentia); W.D. Foulkes (William); B.L. Fridley (Brooke); E. Friedman (Eitan); D. Frost (Debra); Gambino, G. (Gaetana); P.A. Ganz (Patricia A.); J. Garber (Judy); M. García-Closas (Montserrat); A. Gentry-Maharaj (Aleksandra); M. Ghoussaini (Maya); G.G. Giles (Graham); R. Glasspool (Rosalind); A.K. Godwin (Andrew K.); M.S. Goldberg (Mark); D. Goldgar (David); A. González-Neira (Anna); E.L. Goode (Ellen); M.T. Goodman (Marc); M.H. Greene (Mark H.); J. Gronwald (Jacek); P. Guénel (Pascal); C.A. Haiman (Christopher A.); P. Hall (Per); Hallberg, E. (Emily); U. Hamann (Ute); T.V.O. Hansen (Thomas); P. harrington (Patricia); J.M. Hartman (Joost); N. Hassan (Norhashimah); S. Healey (Sue); P.U. Heitz; J. Herzog (Josef); E. Høgdall (Estrid); C.K. Høgdall (Claus); F.B.L. Hogervorst (Frans); A. Hollestelle (Antoinette); J.L. Hopper (John); P.J. Hulick (Peter); T. Huzarski (Tomasz); E.N. Imyanitov (Evgeny); C. Isaacs (Claudine); H. Ito (Hidemi); A. Jakubowska (Anna); R. Janavicius (Ramunas); A. Jensen (Allan); E.M. John (Esther); Johnson, N. (Nichola); M. Kabisch (Maria); D. Kang (Daehee); M.K. Kapuscinski (Miroslav K.); Karlan, B.Y. (Beth Y.); S. Khan (Sofia); L.A.L.M. Kiemeney (Bart); M. Kjaer (Michael); J.A. Knight (Julia); I. Konstantopoulou (I.); V-M. Kosma (Veli-Matti); V. Kristensen (Vessela); J. Kupryjanczyk (Jolanta); A. Kwong (Ava); M. de La Hoya (Miguel); Y. Laitman (Yael); Lambrechts, D. (Diether); N.D. Le (Nhu D.); K. De Leeneer (Kim); K.J. Lester (Kathryn); D.A. Levine (Douglas); J. Li (Jingmei); A. Lindblom (Annika); J. Long (Jirong); A. Lophatananon (Artitaya); J.T. Loud (Jennifer); K.H. Lu (Karen); J. Lubinski (Jan); A. Mannermaa (Arto); S. Manoukian (Siranoush); L. Le Marchand (Loic); S. Margolin (Sara); F. Marme (Frederick); L.F. Massuger (Leon); K. Matsuo (Keitaro); S. Mazoyer (Sylvie); L. McGuffog (Lesley); C.A. McLean (Catriona Ann); I. McNeish (Iain); A. Meindl (Alfons); U. Menon (Usha); Mensenkamp, A.R. (Arjen R.); R.L. Milne (Roger); M. Montagna (Marco); K.B. Moysich (Kirsten); K.R. Muir (K.); A.-M. Mulligan (Anna-Marie); K.L. Nathanson (Katherine); R.B. Ness (Roberta); S.L. Neuhausen (Susan); H. Nevanlinna (Heli); S. Nord (Silje); R.L. Nussbaum (Robert L.); K. Odunsi (Kunle); K. Offit (Kenneth); E. Olah; O.I. Olopade (Olufunmilayo I.); J.E. Olson (Janet); C. Olswold (Curtis); D.M. O'Malley (David M.); I. Orlow (Irene); N. Orr (Nick); A. Osorio (Ana); Park, S.K. (Sue Kyung); C.L. Pearce (Celeste); T. Pejovic (Tanja); P. Peterlongo (Paolo); G. Pfeiler (Georg); C. Phelan (Catherine); E.M. Poole (Elizabeth); K. Pykäs (Katri); P. Radice (Paolo); J. Rantala (Johanna); M.U. Rashid (Muhammad); G. Rennert (Gad); V. Rhenius (Valerie); K. Rhiem (Kerstin); H. Risch (Harvey); G.C. Rodriguez (Gustavo); M.A. Rossing (Mary Anne); Rudolph, A. (Anja); H.B. Salvesen (Helga); Sangrajrang, S. (Suleeporn); Sawyer, E.J. (Elinor J.); J.M. Schildkraut (Joellen); M.K. Schmidt (Marjanka); R.K. Schmutzler (Rita); T.A. Sellers (Thomas A.); C.M. Seynaeve (Caroline); Shah, M. (Mitul); C.-Y. Shen (Chen-Yang); X.-O. Shu (Xiao-Ou); W. Sieh (Weiva); C.F. Singer (Christian); O. Sinilnikova (Olga); S. Slager (Susan); H. Song (Honglin); Soucy, P. (Penny); M.C. Southey (Melissa); M. Stenmark-Askmalm (Marie); D. Stoppa-Lyonnet (Dominique); C. Sutter (Christian); A.J. Swerdlow (Anthony ); Tchatchou, S. (Sandrine); P.J. Teixeira; S.-H. Teo; K.L. Terry (Kathryn); M.B. Terry (Mary Beth); M. Thomassen (Mads); M.G. Tibiletti (Maria Grazia); L. Tihomirova (Laima); S. Tognazzo (Silvia); A.E. Toland (Amanda); I.P. Tomlinson (Ian); D. Torres (Diana); T. Truong (Thérèse); C.-C. Tseng (Chiu-Chen); N. Tung (Nadine); Tworoger, S.S. (Shelley S.); C. Vachon (Celine); Van Den Ouweland, A.M.W. (Ans M.W.); Van Doorn, H.C. (Helena C.); E.J. van Rensburg (Elizabeth); L.J. van 't Veer (Laura); A. Vanderstichele (Adriaan); I. Vergote (Ignace); J. Vijai (Joseph); Wang, Q. (Qin); S. Wang-Gohrke (Shan); J.N. Weitzel (Jeffrey); N. Wentzensen (N.); A.S. Whittemore (Alice); H. Wildiers (Hans); R. Winqvist (Robert); A.H. Wu (Anna); Yannoukakos, D. (Drakoulis); S.-Y. Yoon (Sook-Yee); J-C. Yu (Jyh-Cherng); W. Zheng (Wei); Y. Zheng (Ying); Khanna, K.K. (Kum Kum); J. Simard (Jacques); A.N.A. Monteiro (Alvaro N.); J.D. French (Juliet); F.J. Couch (Fergus); M. Freedman (Matthew); D.F. Easton (Douglas F.); A.M. Dunning (Alison); P.D.P. Pharoah (Paul); S.L. Edwards (Stacey); G. Chenevix-Trench (Georgia); A.C. Antoniou (Antonis C.); S.A. Gayther (Simon); D. Bowtell (David); A. DeFazio (Anna); P. Webb (Penny); M.-A. Collonge-Rame; Damette, A. (Alexandre); E. Barouk-Simonet (Emmanuelle); F. Bonnet (Françoise); V. Bubien (Virginie); N. Sevenet (Nicolas); M. Longy (Michel); P. Berthet (Pascaline); D. Vaur (Dominique); L. Castera (Laurent); S.F. Ferrer; Y.-J. Bignon (Yves-Jean); N. Uhrhammer (Nancy); F. Coron (Fanny); L. Faivre (Laurence); Baurand, A. (Amandine); Jacquot, C. (Caroline); Bertolone, G. (Geoffrey); Lizard, S. (Sarab); D. Leroux (Dominique); H. Dreyfus (Hélène); C. Rebischung (Christine); Peysselon, M. (Magalie); J.-P. Peyrat; J. Fournier (Joëlle); F. Révillion (Françoise); C. Adenis (Claude); L. Vénat-Bouvet (Laurence); M. Léone (Mélanie); N. Boutry-Kryza (N.); A. Calender (Alain); S. Giraud (Sophie); C. Verny-Pierre (Carole); C. Lasset (Christine); V. Bonadona (Valérie); Barjhoux, L. (Laure); H. Sobol (Hagay); V. Bourdon (Violaine); Noguchi, T. (Tetsuro); A. Remenieras (Audrey); I. Coupier (Isabelle); P. Pujol (Pascal); J. Sokolowska (Johanna); M. Bronner (Myriam); C.D. Delnatte (Capucine); Bézieau, S. (Stéphane); Mari, V. (Véronique); M. Gauthier-Villars (Marion); B. Buecher (Bruno); E. Rouleau (Etienne); L. Golmard (Lisa); V. Moncoutier (Virginie); M. Belotti (Muriel); A. de Pauw (Antoine); Elan, C. (Camille); Fourme, E. (Emmanuelle); Birot, A.-M. (Anne-Marie); Saule, C. (Claire); Laurent, M. (Maïté); C. Houdayer (Claude); F. Lesueur (Fabienne); N. Mebirouk (Noura); F. Coulet (Florence); C. Colas (Chrystelle); F. Soubrier; Warcoin, M. (Mathilde); F. Prieur (Fabienne); M. Lebrun (Marine); C. Kientz (Caroline); D.W. Muller (Danièle); J.P. Fricker (Jean Pierre); C. Toulas (Christine); R. Guimbaud (Rosine); L. Gladieff (Laurence); V. Feillel (Viviane); I. Mortemousque (Isabelle); B. Bressac-de Paillerets (Brigitte); O. Caron (Olivier); M. Guillaud-Bataille (Marine); H. Gregory (Helen); Z. Miedzybrodzka (Zosia); P.J. Morrison (Patrick); A. Donaldson (Alan); M.T. Rogers (Mark); M.J. Kennedy (John); M.E. Porteous (Mary); A. Brady (A.); J. Barwell (Julian); Foo, C. (Claire); F. Lalloo (Fiona); L. Side (Lucy); J. Eason (Jacqueline); Henderson, A. (Alex); L.J. Walker (Lisa); J. Cook (Jackie); Snape, K. (Katie); A. Murray (Alexandra); E. McCann (Emma); M.A. Rookus (Matti); F.E. van Leeuwen (F.); L. van der Kolk (Lizet); M.K. Schmidt (Marjanka); N.S. Russell (Nicola); J.L. de Lange (J.); Wijnands, R.; J.M. Collée; M.J. Hooning (Maartje); Seynaeve, C.; C.H.M. van Deurzen (Carolien); A.I.M. Obdeijn (Inge-Marie); C.J. van Asperen (Christi); R.A.E.M. Tollenaar (Rob); T.C.T.E.F. van Cronenburg; C.M. Kets; M.G.E.M. Ausems (Margreet); C. van der Pol (Carmen); T.A.M. van Os (Theo); Q. Waisfisz (Quinten); E.J. Meijers-Heijboer (Hanne); E.B. Gómez García (Encarna); J.C. Oosterwijk (Jan); M.J. Mourits; G.H. de Bock (Geertruida); H. Vasen (Hans); Siesling, S.; Verloop, J.; L.I.H. Overbeek (Lucy); S.B. Fox (Stephen); J. Kirk (Judy); G.J. Lindeman; M. Price (Melanie)

    2016-01-01

    textabstractA locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20

  15. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

    NARCIS (Netherlands)

    Lawrenson, K.; Kar, S.; McCue, K.; Kuchenbaeker, K.; Michailidou, K.; Tyrer, J.; Beesley, J.; Ramus, S.J.; Li, Q.; Delgado, M.K.; Lee, J.M.; Aittomaki, K.; Andrulis, I.L.; Anton-Culver, H.; Arndt, V.; Arun, B.K.; Arver, B.; Bandera, E.V.; Barile, M.; Barkardottir, R.B.; Barrowdale, D.; Beckmann, M.W.; Benitez, J.; Berchuck, A.; Bisogna, M.; Bjorge, L.; Blomqvist, C.; Blot, W.; Bogdanova, N.; Bojesen, A.; Bojesen, S.E.; Bolla, M.K.; Bonanni, B.; Borresen-Dale, A.L.; Brauch, H.; Brennan, P.; Brenner, H.; Bruinsma, F.; Brunet, J.; Buhari, S.A.; Burwinkel, B.; Butzow, R.; Buys, S.S.; Cai, Q.; Caldes, T.; Campbell, I.; Canniotto, R.; Chang-Claude, J.; Chiquette, J.; Choi, J.Y.; Claes, K.B.; Cook, L.S.; Cox, A; Cramer, D.W; Cross, S.S.; Cybulski, C.; Czene, K.; Daly, M.B.; Damiola, F.; Dansonka-Mieszkowska, A.; Darabi, H.; Dennis, J.; Devilee, P.; Diez, O.; Doherty, J.A.; Domchek, S.M.; Dorfling, C.M.; Dork, T.; Dumont, M.; Ehrencrona, H.; Ejlertsen, B.; Ellis, S.; Engel, C.; Lee, E.; Evans, D.G.; Fasching, P.A.; Feliubadalo, L.; Figueroa, J.; Flesch-Janys, D.; Fletcher, O.; Flyger, H.; Foretova, L.; Fostira, F.; Foulkes, W.D.; Fridley, B.L.; Friedman, E.; Frost, D.; Gambino, G.; Ganz, P.A.; Garber, J.; Garcia-Closas, M.; Gentry-Maharaj, A.; Ghoussaini, M.; Giles, G.G.; Glasspool, R.; Godwin, A.K.; Goldberg, M.S.; Goldgar, D.E.; Gonzalez-Neira, A.; Goode, E.L.; Kiemeney, B.; Massuger, L.F.A.G.; Mensenkamp, A.R.

    2016-01-01

    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 x 10(-20)),

  16. Genome-wide linkage study suggests a susceptibility locus for isolated bilateral microtia on 4p15.32-4p16.2.

    Directory of Open Access Journals (Sweden)

    Xin Li

    Full Text Available Microtia is a congenital deformity where the external ear is underdeveloped. Genetic investigations have identified many susceptibility genes of microtia-related syndromes. However, no causal genes were reported for isolated microtia, the main form of microtia. We conducted a genome-wide linkage analysis on a 5-generation Chinese pedigree with isolated bilateral microtia. We identified a suggestive linkage locus on 4p15.32-4p16.2 with parametric LOD score of 2.70 and nonparametric linkage score (Zmean of 12.28 (simulated occurrence per genome scan equal to 0.46 and 0.47, respectively. Haplotype reconstruction analysis of the 4p15.32-4p16.2 region further confined the linkage signal to a 10-Mb segment located between rs12505562 and rs12649803 (9.65-30.24 cM; 5.54-15.58 Mb. Various human organ developmental genes reside in this 10-Mb susceptibility region, such as EVC, EVC2, SLC2A9, NKX3-2, and HMX1. The coding regions of three genes, EVC known for cartilage development and NKX3-2, HMX1 involved in microtia, were selected for sequencing with 5 individuals from the pedigree. Of the 38 identified sequence variants, none segregates along with the disease phenotype. Other genes or DNA sequences of the 10-Mb region warrant for further investigation. In conclusion, we report a susceptibility locus of isolated microtia, and this finding will encourage future studies on the genetic basis of ear deformity.

  17. Genome-wide linkage study suggests a susceptibility locus for isolated bilateral microtia on 4p15.32-4p16.2.

    Science.gov (United States)

    Li, Xin; Hu, Jintian; Zhang, Jiao; Jin, Qian; Wang, Duen-Mei; Yu, Jun; Zhang, Qingguo; Zhang, Yong-Biao

    2014-01-01

    Microtia is a congenital deformity where the external ear is underdeveloped. Genetic investigations have identified many susceptibility genes of microtia-related syndromes. However, no causal genes were reported for isolated microtia, the main form of microtia. We conducted a genome-wide linkage analysis on a 5-generation Chinese pedigree with isolated bilateral microtia. We identified a suggestive linkage locus on 4p15.32-4p16.2 with parametric LOD score of 2.70 and nonparametric linkage score (Zmean) of 12.28 (simulated occurrence per genome scan equal to 0.46 and 0.47, respectively). Haplotype reconstruction analysis of the 4p15.32-4p16.2 region further confined the linkage signal to a 10-Mb segment located between rs12505562 and rs12649803 (9.65-30.24 cM; 5.54-15.58 Mb). Various human organ developmental genes reside in this 10-Mb susceptibility region, such as EVC, EVC2, SLC2A9, NKX3-2, and HMX1. The coding regions of three genes, EVC known for cartilage development and NKX3-2, HMX1 involved in microtia, were selected for sequencing with 5 individuals from the pedigree. Of the 38 identified sequence variants, none segregates along with the disease phenotype. Other genes or DNA sequences of the 10-Mb region warrant for further investigation. In conclusion, we report a susceptibility locus of isolated microtia, and this finding will encourage future studies on the genetic basis of ear deformity.

  18. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age.

    Science.gov (United States)

    Deelen, Joris; Beekman, Marian; Uh, Hae-Won; Broer, Linda; Ayers, Kristin L; Tan, Qihua; Kamatani, Yoichiro; Bennet, Anna M; Tamm, Riin; Trompet, Stella; Guðbjartsson, Daníel F; Flachsbart, Friederike; Rose, Giuseppina; Viktorin, Alexander; Fischer, Krista; Nygaard, Marianne; Cordell, Heather J; Crocco, Paolina; van den Akker, Erik B; Böhringer, Stefan; Helmer, Quinta; Nelson, Christopher P; Saunders, Gary I; Alver, Maris; Andersen-Ranberg, Karen; Breen, Marie E; van der Breggen, Ruud; Caliebe, Amke; Capri, Miriam; Cevenini, Elisa; Collerton, Joanna C; Dato, Serena; Davies, Karen; Ford, Ian; Gampe, Jutta; Garagnani, Paolo; de Geus, Eco J C; Harrow, Jennifer; van Heemst, Diana; Heijmans, Bastiaan T; Heinsen, Femke-Anouska; Hottenga, Jouke-Jan; Hofman, Albert; Jeune, Bernard; Jonsson, Palmi V; Lathrop, Mark; Lechner, Doris; Martin-Ruiz, Carmen; Mcnerlan, Susan E; Mihailov, Evelin; Montesanto, Alberto; Mooijaart, Simon P; Murphy, Anne; Nohr, Ellen A; Paternoster, Lavinia; Postmus, Iris; Rivadeneira, Fernando; Ross, Owen A; Salvioli, Stefano; Sattar, Naveed; Schreiber, Stefan; Stefánsson, Hreinn; Stott, David J; Tiemeier, Henning; Uitterlinden, André G; Westendorp, Rudi G J; Willemsen, Gonneke; Samani, Nilesh J; Galan, Pilar; Sørensen, Thorkild I A; Boomsma, Dorret I; Jukema, J Wouter; Rea, Irene Maeve; Passarino, Giuseppe; de Craen, Anton J M; Christensen, Kaare; Nebel, Almut; Stefánsson, Kári; Metspalu, Andres; Magnusson, Patrik; Blanché, Hélène; Christiansen, Lene; Kirkwood, Thomas B L; van Duijn, Cornelia M; Franceschi, Claudio; Houwing-Duistermaat, Jeanine J; Slagboom, P Eline

    2014-08-15

    The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥ 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

  19. A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23.

    Science.gov (United States)

    Wu, Xifeng; Scelo, Ghislaine; Purdue, Mark P; Rothman, Nathaniel; Johansson, Mattias; Ye, Yuanqing; Wang, Zhaoming; Zelenika, Diana; Moore, Lee E; Wood, Christopher G; Prokhortchouk, Egor; Gaborieau, Valerie; Jacobs, Kevin B; Chow, Wong-Ho; Toro, Jorge R; Zaridze, David; Lin, Jie; Lubinski, Jan; Trubicka, Joanna; Szeszenia-Dabrowska, Neonilia; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Mates, Dana; Jinga, Viorel; Bencko, Vladimir; Slamova, Alena; Holcatova, Ivana; Navratilova, Marie; Janout, Vladimir; Boffetta, Paolo; Colt, Joanne S; Davis, Faith G; Schwartz, Kendra L; Banks, Rosamonde E; Selby, Peter J; Harnden, Patricia; Berg, Christine D; Hsing, Ann W; Grubb, Robert L; Boeing, Heiner; Vineis, Paolo; Clavel-Chapelon, Françoise; Palli, Domenico; Tumino, Rosario; Krogh, Vittorio; Panico, Salvatore; Duell, Eric J; Quirós, José Ramón; Sanchez, Maria-José; Navarro, Carmen; Ardanaz, Eva; Dorronsoro, Miren; Khaw, Kay-Tee; Allen, Naomi E; Bueno-de-Mesquita, H Bas; Peeters, Petra H M; Trichopoulos, Dimitrios; Linseisen, Jakob; Ljungberg, Börje; Overvad, Kim; Tjønneland, Anne; Romieu, Isabelle; Riboli, Elio; Stevens, Victoria L; Thun, Michael J; Diver, W Ryan; Gapstur, Susan M; Pharoah, Paul D; Easton, Douglas F; Albanes, Demetrius; Virtamo, Jarmo; Vatten, Lars; Hveem, Kristian; Fletcher, Tony; Koppova, Kvetoslava; Cussenot, Olivier; Cancel-Tassin, Geraldine; Benhamou, Simone; Hildebrandt, Michelle A; Pu, Xia; Foglio, Mario; Lechner, Doris; Hutchinson, Amy; Yeager, Meredith; Fraumeni, Joseph F; Lathrop, Mark; Skryabin, Konstantin G; McKay, James D; Gu, Jian; Brennan, Paul; Chanock, Stephen J

    2012-01-15

    Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome-wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r(2) = 0.64, D ' = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 × 10(-10) and P = 6.07 × 10(-9), respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13-1.26] for rs718314 and 1.18 (95% CI: 1.12-1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist-hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR.

  20. Diabetes susceptibility at IDDM2 cannot be positively mapped to the VNTR locus of the insulin gene.

    Science.gov (United States)

    Doria, A; Lee, J; Warram, J H; Krolewski, A S

    1996-05-01

    An inconsistency has come to light between the conclusion of Lucassen et al. that IDDM2 (11p15.5) must lie within a 4.1 kilobase (kb) segment at the insulin (INS) locus and their own data showing statistically significant associations between insulin-dependent diabetes mellitus (IDDM) and markers beyond the boundaries of that segment. We present data from an independent study of 201 IDDM patients and 107 non-diabetic control subjects that also show significant association with a marker 5' of the INS locus. Patients and control subjects were genotyped at INS/+ 1140 A/C (a surrogate for the variable number tandem repeat (VNTR) polymorphism in the regulatory part of the INS gene) and a marker 5' of the tyrosine hydroxylase (TH) gene, TH/pINS500-RsaI, making it 10 kb 5' of the VNTR. Homozygotes for INS/ + 1140 allele '+' were significantly more frequent among IDDM patients than among control subjects (73 vs 45%, p < 0.001) giving an odds ratio of 3.3 (95% confidence interval (CI): 2.0-5.3). A very similar association was found for homozygotes for the TH/RsaI allele '+' (53 vs 31%, p < 0.001) giving an odds ratio of 2.6 (95%CI 1.6-4.2). By multilocus analysis, the TH/RsaI allele '+' identified a subset of INS/ + 1140 alleles '+' haplotypes that are more specifically associated with IDDM (odds ratio = 5.4, 95%CI 2.9-10.4) than allele + 1140 '+' as a whole. In conclusion, the segment of chromosome 11 that is associated with IDDM spans, at least, the INS and TH loci. No legitimate claim can be made that IDDM2 corresponds to the VNTR polymorphism at the INS locus until the correct boundaries for IDDM2 have been defined and other loci within them have been excluded as determinants of IDDM.

  1. Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility.

    Science.gov (United States)

    Pöllänen, Petra M; Lempainen, Johanna; Laine, Antti-Pekka; Toppari, Jorma; Veijola, Riitta; Vähäsalo, Paula; Ilonen, Jorma; Siljander, Heli; Knip, Mikael

    2017-07-01

    In this study, we aimed to characterise rapid progressors to type 1 diabetes among children recruited from the general population, on the basis of HLA-conferred disease susceptibility. We monitored 7410 HLA-predisposed children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study for the development of beta cell autoimmunity and type 1 diabetes from birth over a median follow-up time of 16.2 years (range 0.9-21.1 years). Islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD (GADA) and islet antigen 2 (IA-2A) were assessed as markers of beta cell autoimmunity. Rapid progression was defined as progression to clinical type 1 diabetes within 1.5 years of autoantibody seroconversion. We analysed the association between rapid progression and demographic and autoantibody characteristics as well as genetic markers, including 25 non-HLA SNPs predisposing to type 1 diabetes. Altogether, 1550 children (21%) tested positive for at least one diabetes-associated autoantibody in at least two samples, and 248 (16%) of seroconverters progressed to type 1 diabetes by the end of 2015. The median time from seroconversion to diagnosis was 0.51 years in rapid progressors (n = 42, 17%) and 5.4 years in slower progressors. Rapid progression was observed both among young (7 years), resulting in a double-peak distribution of seroconversion age. Compared with slower progressors, rapid progressors had a higher frequency of positivity for multiple (≥2) autoantibodies and had higher titres of ICA, IAA and IA-2A at seroconversion, and there was a higher prevalence of the secretor genotype in the FUT2 gene among those carrying the high-risk HLA genotype. Compared with autoantibody-positive non-progressors, rapid progressors were younger, were more likely to carry the high-risk HLA genotype and a predisposing SNP in the PTPN22 gene, had higher frequency of ICA, IAA, GADA and IA-2A positivity and multipositivity, and had higher titres of all

  2. A shared HLA-DRB1 sequence confers RA susceptibility in Greeks.

    Science.gov (United States)

    Carthy, D; Ollier, W; Papasteriades, C; Pappas, H; Thomson, W

    1993-10-01

    Previous serological studies of Greek rheumatoid arthritis (RA) patients have failed to demonstrate an association with DR4. Using sequence specific oligonucleotide typing we have identified the DRB1 alleles in panels of Greek RA patients and controls. When patient and control HLA-DRB1 frequencies were compared, significantly higher frequencies of DRB1*0101 (23.3% vs. 7.0%, odds ratio [OR] 4.0, 95% confidence intervals [CI] 1.4-12.0) and DRB1*1001 (20.9% vs. 5.8%, OR 4.3, 95% CI 1.3-13.7) were found in RA patients compared with controls. No association of DRB1*04 with RA was observed (20.9% vs. 14.0% in controls) confirming earlier reports. However DRB1*04 subtyping demonstrated a small but significant increase of DRB1*0405 in patients (14.0% vs. 3.5%, OR 4.5, 95% CI 1.1-18.9). When the frequency of individuals carrying the shared RA susceptibility epitope was compared between patients and controls it was found to be significantly higher in RA patients (60.5% vs. 22.1%, OR 5.4, 95% CI 2.4-12.0). We conclude that the shared epitope is significantly associated with RA in this population, but that it is predominantly accounted for by DRB1*0101 and DRB1*1001. Previous studies of UK RA patients have demonstrated a negative association of DR2 with disease and articular erosions. HLA-DR2 variants, DRB1*1501 and *1502 are not at reduced frequency in Greek RA patients (DRB1*1501, 14.0% in patients vs. 7.0% in controls; DRB1*1502, 7.0% in patients vs. 7.0% in controls). Genes conferring RA resistance may be in linkage disequilibrium with DR2 in UK patients. This does not appear to be the case in Greek RA patients. No association was seen between RA and HLA-DPB1 type.

  3. Validation of genome-wide intervertebral disc calcification associations in Dachshund and further investigation of the chromosome 12 susceptibility locus

    Directory of Open Access Journals (Sweden)

    Mette Sloth eMogensen

    2012-11-01

    Full Text Available Herniation of the intervertebral disc is a common cause of neurological dysfunction in the dog, particularly in the Dachshund. Using the Illumina CanineHD BeadChip, we have previously identified a major locus on canine chromosome 12 nucleotide positions 36,750,205-38,524,449 that strongly associates with intervertebral disc calcification in Danish wire-haired Dachshunds. In this study, targeted resequencing identified two synonymous variants in MB21D1 and one in the 5’-untranslated region of KCNQ5 that associates with intervertebral disc calcification in an independent sample of wire-haired Dachshunds. Haploview identified seven linkage disequilibrium blocks across the disease associated region. The effect of haplotype windows on disc calcification shows that all haplotype windows are significantly associated with disc calcification. However, our predictions imply that the causal variant(s are most likely to be found between nucleotide 36,750,205-37,494,845 as this region explains the highest proportion of variance in the dataset. Finally, we develop a risk prediction model for wire-haired Dachshunds.We validated the association of the chromosome 12 locus with disc calcification in an independent sample of wire-haired Dachshunds and identify potential risk variants. Additionally, we estimated haplotype effects and set up a model for prediction of disc calcifications in wire-haired dachshunds based on genotype data. This genetic prediction model may prove useful in selection of breeding animals in future breeding programs

  4. A genome-wide association study identifies a region at chromosome 12 as a potential susceptibility locus for restenosis after percutaneous coronary intervention

    Science.gov (United States)

    Sampietro, M. Lourdes; Trompet, Stella; Verschuren, Jeffrey J.W.; Talens, Rudolf P.; Deelen, Joris; Heijmans, Bastiaan T.; de Winter, Robbert J.; Tio, Rene A.; Doevendans, Pieter A.F.M.; Ganesh, Santhi K.; Nabel, Elizabeth G.; Westra, Harm-Jan; Franke, Lude; van den Akker, Erik B.; Westendorp, Rudi G.J.; Zwinderman, Aeilko H.; Kastrati, Adnan; Koch, Werner; Slagboom, P.Eline; de Knijff, Peter; Jukema, J. Wouter

    2011-01-01

    Percutaneous coronary intervention (PCI) has become an effective therapy to treat obstructive coronary artery diseases (CAD). However, one of the major drawbacks of PCI is the occurrence of restenosis in 5–25% of all initially treated patients. Restenosis is defined as the re-narrowing of the lumen of the blood vessel, resulting in renewed symptoms and the need for repeated intervention. To identify genetic variants that are associated with restenosis, a genome-wide association study (GWAS) was conducted in 295 patients who developed restenosis (cases) and 571 who did not (controls) from the GENetic Determinants of Restenosis (GENDER) study. Analysis of ∼550 000 single nucleotide polymorphisms (SNPs) in GENDER was followed by a replication phase in three independent case–control populations (533 cases and 3067 controls). A potential susceptibility locus for restenosis at chromosome 12, including rs10861032 (Pcombined = 1.11 × 10−7) and rs9804922 (Pcombined = 1.45 × 10−6), was identified in the GWAS and replication phase. In addition, both SNPs were also associated with coronary events (rs10861032, Padditive = 0.005; rs9804922, Padditive = 0.023) in a trial based cohort set of elderly patients with (enhanced risk of) CAD (PROSPER) and all-cause mortality in PROSPER (rs10861032, Padditive = 0.007; rs9804922, Padditive = 0.013) and GENDER (rs10861032, Padditive = 0.005; rs9804922, Padditive = 0.023). Further analysis suggests that this locus could be involved in regulatory functions. PMID:21878436

  5. Mapping of a Leishmania major gene/locus that confers pentamidine resistance by deletion and insertion of transposable element

    Directory of Open Access Journals (Sweden)

    Coelho Adriano C.

    2004-01-01

    Full Text Available Pentamidine (PEN is an alternative compound to treat antimony-resistant leishmaniasis patients, which cellular target remains unclear. One approach to the identification of prospective targets is to identify genes able to mediate PEN resistance following overexpression. Starting from a genomic library of transfected parasites bearing a multicopy episomal cosmid vector containing wild-type Leishmania major DNA, we isolated one locus capable to render PEN resistance to wild type cells after DNA transfection. In order to map this Leishmania locus, cosmid insert was deleted by two successive sets of partial digestion with restriction enzymes, followed by transfection into wild type cells, overexpression, induction and functional tests in the presence of PEN. To determine the Leishmania gene related to PEN resistance, nucleotide sequencing experiments were done through insertion of the transposon Mariner element of Drosophila melanogaster (mosK into the deleted insert to work as primer island. Using general molecular techniques, we described here this method that permits a quickly identification of a functional gene facilitating nucleotide sequence experiments from large DNA fragments. Followed experiments revealed the presence of a P-Glycoprotein gene in this locus which role in Leishmania metabolism has now been analyzed.

  6. Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24

    NARCIS (Netherlands)

    Birnbaum, Stefanie; Ludwig, Kerstin U.; Reutter, Heiko; Herms, Stefan; Steffens, Michael; Rubini, Michele; Baluardo, Carlotta; Ferrian, Melissa; de Assis, Nilma Almeida; Alblas, Margrieta A.; Barth, Sandra; Freudenberg, Jan; Lauster, Carola; Schmidt, Guel; Scheer, Martin; Braumann, Bert; Berge, Stefaan J.; Reich, Rudolf H.; Schiefke, Franziska; Hemprich, Alexander; Poetzsch, Simone; Steegers-Theunissen, Regine P.; Poetzsch, Bernd; Moebus, Susanne; Horsthemke, Bernhard; Kramer, Franz-Josef; Wienker, Thomas F.; Mossey, Peter A.; Propping, Peter; Cichon, Sven; Hoffmann, Per; Knapp, Michael; Noethen, Markus M.; Mangold, Elisabeth

    We conducted a genome-wide association study involving 224 cases and 383 controls of Central European origin to identify susceptibility loci for nonsyndromic cleft lip with or without cleft palate (NSCL/P). A 640-kb region at chromosome 8q24.21 was found to contain multiple markers with highly

  7. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

    DEFF Research Database (Denmark)

    Permuth-Wey, Jennifer; Lawrenson, Kate; Shen, Howard C

    2013-01-01

    Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent fu...

  8. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

    NARCIS (Netherlands)

    Permuth-Wey, J.; Lawrenson, K.; Shen, H.C.; Velkova, A.; Tyrer, J.P.; Chen, Z.; Lin, H.Y.; Ann Chen, Y.; Tsai, Y.Y.; Qu, X.; Ramus, S.J.; Karevan, R.; Lee, J. van der; Lee, N.; Larson, M.C.; Aben, K.K.H.; Anton-Culver, H.; Antonenkova, N.; Antoniou, A.C.; Armasu, S.M.; Bacot, F.; Baglietto, L.; Bandera, E.V.; Barnholtz-Sloan, J.; Beckmann, M.W.; Birrer, M.J.; Bloom, G.; Bogdanova, N.; Brinton, L.A.; Brooks-Wilson, A.; Brown, R.; Butzow, R.; Cai, Q.; Campbell, I.; Chang-Claude, J.; Chanock, S.; Chenevix-Trench, G.; Cheng, J.Q.; Cicek, M.S.; Coetzee, G.A.; Cook, L.S.; Couch, F.J.; Cramer, D.W; Cunningham, J.M.; Dansonka-Mieszkowska, A.; Despierre, E.; Doherty, J.A.; Dork, T.; Bois, A. du; Durst, M.; Easton, D.F.; Eccles, D.; Edwards, R.; Ekici, A.B.; Fasching, P.A.; Fenstermacher, D.A.; Flanagan, J.M.; Garcia-Closas, M.; Gentry-Maharaj, A.; Giles, G.G.; Glasspool, R.M.; Gonzalez-Bosquet, J.; Goodman, M.T.; Gore, M.; Gorski, B.; Gronwald, J.; Hall, P.; Halle, M.K.; Harter, P.; Heitz, F.; Hillemanns, P.; Hoatlin, M.; Hogdall, C.K.; Hogdall, E.; Hosono, S.; Jakubowska, A.; Jensen, A.; Jim, H.; Kalli, K.R.; Karlan, B.Y.; Kaye, S.B.; Kelemen, L.E.; Kiemeney, L.A.L.M.; Kikkawa, F.; Konecny, G.E.; Krakstad, C.; Kruger Kjaer, S.; Kupryjanczyk, J.; Lambrechts, D.; Lambrechts, S.; Lancaster, J.M.; Le, N.D.; Leminen, A.; Levine, D.A.; Liang, D.; Kiong Lim, B.; Lin, J.; Massuger, L.F.A.G.; Altena, A.M. van

    2013-01-01

    Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent funct

  9. A novel Dock8 gene mutation confers diabetogenic susceptibility in the LEW.1AR1/Ztm-iddm rat, an animal model of human type 1 diabetes

    NARCIS (Netherlands)

    Arndt, Tanja; Wedekind, Dirk; Jörns, Anne; Tsiavaliaris, Georgios; Cuppen, Edwin; Hedrich, Hans-Jürgen; Lenzen, Sigurd

    2015-01-01

    AIMS/HYPOTHESIS: The LEW.1AR1-iddm rat, an animal model of human type 1 diabetes, arose through a spontaneous mutation within the inbred strain LEW.1AR1. A susceptibility locus (Iddm8) on rat chromosome 1 (RNO1) has been identified previously, which is accompanied by autoimmune diabetes and the addi

  10. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

    DEFF Research Database (Denmark)

    Lawrenson, Kate; Kar, Siddhartha; McCue, Karen

    2016-01-01

    BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P...A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative...

  11. A novel third chromosomal locus controls susceptibility to Autographa californica multiple nucleopolyhedrovirus in the silkworm, Bombyx mori.

    Science.gov (United States)

    Xu, Jian; Kusakabe, Takahiro; Yamamoto, Kimiko; Suetsugu, Yoshitaka; Mon, Hiroaki; Li, Zhiqing; Zhu, Li; Iiyama, Kazuhiro; Banno, Yutaka; Yoshimura, Kaito; Lee, Jae Man

    2014-04-01

    Baculovirus demonstrates specific infection spectrums and thus one certain host exhibits particular response to single baculovirus isolate. Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is considered to be not an innate pathogen to Bombyx mori, but some silkworm strains have been identified to be permissive to AcMNPV, indicating the positive or negative involvement of certain host factors in baculovirus replications in vivo. To provide a fundamental knowledge of this process, we performed large-scale screening to investigate the responses of 448 silkworm strains against recombinant AcMNPV inoculation. By genetic analysis between permissive and resistant strains identified, we further confirmed that a potential corresponding locus on chromosome 3 regulates host responses to AcMNPV in silkworm. Additionally, we found that it is available for AcMNPV-silkworm baculovirus expression vector system to produce proteins of interest.

  12. Validation of genome-wide intervertebral disk calcification associations in Dachshund and further investigation of the chromosome 12 susceptibility locus

    DEFF Research Database (Denmark)

    Ryt-Hansen, Mette Egesborg; Scheibye-Alsing, Karsten; Karlskov-Mortensen, Peter;

    2012-01-01

    associates with intervertebral disk calcification in Danish wire-haired Dachshunds. In this study, targeted resequencing identified two synonymous variants in MB21D1 and one in the 5'-untranslated region of KCNQ5 that associates with intervertebral disk calcification in an independent sample of wire......-haired Dachshunds. Haploview identified seven linkage disequilibrium blocks across the disease-associated region. The effect of haplotype windows on disk calcification shows that all haplotype windows are significantly associated with disk calcification. However, our predictions imply that the causal variant......(s) are most likely to be found between nucleotide 36,750,205-37,494,845 as this region explains the highest proportion of variance in the dataset. Finally, we develop a risk prediction model for wire-haired Dachshunds. We validated the association of the chromosome 12 locus with disk calcification...

  13. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

    OpenAIRE

    Lawrenson, Kate; Kar, Siddhartha; McCue, Karen; Kuchenbaeker, Karoline; Michailidou, Kyriaki; Tyrer, Jonathan; Beesley, Jonathan; Ramus, Susan J.; Li, Qiyuan; Delgado, Melissa K; Lee, Janet M.; Aittomäki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker

    2016-01-01

    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10−20), ER-negative BC (P=1.1 × 10−13), BRCA1-associated BC (P=7.7 × 10−16) and triple negative BC (P-diff=2 × 10−5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10...

  14. Evidence for association of D1S249 locus on human chromosome 1 with the susceptibility to essential hypertension in Han Chinese

    Institute of Scientific and Technical Information of China (English)

    ZHENG; Yong; (

    2001-01-01

    [1]Jeunemaitre, X., Soubrier, F., Kotelevtsev, Y. V. et al., Molecular basis of hypertension: role of angiotensinogen, Cell, 1993, 71: 169.[2]Hingorani, A. D., Sharma, P., Jia, H. et al., Blood pressure and M235T polymorphism of the angiotensinogen gene, Hypertension, 1996, 28: 907.[3]Liu, Y., Zhou, W. Y., Qiu, C. C. et al., Association analysis of polymorphisms of ACE gene and AGT gene with essential hypertension in Chinese Han's population, Chin. Med. Sci. J., 1998, 13(2): 71.[4]Davies, E., Bonnar, D. A., Lathrop, G. M. et al., Human angiotensin II type I receptor locus, CA repeat polymorphism and genetic mapping, Hum. Mol. Genet., 1994, 3: 838.[5]Kainulainen, K., Perola, M., Terwilliger, J. et al., Evidence for involvement of the type I angiotensin II receptor locus in essential hypertension, Hypertension, 1999, 33: 844.[6]Wang, W. Y. S., Zee, R. Y. L., Morris, B. J. et al., Association of angiotensin II type I receptor gene polymorphism with essential hypertension, Clin. Genet., 1997, 51: 31.[7]Mastana, S., Nunn, J., Angiotensin-converting enzyme deletion polymorphism is associated with hypertension in a sikh population, Human Hered., 1997, 47: 250.[8]Poirier, O., Georges, J. L., Ricard, S. et al., New polymorphisms of the angiotensin II type I receptor gene and their associations with myocardial infarction and blood pressure: the ECTIM study, J. of Hypertension, 1998, 16: 1443.[9]Liu, Y., Qiu, C. C., Zhou, W. Y. et al., Gene polymorphisms of the renin-angiotensin system in essential hypertension, Chinese Medical Journal, 1999, 112(2): 115.[10] Todd, J. A., Genetic analysis of type I diabetes using whole genome approaches, Proc. Natl. Acad. Sci. USA, 1995, 92: 8560.[11] Hanis, C. L., Boerwinkle, E., Chakraborty, R. et al., A genome-wide search for human non-insulin-dependent (type II) diabetes genes reveals a major susceptibility locus on chromosome 2, Nature Genetics, 1996, 13: 161.[12] Hager, J., Dina, C

  15. HLA-DRB1-DQB1 Haplotypes Confer Susceptibility and Resistance to Multiple Sclerosis in Sardinia

    Science.gov (United States)

    Cocco, Eleonora; Sardu, Claudia; Pieroni, Enrico; Valentini, Maria; Murru, Raffaele; Costa, Gianna; Tranquilli, Stefania; Frau, Jessica; Coghe, Giancarlo; Carboni, Nicola; Floris, Matteo; Contu, Paolo; Marrosu, Maria Giovanna

    2012-01-01

    :02, *06:01 alleles. Conclusions These findings show that the association of specific, independent DRB1*-DQB1* haplotypes confers susceptibility or resistance to MS in the MS-prone Sardinian population. The data also supports a functional role for specific residues of the DRB1 and DQB1 proteins in predisposing patients to MS. PMID:22509268

  16. The gene desert mammary carcinoma susceptibility locus Mcs1a regulates Nr2f1 modifying mammary epithelial cell differentiation and proliferation.

    Directory of Open Access Journals (Sweden)

    Bart M G Smits

    2013-06-01

    Full Text Available Genome-wide association studies have revealed that many low-penetrance breast cancer susceptibility loci are located in non-protein coding genomic regions; however, few have been characterized. In a comparative genetics approach to model such loci in a rat breast cancer model, we previously identified the mammary carcinoma susceptibility locus Mcs1a. We now localize Mcs1a to a critical interval (277 Kb within a gene desert. Mcs1a reduces mammary carcinoma multiplicity by 50% and acts in a mammary cell-autonomous manner. We developed a megadeletion mouse model, which lacks 535 Kb of sequence containing the Mcs1a ortholog. Global gene expression analysis by RNA-seq revealed that in the mouse mammary gland, the orphan nuclear receptor gene Nr2f1/Coup-tf1 is regulated by Mcs1a. In resistant Mcs1a congenic rats, as compared with susceptible congenic control rats, we found Nr2f1 transcript levels to be elevated in mammary gland, epithelial cells, and carcinoma samples. Chromatin looping over ∼820 Kb of sequence from the Nr2f1 promoter to a strongly conserved element within the Mcs1a critical interval was identified. This element contains a 14 bp indel polymorphism that affects a human-rat-mouse conserved COUP-TF binding motif and is a functional Mcs1a candidate. In both the rat and mouse models, higher Nr2f1 transcript levels are associated with higher abundance of luminal mammary epithelial cells. In both the mouse mammary gland and a human breast cancer global gene expression data set, we found Nr2f1 transcript levels to be strongly anti-correlated to a gene cluster enriched in cell cycle-related genes. We queried 12 large publicly available human breast cancer gene expression studies and found that the median NR2F1 transcript level is consistently lower in 'triple-negative' (ER-PR-HER2- breast cancers as compared with 'receptor-positive' breast cancers. Our data suggest that the non-protein coding locus Mcs1a regulates Nr2f1, which is a candidate

  17. Aim2-deficiency stimulates the expression of interferon-inducible Ifi202, a lupus susceptibility murine gene within the Nba2 autoimmune susceptibility locus

    Science.gov (United States)

    Panchanathan, Ravichandran; Duan, Xin; Shen, Hui; Rathinam, Vijay A. K.; Erickson, Loren D.; Fitzgerald, Katherine A; Choubey, Divaker

    2010-01-01

    Murine Aim2 and p202 proteins (encoded by the Aim2 and Ifi202 genes) are members of the interferon (IFN)-inducible p200-protein family. Both proteins can sense double-stranded DNA (dsDNA) in the cytoplasm. However, upon sensing dsDNA, only the Aim2 protein through its pyrin domain (PYD) can form an inflammasome to activate caspase-1 and induce cell death. Given that the p202 protein has been predicted to inhibit the activation of caspase-1 by the Aim2 protein and that increased levels of the p202 protein in female mice of certain strains are associated with lupus susceptibility, we compared the expression of Aim2 and Ifi202 genes between Aim2-deficient and age-matched wild type mice. We found that the Aim2-deficiency in immune cells stimulated the expression of Ifi202 gene. The increased levels of the p202 protein in cells were associated with increases in the expression of IFN-β, STAT1, and IFN-inducible genes. Moreover, after knockdown of Aim2 expression in the murine macrophage cell line J774.A1, IFN-β treatment of cells robustly increased STAT1 protein levels (as compared to control cells), increased the activating phosphorylation of STAT1 on Tyr-701, and stimulated the activity of an IFN-responsive reporter. Notably, the expression of Aim2 in non lupus-prone (C57BL/6 and B6.Nba2-C) and lupus-prone B6.Nba2-ABC splenic cells and in a murine macrophage cell line that overexpressed p202 protein was found to be inversely correlated with Ifi202. Collectively, our observations demonstrate an inverse correlation between Aim2 and p202 expressions. We predict that defects in Aim2 expression within immune cells contribute to increased susceptibility to lupus. PMID:21057088

  18. 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

    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.

  19. Positive replication and linkage disequilibrium mapping of the Chromosome 21q22.1 malaria susceptibility locus

    Science.gov (United States)

    Khor, Chiea C.; Vannberg, Fredrik O.; Chapman, Stephen J.; Walley, Andrew; Aucan, Christophe; Loke, Hsin; White, Nicholas J.; Peto, Tim; Khor, Lih K.; Kwiatkowski, Dominic; Day, Nick; Scott, Anthony; Berkley, James A.; Marsh, Kevin; Peshu, Norbert; Maitland, Kathryn; Williams, Thomas N.; Hill, Adrian V. S.

    2009-01-01

    Four cytokine receptor genes are located on Chr21q22.11, encoding the α and β subunits of the interferon alpha receptor (IFNAR1 and IFNAR2), the β subunit of the interleukin 10 receptor (IL10RB), and the second subunit of the interferon gamma receptor (IFNGR2). We previously reported that two variants in IFNAR1 were associated with susceptibility to malaria in Gambians. We now present an extensive fine-scale mapping of the associated region utilizing 45 additional genetic markers obtained from public databases and by sequencing a 44kb region in and around the IFNAR1 gene in 24 Gambian children (12 cases/ 12 controls). Within the IFNAR1 gene a newly studied C→G single nucleotide polymorphism (IFNAR1 272354c-g) at position −576 relative to the transcription start was found to be more strongly associated with susceptibility to severe malaria. Association was observed in three populations: in Gambian (P=0.002), Kenyan (P=0.022) and Vietnamese (P=0.005) case control studies. When all three studies were combined, using the Mantel-Haenszel test, the presence of IFNAR1 −576G was associated with a substantially elevated risk of severe malaria (N=2444, OR=1.38, 95%CI: 1.17-1.64; P=1.7×10−4). This study builds on previous work to further highlight the importance of the type I interferon pathway in malaria susceptibility and illustrates the utility of typing SNPs within regions of high linkage disequilibrium in multiple populations to confirm initial positive associations. PMID:17703179

  20. Positive replication and linkage disequilibrium mapping of the Chromosome 21q22.1 malaria susceptibility locus

    OpenAIRE

    Khor, Chiea C.; Vannberg, Fredrik O.; Chapman, Stephen J.; Walley, Andrew; Aucan, Christophe; Loke, Hsin; White, Nicholas J.; Peto, Tim; Khor, Lih K.; Kwiatkowski, Dominic; Day, Nick; Scott, Anthony; Berkley, James A.; Marsh, Kevin; Peshu, Norbert

    2007-01-01

    Four cytokine receptor genes are located on Chr21q22.11, encoding the α and β subunits of the interferon alpha receptor (IFNAR1 and IFNAR2), the β subunit of the interleukin 10 receptor (IL10RB), and the second subunit of the interferon gamma receptor (IFNGR2). We previously reported that two variants in IFNAR1 were associated with susceptibility to malaria in Gambians. We now present an extensive fine-scale mapping of the associated region utilizing 45 additional genetic markers obtained fro...

  1. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer

    Science.gov (United States)

    Amundadottir, Laufey; Kraft, Peter; Stolzenberg-Solomon, Rachael Z.; Fuchs, Charles S.; Petersen, Gloria M.; Arslan, Alan A.; Bueno-de-Mesquita, H. Bas; Gross, Myron; Helzlsouer, Kathy; Jacobs, Eric J.; LaCroix, Andrea; Zheng, Wei; Albanes, Demetrius; Bamlet, William; Berg, Christine D.; Berrino, Franco; Bingham, Sheila; Buring, Julie E.; Bracci, Paige M.; Canzian, Federico; Clavel-Chapelon, Françoise; Clipp, Sandra; Cotterchio, Michelle; de Andrade, Mariza; Duell, Eric J.; Fox, John W.; Gallinger, Steven; Gaziano, J. Michael; Giovannucci, Edward L.; Goggins, Michael; González, Carlos A.; Hallmans, Göran; Hankinson, Susan E.; Hassan, Manal; Holly, Elizabeth A.; Hunter, David J.; Hutchinson, Amy; Jackson, Rebecca; Jacobs, Kevin B.; Jenab, Mazda; Kaaks, Rudolf; Klein, Alison P.; Kooperberg, Charles; Kurtz, Robert C.; Li, Donghui; Lynch, Shannon M.; Mandelson, Margaret; McWilliams, Robert R.; Mendelsohn, Julie B.; Michaud, Dominique S.; Olson, Sara H.; Overvad, Kim; Patel, Alpa V.; Peeters, Petra H.M.; Rajkovic, Aleksandar; Riboli, Elio; Risch, Harvey A.; Shu, Xiao-Ou; Thomas, Gilles; Tobias, Geoffrey S.; Trichopoulos, Dimitrios; Van Den Eeden, Stephen K.; Virtamo, Jarmo; Wactawski-Wende, Jean; Wolpin, Brian M.; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Chanock, Stephen J.; Hartge, Patricia; Hoover, Robert N.

    2010-01-01

    We conducted a two-stage genome-wide association study (GWAS) of pancreatic cancer, a cancer with one of the poorest survival rates worldwide. Initially, we genotyped 558,542 single nucleotide polymorphisms in 1,896 incident cases and 1,939 controls drawn from twelve prospective cohorts plus one hospital-based case-control study. In a combined analysis adjusted for study, sex, ancestry and five principal components that included an additional 2,457 cases and 2,654 controls from eight case-control studies, we identified an association between a locus on 9q34 and pancreatic cancer marked by the single nucleotide polymorphism, rs505922 (combined P=5.37 × 10-8; multiplicative per-allele odds ratio (OR) 1.20; 95% CI 1.12-1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B. PMID:19648918

  2. A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13.

    Science.gov (United States)

    Cho, Michael H; Castaldi, Peter J; Wan, Emily S; Siedlinski, Mateusz; Hersh, Craig P; Demeo, Dawn L; Himes, Blanca E; Sylvia, Jody S; Klanderman, Barbara J; Ziniti, John P; Lange, Christoph; Litonjua, Augusto A; Sparrow, David; Regan, Elizabeth A; Make, Barry J; Hokanson, John E; Murray, Tanda; Hetmanski, Jacqueline B; Pillai, Sreekumar G; Kong, Xiangyang; Anderson, Wayne H; Tal-Singer, Ruth; Lomas, David A; Coxson, Harvey O; Edwards, Lisa D; MacNee, William; Vestbo, Jørgen; Yates, Julie C; Agusti, Alvar; Calverley, Peter M A; Celli, Bartolome; Crim, Courtney; Rennard, Stephen; Wouters, Emiel; Bakke, Per; Gulsvik, Amund; Crapo, James D; Beaty, Terri H; Silverman, Edwin K

    2012-02-15

    The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genome-wide significant locus on chromosome 19q13 (rs7937, OR = 0.74, P = 2.9 × 10(-9)). Genotyping this single nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P = 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV(1) (P = 0.08 and 0.04) and severe (GOLD 3&4) COPD (P = 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.

  3. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus

    Science.gov (United States)

    Lawrenson, Kate; Kar, Siddhartha; McCue, Karen; Kuchenbaeker, Karoline; Michailidou, Kyriaki; Tyrer, Jonathan; Beesley, Jonathan; Ramus, Susan J.; Li, Qiyuan; Delgado, Melissa K.; Lee, Janet M.; Aittomäki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K.; Arver, Brita; Bandera, Elisa V.; Barile, Monica; Barkardottir, Rosa B.; Barrowdale, Daniel; Beckmann, Matthias W.; Benitez, Javier; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Blomqvist, Carl; Blot, William; Bogdanova, Natalia; Bojesen, Anders; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Bruinsma, Fiona; Brunet, Joan; Buhari, Shaik Ahmad; Burwinkel, Barbara; Butzow, Ralf; Buys, Saundra S.; Cai, Qiuyin; Caldes, Trinidad; Campbell, Ian; Canniotto, Rikki; Chang-Claude, Jenny; Chiquette, Jocelyne; Choi, Ji-Yeob; Claes, Kathleen B. M.; Collonge-Rame, Marie- Agnès; Damette, Alexandre; Barouk-Simonet, Emmanuelle; Bonnet, Françoise; Bubien, Virginie; Sevenet, Nicolas; Longy, Michel; Berthet, Pascaline; Vaur, Dominique; Castera, Laurent; Ferrer, Sandra Fert; Bignon, Yves-Jean; Uhrhammer, Nancy; Coron, Fanny; Faivre, Laurence; Baurand, Amandine; Jacquot, Caroline; Bertolone, Geoffrey; Lizard, Sarab; Leroux, Dominique; Dreyfus, Hélène; Rebischung, Christine; Peysselon, Magalie; Peyrat, Jean-Philippe; Fournier, Joëlle; Révillion, Françoise; Adenis, Claude; Vénat-Bouvet, Laurence; Léone, Mélanie; Boutry-Kryza, Nadia; Calender, Alain; Giraud, Sophie; Verny-Pierre, Carole; Lasset, Christine; Bonadona, Valérie; Barjhoux, Laure; Sobol, Hagay; Bourdon, Violaine; Noguchi, Tetsuro; Remenieras, Audrey; Coupier, Isabelle; Pujol, Pascal; Sokolowska, Johanna; Bronner, Myriam; Delnatte, Capucine; Bézieau, Stéphane; Mari, Véronique; Gauthier-Villars, Marion; Buecher, Bruno; Rouleau, Etienne; Golmard, Lisa; Moncoutier, Virginie; Belotti, Muriel; de Pauw, Antoine; Elan, Camille; Fourme, Emmanuelle; Birot, Anne-Marie; Saule, Claire; Laurent, Maïté; Houdayer, Claude; Lesueur, Fabienne; Mebirouk, Noura; Coulet, Florence; Colas, Chrystelle; Soubrier, Florent; Warcoin, Mathilde; Prieur, Fabienne; Lebrun, Marine; Kientz, Caroline; Muller, Danièle; Fricker, Jean-Pierre; Toulas, Christine; Guimbaud, Rosine; Gladieff, Laurence; Feillel, Viviane; Mortemousque, Isabelle; Bressac-de-Paillerets, Brigitte; Caron, Olivier; Guillaud-Bataille, Marine; Cook, Linda S.; Cox, Angela; Cramer, Daniel W.; Cross, Simon S.; Cybulski, Cezary; Czene, Kamila; Daly, Mary B.; Damiola, Francesca; Dansonka-Mieszkowska, Agnieszka; Darabi, Hatef; Dennis, Joe; Devilee, Peter; Diez, Orland; Doherty, Jennifer A.; Domchek, Susan M.; Dorfling, Cecilia M.; Dörk, Thilo; Dumont, Martine; Ehrencrona, Hans; Ejlertsen, Bent; Ellis, Steve; Gregory, Helen; Miedzybrodzka, Zosia; Morrison, Patrick J.; Donaldson, Alan; Rogers, Mark T.; Kennedy, M. John; Porteous, Mary E.; Brady, Angela; Barwell, Julian; Foo, Claire; Lalloo, Fiona; Side, Lucy E.; Eason, Jacqueline; Henderson, Alex; Walker, Lisa; Cook, Jackie; Snape, Katie; Murray, Alex; McCann, Emma; Engel, Christoph; Lee, Eunjung; Evans, D. Gareth; Fasching, Peter A.; Feliubadalo, Lidia; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Foretova, Lenka; Fostira, Florentia; Foulkes, William D.; Fridley, Brooke L.; Friedman, Eitan; Frost, Debra; Gambino, Gaetana; Ganz, Patricia A.; Garber, Judy; García-Closas, Montserrat; Gentry-Maharaj, Aleksandra; Ghoussaini, Maya; Giles, Graham G.; Glasspool, Rosalind; Godwin, Andrew K.; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Goode, Ellen L.; Goodman, Marc T.; Greene, Mark H.; Gronwald, Jacek; Guénel, Pascal; Haiman, Christopher A.; Hall, Per; Hallberg, Emily; Hamann, Ute; Hansen, Thomas V. O.; Harrington, Patricia A.; Hartman, Mikael; Hassan, Norhashimah; Healey, Sue; Rookus, M. A.; van Leeuwen, F. E.; van der Kolk, L. E.; Schmidt, M. K.; Russell, N. S.; de Lange, J. L.; Wijnands, R.; Collée, J. M.; Hooning, M. J.; Seynaeve, C.; van Deurzen, C. H. M.; Obdeijn, I. M.; van Asperen, C. J.; Tollenaar, R. A. E. M.; van Cronenburg, T. C. T. E. F.; Kets, C. M.; Ausems, M. G. E. M.; van der Pol, C. C.; van Os, T. A. M.; Waisfisz, Q.; Meijers-Heijboer, H. E. J.; Gómez-Garcia, E. B.; Oosterwijk, J. C.; Mourits, M. J.; de Bock, G. H.; Vasen, H. F.; Siesling, S.; Verloop, J.; Overbeek, L. I. H.; Heitz, Florian; Herzog, Josef; Høgdall, Estrid; Høgdall, Claus K.; Hogervorst, Frans B. L.; Hollestelle, Antoinette; Hopper, John L.; Hulick, Peter J.; Huzarski, Tomasz; Imyanitov, Evgeny N.; Fox, Stephen; Kirk, Judy; Lindeman, Geoff; Price, Melanie; Bowtell, David; deFazio, Anna; Webb, Penny; Isaacs, Claudine; Ito, Hidemi; Jakubowska, Anna; Janavicius, Ramunas; Jensen, Allan; John, Esther M.; Johnson, Nichola; Kabisch, Maria; Kang, Daehee; Kapuscinski, Miroslav; Karlan, Beth Y.; Khan, Sofia; Kiemeney, Lambertus A.; Kjaer, Susanne Kruger; Knight, Julia A.; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela; Kupryjanczyk, Jolanta; Kwong, Ava; de la Hoya, Miguel; Laitman, Yael; Lambrechts, Diether; Le, Nhu; De Leeneer, Kim; Lester, Jenny; Levine, Douglas A.; Li, Jingmei; Lindblom, Annika; Long, Jirong; Lophatananon, Artitaya; Loud, Jennifer T.; Lu, Karen; Lubinski, Jan; Mannermaa, Arto; Manoukian, Siranoush; Le Marchand, Loic; Margolin, Sara; Marme, Frederik; Massuger, Leon F. A. G.; Matsuo, Keitaro; Mazoyer, Sylvie; McGuffog, Lesley; McLean, Catriona; McNeish, Iain; Meindl, Alfons; Menon, Usha; Mensenkamp, Arjen R.; Milne, Roger L.; Montagna, Marco; Moysich, Kirsten B.; Muir, Kenneth; Mulligan, Anna Marie; Nathanson, Katherine L.; Ness, Roberta B.; Neuhausen, Susan L.; Nevanlinna, Heli; Nord, Silje; Nussbaum, Robert L.; Odunsi, Kunle; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I.; Olson, Janet E.; Olswold, Curtis; O'Malley, David; Orlow, Irene; Orr, Nick; Osorio, Ana; Park, Sue Kyung; Pearce, Celeste L.; Pejovic, Tanja; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M.; Poole, Elizabeth M.; Pylkäs, Katri; Radice, Paolo; Rantala, Johanna; Rashid, Muhammad Usman; Rennert, Gad; Rhenius, Valerie; Rhiem, Kerstin; Risch, Harvey A.; Rodriguez, Gus; Rossing, Mary Anne; Rudolph, Anja; Salvesen, Helga B.; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schildkraut, Joellen M.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Sellers, Thomas A.; Seynaeve, Caroline; Shah, Mitul; Shen, Chen-Yang; Shu, Xiao-Ou; Sieh, Weiva; Singer, Christian F.; Sinilnikova, Olga M.; Slager, Susan; Song, Honglin; Soucy, Penny; Southey, Melissa C.; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Sutter, Christian; Swerdlow, Anthony; Tchatchou, Sandrine; Teixeira, Manuel R.; Teo, Soo H.; Terry, Kathryn L.; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; Toland, Amanda Ewart; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Tseng, Chiu-chen; Tung, Nadine; Tworoger, Shelley S.; Vachon, Celine; van den Ouweland, Ans M. W.; van Doorn, Helena C.; van Rensburg, Elizabeth J.; Van't Veer, Laura J.; Vanderstichele, Adriaan; Vergote, Ignace; Vijai, Joseph; Wang, Qin; Wang-Gohrke, Shan; Weitzel, Jeffrey N.; Wentzensen, Nicolas; Whittemore, Alice S.; Wildiers, Hans; Winqvist, Robert; Wu, Anna H.; Yannoukakos, Drakoulis; Yoon, Sook-Yee; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Khanna, Kum Kum; Simard, Jacques; Monteiro, Alvaro N.; French, Juliet D.; Couch, Fergus J.; Freedman, Matthew L.; Easton, Douglas F.; Dunning, Alison M.; Pharoah, Paul D.; Edwards, Stacey L.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Gayther, Simon A.

    2016-01-01

    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10−20), ER-negative BC (P=1.1 × 10−13), BRCA1-associated BC (P=7.7 × 10−16) and triple negative BC (P-diff=2 × 10−5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10−3) and ABHD8 (P<2 × 10−3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk. PMID:27601076

  4. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.

    Science.gov (United States)

    Lawrenson, Kate; Kar, Siddhartha; McCue, Karen; Kuchenbaeker, Karoline; Michailidou, Kyriaki; Tyrer, Jonathan; Beesley, Jonathan; Ramus, Susan J; Li, Qiyuan; Delgado, Melissa K; Lee, Janet M; Aittomäki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K; Arver, Brita; Bandera, Elisa V; Barile, Monica; Barkardottir, Rosa B; Barrowdale, Daniel; Beckmann, Matthias W; Benitez, Javier; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Blomqvist, Carl; Blot, William; Bogdanova, Natalia; Bojesen, Anders; Bojesen, Stig E; Bolla, Manjeet K; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Bruinsma, Fiona; Brunet, Joan; Buhari, Shaik Ahmad; Burwinkel, Barbara; Butzow, Ralf; Buys, Saundra S; Cai, Qiuyin; Caldes, Trinidad; Campbell, Ian; Canniotto, Rikki; Chang-Claude, Jenny; Chiquette, Jocelyne; Choi, Ji-Yeob; Claes, Kathleen B M; Cook, Linda S; Cox, Angela; Cramer, Daniel W; Cross, Simon S; Cybulski, Cezary; Czene, Kamila; Daly, Mary B; Damiola, Francesca; Dansonka-Mieszkowska, Agnieszka; Darabi, Hatef; Dennis, Joe; Devilee, Peter; Diez, Orland; Doherty, Jennifer A; Domchek, Susan M; Dorfling, Cecilia M; Dörk, Thilo; Dumont, Martine; Ehrencrona, Hans; Ejlertsen, Bent; Ellis, Steve; Engel, Christoph; Lee, Eunjung; Evans, D Gareth; Fasching, Peter A; Feliubadalo, Lidia; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Foretova, Lenka; Fostira, Florentia; Foulkes, William D; Fridley, Brooke L; Friedman, Eitan; Frost, Debra; Gambino, Gaetana; Ganz, Patricia A; Garber, Judy; García-Closas, Montserrat; Gentry-Maharaj, Aleksandra; Ghoussaini, Maya; Giles, Graham G; Glasspool, Rosalind; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Goode, Ellen L; Goodman, Marc T; Greene, Mark H; Gronwald, Jacek; Guénel, Pascal; Haiman, Christopher A; Hall, Per; Hallberg, Emily; Hamann, Ute; Hansen, Thomas V O; Harrington, Patricia A; Hartman, Mikael; Hassan, Norhashimah; Healey, Sue; Heitz, Florian; Herzog, Josef; Høgdall, Estrid; Høgdall, Claus K; Hogervorst, Frans B L; Hollestelle, Antoinette; Hopper, John L; Hulick, Peter J; Huzarski, Tomasz; Imyanitov, Evgeny N; Isaacs, Claudine; Ito, Hidemi; Jakubowska, Anna; Janavicius, Ramunas; Jensen, Allan; John, Esther M; Johnson, Nichola; Kabisch, Maria; Kang, Daehee; Kapuscinski, Miroslav; Karlan, Beth Y; Khan, Sofia; Kiemeney, Lambertus A; Kjaer, Susanne Kruger; Knight, Julia A; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela; Kupryjanczyk, Jolanta; Kwong, Ava; de la Hoya, Miguel; Laitman, Yael; Lambrechts, Diether; Le, Nhu; De Leeneer, Kim; Lester, Jenny; Levine, Douglas A; Li, Jingmei; Lindblom, Annika; Long, Jirong; Lophatananon, Artitaya; Loud, Jennifer T; Lu, Karen; Lubinski, Jan; Mannermaa, Arto; Manoukian, Siranoush; Le Marchand, Loic; Margolin, Sara; Marme, Frederik; Massuger, Leon F A G; Matsuo, Keitaro; Mazoyer, Sylvie; McGuffog, Lesley; McLean, Catriona; McNeish, Iain; Meindl, Alfons; Menon, Usha; Mensenkamp, Arjen R; Milne, Roger L; Montagna, Marco; Moysich, Kirsten B; Muir, Kenneth; Mulligan, Anna Marie; Nathanson, Katherine L; Ness, Roberta B; Neuhausen, Susan L; Nevanlinna, Heli; Nord, Silje; Nussbaum, Robert L; Odunsi, Kunle; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Olswold, Curtis; O'Malley, David; Orlow, Irene; Orr, Nick; Osorio, Ana; Park, Sue Kyung; Pearce, Celeste L; Pejovic, Tanja; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M; Poole, Elizabeth M; Pylkäs, Katri; Radice, Paolo; Rantala, Johanna; Rashid, Muhammad Usman; Rennert, Gad; Rhenius, Valerie; Rhiem, Kerstin; Risch, Harvey A; Rodriguez, Gus; Rossing, Mary Anne; Rudolph, Anja; Salvesen, Helga B; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schildkraut, Joellen M; Schmidt, Marjanka K; Schmutzler, Rita K; Sellers, Thomas A; Seynaeve, Caroline; Shah, Mitul; Shen, Chen-Yang; Shu, Xiao-Ou; Sieh, Weiva; Singer, Christian F; Sinilnikova, Olga M; Slager, Susan; Song, Honglin; Soucy, Penny; Southey, Melissa C; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Sutter, Christian; Swerdlow, Anthony; Tchatchou, Sandrine; Teixeira, Manuel R; Teo, Soo H; Terry, Kathryn L; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; Toland, Amanda Ewart; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Tseng, Chiu-Chen; Tung, Nadine; Tworoger, Shelley S; Vachon, Celine; van den Ouweland, Ans M W; van Doorn, Helena C; van Rensburg, Elizabeth J; Van't Veer, Laura J; Vanderstichele, Adriaan; Vergote, Ignace; Vijai, Joseph; Wang, Qin; Wang-Gohrke, Shan; Weitzel, Jeffrey N; Wentzensen, Nicolas; Whittemore, Alice S; Wildiers, Hans; Winqvist, Robert; Wu, Anna H; Yannoukakos, Drakoulis; Yoon, Sook-Yee; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Khanna, Kum Kum; Simard, Jacques; Monteiro, Alvaro N; French, Juliet D; Couch, Fergus J; Freedman, Matthew L; Easton, Douglas F; Dunning, Alison M; Pharoah, Paul D; Edwards, Stacey L; Chenevix-Trench, Georgia; Antoniou, Antonis C; Gayther, Simon A

    2016-09-07

    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

  5. Positional mapping and candidate gene analysis of the mouse Ccs3 locus that regulates differential susceptibility to carcinogen-induced colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Charles Meunier

    Full Text Available The Ccs3 locus on mouse chromosome 3 regulates differential susceptibility of A/J (A, susceptible and C57BL/6J (B6, resistant mouse strains to chemically-induced colorectal cancer (CRC. Here, we report the high-resolution positional mapping of the gene underlying the Ccs3 effect. Using phenotype/genotype correlation in a series of 33 AcB/BcA recombinant congenic mouse strains, as well as in groups of backcross populations bearing unique recombinant chromosomes for the interval, and in subcongenic strains, we have delineated the maximum size of the Ccs3 physical interval to a ∼2.15 Mb segment. This interval contains 12 annotated transcripts. Sequencing of positional candidates in A and B6 identified many either low-priority coding changes or non-protein coding variants. We found a unique copy number variant (CNV in intron 15 of the Nfkb1 gene. The CNV consists of two copies of a 54 bp sequence immediately adjacent to the exon 15 splice site, while only one copy is found in CRC-susceptible A. The Nfkb1 protein (p105/p50 expression is much reduced in A tumors compared to normal A colonic epithelium as analyzed by immunohistochemistry. Studies in primary macrophages from A and B6 mice demonstrate a marked differential activation of the NfκB pathway by lipopolysaccharide (kinetics of stimulation and maximum levels of phosphorylated IκBα, with a more robust activation being associated with resistance to CRC. NfκB has been previously implicated in regulating homeostasis and inflammatory response in the intestinal mucosa. The interval contains another positional candidate Slc39a8 that is differentially expressed in A vs B6 colons, and that has recently been associated in CRC tumor aggressiveness in humans.

  6. Mapping of loci from Solanum lycopersicoides conferring resistance or susceptibility to Botrytis cinerea in tomato.

    Science.gov (United States)

    Davis, Joel; Yu, Daozhan; Evans, Wendy; Gokirmak, Tufan; Chetelat, Roger T; Stotz, Henrik U

    2009-07-01

    Cultivated tomato (Solanum lycopersicum, syn. Lycopersicon esculentum) is susceptible to the necrotrophic ascomycete and causal agent of gray mold, Botrytis cinerea. Resistance to this fungal pathogen is elevated in wild relatives of tomato, including Solanum lycopersicoides. An introgression line population (IL) containing chromosomal segments of S. lycopersicoides within the background of tomato cv. VF36 was used to screen the genome for foliar resistance and susceptibility to B. cinerea. Based on this screen, putative quantitative trait loci (QTL) were identified, five for resistance and two for susceptibility. Four resistance QTL decreased infection frequency while the fifth reduced lesion diameter. One susceptibility QTL increased infection frequency whereas the other increased lesion diameter. Overlapping chromosomal segments provided strong evidence for partial resistance on chromosomes 1 and 9 and for elevated susceptibility on chromosome 11. Segregation analysis confirmed the major resistance QTL on the long arm of chromosome 1 and susceptibility on chromosome 11. Linkage of partial resistance to chromosome 9 could not be confirmed. The usefulness of these data for resistance breeding and for map-based cloning of foliar resistance to B. cinerea is discussed.

  7. DNA methylation of a novel PAK4 locus influences ototoxicity susceptibility following cisplatin and radiation therapy for pediatric embryonal tumors.

    Science.gov (United States)

    Brown, Austin L; Foster, Kayla L; Lupo, Philip J; Peckham-Gregory, Erin C; Murray, Jeffrey C; Okcu, M Fatih; Lau, Ching C; Rednam, Surya P; Chintagumpala, Murali; Scheurer, Michael E

    2017-10-01

    Ototoxicity is a common adverse side effect of platinum chemotherapy and cranial radiation therapy; however, individual susceptibility is highly variable. Therefore, our objective was to conduct an epigenome-wide association study to identify differentially methylated cytosine-phosphate-guanine (CpG) sites associated with ototoxicity susceptibility among cisplatin-treated pediatric patients with embryonal tumors. Samples were collected for a discovery cohort (n = 62) and a replication cohort (n = 18) of medulloblastoma and primitive neuroectodermal tumor patients. Posttreatment audiograms were evaluated using the International Society of Paediatric Oncology (SIOP) Boston Ototoxicity Scale. Genome-wide associations between CpG methylation and ototoxicity were examined using multiple linear regression, controlling for demographic and treatment factors. The mean cumulative dose of cisplatin was 330 mg/m2 and the mean time from end of therapy to the last available audiogram was 6.9 years. In the discovery analysis of 435233 CpG sites, 6 sites were associated with ototoxicity grade (P ototoxicity severity. Methylation at cg14010619 may modify PAK4 activity, which has been implicated in cisplatin resistance in malignant cell lines.

  8. Linkage Disequilibrium Mapping of the Chromosome 6q21–22.31 Bipolar I Disorder Susceptibility Locus

    Science.gov (United States)

    Fan, Jinbo; Ionita-Laza, Iuliana; McQueen, Matthew B.; Devlin, Bernie; Purcell, Shaun; Faraone, Stephen V.; Allen, Michael H.; Bowden, Charles L.; Calabrese, Joseph R.; Fossey, Mark D.; Friedman, Edward S.; Gyulai, Laszlo; Hauser, Peter; Ketter, Terence B.; Marangell, Lauren B.; Miklowitz, David J.; Nierenberg, Andrew A.; Patel, Jayendra K.; Sachs, Gary S.; Thase, Michael E.; Molay, Francine B.; Escamilla, Michael A.; Nimgaonkar, Vishwajit L.; Sklar, Pamela; Laird, Nan M.; Smoller, Jordan W.

    2014-01-01

    We previously reported genome-wide significant evidence for linkage between chromosome 6q and bipolar I disorder (BPI) by performing a meta-analysis of original genotype data from 11 genome scan linkage studies. We now present follow-up linkage disequilibrium mapping of the linked region utilizing 3,047 single nucleotide polymorphism (SNP) markers in a case–control sample (N = 530 cases, 534 controls) and family-based sample (N = 256 nuclear families, 1,301 individuals). The strongest single SNP result (rs6938431, P=6.72× 10−5) was observed in the case–control sample, near the solute carrier family 22, member 16 gene (SLC22A16). In a replication study, we genotyped 151 SNPs in an independent sample (N = 622 cases, 1,181 controls) and observed further evidence of association between variants at SLC22A16 and BPI. Although consistent evidence of association with any single variant was not seen across samples, SNP-wise and gene-based test results in the three samples provided convergent evidence for association with SLC22A16, a carnitine transporter, implicating this gene as a novel candidate for BPI risk. Further studies in larger samples are warranted to clarify which, if any, genes in the 6q region confer risk for bipolar disorder. PMID:19308960

  9. Powdery mildew resistant cucurbit rootstocks confer tolerance to grafted susceptible watermelon scions

    Science.gov (United States)

    Cucurbit powdery mildew (PM) caused by Podosphaera xanthii can impact seedling growth and cause serious losses in greenhouse and open fields. We have developed watermelon and bottle gourd germplasm lines with high levels of resistance to PM. A PM susceptible watermelon cultivar Mickey Lee (ML) was g...

  10. Tolerance to powdery mildew conferred in susceptible watermelon scion by grafting on resistant rootstocks

    Science.gov (United States)

    Cucurbit powdery mildew (PM) caused by Podosphaera xanthii, can impact seedling growth and cause serious losses in greenhouse and open field production. We have developed several watermelon and bottle gourd germplasm lines with high levels of resistance to PM. A PM susceptible cultivar Mickey Lee ...

  11. HLA-DQB1*03 confers susceptibility to chronic hepatitis C in Japanese: a genome-wide association study.

    Directory of Open Access Journals (Sweden)

    Daiki Miki

    Full Text Available Hepatitis C virus (HCV establishes a chronic infection in 70-80% of infected individuals. Many researchers have examined the effect of human leukocyte antigen (HLA on viral persistence because of its critical role in the immune response against exposure to HCV, but almost all studies have proven to be inconclusive. To identify genetic risk factors for chronic HCV infection, we analyzed 458,207 single nucleotide polymorphisms (SNPs in 481 chronic HCV patients and 2,963 controls in a Japanese cohort. Next, we performed a replication study with an independent panel of 4,358 cases and 1,114 controls. We further confirmed the association in 1,379 cases and 25,817 controls. In the GWAS phase, we found 17 SNPs that showed suggestive association (P < 1 × 10⁻⁵. After the first replication study, we found one intronic SNP in the HLA-DQ locus associated with chronic HCV infection, and when we combined the two studies, the association reached the level of genome-wide significance. In the second replication study, we again confirmed the association (P(combined = 3.59 × 10⁻¹⁶, odds ratio [OR] = 0.79. Subsequent analysis revealed another SNP, rs1130380, with a stronger association (OR=0.72. This nucleotide substitution causes an amino acid substitution (R55P in the HLA-DQB1 protein specific to the DQB1*03 allele, which is common worldwide. In addition, we confirmed an association with the previously reported IFNL3-IFNL4 locus and propose that the effect of DQB1*03 on HCV persistence might be affected by the IFNL4 polymorphism. Our findings suggest that a common amino acid substitution in HLA-DQB1 affects susceptibility to chronic infection with HCV in the Japanese population and may not be independent of the IFNL4 genotype.

  12. Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.

    Science.gov (United States)

    Hamdi, Yosr; Soucy, Penny; Adoue, Véronique; Michailidou, Kyriaki; Canisius, Sander; Lemaçon, Audrey; Droit, Arnaud; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Baynes, Caroline; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bolla, Manjeet K; Bonanni, Bernardo; Borresen-Dale, Anne-Lise; Brand, Judith S; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Burwinkel, Barbara; Chang-Claude, Jenny; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Devilee, Peter; Dörk, Thilo; Dos-Santos-Silva, Isabel; Eriksson, Mikael; Fasching, Peter A; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G; Goldberg, Mark S; González-Neira, Anna; Grenaker-Alnæs, Grethe; Guénel, Pascal; Haeberle, Lothar; Haiman, Christopher A; Hamann, Ute; Hallberg, Emily; Hooning, Maartje J; Hopper, John L; Jakubowska, Anna; Jones, Michael; Kabisch, Maria; Kataja, Vesa; Lambrechts, Diether; Le Marchand, Loic; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Maranian, Mel; Margolin, Sara; Marme, Frederik; Milne, Roger L; Neuhausen, Susan L; Nevanlinna, Heli; Neven, Patrick; Olswold, Curtis; Peto, Julian; Plaseska-Karanfilska, Dijana; Pylkäs, Katri; Radice, Paolo; Rudolph, Anja; Sawyer, Elinor J; Schmidt, Marjanka K; Shu, Xiao-Ou; Southey, Melissa C; Swerdlow, Anthony; Tollenaar, Rob A E M; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Vachon, Celine; Van Den Ouweland, Ans M W; Wang, Qin; Winqvist, Robert; Zheng, Wei; Benitez, Javier; Chenevix-Trench, Georgia; Dunning, Alison M; Pharoah, Paul D P; Kristensen, Vessela; Hall, Per; Easton, Douglas F; Pastinen, Tomi; Nord, Silje; Simard, Jacques

    2016-12-06

    There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.

  13. Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21

    Science.gov (United States)

    Adoue, Véronique; Michailidou, Kyriaki; Canisius, Sander; Lemaçon, Audrey; Droit, Arnaud; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Baynes, Caroline; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Borresen-Dale, Anne-Lise; Brand, Judith S.; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Burwinkel, Barbara; Chang-Claude, Jenny; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Devilee, Peter; Dörk, Thilo; Dos-Santos-Silva, Isabel; Eriksson, Mikael; Fasching, Peter A.; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G.; Goldberg, Mark S.; González-Neira, Anna; Grenaker-Alnæs, Grethe; Guénel, Pascal; Haeberle, Lothar; Haiman, Christopher A.; Hamann, Ute; Hallberg, Emily; Hooning, Maartje J.; Hopper, John L.; Jakubowska, Anna; Jones, Michael; Kabisch, Maria; Kataja, Vesa; Lambrechts, Diether; Marchand, Loic Le; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Maranian, Mel; Margolin, Sara; Marme, Frederik; Milne, Roger L.; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Olswold, Curtis; Peto, Julian; Plaseska-Karanfilska, Dijana; Pylkäs, Katri; Radice, Paolo; Rudolph, Anja; Sawyer, Elinor J.; Schmidt, Marjanka K.; Shu, Xiao-Ou; Southey, Melissa C.; Swerdlow, Anthony; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Vachon, Celine; Van Den Ouweland, Ans M. W.; Wang, Qin; Winqvist, Robert; Investigators, kConFab/AOCS; Zheng, Wei; Benitez, Javier; Chenevix-Trench, Georgia; Dunning, Alison M.; Pharoah, Paul D. P.; Kristensen, Vessela; Hall, Per; Easton, Douglas F.; Pastinen, Tomi; Nord, Silje; Simard, Jacques

    2016-01-01

    There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas. PMID:27792995

  14. Functional characterization of a gene locus from an uncultured gut Bacteroides conferring xylo-oligosaccharides utilization to Escherichia coli.

    Science.gov (United States)

    Tauzin, Alexandra S; Laville, Elisabeth; Xiao, Yao; Nouaille, Sébastien; Le Bourgeois, Pascal; Heux, Stéphanie; Portais, Jean-Charles; Monsan, Pierre; Martens, Eric C; Potocki-Veronese, Gabrielle; Bordes, Florence

    2016-11-01

    In prominent gut Bacteroides strains, sophisticated strategies have been evolved to achieve the complete degradation of dietary polysaccharides such as xylan, which is one of the major components of the plant cell wall. Polysaccharide Utilization Loci (PULs) consist of gene clusters encoding different proteins with a vast arsenal of functions, including carbohydrate binding, transport and hydrolysis. Transport is often attributed to TonB-dependent transporters, although major facilitator superfamily (MFS) transporters have also been identified in some PULs. However, until now, few of these transporters have been biochemically characterized. Here, we targeted a PUL-like system from an uncultivated Bacteroides species that is highly prevalent in the human gut metagenome. It encodes three glycoside-hydrolases specific for xylo-oligosaccharides, a SusC/SusD tandem homolog and a MFS transporter. We combined PUL rational engineering, metabolic and transcriptional analysis in Escherichia coli to functionally characterize this genomic locus. We demonstrated that the SusC and the MFS transporters are specific for internalization of linear xylo-oligosaccharides of polymerization degree up to 3 and 4 respectively. These results were strengthened by the study of growth dynamics and transcriptional analyses in response to XOS induction of the PUL in the native strain, Bacteroides vulgatus. © 2016 The Authors. Molecular Microbiology Published by John Wiley & Sons Ltd.

  15. A combined analysis of D22S278 marker alleles in affected sib-pairs: Support for a susceptibility locus for schizophrenia at chromosome 22q12

    Energy Technology Data Exchange (ETDEWEB)

    Gill, M.; Vallada, H.; Collier, D. [Institute of Psychiatry, London (United Kingdom)] [and others

    1996-02-16

    Several groups have reported weak evidence for linkage between schizophrenia and genetic markers located on chromosome 22q using the lod score method of analysis. However these findings involved different genetic markers and methods of analysis, and so were not directly comparable. To resolve this issue we have performed a combined analysis of genotypic data from the marker D22S278 in multiply affected schizophrenic families derived from 11 independent research groups worldwide. This marker was chosen because it showed maximum evidence for linkage in three independent datasets. Using the affected sib-pair method as implemented by the program ESPA, the combined dataset showed 252 alleles shared compared with 188 alleles not shared (chi-square 9.31, 1df, P = 0.001) where parental genotype data was completely known. When sib-pairs for whom parental data was assigned according to probability were included the number of alleles shared was 514.1 compared with 437.8 not shared (chi-square 6.12, 1df, P = 0.006). Similar results were obtained when a likelihood ratio method for sib-pair analysis was used. These results indicate that there may be a susceptibility locus for schizophrenia at 22q12. 27 refs., 3 tabs.

  16. Rapid identification of international multidrug-resistant Pseudomonas aeruginosa clones by multiple-locus variable number of tandem repeats analysis and investigation of their susceptibility to lytic bacteriophages.

    Science.gov (United States)

    Larché, Jérôme; Pouillot, Flavie; Essoh, Christiane; Libisch, Balázs; Straut, Monica; Lee, Je Chul; Soler, Charles; Lamarca, Richard; Gleize, Elodie; Gabard, Jérôme; Vergnaud, Gilles; Pourcel, Christine

    2012-12-01

    The objective of this study was to determine the genetic diversity of multidrug-resistant (MDR) Pseudomonas aeruginosa strains isolated over a period of 12 months in two French hospitals and to test their susceptibility to bacteriophages. A total of 47 MDR isolates recovered from hospitalized patients were genotyped using multiple-locus variable number of tandem repeats analysis. The genotypes were distributed into five clones (including 19, 5, 5, 3, and 3 isolates, respectively) and 12 singletons. Comparison to 77 MDR strains from three other countries, and MLST analysis of selected isolates showed the predominance of international MDR clones. The larger clone, CC235, contained 59 isolates displaying different antibiotic resistance mechanisms, including the presence of the GES1, VIM-2, VIM-4, and IMP-1 β-lactamases. Three newly isolated P. aeruginosa bacteriophages were found to lyse 42 of the 44 analyzed strains, distributed into the different clonal complexes. This pilot study suggests that systematic genotyping of P. aeruginosa MDR strains could improve our epidemiological understanding of transmission at both the local (hospital) and the national level and that phage therapy could be an alternative or a complementary treatment to antibiotics for treating MDR-infected patients.

  17. A New Susceptibility Locus for Myocardial Infarction, Hypertension, Type 2 Diabetes Mellitus, and Dyslipidemia on Chromosome 12q24

    Directory of Open Access Journals (Sweden)

    Salma M. Wakil

    2014-01-01

    Full Text Available We examined the role of hepatic nuclear factor-1 alpha (HNF1a gene polymorphism on coronary artery disease (CAD traits in 4631 Saudi angiographed individuals (2419 CAD versus 2212 controls using TaqMan assay on ABI Prism 7900HT sequence detection system. Following adjustment for confounders, the rs2259820_CC (1.19 (1.01–1.42; P=0.041, rs2464196_TT (1.19 (1.00–1.40; P=0.045, and rs2259816_T (1.13 (1.01–1.26; P=0.031 were associated with MI. The rs2259820_T (1.14 (1.03–1.26; P=0.011 and rs2464196_C (1.12 (1.02–1.24; P=0.024 were associated with type 2 diabetes mellitus (T2DM, while the rs2393791_T (1.14 (1.01–1.28; P=0.032, rs7310409_G (1.16 (1.03–1.30; P=0.013, and rs2464196_AG+GG (1.25 (1.05–1.49; P=0.012 were implicated in hypertension. Hypertriglyceridemia was linked to the rs2393791_T (1.14 (1.02–1.27; P=0.018, rs7310409_G (1.12 (1.01–1.25; P=0.031, rs1169310_G (1.15 (1.04–1.28; P=0.010, and rs1169313_CT+TT (1.24 (1.06–1.45; P=0.008 and high low density lipoprotein-cholesterol levels were associated with rs2259820_T (1.23 (1.07–1.41; P=0.004, rs2464196_T (1.22 (1.06–1.39; P=0.004, and rs2259816_T (1.18 (1.02–1.36; P=0.023. A 7-mer haplotype CATATAC (χ2=7.50; P=0.0062, constructed from the studied SNPs, was associated with MI, and CATATA implicated in T2DM (χ2=3.94; P=0.047. Hypertriglyceridemia was linked to TGCGGG (χ2=4.26; P=0.039, and obesity to ACGGGT (χ2=5.04; P=0.025. Our results suggest that the HNF1a is a common susceptibility gene for MI, T2DM, hypertension, and dyslipidemia.

  18. Interleukin 8 Receptor Deficiency Confers Susceptibility to Acute Experimental Pyelonephritis and May Have a Human Counterpart

    Science.gov (United States)

    Frendéus, Björn; Godaly, Gabriela; Hang, Long; Karpman, Diana; Lundstedt, Ann-Charlotte; Svanborg, Catharina

    2000-01-01

    Neutrophils migrate to infected mucosal sites that they protect against invading pathogens. Their interaction with the epithelial barrier is controlled by CXC chemokines and by their receptors. This study examined the change in susceptibility to urinary tract infection (UTI) after deletion of the murine interleukin 8 receptor homologue (mIL-8Rh). Experimental UTIs in control mice stimulated an epithelial chemokine response and increased chemokine receptor expression. Neutrophils migrated through the tissues to the epithelial barrier that they crossed into the lumen, and the mice developed pyuria. In mIL-8Rh knockout (KO) mice, the chemokine response was intact, but the epithelial cells failed to express IL-8R, and neutrophils accumulated in the tissues. The KO mice were unable to clear bacteria from kidneys and bladders and developed bacteremia and symptoms of systemic disease, but control mice were fully resistant to infection. The experimental UTI model demonstrated that IL-8R–dependent mechanisms control the urinary tract defense, and that neutrophils are essential host effector cells. Patients prone to acute pyelonephritis also showed low CXC chemokine receptor 1 expression compared with age-matched controls, suggesting that chemokine receptor expression may also influence the susceptibility to UTIs in humans. The results provide a first molecular clue to disease susceptibility of patients prone to acute pyelonephritis. PMID:10993918

  19. Constitutive expression of MKS1 confers susceptibility to Botrytis cinerea infection independent of PAD3 expression.

    Science.gov (United States)

    Fiil, Berthe Katrine; Petersen, Morten

    2011-10-01

    Signal transduction through MAPK cascades is essential for eukaryotic cell response to various extracellular stimuli, such as the induction of innate immune responses. Arabidopsis thaliana relies in particular on three of its 20 MAPKs, MPK3,-4,-6, for a proper immune response. Recently we showed that one MPK4-substrate, MKS1, is required for basal resistance against the virulent Pseudomonas syringae and the oomycete Hyaloperonospora arabidopsidis. Overexpression of MKS1 (35S-MKS1) led to increased resistance to the same pathogens but also to an increased susceptibility towards the fungi Botrytis cinerea. MKS1 interacts with the transcription factor WRKY33, which in turn controls the regulation of PAD3 and CYP71A13, two genes, required for proper resistance to B. cinerea. Therefore, we tested if the increased susceptibility towards B. cinerea from 35S-MKS1 was due to deregulation of WRKY33 targets. PAD3 and CYP71A13 expression is similar in 35S-MKS1 and WT after B. cinerea treatment suggesting another mechanism controls 35S-MKS1 susceptibility.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. Common variants in the COL4A4 gene confer susceptibility to lattice degeneration of the retina.

    Directory of Open Access Journals (Sweden)

    Akira Meguro

    Full Text Available Lattice degeneration of the retina is a vitreoretinal disorder characterized by a visible fundus lesion predisposing the patient to retinal tears and detachment. The etiology of this degeneration is still uncertain, but it is likely that both genetic and environmental factors play important roles in its development. To identify genetic susceptibility regions for lattice degeneration of the retina, we performed a genome-wide association study (GWAS using a dense panel of 23,465 microsatellite markers covering the entire human genome. This GWAS in a Japanese cohort (294 patients with lattice degeneration and 294 controls led to the identification of one microsatellite locus, D2S0276i, in the collagen type IV alpha 4 (COL4A4 gene on chromosome 2q36.3. To validate the significance of this observation, we evaluated the D2S0276i region in the GWAS cohort and in an independent Japanese cohort (280 patients and 314 controls using D2S0276i and 47 single nucleotide polymorphisms covering the region. The strong associations were observed in D2S0276i and rs7558081 in the COL4A4 gene (Pc = 5.8 × 10(-6, OR = 0.63 and Pc = 1.0 × 10(-5, OR = 0.69 in a total of 574 patients and 608 controls, respectively. Our findings suggest that variants in the COL4A4 gene may contribute to the development of lattice degeneration of the retina.

  2. Genetic analysis of dilated cardiomyopathy--HLA and immunoglobulin genes may confer susceptibility.

    Science.gov (United States)

    Nishi, H; Kimura, A; Fukuta, S; Kusukawa, R; Kawamura, K; Nimura, Y; Nagano, M; Yasuda, H; Kawai, C; Sugimoto, T

    1992-10-01

    To identify genetic factors in the immune system which control the susceptibility to dilated cardiomyopathy (DCM), HLA class II DNA typing was performed in 61 Japanese patients, using PCR/SSO probe analyses. The frequencies of HLA-DQB1*0503 (15% vs 5%; RR = 3.06, chi 2 = 7.19) and DQB1*0604 (21% vs 10%; RR = 2.41, chi 2 = 6.20) were significantly increased and that of HLA-DQB1*0502 (RR = 1.74) was slightly increased in the DCM patients. The frequency of DQB1*0303 (16% vs 31%; RR = 0.44, chi 2 = 5.16) was significantly decreased in the patients. The increased HLA-DQB1 alleles have a histidine residue in common at the 30th codon for the HLA-DQ beta chain. Among the genetic markers studied by Southern blot analyses, IGLV (immunoglobulin lambda light chain, pV3.3) showed a strong association with DCM, i.e. A2/A2 genotype was found in 37.7% of patients whereas it was observed in only 18.9% of the control subjects (RR = 2.6, chi 2 = 7.77). The frequency of this genotype was higher in patients under age 45 years at the time of diagnosis (45.5%, RR = 3.6, chi 2 = 10.02). These results suggest that HLA and immunoglobulin genes are closely linked to susceptibility to DCM.

  3. Candidate-Gene Screening and Association Analysis at the Autism-Susceptibility Locus on Chromosome 16p: Evidence of Association at GRIN2A and ABAT

    Science.gov (United States)

    Barnby, Gabrielle; Abbott, Aaron; Sykes, Nuala; Morris, Andrew; Weeks, Daniel E.; Mott, Richard; Lamb, Janine; Bailey, Anthony J.; Monaco, Anthony P.

    2005-01-01

    Autism is a highly heritable neurodevelopmental disorder whose underlying genetic causes have yet to be identified. To date, there have been eight genome screens for autism, two of which identified a putative susceptibility locus on chromosome 16p. In the present study, 10 positional candidate genes that map to 16p11-13 were examined for coding variants: A2BP1, ABAT, BFAR, CREBBP, EMP2, GRIN2A, MRTF-B, SSTR5, TBX6, and UBN1. Screening of all coding and regulatory regions by denaturing high-performance liquid chromatography identified seven nonsynonymous changes. Five of these mutations were found to cosegregate with autism, but the mutations are not predicted to have deleterious effects on protein structure and are unlikely to represent significant etiological variants. Selected variants from candidate genes were genotyped in the entire International Molecular Genetics Study of Autism Consortium collection of 239 multiplex families and were tested for association with autism by use of the pedigree disequilibrium test. Additionally, genotype frequencies were compared between 239 unrelated affected individuals and 192 controls. Patterns of linkage disequilibrium were investigated, and the transmission of haplotypes across candidate genes was tested for association. Evidence of single-marker association was found for variants in ABAT, CREBBP, and GRIN2A. Within these genes, 12 single-nucleotide polymorphisms (SNPs) were subsequently genotyped in 91 autism trios (one affected individual and two unaffected parents), and the association was replicated within GRIN2A (Fisher's exact test, P<.0001). Logistic regression analysis of SNP data across GRIN2A and ABAT showed a trend toward haplotypic differences between cases and controls. PMID:15830322

  4. Common variants of OPA1 conferring genetic susceptibility to leprosy in Han Chinese from Southwest China.

    Science.gov (United States)

    Xiang, Yang-Lin; Zhang, Deng-Feng; Wang, Dong; Li, Yu-Ye; Yao, Yong-Gang

    2015-11-01

    Leprosy is an ancient chronic infection caused by Mycobacterium leprae. Onset of leprosy was highly affected by host nutritional condition and energy production, (partially) due to genomic loss and parasitic life style of M. leprae. The optic atrophy 1 (OPA1) gene plays an essential role in mitochondria, which function in cellular energy supply and innate immunity. To investigate the potential involvement of OPA1 in leprosy. We analyzed 7 common genetic variants of OPA1 in 1110 Han Chinese subjects with and without leprosy, followed by mRNA expression profiling and protein-protein interaction (PPI) network analysis. We observed positive associations between OPA1 variants rs9838374 (Pgenotypic=0.003) and rs414237 (Pgenotypic=0.002) with lepromatous leprosy. expression quantitative trait loci (eQTL) analysis showed that the leprosy-related risk allele C of rs414237 is correlated with lower OPA1 mRNA expression level. Indeed, we identified a decrease of OPA1 mRNA expression in both with patients and cellular model of leprosy. In addition, the PPI analysis showed that OPA1 protein was actively involved in the interaction network of M. leprae induced differentially expressed genes. Our results indicated that OPA1 variants confer risk of leprosy and may affect OPA1 expression, mitochondrial function and antimicrobial pathways. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. Advancement in genetic variants conferring obesity susceptibility from genome-wide association studies.

    Science.gov (United States)

    Wang, Tao; Jia, Weiping; Hu, Cheng

    2015-06-01

    Obesity prevalence has increased in recent years. Lifestyle change fuels obesity, but genetic factors cause more than 50% of average variations in obesity. The advent of genome-wide association studies (GWAS) has hastened the progress of polygenic obesity research. As of this writing, more than 73 obesity susceptibility loci have been identified in ethnic groups through GWAS. The identified loci explain only 2% to 4% of obesity heritability, thereby indicating that a large proportion of loci remain undiscovered. Thus, the next step is to identify and confirm novel loci, which may exhibit smaller effects and lower allele frequencies than established loci. However, achieving these tasks has been difficult for researchers. GWAS help researchers discover the causal loci. Moreover, numerous biological studies have been performed on the polygenic effects on obesity, such as studies on fat mass- and obesity-associated gene (FTO), but the role of these polygenic effects in the mechanism of obesity remains unclear. Thus, obesity-causing variations should be identified, and insights into the biology of polygenic effects on obesity are needed.

  6. Expression of budding yeast FKBP12 confers rapamycin susceptibility to the unicellular red alga Cyanidioschyzon merolae.

    Science.gov (United States)

    Imamura, Sousuke; Ishiwata, Aiko; Watanabe, Satoru; Yoshikawa, Hirofumi; Tanaka, Kan

    2013-09-20

    The target of rapamycin (TOR) is serine/threonine protein kinase that is highly conserved among eukaryotes and can be inactivated by the antibiotic rapamycin through the formation of a ternary complex composed of rapamycin and two proteins, TOR and FKBP12. Differing from fungi and animals, plant FKBP12 proteins are unable to form the ternary complex, and thus plant TORs are insensitive to rapamycin. This has led to a poor understanding of TOR functions in plants. As a first step toward the understanding of TOR function in a rapamycin-insensitive unicellular red alga, Cyanidioschyzon merolae, we constructed a rapamycin-susceptible strain in which the Saccharomyces cerevisiae FKBP12 protein (ScFKBP12) was expressed. Treatment with rapamycin resulted in growth inhibition and decreased polysome formation in this strain. Binding of ScFKBP12 with C. merolae TOR in the presence of rapamycin was demonstrated in vivo and in vitro by pull-down experiments. Moreover, in vitro kinase assay showed that inhibition of C. merolae TOR kinase activity was dependent on ScFKBP12 and rapamycin. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. A TagSNP in SIRT1 gene confers susceptibility to myocardial infarction in a Chinese Han population.

    Directory of Open Access Journals (Sweden)

    Jie Cheng

    Full Text Available SIRT1 exerts protective effects against endothelial cells dysfunction, inflammation and atherosclerosis, indicating an important role on myocardial infarction (MI pathogenesis. Nonetheless, the effects of SIRT1 variants on MI risk remain poorly understood. Here we aimed to investigate the influence of SIRT1 polymorphisms on individual susceptibility to MI. Genotyping of three tagSNPs (rs7069102, rs3818292 and rs4746720 in SIRT1 gene was performed in a Chinese Han population, consisting of 287 MI cases and 654 control subjects. In a logistic regression analysis, we found that G allele of rs7069102 had increased MI risk with odds ratio (OR of 1.57 [95% confidence interval (CI = 1.15-2.16, Bonferroni corrected P (Pc = 0.015] after adjustment for conventional risk factors compared to C allele. Similarly, the combined CG/GG genotypes was associated with the increased MI risk (OR = 1.64, 95% CI = 1.14-2.35, Pc = 0.021 compared to the CC genotype. Further stratified analysis revealed a more significant association with MI risk among younger subjects (≤ 55 years old. Consistent with these results, the haplotype rs7069102G-rs3818292A-rs4746720T containing the rs7069102 G allele was also associated with the increased MI risk (OR = 1.41, 95% CI = 1.09-1.84, Pc = 0.040. However, we did not detect any association of rs3818292 and rs4746720 with MI risk. Our study provides the first evidence that the tagSNP rs7069102 and haplotype rs7069102G-rs3818292A-rs4746720T in SIRT1 gene confer susceptibility to MI in the Chinese Han population.

  8. Antisense expression of peach mildew resistance locus O (PpMlo1) gene confers cross-species resistance to powdery mildew in Fragaria x ananassa.

    Science.gov (United States)

    Jiwan, Derick; Roalson, Eric H; Main, Dorrie; Dhingra, Amit

    2013-12-01

    Powdery mildew (PM) is one of the major plant pathogens. The conventional method of PM control includes frequent use of sulfur-based fungicides adding to production costs and potential harm to the environment. PM remains a major scourge for Rosaceae crops where breeding approaches mainly resort to gene-for-gene resistance. We have tested an alternate source of PM resistance in Rosaceae. Mildew resistance locus O (MLO) has been well studied in barley due to its role in imparting broad spectrum resistance to PM. We identified PpMlo1 (Prunus persica Mlo) in peach and characterized it further to test if a similar mechanism of resistance is conserved in Rosaceae. Due to its recalcitrance in tissue culture, reverse genetic studies involving PpMloI were not feasible in peach. Therefore, Fragaria x ananassa LF9 line, a taxonomic surrogate, was used for functional analysis of PpMlo1. Agrobacterium-mediated transformation yielded transgenic strawberry plants expressing PpMlo1 in sense and antisense orientation. Antisense expression of PpMlo1 in transgenic strawberry plants conferred resistance to Fragaria-specific powdery mildew, Podosphaera macularis. Phylogenetic analysis of 208 putative Mlo gene copies from 35 plant species suggests a large number of duplications of this gene family prior to the divergence of monocots and eudicots, early in eudicot diversification. Our results indicate that the Mlo-based resistance mechanism is functional in Rosaceae, and that Fragaria can be used as a host to test mechanistic function of genes derived from related tree species. To the best of our knowledge, this work is one of the first attempts at testing the potential of using a Mlo-based resistance strategy to combat powdery mildew in Rosaceae.

  9. Haplotype variation of Glu-D1 locus and the origin of Glu-D1d allele conferring superior end-use qualities in common wheat.

    Directory of Open Access Journals (Sweden)

    Zhenying Dong

    Full Text Available In higher plants, seed storage proteins (SSPs are frequently expressed from complex gene families, and allelic variation of SSP genes often affects the quality traits of crops. In common wheat, the Glu-D1 locus, encoding 1Dx and 1Dy SSPs, has multiple alleles. The Glu-D1d allele frequently confers superior end-use qualities to commercial wheat varieties. Here, we studied the haplotype structure of Glu-D1 genomic region and the origin of Glu-D1d. Using seven diagnostic DNA markers, 12 Glu-D1 haplotypes were detected among common wheat, European spelt wheat (T. spelta, a primitive hexaploid relative of common wheat, and Aegilops tauschii (the D genome donor of hexaploid wheat. By comparatively analyzing Glu-D1 haplotypes and their associated 1Dx and 1Dy genes, we deduce that the haplotype carrying Glu-D1d was likely differentiated in the ancestral hexaploid wheat around 10,000 years ago, and was subsequently transmitted to domesticated common wheat and T. spelta. A group of relatively ancient Glu-D1 haplotypes was discovered in Ae. tauschii, which may serve for the evolution of other haplotypes. Moreover, a number of new Glu-D1d variants were found in T. spelta. The main steps in Glu-D1d differentiation are proposed. The implications of our work for enhancing the utility of Glu-D1d in wheat quality improvement and studying the SSP alleles in other crop species are discussed.

  10. Increased radiosensitivity as an indicator of genes conferring breast cancer susceptibility

    Energy Technology Data Exchange (ETDEWEB)

    Varga, D.; Kreienberg, R.; Deissler, H.; Sauer, G. [Dept. of Gynecology and Obstetrics, Univ. of Ulm Medical School (Germany); Vogel, W.; Bender, A.; Surowy, H.; Maier, C. [Dept. of Genetics, Univ. of Ulm Medical School (Germany)

    2007-12-15

    Purpose: This paper briefly summarizes the research on increased radiosensitivity in breast cancer patients measured by the micronucleus test (MNT) and its association to genetic variants in DNA repair genes. More preliminary data are presented on the distribution of chromosomes and chromosome fragments in micronuclei (MN) in order to gain more information on clastogenic and aneugenic effects and better understand the phenotype of increased radiosensitivity. Material and Methods: Reports of relevant studies obtained from a search of PubMed and studies referenced in those reports were reviewed. In four patients with high MN frequency (three cancer patients, one control) and four probands with low MN frequency, the presence of chromosome fragments or whole chromosomes in MN was determined by fluorescence in situ hybridization analysis for chromosomes 1, 7, and 17. Results: An increased MN frequency in breast cancer patients compared to controls has consistently been reported with high significance. Higher MN frequencies were observed in 20-50% of breast cancer patients. Chromosomal fragments of chromosome 17, but not of chromosomes 1 and 7 were more frequent in the probands with high MN frequency than in those with low frequency (p = 0.045). Conclusion: The MNT detects a cellular phenotype common to a portion of sporadic breast cancer patients. This phenotype is very likely to be genetically determined. For the genetic dissection of breast cancer susceptibility this phenotype may turn out to be more efficient than breast cancer itself. Additional parameters which can be measured simultaneously with the MN frequency may be able to further enhance its usefulness. (orig.)

  11. ALDH2 Glu504Lys Confers Susceptibility to Schizophrenia and Impacts Hippocampal-Prefrontal Functional Connectivity.

    Science.gov (United States)

    Zheng, Fanfan; Yan, Hao; Liu, Bing; Yue, Weihua; Fan, Lingzhong; Liao, Jinmin; Cui, Yue; Lu, Tianlan; Jiang, Tianzi; Zhang, Dai

    2017-03-01

    Although previous evidence suggested that ALDH2 is a candidate gene for schizophrenia, the association and underlying mechanisms have never been investigated. Therefore, we investigated ALDH2 as a susceptibility gene for schizophrenia and explored the effect of its polymorphisms on brain functions. In the discovery stage, we detected a positive association between a dominant-negative mutant, Glu504Lys, and schizophrenia (P= 8.01E-5, OR = 1.34, 95% CI = 1.16-1.55). This association was confirmed in the validation stage (P= 3.48E-6, OR = 1.28, 95% CI = 1.15-1.42). The combined P reached a genome-wide significance (Pcombined= 1.32E-9, OR = 1.30, 95% CI = 1.20-1.42). To investigate the neural mechanism linking Glu504Lys to schizophrenia, we calculated the functional connectivity (FC) and applied an imaging genetics strategy using resting-state fMRI data. The imaging analysis revealed a significant interaction of diagnostic group by genotype for FC between the left hippocampus and the prefrontal cortex. In the Glu homozygotes, hippocampal-prefrontal FC correlated inversely with memory performance in the healthy controls and with the PANSS negative score in the schizophrenia patients. Our results supported a role for ALDH2 in the pathophysiology of schizophrenia. Moreover, variation at Glu504Lys disrupts hippocampal-prefrontal FC, which might be the neural mechanism linking it to the disease. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  12. A rare functional noncoding variant at the GWAS-implicated MIR137/MIR2682 locus might confer risk to schizophrenia and bipolar disorder.

    Science.gov (United States)

    Duan, Jubao; Shi, Jianxin; Fiorentino, Alessia; Leites, Catherine; Chen, Xiangning; Moy, Winton; Chen, Jingchun; Alexandrov, Boian S; Usheva, Anny; He, Deli; Freda, Jessica; O'Brien, Niamh L; McQuillin, Andrew; Sanders, Alan R; Gershon, Elliot S; DeLisi, Lynn E; Bishop, Alan R; Gurling, Hugh M D; Pato, Michele T; Levinson, Douglas F; Kendler, Kenneth S; Pato, Carlos N; Gejman, Pablo V

    2014-12-04

    Schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in >100 susceptibility loci; however, the contribution of rare variants at these loci remains largely unexplored. One of the strongly associated loci spans MIR137 (miR137) and MIR2682 (miR2682), two microRNA genes important for neuronal function. We sequenced ∼6.9 kb MIR137/MIR2682 and upstream regulatory sequences in 2,610 SZ cases and 2,611 controls of European ancestry. We identified 133 rare variants with minor allele frequency (MAF) T, presented exclusively in 11 SZ cases (nominal p = 4.8 × 10(-4)). We further identified its risk allele T in 2 of 2,434 additional SZ cases, 11 of 4,339 bipolar (BP) cases, and 3 of 3,572 SZ/BP study controls and 1,688 population controls; yielding combined p values of 0.0007, 0.0013, and 0.0001 for SZ, BP, and SZ/BP, respectively. The risk allele T of 1:g.98515539A>T reduced enhancer activity of its flanking sequence by >50% in human neuroblastoma cells, predicting lower expression of MIR137/MIR2682. Both empirical and computational analyses showed weaker transcription factor (YY1) binding by the risk allele. Chromatin conformation capture (3C) assay further indicated that 1:g.98515539A>T influenced MIR137/MIR2682, but not the nearby DPYD or LOC729987. Our results suggest that rare noncoding risk variants are associated with SZ and BP at MIR137/MIR2682 locus, with risk alleles decreasing MIR137/MIR2682 expression. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  13. Nonlinkage of D6S260, a putative schizophrenia locus, to bipolar affective disorder

    Energy Technology Data Exchange (ETDEWEB)

    Adams, L.J.; Mitchell, P.B. [Univ. of South Wales (Australia); Salmon, J. [Garvan Institute of Medical Research, Sydney, New South Wales (Australia)] [and others

    1996-09-20

    To examine whether genes that predispose to schizophrenia also confer a predisposition to other psychiatric disorders such as bipolar affective disorder (BAD), we tested for linkage between the recently identified schizophrenia susceptibility locus D6S260 and the inheritance of BAD in 12 large Australian pedigrees. We found no evidence for linkage over a region of 12-27 cM from the D6S260 locus, depending on the model used. Our results therefore do not provide support for the continuum theory of psychosis. 13 refs., 2 tabs.

  14. Two HLA DRB 1 alleles confer independent genetic susceptibility to Graves disease: relevance of cross-population studies.

    Science.gov (United States)

    Marga, M; Denisova, A; Sochnev, A; Pirags, V; Farid, N R

    2001-08-01

    Recent studies of Graves disease (GD) employing genome scanning techniques excluded the major histocompatibility complex as a contributor to disease liability. These findings contradict earlier population association studies. Our own earlier studies have also emphasized that genetic variation in human populations may give novel clues to disease liability and manifestations. To this end, we studied HLA class II alleles in 47 Latvian GD patients and 111 matched healthy controls. As expected, we found that DRB1*03 and DQA1*0501 (OR = 3.6, P = 0.029 and OR 2.35, P = 0.0373, respectively) were associated with GD. Unforeseen, DRB1*04 was found to be significantly increased in the patients compared to controls (OR 3.267, corrected P = 0.0319). The two DRB1 alleles conferred two non-overlapping and independent susceptibilities to GD, in that only three patients were positive for both alleles, and the removal of each allele in turn resulted in only the other DRB1 allele showing significant association with the disease. There was no heterogeneity between the two patient groups (DRB1*03 positive and DRB1*04 positive) in clinical characteristics or disease manifestations. The phenotype DRB1*03 and/or DRB1*04 was found in 34/47 patients compared to 27/111 controls yielding an OR of 7.395 (P corrected = 0.000019). We examined the structural basis of DRB1 susceptibility to GD in light of this and previous studies, showing that DRB1*03, 04, and 08 were positively associated with the disease, whereas DRB1*07 was negatively associated. Differences in protein sequences were noted at residues 54, 57, 59, and 66; positions 54, 57, and 66 are on the same face of the alpha helix. The canonical arginine 54 is replaced by glutamine in DRB1*07. At position 66, asparagine in DRB1*03 and tyrosine in DRB1*04 are replaced by phenylalanine in DRB1*07. Residue 59, likely involved in pocket formation in the antigen binding groove, is modified by replacement of tyrosine in DRB1*03, 08, and 04 and

  15. Combination of KIR 2DL2 and HLA-C1 (Asn 80) confers susceptibility to type 1 diabetes in Latvians.

    Science.gov (United States)

    Shastry, A; Sedimbi, S K; Rajalingam, R; Nikitina-Zake, L; Rumba, I; Wigzell, H; Sanjeevi, C B

    2008-12-01

    Killer immunoglobulin-like receptors (KIRs) are known to modulate natural killer (NK) and NK T-cell function by interacting with human leucocyte antigen (HLA) class I ligands on target cells. The aim of our study was to investigate the influence of KIR2D genes with their HLA-C ligands in susceptibility to type 1 diabetes. A total of 98 type 1 diabetes patients and 70 healthy subjects from Latvia were typed for KIR genes and HLA-C ligands using polymerase chain reaction-based genotyping. The HLA C1+/C2+ combination was positively, and C1-/C2+ combination was negatively, associated with type 1 diabetes. Stratification analysis of KIR/HLA-C ligand combinations showed 2DL2+/C1+, 2DL3+/C1+, and 2DS2+ /C1+ to be positively, and 2DL2-/C1- and 2DS2-/ C1- to be negatively, associated. The presence of 2DL2-HLA-C1 in the absence of 2DS1, 2DS2 confers maximum susceptibility. Absence of 2DL2 and HLA-C1 along with absence of 2DS1 and 2DS2 confer maximum protection. A hypothetical model of KIR/ligand combinations on immune responses and type 1 diabetes susceptibility is proposed. Our results suggest that a combination KIR2DL2- HLA-C1 plays a critical role in susceptibility or protection in Latvians against type 1 diabetes.

  16. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

    NARCIS (Netherlands)

    Lawrenson, K.; Li, Q.; Kar, S.; Seo, J.H.; Tyrer, J.; Spindler, T.J.; Lee, J. van der; Chen, Y; Karst, A.; Drapkin, R.; Aben, K.K.H.; Anton-Culver, H.; Antonenkova, N.; Baker, H.; Bandera, E.V.; Bean, Y.; Beckmann, M.W.; Berchuck, A.; Bisogna, M.; Bjorge, L.; Bogdanova, N.; Brinton, L.A.; Brooks-Wilson, A.; Bruinsma, F.; Butzow, R.; Campbell, I.G.; Carty, K.; Chang-Claude, J.; Chenevix-Trench, G.; Chen, A; Chen, Z.; Cook, L.S.; Cramer, D.W; Cunningham, J.M.; Cybulski, C.; Dansonka-Mieszkowska, A.; Dennis, J.; Dicks, E.; Doherty, J.A.; Dork, T.; Bois, A. du; Durst, M.; Eccles, D.; Easton, D.T.; Edwards, R.P.; Eilber, U.; Ekici, A.B.; Fasching, P.A.; Fridley, B.L.; Gao, Y.T.; Gentry-Maharaj, A.; Giles, G.G.; Glasspool, R.; Goode, E.L.; Goodman, M.T.; Grownwald, J.; Harrington, P.; Harter, P.; Hasmad, H.N.; Hein, A.; Heitz, F.; Hildebrandt, M.A.; Hillemanns, P.; Hogdall, E.; Hogdall, C.; Hosono, S.; Iversen, E.S.; Jakubowska, A.; James, P.; Jensen, A.; Ji, B.T.; Karlan, B.Y.; Kjaer, S. Kruger; Kelemen, L.E.; Kellar, M.; Kelley, J.L.; Kiemeney, L.A.; Krakstad, C.; Kupryjanczyk, J.; Lambrechts, D.; Lambrechts, S.; Le, N.D.; Lee, A.W.; Lele, S.; Leminen, A.; Lester, J.; Levine, D.A.; Liang, D.; Lissowska, J.; Lu, K.; Lubinski, J.; Lundvall, L.; Massuger, L.F.; Matsuo, K.; McGuire, V.; McLaughlin, J.R.; Nevanlinna, H.; McNeish, I.; Menon, U.; Modugno, F.

    2015-01-01

    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associat

  17. D-alanine modification of a protease-susceptible outer membrane component by the Bordetella pertussis dra locus promotes resistance to antimicrobial peptides and polymorphonuclear leukocyte-mediated killing.

    Science.gov (United States)

    Taneja, Neetu Kumra; Ganguly, Tridib; Bakaletz, Lauren O; Nelson, Kimberly J; Dubey, Purnima; Poole, Leslie B; Deora, Rajendar

    2013-11-01

    Bordetella pertussis is the causative agent of pertussis, a highly contagious disease of the human respiratory tract. Despite very high vaccine coverage, pertussis has reemerged as a serious threat in the United States and many developing countries. Thus, it is important to pursue research to discover unknown pathogenic mechanisms of B. pertussis. We have investigated a previously uncharacterized locus in B. pertussis, the dra locus, which is homologous to the dlt operons of Gram-positive bacteria. The absence of the dra locus resulted in increased sensitivity to the killing action of antimicrobial peptides (AMPs) and human phagocytes. Compared to the wild-type cells, the mutant cells bound higher levels of cationic proteins and peptides, suggesting that dra contributes to AMP resistance by decreasing the electronegativity of the cell surface. The presence of dra led to the incorporation of d-alanine into an outer membrane component that is susceptible to proteinase K cleavage. We conclude that dra encodes a virulence-associated determinant and contributes to the immune resistance of B. pertussis. With these findings, we have identified a new mechanism of surface modification in B. pertussis which may also be relevant in other Gram-negative pathogens.

  18. A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23

    NARCIS (Netherlands)

    Wu, Xifeng; Scelo, Ghislaine; Purdue, Mark P.; Rothman, Nathaniel; Johansson, Mattias; Ye, Yuanqing; Wang, Zhaoming; Zelenika, Diana; Moore, Lee E.; Wood, Christopher G.; Prokhortchouk, Egor; Gaborieau, Valerie; Jacobs, Kevin B.; Chow, Wong-Ho; Toro, Jorge R.; Zaridze, David; Lin, Jie; Lubinski, Jan; Trubicka, Joanna; Szeszenia-Dabrowska, Neonilia; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Mates, Dana; Jinga, Viorel; Bencko, Vladimir; Slamova, Alena; Holcatova, Ivana; Navratilova, Marie; Janout, Vladimir; Boffetta, Paolo; Colt, Joanne S.; Davis, Faith G.; Schwartz, Kendra L.; Banks, Rosamonde E.; Selby, Peter J.; Harnden, Patricia; Berg, Christine D.; Hsing, Ann W.; Grubb, Robert L.; Boeing, Heiner; Vineis, Paolo; Clavel-Chapelon, Francoise; Palli, Domenico; Tumino, Rosario; Krogh, Vittorio; Panico, Salvatore; Duell, Eric J.; Ramon Quiros, Jose; Sanchez, Maria-Jose; Navarro, Carmen; Ardanaz, Eva; Dorronsoro, Miren; Khaw, Kay-Tee; Allen, Naomi E.; Bueno-de-Mesquita, H. Bas; Peeters, Petra H. M.; Trichopoulos, Dimitrios; Linseisen, Jakob; Ljungberg, Borje; Overvad, Kim; Tjonneland, Anne; Romieu, Isabelle; Riboli, Elio; Stevens, Victoria L.; Thun, Michael J.; Diver, W. Ryan; Gapstur, Susan M.; Pharoah, Paul D.; Easton, Douglas F.; Albanes, Demetrius; Virtamo, Jarmo; Vatten, Lars; Hveem, Kristian; Fletcher, Tony; Koppova, Kvetoslava; Cussenot, Olivier; Cancel-Tassin, Geraldine; Benhamou, Simone; Hildebrandt, Michelle A.; Pu, Xia; Foglio, Mario; Lechner, Doris; Hutchinson, Amy; Yeager, Meredith; Fraumeni, Joseph F.; Lathrop, Mark; Skryabin, Konstantin G.; McKay, James D.; Gu, Jian; Brennan, Paul; Chanock, Stephen J.

    2012-01-01

    Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome- wide association study (GWAS). We analyzed 533 191 single nucleotide poly

  19. A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23

    NARCIS (Netherlands)

    Wu, Xifeng; Scelo, Ghislaine; Purdue, Mark P.; Rothman, Nathaniel; Johansson, Mattias; Ye, Yuanqing; Wang, Zhaoming; Zelenika, Diana; Moore, Lee E.; Wood, Christopher G.; Prokhortchouk, Egor; Gaborieau, Valerie; Jacobs, Kevin B.; Chow, Wong-Ho; Toro, Jorge R.; Zaridze, David; Lin, Jie; Lubinski, Jan; Trubicka, Joanna; Szeszenia-Dabrowska, Neonilia; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Mates, Dana; Jinga, Viorel; Bencko, Vladimir; Slamova, Alena; Holcatova, Ivana; Navratilova, Marie; Janout, Vladimir; Boffetta, Paolo; Colt, Joanne S.; Davis, Faith G.; Schwartz, Kendra L.; Banks, Rosamonde E.; Selby, Peter J.; Harnden, Patricia; Berg, Christine D.; Hsing, Ann W.; Grubb, Robert L.; Boeing, Heiner; Vineis, Paolo; Clavel-Chapelon, Francoise; Palli, Domenico; Tumino, Rosario; Krogh, Vittorio; Panico, Salvatore; Duell, Eric J.; Ramon Quiros, Jose; Sanchez, Maria-Jose; Navarro, Carmen; Ardanaz, Eva; Dorronsoro, Miren; Khaw, Kay-Tee; Allen, Naomi E.; Bueno-de-Mesquita, H. Bas; Peeters, Petra H. M.; Trichopoulos, Dimitrios; Linseisen, Jakob; Ljungberg, Borje; Overvad, Kim; Tjonneland, Anne; Romieu, Isabelle; Riboli, Elio; Stevens, Victoria L.; Thun, Michael J.; Diver, W. Ryan; Gapstur, Susan M.; Pharoah, Paul D.; Easton, Douglas F.; Albanes, Demetrius; Virtamo, Jarmo; Vatten, Lars; Hveem, Kristian; Fletcher, Tony; Koppova, Kvetoslava; Cussenot, Olivier; Cancel-Tassin, Geraldine; Benhamou, Simone; Hildebrandt, Michelle A.; Pu, Xia; Foglio, Mario; Lechner, Doris; Hutchinson, Amy; Yeager, Meredith; Fraumeni, Joseph F.; Lathrop, Mark; Skryabin, Konstantin G.; McKay, James D.; Gu, Jian; Brennan, Paul; Chanock, Stephen J.

    2012-01-01

    Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome- wide association study (GWAS). We analyzed 533 191 single nucleotide poly

  20. Association study of nicotinic acetylcholine receptor genes identifies a novel lung cancer susceptibility locus near CHRNA1 in African-Americans

    OpenAIRE

    Walsh, Kyle M.; Christopher I Amos; Wenzlaff, Angela S.; Gorlov, Ivan P; Sison, Jennette D.; Wu, Xifeng; Spitz, Margaret R; Hansen, Helen M.; Lu, Emily Y.; Wei, Chongjuan; Zhang, Huifeng; Chen, Wei; Lloyd, Stacy M.; Frazier, Marsha L.; Paige M Bracci

    2012-01-01

    Studies in European and East Asian populations have identified lung cancer susceptibility loci in nicotinic acetylcholine receptor (nAChR) genes on chromosome 15q25.1 which also appear to influence smoking behaviors. We sought to determine if genetic variation in nAChR genes influences lung cancer susceptibly in African-Americans, and evaluated the association of these cancer susceptibility loci with smoking behavior. A total of 1308 African-Americans with lung cancer and 1241 African-America...

  1. The human beta-globin locus control region confers an early embryonic erythroid-specific expression pattern to a basic promoter driving the bacterial lacZ gene

    NARCIS (Netherlands)

    R. Tewari (Rita); N. Gillemans (Nynke); A. Harper; M.G.J.M. Wijgerde (Mark); G. Zafarana (Gaetano); D.D. Drabek (Dubravka); F.G. Grosveld (Frank); J.N.J. Philipsen (Sjaak)

    1996-01-01

    textabstractThe beta-globin locus control region (LCR) is contained on a 20 kb DNA fragment and is characterized by the presence of five DNaseI hypersensitive sites in erythroid cells, termed 5'HS1-5. A fully active 6.5 kb version of the LCR, called the muLCR, has been

  2. The human β-globin locus control region confers an early embryonic erythroid-specific expression pattern to a basic promoter driving the bacterial β-galactosidase gene.

    NARCIS (Netherlands)

    R. Tewari (Rita); N. Gillemans (Nynke); A. Harper; M.G.J.M. Wijgerde (Mark); G. Zafarana (Gaetano); D.D. Drabek (Dubravka); F.G. Grosveld (Frank); J.N.J. Philipsen (Sjaak)

    1996-01-01

    textabstractThe beta-globin locus control region (LCR) is contained on a 20 kb DNA fragment and is characterized by the presence of five DNaseI hypersensitive sites in erythroid cells, termed 5'HS1-5. A fully active 6.5 kb version of the LCR, called the muLCR, has been described. Expression of the

  3. HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region

    Energy Technology Data Exchange (ETDEWEB)

    Wordsworth, B.P.; Bell, J.I. (Univ. of Oxford (England)); Lanchbury, J.S.S.; Sakkas, L.I.; Welsh, K.I.; Panayi, G.S. (Guy' s Hospital, London (England))

    1989-12-01

    Susceptibility to rheumatoid arthritis (RA) may be due to the presence of shared functional epitopes common the HLA-DR {beta} chains of several RA-associated haplotypes. The authors have obtained direct evidence for this hypothesis by using the polymerase chain reaction and sequencing the DRB1 and DQB1 genes from RA patients. A highly conserved epitope present on DR {beta} chains of DR4 and DR1 haplotypes was found in 83% of 149 patients with classical or definite RA but was found in only 46% of 100 control individuals. Two Dw subtypes of DR4 (Dw4 and Dw14) were associated with disease susceptibility but two other subtypes (Dw10 and Dw13) were not. Sequence differences between these subtypes implicate those residues around the putative antigen binding site of the DR {beta} molecule in the pathogenesis of RA. These data provide a basis for understanding host susceptibility to RA at a molecular level.

  4. Association of ulcerative colitis with the inflammatory bowel disease susceptibility locus IBD2 in non-Jewish Caucasians and evidence of genetic heterogeneity among racial and ethnic populations with Crohn disease.

    Science.gov (United States)

    Uthoff, Sonja M S; Crawford, Nigel P S; Eichenberger, M Robert; Hamilton, Crystal J; Petras, Robert E; Martin, Eden R; Galandiuk, Susan

    2002-12-01

    Genomewide scanning has been used to identify chromosomal regions encoding susceptibility loci to inflammatory bowel disease (IBD). The greatest evidence for linkage to IBD has been reported for a region of chromosome 12q14 surrounding the microsatellite marker D12S83, with a logarithm of odds score of 5.47 and a positive transmission disequilibrium test, and which was subsequently named IBD2. We wished to confirm this locus by genotyping the highly polymorphic microsatellites D12S1022, D12S1056, and D12S83, spanning a continuous region on chromosome 12 of 342 kb, in a cohort of nonrelated individuals with ulcerative colitis (89 patients), Crohn disease (121 patients), and population-based control subjects (100 patients). In non-Jewish Caucasians, one D12S1022 allele, one D12S1056 genotype, and three D12S83 alleles were found to have statistically significant differences in distribution between the two disease groups and the control population. These data support a significant association of IBD with the IBD2 locus in close vicinity to the three markers studied. The replication of genetic risk loci in a case control association study may indicate susceptibility genes in this region and may facilitate identification of candidate genes for IBD. Subgroup analysis revealed a notable difference in genotype distribution among Jewish Caucasian and African American patients affected with Crohn disease when compared with similarly affected non-Jewish Caucasians. Using Fisher exact test, statistically significant distribution differences were observed for D12S1022 and D12S83. These data indicate that there may be significant genetic heterogeneity between different ethnic and racial IBD populations or may simply reflect differences in marker allele frequencies among populations. Copyright 2002 Wiley-Liss, Inc.

  5. Campylobacter multi-locus sequence types and antimicrobial susceptibility of broiler cecal isolates: a two year study of 143 commercial flocks

    Science.gov (United States)

    The objective of this study was to assess genetic diversity and antimicrobial susceptibility of Campylobacter jejuni and coli recovered from broiler ceca at slaughter. Ceca from one broiler were collected from the evisceration line in a commercial processing plant, once or twice weekly for two year...

  6. Multi-stage genome-wide association study identifies new susceptibility locus for testicular germ cell tumour on chromosome 3q25

    DEFF Research Database (Denmark)

    Litchfield, Kevin; Sultana, Razvan; Renwick, Anthony

    2015-01-01

    Recent genome-wide association studies (GWAS) and subsequent meta-analyses have identified over 25 SNPs at 18 loci, together accounting for >15% of the genetic susceptibility to testicular germ cell tumour (TGCT). To identify further common SNPs associated with TGCT, here we report a three-stage ...

  7. Accurate and Practical Identification of 20 Fusarium Species by Seven-Locus Sequence Analysis and Reverse Line Blot Hybridization, and an In Vitro Antifungal Susceptibility Study▿†

    Science.gov (United States)

    Wang, He; Xiao, Meng; Kong, Fanrong; Chen, Sharon; Dou, Hong-Tao; Sorrell, Tania; Li, Ruo-Yu; Xu, Ying-Chun

    2011-01-01

    Eleven reference and 25 clinical isolates of Fusarium were subject to multilocus DNA sequence analysis to determine the species and haplotypes of the fusarial isolates from Beijing and Shandong, China. Seven loci were analyzed: the translation elongation factor 1 alpha gene (EF-1α); the nuclear rRNA internal transcribed spacer (ITS), large subunit (LSU), and intergenic spacer (IGS) regions; the second largest subunit of the RNA polymerase gene (RPB2); the calmodulin gene (CAM); and the mitochondrial small subunit (mtSSU) rRNA gene. We also evaluated an IGS-targeted PCR/reverse line blot (RLB) assay for species/haplotype identification of Fusarium. Twenty Fusarium species and seven species complexes were identified. Of 25 clinical isolates (10 species), the Gibberella (Fusarium) fujikuroi species complex was the commonest (40%) and was followed by the Fusarium solani species complex (FSSC) (36%) and the F. incarnatum-F. equiseti species complex (12%). Six FSSC isolates were identified to the species level as FSSC-3+4, and three as FSSC-5. Twenty-nine IGS, 27 EF-1α, 26 RPB2, 24 CAM, 18 ITS, 19 LSU, and 18 mtSSU haplotypes were identified; 29 were unique, and haplotypes for 24 clinical strains were novel. By parsimony informative character analysis, the IGS locus was the most phylogenetically informative, and the rRNA gene regions were the least. Results by RLB were concordant with multilocus sequence analysis for all isolates. Amphotericin B was the most active drug against all species. Voriconazole MICs were high (>8 μg/ml) for 15 (42%) isolates, including FSSC. Analysis of larger numbers of isolates is required to determine the clinical utility of the seven-locus sequence analysis and RLB assay in species classification of fusaria. PMID:21389150

  8. HLA non-class II genes may confer type I diabetes susceptibility in a Mapuche (Amerindian) affected family.

    Science.gov (United States)

    Pérez-Bravo, Francisco; Martinez-Laso, Jorge; Martin-Villa, Jose M; Moscoso, Juan; Moreno, Almudena; Serrano-Vela, Juan I; Zamora, Jorge; Asenjo, Silvia; Gleisner, Andrea; Arnaiz-Villena, Antonio

    2006-01-01

    A rare case of type I diabetes is studied in an Amerindian (Mapuche) family from Chile, analyzing glutamic acid decarboxylase, islet-cell autoantibodies and human leukocyte antigen (HLA) genes. The affected sib is the only one that has one specific HLA haplotype combination that differs from the other sibs only in the HLA class I genes. It is concluded that HLA diabetes susceptibility factors may be placed outside the class II region or even that susceptibility factors do not exist in the HLA region in this Amerindian family.

  9. Fine Mapping of Leishmania major Susceptibility Locus lmr2 and Evidence of a Role for Fli1 in Disease and Wound Healing▿

    OpenAIRE

    Sakthianandeswaren, Anuratha; Curtis, Joan M.; Elso, Colleen; Kumar, Beena; Baldwin, Tracey M.; Lopaticki, Sash; Kedzierski, Lukasz; Gordon K. Smyth; Foote, Simon J.; Handman, Emanuela

    2010-01-01

    Genetic linkage studies of the host response to Leishmania major, the causative agent of cutaneous leishmaniasis, have identified significant genetic complexity in humans and mice. In the mouse model, multiple loci have been implicated in susceptibility to infection, but to date, the genes underlying these loci have not been identified. We now describe the contribution of a novel candidate gene, Fli1, to both L. major resistance and enhanced wound healing. We have previously mapped the L. maj...

  10. Identification of a breast cancer susceptibility locus at 4q31.22 using a genome-wide association study paradigm.

    Directory of Open Access Journals (Sweden)

    Yadav Sapkota

    Full Text Available More than 40 single nucleotide polymorphisms (SNPs for breast cancer susceptibility were identified by genome-wide association studies (GWASs. However, additional SNPs likely contribute to breast cancer susceptibility and overall genetic risk, prompting this investigation for additional variants. Six putative breast cancer susceptibility SNPs identified in a two-stage GWAS that we reported earlier were replicated in a follow-up stage 3 study using an independent set of breast cancer cases and controls from Canada, with an overall cumulative sample size of 7,219 subjects across all three stages. The study design also encompassed the 11 variants from GWASs previously reported by various consortia between the years 2007-2009 to (i enable comparisons of effect sizes, and (ii identify putative prognostic variants across studies. All SNP associations reported with breast cancer were also adjusted for body mass index (BMI. We report a strong association with 4q31.22-rs1429142 (combined per allele odds ratio and 95% confidence interval = 1.28 [1.17-1.41] and P combined = 1.5×10(-7, when adjusted for BMI. Ten of the 11 breast cancer susceptibility loci reported by consortia also showed associations in our predominantly Caucasian study population, and the associations were independent of BMI; four FGFR2 SNPs and TNRC9-rs3803662 were among the most notable associations. Since the original report by Garcia-Closas et al. 2008, this is the second study to confirm the association of 8q24.21-rs13281615 with breast cancer outcomes.

  11. PTPN22 is associated with susceptibility to psoriatic arthritis but not psoriasis: evidence for a further PsA-specific risk locus.

    LENUS (Irish Health Repository)

    Bowes, John

    2015-04-28

    Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis; it has a higher estimated genetic component than psoriasis alone, however most genetic susceptibility loci identified for PsA to date are also shared with psoriasis. Here we attempt to validate novel single nucleotide polymorphisms selected from our recent PsA Immunochip study and determine specificity to PsA.

  12. Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry.

    Science.gov (United States)

    Figueroa, Jonine D; Middlebrooks, Candace D; Banday, A Rouf; Ye, Yuanqing; Garcia-Closas, Montserrat; Chatterjee, Nilanjan; Koutros, Stella; Kiemeney, Lambertus A; Rafnar, Thorunn; Bishop, Timothy; Furberg, Helena; Matullo, Giuseppe; Golka, Klaus; Gago-Dominguez, Manuela; Taylor, Jack A; Fletcher, Tony; Siddiq, Afshan; Cortessis, Victoria K; Kooperberg, Charles; Cussenot, Olivier; Benhamou, Simone; Prescott, Jennifer; Porru, Stefano; Dinney, Colin P; Malats, Núria; Baris, Dalsu; Purdue, Mark P; Jacobs, Eric J; Albanes, Demetrius; Wang, Zhaoming; Chung, Charles C; Vermeulen, Sita H; Aben, Katja K; Galesloot, Tessel E; Thorleifsson, Gudmar; Sulem, Patrick; Stefansson, Kari; Kiltie, Anne E; Harland, Mark; Teo, Mark; Offit, Kenneth; Vijai, Joseph; Bajorin, Dean; Kopp, Ryan; Fiorito, Giovanni; Guarrera, Simonetta; Sacerdote, Carlotta; Selinski, Silvia; Hengstler, Jan G; Gerullis, Holger; Ovsiannikov, Daniel; Blaszkewicz, Meinolf; Castelao, Jose Esteban; Calaza, Manuel; Martinez, Maria Elena; Cordeiro, Patricia; Xu, Zongli; Panduri, Vijayalakshmi; Kumar, Rajiv; Gurzau, Eugene; Koppova, Kvetoslava; Bueno-De-Mesquita, H Bas; Ljungberg, Börje; Clavel-Chapelon, Françoise; Weiderpass, Elisabete; Krogh, Vittorio; Dorronsoro, Miren; Travis, Ruth C; Tjønneland, Anne; Brennan, Paul; Chang-Claude, Jenny; Riboli, Elio; Conti, David; Stern, Marianna C; Pike, Malcolm C; Van Den Berg, David; Yuan, Jian-Min; Hohensee, Chancellor; Jeppson, Rebecca P; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva; Turman, Constance; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J; Kraft, Peter; Lindstrom, Sara; Carta, Angela; Pavanello, Sofia; Arici, Cecilia; Mastrangelo, Giuseppe; Kamat, Ashish M; Zhang, Liren; Gong, Yilei; Pu, Xia; Hutchinson, Amy; Burdett, Laurie; Wheeler, William A; Karagas, Margaret R; Johnson, Alison; Schned, Alan; Monawar Hosain, G M; Schwenn, Molly; Kogevinas, Manolis; Tardón, Adonina; Serra, Consol; Carrato, Alfredo; García-Closas, Reina; Lloreta, Josep; Andriole, Gerald; Grubb, Robert; Black, Amanda; Diver, W Ryan; Gapstur, Susan M; Weinstein, Stephanie; Virtamo, Jarmo; Haiman, Christopher A; Landi, Maria Teresa; Caporaso, Neil E; Fraumeni, Joseph F; Vineis, Paolo; Wu, Xifeng; Chanock, Stephen J; Silverman, Debra T; Prokunina-Olsson, Ludmila; Rothman, Nathaniel

    2016-03-15

    Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.

  13. Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1

    Science.gov (United States)

    LeMaire, Scott A; McDonald, Merry-Lynn N; Guo, Dong-chuan; Russell, Ludivine; Miller, Charles C; Johnson, Ralph J; Bekheirnia, Mir Reza; Franco, Luis M; Nguyen, Mary; Pyeritz, Reed E; Bavaria, Joseph E; Devereux, Richard; Maslen, Cheryl; Holmes, Kathryn W; Eagle, Kim; Body, Simon C; Seidman, Christine; Seidman, J G; Isselbacher, Eric M; Bray, Molly; Coselli, Joseph S; Estrera, Anthony L; Safi, Hazim J; Belmont, John W; Leal, Suzanne M; Milewicz, Dianna M

    2011-01-01

    Although thoracic aortic aneurysms and dissections (TAAD) can be inherited as a single-gene disorder, the genetic predisposition in the majority of affected people is poorly understood. In a multistage genome-wide association study (GWAS), we compared 765 individuals who had sporadic TAAD (STAAD) with 874 controls and identified common SNPs at a 15q21.1 locus that were associated with STAAD, with odds ratios of 1.6–1.8 that achieved genome-wide significance. We followed up 107 SNPs associated with STAAD with P < 1 × 10−5 in the region, in two separate STAAD cohorts. The associated SNPs fall into a large region of linkage disequilibrium encompassing FBN1, which encodes fibrillin-1. FBN1 mutations cause Marfan syndrome, whose major cardiovascular complication is TAAD. This study shows that common genetic variants at 15q21.1 that probably act via FBN1 are associated with STAAD, suggesting a common pathogenesis of aortic disease in Marfan syndrome and STAAD. PMID:21909107

  14. Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.

    Directory of Open Access Journals (Sweden)

    Dan E Arking

    2011-06-01

    Full Text Available Sudden cardiac death (SCD continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10. The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34. We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals. Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006.

  15. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age

    DEFF Research Database (Denmark)

    Deelen, Joris; Beekman, Marian; Uh, Hae-Won;

    2014-01-01

    The genetic contribution to the variation in human lifespan is approximately 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality.We performed a genome-wide association meta-analysis of 7729 long-lived individuals of Eu...

  16. A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD).

    Science.gov (United States)

    Grassmann, Felix; Friedrich, Ulrike; Fauser, Sascha; Schick, Tina; Milenkovic, Andrea; Schulz, Heidi L; von Strachwitz, Claudia N; Bettecken, Thomas; Lichtner, Peter; Meitinger, Thomas; Arend, Nicole; Wolf, Armin; Haritoglou, Christos; Rudolph, Guenther; Chakravarthy, Usha; Silvestri, Giuliana; McKay, Gareth J; Freitag-Wolf, Sandra; Krawczak, Michael; Smith, R Theodore; Merriam, John C; Merriam, Joanna E; Allikmets, Rando; Heid, Iris M; Weber, Bernhard H F

    2015-06-01

    Age-related macular degeneration (AMD) is the leading cause of blindness among white caucasians over the age of 50 years with a prevalence rate expected to increase markedly with an anticipated increase in the life span of the world population. To further expand our knowledge of the genetic architecture of the disease, we pursued a candidate gene approach assessing 25 genes and a total of 109 variants. Of these, synonymous single nucleotide polymorphism (SNP) rs17810398 located in death-associated protein-like 1 (DAPL1) was found to be associated with AMD in a joint analysis of 3,229 cases and 2,835 controls from five studies [combined PADJ = 1.15 × 10(-6), OR 1.332 (1.187-1.496)]. This association was characterized by a highly significant sex difference (Pdiff = 0.0032) in that it was clearly confined to females with genome-wide significance [PADJ = 2.62 × 10(-8), OR 1.541 (1.324-1.796); males: PADJ = 0.382, OR 1.084 (0.905-1.298)]. By targeted resequencing of risk and non-risk associated haplotypes in the DAPL1 locus, we identified additional potentially functional risk variants, namely a common 897-bp deletion and a SNP predicted to affect a putative binding site of an exonic splicing enhancer. We show that the risk haplotype correlates with a reduced retinal transcript level of two, less frequent, non-canonical DAPL1 isoforms. DAPL1 plays a role in epithelial differentiation and may be involved in apoptotic processes thereby suggesting a possible novel pathway in AMD pathogenesis.

  17. The lupus susceptibility locus Sle1 breaches peripheral B cell tolerance at the antibody-forming cell and germinal center checkpoints.

    Science.gov (United States)

    Vuyyuru, Raja; Mohan, Chandra; Manser, Tim; Rahman, Ziaur S M

    2009-11-01

    We have described a line of V(H) knock-in mice termed HKIR in which the transgenic Igh locus partially encodes "dual-reactive" antichromatin and anti-p-azophenylarsonate (Ars) BCRs. HKIR B cells termed canonical, expressing a particular Vkappa L chain, evade central tolerance by down-regulating BCR levels. Canonical HKIR B cells can be recruited into the primary germinal center (GC) and Ab-forming cell (AFC) compartments via Ars immunization. However, their participation in the GC response rapidly wanes and they do not efficiently contribute to the memory compartment, indicating that they are regulated by a GC tolerance checkpoint. We analyzed the influence of the Sle1 genetic interval, shown to break tolerance of chromatin-reactive B cells, on the behavior of HKIR B cells during the anti-Ars response. Canonical B cells from congenic HKIR.Sle1 mice gave rise to elevated short and long-lived AFC responses, and the attenuated GC and memory responses characteristic of these B cells were relieved in adoptive, wild-type recipients. HKIR GC B cells containing Sle1 expressed increased levels of Bcl-2 and c-FLIP and decreased levels of Fas RNA compared with HKIR controls, suggesting direct alteration of the regulation of the GC response by Sle1. High titers of canonical and anti-dsDNA Abs spontaneously developed in many aged HKIR.Sle1 mice. Together, these data indicate that Sle1 perturbs the action of peripheral tolerance checkpoints operative on antinuclear Ag B cells in both the AFC and GC pathways in a cell autonomous fashion.

  18. Genome-wide association study implicates testis-sperm specific FKBP6 as a susceptibility locus for impaired acrosome reaction in stallions.

    Directory of Open Access Journals (Sweden)

    Terje Raudsepp

    Full Text Available Impaired acrosomal reaction (IAR of sperm causes male subfertility in humans and animals. Despite compelling evidence about the genetic control over acrosome biogenesis and function, the genomics of IAR is as yet poorly understood, providing no molecular tools for diagnostics. Here we conducted Equine SNP50 Beadchip genotyping and GWAS using 7 IAR-affected and 37 control Thoroughbred stallions. A significant (PA and g.11040379C>A (p.166H>N in exon 4 that were significantly associated with the IAR phenotype both in the GWAS cohort (n = 44 and in a large multi-breed cohort of 265 horses. All IAR stallions were homozygous for the A-alleles, while this genotype was found only in 2% of controls. The equine FKBP6 was exclusively expressed in testis and sperm and had 5 different transcripts, of which 4 were novel. The expression of this gene in AC/AG heterozygous controls was monoallelic, and we observed a tendency for FKBP6 up-regulation in IAR stallions compared to controls. Because exon 4 SNPs had no effect on the protein structure, it is likely that FKBP6 relates to the IAR phenotype via regulatory or modifying functions. In conclusion, FKBP6 was considered a susceptibility gene of incomplete penetrance for IAR in stallions and a candidate gene for male subfertility in mammals. FKBP6 genotyping is recommended for the detection of IAR-susceptible individuals among potential breeding stallions. Successful use of sperm as a source of DNA and RNA propagates non-invasive sample procurement for fertility genomics in animals and humans.

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

    Directory of Open Access Journals (Sweden)

    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.

  20. A functional 12T-insertion polymorphism in the ATP1A1 promoter confers decreased susceptibility to hypertension in a male Sardinian population.

    Directory of Open Access Journals (Sweden)

    Victoria L Herrera

    Full Text Available Identification of susceptibility genes for essential hypertension in humans has been a challenge due to its multifactorial pathogenesis complicated by gene-gene and gene-environment interactions, developmental programing and sex specific differences. These concurrent features make identification of causal hypertension susceptibility genes with a single approach difficult, thus requiring multiple lines of evidence involving genetic, biochemical and biological experimentation to establish causal functional mutations. Here we report experimental evidence encompassing genetic, biochemical and in vivo modeling that altogether support ATP1A1 as a hypertension susceptibility gene in males in Sardinia, Italy. ATP1A1 encodes the α1Na,K-ATPase isoform, the sole sodium pump in vascular endothelial and renal tubular epithelial cells. DNA-sequencing detected a 12-nucleotide long thymidine (12T insertion(ins/deletion(del polymorphism within a poly-T sequence (38T vs 26T in the ATP1A1 5'-regulatory region associated with hypertension in a male Sardinian population. The 12T-insertion allele confers decreased susceptibility to hypertension (P = 0.035; OR = 0.50 [0.28-0.93] accounting for 12.1 mmHg decrease in systolic BP (P = 0.02 and 6.6 mmHg in diastolic BP (P = 0.046. The ATP1A1 promoter containing the 12T-insertion exhibited decreased transcriptional activity in in vitro reporter-assay systems, indicating decreased α1Na,K-ATPase expression with the 12T-insertion, compared with the 12T-deletion ATP1A1 promoter. To test the effects of decreased α1Na,K-ATPase expression on blood pressure, we measured blood pressure by radiotelemetry in three month-old, highly inbred heterozygous knockout ATP1A1+/- male mice with resultant 58% reduction in ATP1A1 protein levels. Male ATP1A1+/- mice showed significantly lower blood pressure (P < 0.03 than age-matched male wild-type littermate controls. Concordantly, lower ATP1A1 expression is expected to lower Na

  1. Investigating the viability of genetic screening/testing for RA susceptibility using combinations of five confirmed risk loci

    Science.gov (United States)

    McClure, Annie; Lunt, Mark; Eyre, Steve; Ke, Xiayi; Thomson, Wendy; Hinks, Anne; Bowes, John; Gibbons, Laura; Plant, Darren; Wilson, Anthony G.; Marinou, Ioanna; Morgan, Ann W.; Emery, Paul; Steer, Sophia; Hocking, Lynne J.; Reid, David M.; Wordsworth, Paul; Harrison, Pille; Worthington, Jane

    2009-01-01

    Objective. Five loci—the shared epitope (SE) of HLA-DRB1, the PTPN22 gene, a locus on 6q23, the STAT4 gene and a locus mapping to the TRAF1/C5 genetic region—have now been unequivocally confirmed as conferring susceptibility to RA. The largest single effect is conferred by SE. We hypothesized that combinations of susceptibility alleles may increase risk over and above that of any individual locus alone. Methods. We analysed data from 4238 RA cases and 1811 controls, for which genotypes were available at all five loci. Results. Statistical analysis identified eight high-risk combinations conferring an odds ratio >6 compared with carriage of no susceptibility variants and, interestingly, 10% population controls carried a combination conferring high risk. All high-risk combinations included SE, and all but one contained PTPN22. Statistical modelling showed that a model containing only these two loci could achieve comparable sensitivity and specificity to a model including all five. Furthermore, replacing SE (which requires full subtyping at the HLA-DRB1 gene) with DRB1*1/4/10 carriage resulted in little further loss of information (correlation coefficient between models = 0.93). Conclusions. This represents the first exploration of the viability of population screening for RA and identifies several high-risk genetic combinations. However, given the population incidence of RA, genetic screening based on these loci alone is neither sufficiently sensitive nor specific at the current time. PMID:19741008

  2. A cost-effective smartphone-based antimicrobial susceptibility test reader for drug resistance testing (Conference Presentation)

    Science.gov (United States)

    Feng, Steve W.; Tseng, Derek; Di Carlo, Dino; Garner, Omai B.; Ozcan, Aydogan

    2017-03-01

    Antimicrobial susceptibility testing (AST) is commonly used for determining microbial drug resistance, but routine testing, which can significantly reduce the spread of multi-drug resistant organisms, is not regularly performed in resource-limited and field-settings due to technological challenges and lack of trained diagnosticians. We developed a portable cost-effective smartphone-based colorimetric 96-well microtiter plate (MTP) reader capable of automated AST without the need for a trained diagnostician. This system is composed of a smartphone used in conjunction with a 3D-printed opto-mechanical attachment, which holds a set of inexpensive light-emitting-diodes and fiber-optic cables coupled to the 96-well MTP for enabling the capture of the transmitted light through each well by the smartphone camera. Images of the MTP plate are captured at multiple exposures and uploaded to a local or remote server (e.g., a laptop) for automated processing/analysis of the results using a custom-designed smartphone application. Each set of images are combined to generate a high dynamic-range image and analyzed for well turbidity (indicative of bacterial growth), followed by interpretative analysis per plate to determine minimum inhibitory concentration (MIC) and drug susceptibility for the specific bacterium. Results are returned to the originating device within 1 minute and shown to the user in tabular form. We demonstrated the capability of this platform using MTPs prepared with 17 antibiotic drugs targeting Gram-negative bacteria and tested 82 patient isolate MTPs of Klebsiella pneumoniae, achieving well turbidity accuracy of 98.19%, MIC accuracy of 95.15%, and drug susceptibility interpretation accuracy of 99.06%, meeting the FDA defined criteria for AST.

  3. Selection of SNP subsets for association studies in candidate genes: comparison of the power of different strategies to detect single disease susceptibility locus effects

    Directory of Open Access Journals (Sweden)

    Deleuze Jean-Francois

    2006-04-01

    Full Text Available Abstract Background The recent advances in genotyping and molecular techniques have greatly increased the knowledge of the human genome structure. Millions of polymorphisms are reported and freely available in public databases. As a result, there is now a need to identify among all these data, the relevant markers for genetic association studies. Recently, several methods have been published to select subsets of markers, usually Single Nucleotide Polymorphisms (SNPs, that best represent genetic polymorphisms in the studied candidate gene or region. Results In this paper, we compared four of these selection methods, two based on haplotype information and two based on pairwise linkage disequilibrium (LD. The methods were applied to the genotype data on twenty genes with different patterns of LD and different numbers of SNPs. A measure of the efficiency of the different methods to select SNPs was obtained by comparing, for each gene and under several single disease susceptibility models, the power to detect an association that will be achieved with the selected SNP subsets. Conclusion None of the four selection methods stands out systematically from the others. Methods based on pairwise LD information turn out to be the most interesting methods in a context of association study in candidate gene. In a context where the number of SNPs to be tested in a given region needs to be more limited, as in large-scale studies or wide genome scans, one of the two methods based on haplotype information, would be more suitable.

  4. Does the oxytocin receptor (OXTR) polymorphism (rs2254298) confer 'vulnerability' for psychopathology or 'differential susceptibility'? Insights from evolution.

    Science.gov (United States)

    Brüne, Martin

    2012-04-17

    The diathesis-stress model of psychiatric conditions has recently been challenged by the view that it might be more accurate to speak of 'differential susceptibility' or 'plasticity' genes, rather than one-sidedly focusing on individual vulnerability. That is, the same allelic variation that predisposes to a psychiatric disorder if associated with (developmentally early) environmental adversity may lead to a better-than-average functional outcome in the same domain under thriving (or favourable) environmental conditions. Studies of polymorphic variations of the serotonin transporter gene, the monoamino-oxidase-inhibitor A coding gene or the dopamine D4 receptor gene indicate that the early environment plays a crucial role in the development of favourable versus unfavourable outcomes. Current evidence is limited, however, to establishing a link between genetic variation and behavioural phenotypes. In contrast, little is known about how plasticity may be expressed at the neuroanatomical level as a 'hard-wired' correlate of observable behaviour. The present review article seeks to further strengthen the argument in favour of the differential susceptibility theory by incorporating findings from behavioural and neuroanatomical studies in relation to genetic variation of the oxytocin receptor gene. It is suggested that polymorphic variation at the oxytocin receptor gene (rs2254298) is associated with sociability, amygdala volume and differential risk for psychiatric conditions including autism, depression and anxiety disorder, depending on the quality of early environmental experiences. Seeing genetic variation at the core of developmental plasticity can explain, in contrast to the diathesis-stress perspective, why evolution by natural selection has maintained such 'risk' alleles in the gene pool of a population.

  5. Does the oxytocin receptor polymorphism (rs2254298 confer 'vulnerability' for psychopathology or 'differential susceptibility'? insights from evolution

    Directory of Open Access Journals (Sweden)

    Brüne Martin

    2012-04-01

    Full Text Available Abstract The diathesis-stress model of psychiatric conditions has recently been challenged by the view that it might be more accurate to speak of 'differential susceptibility' or 'plasticity' genes, rather than one-sidedly focusing on individual vulnerability. That is, the same allelic variation that predisposes to a psychiatric disorder if associated with (developmentally early environmental adversity may lead to a better-than-average functional outcome in the same domain under thriving (or favourable environmental conditions. Studies of polymorphic variations of the serotonin transporter gene, the monoamino-oxidase-inhibitor A coding gene or the dopamine D4 receptor gene indicate that the early environment plays a crucial role in the development of favourable versus unfavourable outcomes. Current evidence is limited, however, to establishing a link between genetic variation and behavioural phenotypes. In contrast, little is known about how plasticity may be expressed at the neuroanatomical level as a 'hard-wired' correlate of observable behaviour. The present review article seeks to further strengthen the argument in favour of the differential susceptibility theory by incorporating findings from behavioural and neuroanatomical studies in relation to genetic variation of the oxytocin receptor gene. It is suggested that polymorphic variation at the oxytocin receptor gene (rs2254298 is associated with sociability, amygdala volume and differential risk for psychiatric conditions including autism, depression and anxiety disorder, depending on the quality of early environmental experiences. Seeing genetic variation at the core of developmental plasticity can explain, in contrast to the diathesis-stress perspective, why evolution by natural selection has maintained such 'risk' alleles in the gene pool of a population. Please see related manuscript: http://www.biomedcentral.com/1741-7015/10/37

  6. Common Variants in CLDN2 and MORC4 Genes Confer Disease Susceptibility in Patients with Chronic Pancreatitis.

    Directory of Open Access Journals (Sweden)

    Anil K Giri

    Full Text Available A recent genome-wide association study (GWAS identified association with variants in X-linked CLDN2 and MORC4, and PRSS1-PRSS2 loci with chronic pancreatitis (CP in North American patients of European ancestry. We selected 9 variants from the reported GWAS and replicated the association with CP in Indian patients by genotyping 1807 unrelated Indians of Indo-European ethnicity, including 519 patients with CP and 1288 controls. The etiology of CP was idiopathic in 83.62% and alcoholic in 16.38% of 519 patients. Our study confirmed a significant association of 2 variants in CLDN2 gene (rs4409525-OR 1.71, P = 1.38 x 10-09; rs12008279-OR 1.56, P = 1.53 x 10-04 and 2 variants in MORC4 gene (rs12688220-OR 1.72, P = 9.20 x 10-09; rs6622126-OR 1.75, P = 4.04x10-05 in Indian patients with CP. We also found significant association at PRSS1-PRSS2 locus (OR 0.60; P = 9.92 x 10-06 and SAMD12-TNFRSF11B (OR 0.49, 95% CI [0.31-0.78], P = 0.0027. A variant in the gene MORC4 (rs12688220 showed significant interaction with alcohol (OR for homozygous and heterozygous risk allele -14.62 and 1.51 respectively, P = 0.0068 suggesting gene-environment interaction. A combined analysis of the genes CLDN2 and MORC4 based on an effective risk allele score revealed a higher percentage of individuals homozygous for the risk allele in CP cases with 5.09 fold enhanced risk in individuals with 7 or more effective risk alleles compared with individuals with 3 or less risk alleles (P = 1.88 x 10-14. Genetic variants in CLDN2 and MORC4 genes were associated with CP in Indian patients.

  7. Genome-wide association studies in women of African ancestry identified 3q26.21 as a novel susceptibility locus for oestrogen receptor negative breast cancer.

    Science.gov (United States)

    Huo, Dezheng; Feng, Ye; Haddad, Stephen; Zheng, Yonglan; Yao, Song; Han, Yoo-Jeong; Ogundiran, Temidayo O; Adebamowo, Clement; Ojengbede, Oladosu; Falusi, Adeyinka G; Zheng, Wei; Blot, William; Cai, Qiuyin; Signorello, Lisa; John, Esther M; Bernstein, Leslie; Hu, Jennifer J; Ziegler, Regina G; Nyante, Sarah; Bandera, Elisa V; Ingles, Sue A; Press, Michael F; Deming, Sandra L; Rodriguez-Gil, Jorge L; Nathanson, Katherine L; Domchek, Susan M; Rebbeck, Timothy R; Ruiz-Narváez, Edward A; Sucheston-Campbell, Lara E; Bensen, Jeannette T; Simon, Michael S; Hennis, Anselm; Nemesure, Barbara; Leske, M Cristina; Ambs, Stefan; Chen, Lin S; Qian, Frank; Gamazon, Eric R; Lunetta, Kathryn L; Cox, Nancy J; Chanock, Stephen J; Kolonel, Laurence N; Olshan, Andrew F; Ambrosone, Christine B; Olopade, Olufunmilayo I; Palmer, Julie R; Haiman, Christopher A

    2016-11-01

    Multiple breast cancer loci have been identified in previous genome-wide association studies, but they were mainly conducted in populations of European ancestry. Women of African ancestry are more likely to have young-onset and oestrogen receptor (ER) negative breast cancer for reasons that are unknown and understudied. To identify genetic risk factors for breast cancer in women of African descent, we conducted a meta-analysis of two genome-wide association studies of breast cancer; one study consists of 1,657 cases and 2,029 controls genotyped with Illumina’s HumanOmni2.5 BeadChip and the other study included 3,016 cases and 2,745 controls genotyped using Illumina Human1M-Duo BeadChip. The top 18,376 single nucleotide polymorphisms (SNP) from the meta-analysis were replicated in the third study that consists of 1,984 African Americans cases and 2,939 controls. We found that SNP rs13074711, 26.5 Kb upstream of TNFSF10 at 3q26.21, was significantly associated with risk of oestrogen receptor (ER)-negative breast cancer (odds ratio [OR]=1.29, 95% CI: 1.18-1.40; P = 1.8 × 10 − 8). Functional annotations suggest that the TNFSF10 gene may be involved in breast cancer aetiology, but further functional experiments are needed. In addition, we confirmed SNP rs10069690 was the best indicator for ER-negative breast cancer at 5p15.33 (OR = 1.30; P = 2.4 × 10 − 10) and identified rs12998806 as the best indicator for ER-positive breast cancer at 2q35 (OR = 1.34; P = 2.2 × 10 − 8) for women of African ancestry. These findings demonstrated additional susceptibility alleles for breast cancer can be revealed in diverse populations and have important public health implications in building race/ethnicity-specific risk prediction model for breast cancer.

  8. Galactomannan Catabolism Conferred by a Polysaccharide Utilization Locus of Bacteroides ovatus: ENZYME SYNERGY AND CRYSTAL STRUCTURE OF A β-MANNANASE.

    Science.gov (United States)

    Bågenholm, Viktoria; Reddy, Sumitha K; Bouraoui, Hanene; Morrill, Johan; Kulcinskaja, Evelina; Bahr, Constance M; Aurelius, Oskar; Rogers, Theresa; Xiao, Yao; Logan, Derek T; Martens, Eric C; Koropatkin, Nicole M; Stålbrand, Henrik

    2017-01-06

    A recently identified polysaccharide utilization locus (PUL) from Bacteroides ovatus ATCC 8483 is transcriptionally up-regulated during growth on galacto- and glucomannans. It encodes two glycoside hydrolase family 26 (GH26) β-mannanases, BoMan26A and BoMan26B, and a GH36 α-galactosidase, BoGal36A. The PUL also includes two glycan-binding proteins, confirmed by β-mannan affinity electrophoresis. When this PUL was deleted, B. ovatus was no longer able to grow on locust bean galactomannan. BoMan26A primarily formed mannobiose from mannan polysaccharides. BoMan26B had higher activity on galactomannan with a high degree of galactosyl substitution and was shown to be endo-acting generating a more diverse mixture of oligosaccharides, including mannobiose. Of the two β-mannanases, only BoMan26B hydrolyzed galactoglucomannan. A crystal structure of BoMan26A revealed a similar structure to the exo-mannobiohydrolase CjMan26C from Cellvibrio japonicus, with a conserved glycone region (-1 and -2 subsites), including a conserved loop closing the active site beyond subsite -2. Analysis of cellular location by immunolabeling and fluorescence microscopy suggests that BoMan26B is surface-exposed and associated with the outer membrane, although BoMan26A and BoGal36A are likely periplasmic. In light of the cellular location and the biochemical properties of the two characterized β-mannanases, we propose a scheme of sequential action by the glycoside hydrolases encoded by the β-mannan PUL and involved in the β-mannan utilization pathway in B. ovatus. The outer membrane-associated BoMan26B initially acts on the polysaccharide galactomannan, producing comparably large oligosaccharide fragments. Galactomanno-oligosaccharides are further processed in the periplasm, degalactosylated by BoGal36A, and subsequently hydrolyzed into mainly mannobiose by the β-mannanase BoMan26A. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. IL23R gene confers susceptibility to ankylosing spondylitis concomitant with uveitis in a Han Chinese population.

    Directory of Open Access Journals (Sweden)

    Hongtao Dong

    Full Text Available PURPOSE: The interleukin-23 receptor (IL-23R has been shown to be associated with ankylosing spondylitis (AS in many different populations. This study examined whether IL-23R polymorphisms were associated with susceptibility to this disease in a Chinese Han population. METHODS: Three single-nucleotide polymorphisms (SNP, rs7517847, rs11209032, and rs17375018, were genotyped in 291 AS patients and 312 age-, sex-, and ethnically matched healthy controls using a polymerase chain reaction (PCR restriction fragment length polymorphism (RFLP assay. RESULTS: The genotype and allele frequencies of rs17375018, rs7517847, and rs11209032 were not different between the patients with AS and the healthy controls. On the one hand, stratification analysis indicated that the rs17375018 GG genotype and the G allele were increased in AS patients who were HLA-B27 positive (corrected p = 0.024, odds ratio [OR] 2.35, 95% CI 1.30-4.24; p c = 0.006, OR 1.98, 95% CI 1.28-3.07, respectively. On the other hand, the analysis according to clinical characteristics showed a significantly increased prevalence of the homozygous rs17375018 GG genotype and the G allele in patients with AS and uveitis compared with the controls (p c = 0.024 and p c = 0.024, respectively. In addition, haplotype analysis performed with the SHEsis platform revealed no significant difference concerning the haplotypes between AS patients and healthy controls. CONCLUSIONS: In this study, the results suggested that the rs17375018 of IL23R was positively associated with HLA-B27-positive AS and that the rs17375018 GG of IL-23R was associated with AS concomitant with uveitis. We found no evidence for an association between the other two SNPs of IL-23R and AS.

  10. Genome editing of the disease susceptibility gene CsLOB1 in citrus confers resistance to citrus canker.

    Science.gov (United States)

    Jia, Hongge; Zhang, Yunzeng; Orbović, Vladimir; Xu, Jin; White, Frank F; Jones, Jeffrey B; Wang, Nian

    2017-07-01

    Citrus is a highly valued tree crop worldwide, while, at the same time, citrus production faces many biotic challenges, including bacterial canker and Huanglongbing (HLB). Breeding for disease-resistant varieties is the most efficient and sustainable approach to control plant diseases. Traditional breeding of citrus varieties is challenging due to multiple limitations, including polyploidy, polyembryony, extended juvenility and long crossing cycles. Targeted genome editing technology has the potential to shorten varietal development for some traits, including disease resistance. Here, we used CRISPR/Cas9/sgRNA technology to modify the canker susceptibility gene CsLOB1 in Duncan grapefruit. Six independent lines, DLOB 2, DLOB 3, DLOB 9, DLOB 10, DLOB 11 and DLOB 12, were generated. Targeted next-generation sequencing of the six lines showed the mutation rate was 31.58%, 23.80%, 89.36%, 88.79%, 46.91% and 51.12% for DLOB 2, DLOB 3, DLOB 9, DLOB 10, DLOB 11 and DLOB 12, respectively, of the cells in each line. DLOB 2 and DLOB 3 showed canker symptoms similar to wild-type grapefruit, when inoculated with the pathogen Xanthomonas citri subsp. citri (Xcc). No canker symptoms were observed on DLOB 9, DLOB 10, DLOB 11 and DLOB 12 at 4 days postinoculation (DPI) with Xcc. Pustules caused by Xcc were observed on DLOB 9, DLOB 10, DLOB 11 and DLOB 12 in later stages, which were much reduced compared to that on wild-type grapefruit. The pustules on DLOB 9 and DLOB 10 did not develop into typical canker symptoms. No side effects and off-target mutations were detected in the mutated plants. This study indicates that genome editing using CRISPR technology will provide a promising pathway to generate disease-resistant citrus varieties. © 2016 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

  11. Cytological and molecular characterization of quantitative trait locus qRfg1, which confers resistance to gibberella stalk rot in maize.

    Science.gov (United States)

    Ye, Jianrong; Guo, Yanling; Zhang, Dongfeng; Zhang, Nan; Wang, Chao; Xu, Mingliang

    2013-12-01

    Tremendous progress has been made recently in understanding plant response to Fusarium graminearum infection. Here, the cytological aspect and molecular mechanism of maize defense to F. graminearum infection were characterized using a pair of near-isogenic lines (NIL), the resistant and the susceptible NIL. F. graminearum primarily penetrated the maize root tip and no penetration structure was found. The fungal biomass within the root correlated well with root-disease severity. Following inoculation, R-NIL and S-NIL plants significantly differed in percentage of diseased primary roots. In R-NIL roots, a fraction of exodermal cells collapsed to form cavities, and hyphae were confined to the outer exodermal cells. However, most exodermal cells shrank and turned brown, and fungi colonized the entire S-NIL root. In the R-NIL roots, the exodermal cells exhibited plasmolysis and atropous hyphal growth whereas, in the exodermal cells of the S-NIL roots, severe cellular degradation and membrane-coated, lushly grown hyphae were found. Transcriptome sequencing revealed comprehensive transcription reprogramming, reinforcement of a complex defense network, to enhance the systemic and basal resistance. This study reports a detailed microscopic analysis of F. graminearum infection on maize root, and provides insights into the molecular mechanisms underlying maize resistance to the pathogen.

  12. miRNA Copy Number Variants Confer Susceptibility to Acute Anterior Uveitis With or Without Ankylosing Spondylitis.

    Science.gov (United States)

    Yang, Lu; Du, Liping; Yue, Yingying; Huang, Yike; Zhou, Qingyun; Cao, Shuang; Qi, Jian; Liang, Liang; Wu, Lili; Wang, Chaokui; Ye, Zi; Tian, Yuan; Kijlstra, Aize; Hou, Shengping; Yang, Peizeng

    2017-04-01

    To investigate the association of microRNA (miRNA) copy number variants (CNVs) with acute anterior uveitis (AAU) with or without ankylosing spondylitis (AS) and to assess underlying disease mechanisms. This study included 768 patients with AAU+AS+ or AAU+AS- and 660 controls from a Chinese Han population. Genotyping of CNVs was performed by TaqMan PCR. The expression of miRNAs, transfection efficiency of miR-9-3, and cytokine production were measured by real-time PCR, flow cytometry, or ELISA. The frequency of low copy numbers of miR-143, miR-146a, miR-9-3, and miR-205 and of high copy numbers of miR-301a and miR-23a was increased in patients with AAU+AS+ (P = 3.725 × 10-5 to 8.033 × 10-9). Additionally, the frequency of a low copy number of miR-146a and a high copy number of miR-23a and miR-205 was significantly increased in AAU+AS- patients (P = 0.002-0.001). The frequency of low copy number of miR-205 was increased in AAU+AS+ compared with AAU+AS- (P = 0.001). The mRNA expression of miR-9-3 was significantly decreased in patients with AAU+AS+ compared with controls and positively associated with its copy number. Additionally, the production of IL-1β and IL-6 was shown to be regulated by miR-9-3 in human primary retinal pigment epithelial cells. Low gene copy numbers of miR-143, miR-146a, miR-9-3, miR-205 and high gene copy numbers of miR-301a and miR-23a were associated with susceptibility to AAU+AS+. A low copy number of miR-146a and a high copy number of miR-23a and miR-205 were associated with AAU+AS-.

  13. Interspecies transfer of the penicillin-binding protein 3-encoding gene ftsI between Haemophilus influenzae and Haemophilus haemolyticus can confer reduced susceptibility to β-lactam antimicrobial agents.

    Science.gov (United States)

    Søndergaard, Annette; Witherden, Elizabeth A; Nørskov-Lauritsen, Niels; Tristram, Stephen G

    2015-07-01

    Mutations in ftsI, encoding penicillin-binding protein 3, can cause decreased β-lactam susceptibility in Haemophilus influenzae. Sequencing of ftsI from clinical strains has indicated interspecies recombination of ftsI between H. influenzae and Haemophilus haemolyticus. This study documented apparently unrestricted homologous recombination of ftsI between H. influenzae and H. haemolyticus in vitro. Transfer of ftsI from resistant isolates conferred similar but not identical increases in the MICs of susceptible strains of H. influenzae and H. haemolyticus.

  14. Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

    NARCIS (Netherlands)

    M. Ghoussaini (Maya); J.D. French (Juliet); K. Michailidou (Kyriaki); S. Nord (Silje); J. Beesley (Jonathan); Canisus, S. (Sander); K.M. Hillman (Kristine); S. Kaufmann (Susanne); H. Sivakumaran (Haran); Moradi Marjaneh, M. (Mahdi); J.S. Lee (Jason S); J. Dennis (Joe); M.K. Bolla (Manjeet K.); Wang, Q. (Qin); E. Dicks (Ed); R.L. Milne (Roger); Hopper, J.L. (John L.); Southey, M.C. (Melissa C.); M.K. Schmidt (Marjanka); A. Broeks (Annegien); K.R. Muir (K.); A. Lophatananon (Artitaya); P.A. Fasching (Peter); M.W. Beckmann (Matthias); O. Fletcher (Olivia); Johnson, N. (Nichola); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); B. Burwinkel (Barbara); Marme, F. (Frederik); P. Guénel (Pascal); T. Truong (Thérèse); S.E. Bojesen (Stig); H. Flyger (Henrik); J. Benítez (Javier); A. González-Neira (Anna); M.R. Alonso (M Rosario); G. Pita (G.); S.L. Neuhausen (Susan); H. Anton-Culver (Hoda); H. Brenner (Hermann); Arndt, V. (Volker); A. Meindl (Alfons); R.K. Schmutzler (Rita); H. Brauch (Hiltrud); U. Hamann (Ute); D.C. Tessier (Daniel C.); D. Vincent (Daniel); H. Nevanlinna (Heli); S. Khan (Sofia); Matsuo, K. (Keitaro); H. Ito (Hidemi); T. Dörk (Thilo); N.V. Bogdanova (Natalia); A. Lindblom (Annika); S. Margolin (Sara); A. Mannermaa (Arto); V-M. Kosma (Veli-Matti); A.H. Wu (Anna); D. Van Den Berg (David); Lambrechts, D. (Diether); O.A.M. Floris; J. Chang-Claude (Jenny); Rudolph, A. (Anja); P. Radice (Paolo); M. Barile (Monica); F.J. Couch (Fergus); Hallberg, E. (Emily); Giles, G.G. (Graham G.); C.A. Haiman (Christopher A.); L. Le Marchand (Loic); M.S. Goldberg (Mark); S.-H. Teo; C.H. Yip (Cheng Har); A.-L. Borresen-Dale (Anne-Lise); W. Zheng (Wei); Q. Cai (Qiuyin); R. Winqvist (Robert); K. Pykäs (Katri); I.L. Andrulis (Irene); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); M. García-Closas (Montserrat); J.D. Figueroa (Jonine); P. Hall (Per); K. Czene (Kamila); J.S. Brand (Judith S.); H. Darabi (Hatef); M. Eriksson (Mats); M.J. Hooning (Maartje); Koppert, L.B. (Linetta B.); J. Li (Jingmei); X.-O. Shu (Xiao-Ou); Y. Zheng (Ying); A. Cox (Angela); S.S. Cross (Simon); Shah, M. (Mitul); V. Rhenius (Valerie); Choi, J.-Y. (Ji-Yeob); D. Kang (Daehee); J.M. Hartman (Joost); Chia, K.S. (Kee Seng); M. Kabisch (Maria); D. Torres (Diana); C. Luccarini (Craig); D. Conroy (Don); A. Jakubowska (Anna); J. Lubinski (Jan); Sangrajrang, S. (Suleeporn); P. Brennan (Paul); C. Olswold (Curtis); S. Slager (Susan); C.-Y. Shen (Chen-Yang); M.-F. Hou (Ming-Feng); A.J. Swerdlow (Anthony ); M. Schoemaker (Minouk); J. Simard (Jacques); P.D.P. Pharoah (Paul); V. Kristensen (Vessela); G. Chenevix-Trench (Georgia); D.F. Easton (Douglas F.); A.M. Dunning (Alison); S.L. Edwards (Stacey)

    2016-01-01

    textabstractGenome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium

  15. Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

    NARCIS (Netherlands)

    M. Ghoussaini (Maya); J.D. French (Juliet); K. Michailidou (Kyriaki); S. Nord (Silje); J. Beesley (Jonathan); Canisus, S. (Sander); K.M. Hillman (Kristine); S. Kaufmann (Susanne); H. Sivakumaran (Haran); Moradi Marjaneh, M. (Mahdi); J.S. Lee (Jason S); J. Dennis (Joe); M.K. Bolla (Manjeet K.); Wang, Q. (Qin); E. Dicks (Ed); R.L. Milne (Roger); Hopper, J.L. (John L.); Southey, M.C. (Melissa C.); M.K. Schmidt (Marjanka); A. Broeks (Annegien); K.R. Muir (K.); A. Lophatananon (Artitaya); P.A. Fasching (Peter); M.W. Beckmann (Matthias); O. Fletcher (Olivia); Johnson, N. (Nichola); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); B. Burwinkel (Barbara); Marme, F. (Frederik); P. Guénel (Pascal); T. Truong (Thérèse); S.E. Bojesen (Stig); H. Flyger (Henrik); J. Benítez (Javier); A. González-Neira (Anna); M.R. Alonso (M Rosario); G. Pita (G.); S.L. Neuhausen (Susan); H. Anton-Culver (Hoda); H. Brenner (Hermann); Arndt, V. (Volker); A. Meindl (Alfons); R.K. Schmutzler (Rita); H. Brauch (Hiltrud); U. Hamann (Ute); D.C. Tessier (Daniel C.); D. Vincent (Daniel); H. Nevanlinna (Heli); S. Khan (Sofia); Matsuo, K. (Keitaro); H. Ito (Hidemi); T. Dörk (Thilo); N.V. Bogdanova (Natalia); A. Lindblom (Annika); S. Margolin (Sara); A. Mannermaa (Arto); V-M. Kosma (Veli-Matti); A.H. Wu (Anna); D. Van Den Berg (David); Lambrechts, D. (Diether); O.A.M. Floris; J. Chang-Claude (Jenny); Rudolph, A. (Anja); P. Radice (Paolo); M. Barile (Monica); F.J. Couch (Fergus); Hallberg, E. (Emily); Giles, G.G. (Graham G.); C.A. Haiman (Christopher A.); L. Le Marchand (Loic); M.S. Goldberg (Mark); S.-H. Teo; C.H. Yip (Cheng Har); A.-L. Borresen-Dale (Anne-Lise); W. Zheng (Wei); Q. Cai (Qiuyin); R. Winqvist (Robert); K. Pykäs (Katri); I.L. Andrulis (Irene); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); M. García-Closas (Montserrat); J.D. Figueroa (Jonine); P. Hall (Per); K. Czene (Kamila); J.S. Brand (Judith S.); H. Darabi (Hatef); M. Eriksson (Mats); M.J. Hooning (Maartje); Koppert, L.B. (Linetta B.); J. Li (Jingmei); X.-O. Shu (Xiao-Ou); Y. Zheng (Ying); A. Cox (Angela); S.S. Cross (Simon); Shah, M. (Mitul); V. Rhenius (Valerie); Choi, J.-Y. (Ji-Yeob); D. Kang (Daehee); J.M. Hartman (Joost); Chia, K.S. (Kee Seng); M. Kabisch (Maria); D. Torres (Diana); C. Luccarini (Craig); D. Conroy (Don); A. Jakubowska (Anna); J. Lubinski (Jan); Sangrajrang, S. (Suleeporn); P. Brennan (Paul); C. Olswold (Curtis); S. Slager (Susan); C.-Y. Shen (Chen-Yang); M.-F. Hou (Ming-Feng); A.J. Swerdlow (Anthony ); M. Schoemaker (Minouk); J. Simard (Jacques); P.D.P. Pharoah (Paul); V. Kristensen (Vessela); G. Chenevix-Trench (Georgia); D.F. Easton (Douglas F.); A.M. Dunning (Alison); S.L. Edwards (Stacey)

    2016-01-01

    textabstractGenome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (

  16. Construction of a high-resolution linkage map of Rfd1, a restorer-of-fertility locus for cytoplasmic male sterility conferred by DCGMS cytoplasm in radish (Raphanus sativus L.) using synteny between radish and Arabidopsis genomes.

    Science.gov (United States)

    Cho, Youngcho; Lee, Young-Pyo; Park, Beom-Seok; Han, Tae-Ho; Kim, Sunggil

    2012-08-01

    Cytoplasmic male sterility caused by Dongbu cytoplasmic and genic male-sterility (DCGMS) cytoplasm and its nuclear restorer-of-fertility locus (Rfd1) with a linked molecular marker (A137) have been reported in radish (Raphanus sativus L.). To construct a linkage map of the Rfd1 locus, linked amplified fragment length polymorphism (AFLP) markers were screened using bulked segregant analysis. A 220-bp linked AFLP fragment sequence from radish showed homology with an Arabidopsis coding sequence. Using this Arabidopsis gene sequence, a simple PCR marker (A220) was developed. The A137 and A220 markers flanked the Rfd1 locus. Two homologous Arabidopsis genes with both marker sequences were positioned on Arabidopsis chromosome-3 with an interval of 2.4 Mb. To integrate the Rfd1 locus into a previously reported expressed sequence tag (EST)-simple sequence repeat (SSR) linkage map, the radish EST sequences located in three syntenic blocks within the 2.4-Mb interval were used to develop single nucleotide polymorphism (SNP) markers for tagging each block. The SNP marker in linkage group-2 co-segregated with male fertility in an F(2) population. Using radish ESTs positioned in linkage group-2, five intron length polymorphism (ILP) markers and one cleaved amplified polymorphic sequence (CAPS) marker were developed and used to construct a linkage map of the Rfd1 locus. Two closely linked markers delimited the Rfd1 locus within a 985-kb interval of Arabidopsis chromosome-3. Synteny between the radish and Arabidopsis genomes in the 985-kb interval were used to develop three ILP and three CAPS markers. Two ILP markers further delimited the Rfd1 locus to a 220-kb interval of Arabidopsis chromosome-3.

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

    Directory of Open Access Journals (Sweden)

    Suresh Gopalan

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

  18. I223R mutation in influenza A(H1N1pdm09 neuraminidase confers reduced susceptibility to oseltamivir and zanamivir and enhanced resistance with H275Y.

    Directory of Open Access Journals (Sweden)

    Jérome LeGoff

    Full Text Available BACKGROUND: Resistance of pandemic A(H1N12009 (H1N1pdm09 virus to neuraminidase inhibitors (NAIs has remained limited. A new mutation I223R in the neuraminidase (NA of H1N1pdm09 virus has been reported along with H275Y in immunocompromised patients. The aim of this study was to determine the impact of I223R on oseltamivir and zanamivir susceptibility. METHODS: The NA enzymatic characteristics and susceptibility to NAIs of viruses harbouring the mutations I223R and H275Y alone or in combination were analyzed on viruses produced by reverse genetics and on clinical isolates collected from an immunocompromised patient with sustained influenza H1N1pdm09 virus shedding and treated by oseltamivir (days 0-15 and zanamivir (days 15-25 and 70-80. RESULTS: Compared with the wild type, the NA of recombinant viruses and clinical isolates with H275Y or I223R mutations had about two-fold reduced affinity for the substrate. The H275Y and I223R isolates showed decreased susceptibility to oseltamivir (246-fold and oseltamivir and zanamivir (8.9- and 4.9-fold, respectively. Reverse genetics assays confirmed these results and further showed that the double mutation H275Y and I223R conferred enhanced levels of resistance to oseltamivir and zanamivir (6195- and 15.2-fold. In the patient, six days after initiation of oseltamivir therapy, the mutation H275Y conferring oseltamivir resistance and the I223R mutation were detected in the NA. Mutations were detected concomitantly from day 6-69 but molecular cloning did not show any variant harbouring both mutations. Despite cessation of NAI treatment, the mutation I223R persisted along with additional mutations in the NA and the hemagglutinin. CONCLUSIONS: Reduced susceptibility to both oseltamivir and zanamivir was conferred by the I223R mutation which potentiated resistance to both NAIs when associated with the H275Y mutation in the NA. Concomitant emergence of the I223R and H275Y mutations under oseltamivir treatment

  19. SNP in the genome-wide association study hotspot on chromosome 9p21 confers susceptibility to diabetic nephropathy in type 1 diabetes

    DEFF Research Database (Denmark)

    Fagerholm, E; Ahlqvist, E; Forsblom, C

    2012-01-01

    Parental type 2 diabetes mellitus increases the risk of diabetic nephropathy in offspring with type 1 diabetes mellitus. Several single nucleotide polymorphisms (SNPs) that predispose to type 2 diabetes mellitus have recently been identified. It is, however, not known whether such SNPs also confer...

  20. Fine-Mapping the Wheat Snn1 Locus Conferring Sensitivity to the Parastagonospora nodorum Necrotrophic Effector SnTox1 Using an Eight Founder Multiparent Advanced Generation Inter-Cross Population.

    Science.gov (United States)

    Cockram, James; Scuderi, Alice; Barber, Toby; Furuki, Eiko; Gardner, Keith A; Gosman, Nick; Kowalczyk, Radoslaw; Phan, Huyen P; Rose, Gemma A; Tan, Kar-Chun; Oliver, Richard P; Mackay, Ian J

    2015-09-28

    The necrotrophic fungus Parastagonospora nodorum is an important pathogen of one of the world's most economically important cereal crops, wheat (Triticum aestivum L.). P. nodorum produces necrotrophic protein effectors that mediate host cell death, providing nutrients for continuation of the infection process. The recent discovery of pathogen effectors has revolutionized disease resistance breeding for necrotrophic diseases in crop species, allowing often complex genetic resistance mechanisms to be broken down into constituent parts. To date, three effectors have been identified in P. nodorum. Here we use the effector, SnTox1, to screen 642 progeny from an eight-parent multiparent advanced generation inter-cross (i.e., MAGIC) population, genotyped with a 90,000-feature single-nucleotide polymorphism array. The MAGIC founders showed a range of sensitivity to SnTox1, with transgressive segregation evident in the progeny. SnTox1 sensitivity showed high heritability, with quantitative trait locus analyses fine-mapping the Snn1 locus to the short arm of chromosome 1B. In addition, a previously undescribed SnTox1 sensitivity locus was identified on the long arm of chromosome 5A, termed here QSnn.niab-5A.1. The peak single-nucleotide polymorphism for the Snn1 locus was converted to the KASP genotyping platform, providing breeders and researchers a simple and cheap diagnostic marker for allelic state at Snn1. Copyright © 2015 Cockram et al.

  1. Lactococcus garvieae carries a chromosomally encoded pentapeptide repeat protein that confers reduced susceptibility to quinolones in Escherichia coli producing a cytotoxic effect.

    Science.gov (United States)

    Gibello, Alicia; Díaz de Alba, Paula; Blanco, M Mar; Machuca, Jesus; Cutuli, M Teresa; Rodríguez-Martínez, José Manuel

    2014-09-01

    This study characterises a chromosomal gene of Lactococcus garvieae encoding a pentapeptide repeat protein designated as LgaQnr. This gene has been implicated in reduced susceptibility to quinolones in this bacterium, which is of relevance to both veterinary and human medicine. All of the L. garvieae isolates analysed were positive for the lgaqnr gene. The expression of lgaqnr in Escherichia coli reduced the susceptibility to quinolones, producing an adverse effect. The reduced susceptibility to ciprofloxacin was 16-fold in E. coli ATCC 25922 and 32-fold in E. coli DH10B, compared to the control strains. The minimum inhibitory concentration of nalidixic acid was also increased 4 or 5-fold. The effect of the expression of lgaqnr in E. coli was investigated by electron microscopy and was observed to affect the structure of the cell and the inner membrane of the recombinant cells.

  2. The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.

    Science.gov (United States)

    Landa, Iñigo; Ruiz-Llorente, Sergio; Montero-Conde, Cristina; Inglada-Pérez, Lucía; Schiavi, Francesca; Leskelä, Susanna; Pita, Guillermo; Milne, Roger; Maravall, Javier; Ramos, Ignacio; Andía, Víctor; Rodríguez-Poyo, Paloma; Jara-Albarrán, Antonino; Meoro, Amparo; del Peso, Cristina; Arribas, Luis; Iglesias, Pedro; Caballero, Javier; Serrano, Joaquín; Picó, Antonio; Pomares, Francisco; Giménez, Gabriel; López-Mondéjar, Pedro; Castello, Roberto; Merante-Boschin, Isabella; Pelizzo, Maria-Rosa; Mauricio, Didac; Opocher, Giuseppe; Rodríguez-Antona, Cristina; González-Neira, Anna; Matías-Guiu, Xavier; Santisteban, Pilar; Robledo, Mercedes

    2009-09-01

    In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30-1.70; P = 5.9x10(-9)). Functional assays of rs1867277 (NM_004473.3:c.-283G>A) within the FOXE1 5' UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/alphaCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.

  3. The -141C Ins/Del and Taq1A polymorphism in the dopamine D2 receptor gene may confer susceptibility to schizophrenia in Asian populations.

    Science.gov (United States)

    Wang, Yurong; Liu, Li; Xin, Lihong; Fan, Dazhi; Ding, Ning; Hu, Yanting; Cai, Guoqi; Wang, Li; Xia, Qing; Li, Xiaona; Yang, Xiao; Zou, Yanfeng; Pan, Faming

    2016-08-01

    It has been reported that two single nucleotide polymorphisms (SNP) Taq1A and -141C Ins/Del in the DRD2 gene may be associated with susceptibility to schizophrenia. Due to inconclusive and mixed results, a meta-analysis was conducted to further clarify the relationship between the two SNP and schizophrenia susceptibility. A systematic literature search for the association of these two SNP with schizophrenia susceptibility was conducted using PubMed, ScienceDirect, Chinese Biomedical Literature Database, and Chinese National Knowledge Infrastructure. Odds ratios (OR) with 95% confidence intervals (CI) were used to assess the strength of the associations reported. A total of 5558 schizophrenic patients and 6792 healthy controls from 31 articles were included in this study. Evidence regarding the association between -141C Ins/Del polymorphism and schizophrenia was found in the allele frequency comparison (Ins versus Del: OR 1.29, 95% CI 1.06-1.57; p=0.01, Praw=0.1, PFalse Discovery Rate=0.023). In ethnic subgroup analysis, the result revealed that the 141C Ins/Del polymorphism was associated with schizophrenia in all genetic models in Asians, but not in Caucasians. For Taq1A polymorphism, a significant association was found in the allele frequency (A1 versus A2: OR 0.71, 95% CI 0.52-0.98, p=0.03). Stratification by ethnicity indicated an association between the Taq1A polymorphism and schizophrenia in Asians, but not Caucasians. The present study suggests that the -141C Ins/Del polymorphism carries a significantly increased risk of schizophrenia, while the Taq1A polymorphism carries a significantly decreased risk of schizophrenia susceptibility in Asians.

  4. Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation.

    Science.gov (United States)

    Ghoussaini, Maya; French, Juliet D; Michailidou, Kyriaki; Nord, Silje; Beesley, Jonathan; Canisus, Sander; Hillman, Kristine M; Kaufmann, Susanne; Sivakumaran, Haran; Moradi Marjaneh, Mahdi; Lee, Jason S; Dennis, Joe; Bolla, Manjeet K; Wang, Qin; Dicks, Ed; Milne, Roger L; Hopper, John L; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A; Beckmann, Matthias W; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Alonso, M Rosario; Pita, Guillermo; Neuhausen, Susan L; Anton-Culver, Hoda; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Tessier, Daniel C; Vincent, Daniel; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Ito, Hidemi; Dörk, Thilo; Bogdanova, Natalia V; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Wu, Anna H; Van Den Berg, David; Lambrechts, Diether; Floris, Giuseppe; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Barile, Monica; Couch, Fergus J; Hallberg, Emily; Giles, Graham G; Haiman, Christopher A; Le Marchand, Loic; Goldberg, Mark S; Teo, Soo H; Yip, Cheng Har; Borresen-Dale, Anne-Lise; Zheng, Wei; Cai, Qiuyin; Winqvist, Robert; Pylkäs, Katri; Andrulis, Irene L; Devilee, Peter; Tollenaar, Rob A E M; García-Closas, Montserrat; Figueroa, Jonine; Hall, Per; Czene, Kamila; Brand, Judith S; Darabi, Hatef; Eriksson, Mikael; Hooning, Maartje J; Koppert, Linetta B; Li, Jingmei; Shu, Xiao-Ou; Zheng, Ying; Cox, Angela; Cross, Simon S; Shah, Mitul; Rhenius, Valerie; Choi, Ji-Yeob; Kang, Daehee; Hartman, Mikael; Chia, Kee Seng; Kabisch, Maria; Torres, Diana; Luccarini, Craig; Conroy, Don M; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; Brennan, Paul; Olswold, Curtis; Slager, Susan; Shen, Chen-Yang; Hou, Ming-Feng; Swerdlow, Anthony; Schoemaker, Minouk J; Simard, Jacques; Pharoah, Paul D P; Kristensen, Vessela; Chenevix-Trench, Georgia; Easton, Douglas F; Dunning, Alison M; Edwards, Stacey L

    2016-10-06

    Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER(+)) breast cancer (per-g allele OR ER(+) = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10(-30)). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER(-)) breast cancer (lead SNP rs6864776: per-a allele OR ER(-) = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10(-12)), and a single signal 3 SNP (rs200229088: per-t allele OR ER(+) = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10(-05)). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.

  5. Polymorphism located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 haplotype confer susceptibility to CNS hypersomnias (essential hypersomnia.

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    Taku Miyagawa

    Full Text Available BACKGROUND: SNP rs5770917 located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 haplotype were previously identified as susceptibility loci for narcolepsy with cataplexy. This study was conducted in order to investigate whether these genetic markers are associated with Japanese CNS hypersomnias (essential hypersomnia: EHS other than narcolepsy with cataplexy. PRINCIPAL FINDINGS: EHS was significantly associated with SNP rs5770917 (P(allele = 3.6x10(-3; OR = 1.56; 95% c.i.: 1.12-2.15 and HLA-DRB1*1501-DQB1*0602 haplotype (P(positivity = 9.2x10(-11; OR = 3.97; 95% c.i.: 2.55-6.19. No interaction between the two markers (SNP rs5770917 and HLA-DRB1*1501-DQB1*0602 haplotype was observed in EHS. CONCLUSION: CPT1B, CHKB and HLA are candidates for susceptibility to CNS hypersomnias (EHS, as well as narcolepsy with cataplexy.

  6. DQB1*0602 rather than DRB1*1501 confers susceptibility to multiple sclerosis-like disease induced by proteolipid protein (PLP

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    Kaushansky Nathali

    2012-02-01

    Full Text Available Abstract Background Multiple sclerosis (MS is associated with pathogenic autoimmunity primarily focused on major CNS-myelin target antigens including myelin basic protein (MBP, proteolipidprotein (PLP, myelin oligodendrocyte protein (MOG. MS is a complex trait whereby the HLA genes, particularly class-II genes of HLA-DR15 haplotype, dominate the genetic contribution to disease-risk. Due to strong linkage disequilibrium in HLA-II region, it has been hard to establish precisely whether the functionally relevant effect derives from the DRB1*1501, DQA1*0102-DQB1*0602, or DRB5*0101 loci of HLA-DR15 haplotype, their combinations, or their epistatic interactions. Nevertheless, most genetic studies have indicated DRB1*1501 as a primary risk factor in MS. Here, we used 'HLA-humanized' mice to discern the potential relative contribution of DRB1*1501 and DQB1*0602 alleles to susceptibility to "humanized" MS-like disease induced by PLP, one of the most prominent and encephalitogenic target-antigens implicated in human MS. Methods The HLA-DRB1*1501- and HLA-DQB1*0602-Tg mice (MHC-II-/-, and control non-HLA-DR15-relevant-Tg mice were immunized with a set of overlapping PLP peptides or with recombinant soluble PLP for induction of "humanized" MS-like disease, as well as for ex-vivo analysis of immunogenic/immunodominant HLA-restricted T-cell epitopes and associated cytokine secretion profile. Results PLP autoimmunity in both HLA-DR15-Tg mice was focused on 139-151 and 175-194 epitopes. Strikingly, however, the HLA-DRB1*1501-transgenics were refractory to disease induction by any of the overlapping PLP peptides, while HLA-DQB1*0602 transgenics were susceptible to disease induction by PLP139-151 and PLP175-194 peptides. Although both transgenics responded to both peptides, the PLP139-151- and PLP175-194-reactive T-cells were directed to Th1/Th17 phenotype in DQB1*0602-Tg mice and towards Th2 in DRB1*1501-Tg mice. Conclusions While genome studies map a strong MS

  7. CTLA-4 gene polymorphism confers susceptibility to insulin-dependent diabetes mellitus (IDDM) independently from age and from other genetic or immune disease markers. The Belgian Diabetes Registry.

    Science.gov (United States)

    Van der Auwera, B J; Vandewalle, C L; Schuit, F C; Winnock, F; De Leeuw, I H; Van Imschoot, S; Lamberigts, G; Gorus, F K

    1997-10-01

    Apart from genes in the HLA complex (IDDM1) and the variable number of tandem repeats in the 5' region of the insulin gene (INS VNTR, IDDM2), several other loci have been proposed to contribute to IDDM susceptibility. Recently, linkage and association have been shown between the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) gene on chromosome 2q and IDDM. In a registry-based group of 525 recent-onset IDDM patients immune disease markers (autoantibodies against islet cell cytoplasm (ICA); insulin (IAA); glutamate decarboxylase (GAD65-Ab); IA-2 protein tyrosine phosphatase (IA-2-Ab)) determined within the first week of insulin treatment. In new-onset IDDM patients. G-allele-containing CTLA-4 genotypes (relative risk (RR)= 1.5; 95% confidence interval (CI) = 1.2-2.0; P immune disease markers.

  8. Comparative transcriptome analysis between resistant and susceptible tomato allows the identification of lncRNA16397 conferring resistance to Phytophthora infestans by co-expressing glutaredoxin.

    Science.gov (United States)

    Cui, Jun; Luan, Yushi; Jiang, Ning; Bao, Hang; Meng, Jun

    2017-02-01

    The rapid development of omics sequencing technology has facilitated the identification of thousands of long non-coding (lnc)RNAs in plant species, but the role of lncRNAs in plant-pathogen interactions remains largely unexplored. We used comparative transcriptome analysis of Phytophthora infestans-resistant and -susceptible tomatoes to identify differentially expressed genes (DEGs) and lncRNAs (DELs), and examine lncRNA-mRNA networks. A total of 1037 DEGs and 688 DELs were identified between P. infestans-resistant and -susceptible tomatoes. The co-localization networks, including 128 DEGs and 127 DELs, were performed. We found that lncRNA16397 acted as an antisense transcript of SlGRX22 to regulate its expression, and also induced SlGRX21 expression when lncRNA16397 was overexpressed. In addition, disease symptoms and reactive oxygen species (ROS) accumulation in tomatoes overexpressing lncRNA16397 and SpGRX were fewer and lower than those in wild-type after P. infestans infection. This result suggests that tomato lncRNA16397 induces SlGRX expression to reduce ROS accumulation and alleviate cell membrane injury, resulting in enhanced resistance to P. infestans. Our results provide insight into lncRNAs involved in the response of tomato to P. infestans infection, demonstrate that the lncRNA16397-GRXs network is an important component of the P. infestans network in tomato, and provide candidates for breeding to enhance biotic stress-resistance in tomato.

  9. A missense mutation of the gene encoding synaptic vesicle glycoprotein 2A (SV2A confers seizure susceptibility by disrupting amygdalar synaptic GABA release

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    Kentaro Tokudome

    2016-07-01

    Full Text Available Synaptic vesicle glycoprotein 2A (SV2A is specifically expressed in the membranes of synaptic vesicles and modulates action potential-dependent neurotransmitter release. To explore the role of SV2A in the pathogenesis of epileptic disorders, we recently generated a novel rat model (Sv2aL174Q rat carrying a missense mutation of the Sv2a gene and showed that the Sv2aL174Q rats were hypersensitive to kindling development (Tokudome et al., 2016. Here, we further conducted behavioral and neurochemical studies to clarify the pathophysiological mechanisms underlying the seizure vulnerability in Sv2aL174Q rats. Sv2aL174Q rats were highly susceptible to pentylenetetrazole (PTZ-induced seizures, yielding a significantly higher seizure scores and seizure incidence than the control animals. Brain mapping analysis of Fos expression, a biological marker of neural excitation, revealed that the seizure threshold level of PTZ region-specifically elevated Fos expression in the amygdala in Sv2aL174Q rats. In vivo microdialysis study showed that the Sv2aL174Q mutation preferentially reduced high K+ (depolarization-evoked GABA release, but not glutamate release, in the amygdala. In addition, specific control of GABA release by SV2A was supported by its predominant expression in GABAergic neurons, which were co-stained with antibodies against SV2A and glutamate decarboxylase 1. The present results suggest that dysfunction of SV2A by the missense mutation elevates seizure susceptibility in rats by preferentially disrupting synaptic GABA release in the amygdala, illustrating the crucial role of amygdalar SV2A-GABAergic system in epileptogenesis.

  10. A Missense Mutation of the Gene Encoding Synaptic Vesicle Glycoprotein 2A (SV2A) Confers Seizure Susceptibility by Disrupting Amygdalar Synaptic GABA Release

    Science.gov (United States)

    Tokudome, Kentaro; Okumura, Takahiro; Terada, Ryo; Shimizu, Saki; Kunisawa, Naofumi; Mashimo, Tomoji; Serikawa, Tadao; Sasa, Masashi; Ohno, Yukihiro

    2016-01-01

    Synaptic vesicle glycoprotein 2A (SV2A) is specifically expressed in the membranes of synaptic vesicles and modulates action potential-dependent neurotransmitter release. To explore the role of SV2A in the pathogenesis of epileptic disorders, we recently generated a novel rat model (Sv2aL174Q rat) carrying a missense mutation of the Sv2a gene and showed that the Sv2aL174Q rats were hypersensitive to kindling development (Tokudome et al., 2016). Here, we further conducted behavioral and neurochemical studies to clarify the pathophysiological mechanisms underlying the seizure vulnerability in Sv2aL174Q rats. Sv2aL174Q rats were highly susceptible to pentylenetetrazole (PTZ)-induced seizures, yielding a significantly higher seizure scores and seizure incidence than the control animals. Brain mapping analysis of Fos expression, a biological marker of neural excitation, revealed that the seizure threshold level of PTZ region-specifically elevated Fos expression in the amygdala in Sv2aL174Q rats. In vivo microdialysis study showed that the Sv2aL174Q mutation preferentially reduced high K+ (depolarization)-evoked GABA release, but not glutamate release, in the amygdala. In addition, specific control of GABA release by SV2A was supported by its predominant expression in GABAergic neurons, which were co-stained with antibodies against SV2A and glutamate decarboxylase 1. The present results suggest that dysfunction of SV2A by the missense mutation elevates seizure susceptibility in rats by preferentially disrupting synaptic GABA release in the amygdala, illustrating the crucial role of amygdalar SV2A-GABAergic system in epileptogenesis. PMID:27471467

  11. IL2RA genetic heterogeneity in multiple sclerosis and type 1 diabetes susceptibility and soluble interleukin-2 receptor production.

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    Lisa M Maier

    2009-01-01

    Full Text Available Multiple sclerosis (MS and type 1 diabetes (T1D are organ-specific autoimmune disorders with significant heritability, part of which is conferred by shared alleles. For decades, the Human Leukocyte Antigen (HLA complex was the only known susceptibility locus for both T1D and MS, but loci outside the HLA complex harboring risk alleles have been discovered and fully replicated. A genome-wide association scan for MS risk genes and candidate gene association studies have previously described the IL2RA gene region as a shared autoimmune locus. In order to investigate whether autoimmunity risk at IL2RA was due to distinct or shared alleles, we performed a genetic association study of three IL2RA variants in a DNA collection of up to 9,407 healthy controls, 2,420 MS, and 6,425 T1D subjects as well as 1,303 MS parent/child trios. Here, we report "allelic heterogeneity" at the IL2RA region between MS and T1D. We observe an allele associated with susceptibility to one disease and risk to the other, an allele that confers susceptibility to both diseases, and an allele that may only confer susceptibility to T1D. In addition, we tested the levels of soluble interleukin-2 receptor (sIL-2RA in the serum from up to 69 healthy control subjects, 285 MS, and 1,317 T1D subjects. We demonstrate that multiple variants independently correlate with sIL-2RA levels.

  12. Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

    Science.gov (United States)

    Ghoussaini, Maya; Edwards, Stacey L; Michailidou, Kyriaki; Nord, Silje; Cowper-Sal Lari, Richard; Desai, Kinjal; Kar, Siddhartha; Hillman, Kristine M; Kaufmann, Susanne; Glubb, Dylan M; Beesley, Jonathan; Dennis, Joe; Bolla, Manjeet K; Wang, Qin; Dicks, Ed; Guo, Qi; Schmidt, Marjanka K; Shah, Mitul; Luben, Robert; Brown, Judith; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Klevebring, Daniel; Bojesen, Stig E; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Lambrechts, Diether; Thienpont, Bernard; Neven, Patrick; Wildiers, Hans; Broeks, Annegien; Van't Veer, Laura J; Th Rutgers, Emiel J; Couch, Fergus J; Olson, Janet E; Hallberg, Emily; Vachon, Celine; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Peto, Julian; Dos-Santos-Silva, Isabel; Gibson, Lorna; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Hall, Per; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Noh, Dong-Young; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Wu, Anna H; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O; Benitez, Javier; Zamora, M Pilar; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Qiuyin; Cox, Angela; Cross, Simon S; Reed, Malcolm W R; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Tchatchou, Sandrine; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Lindblom, Annika; Margolin, Sara; Teo, Soo Hwang; Yip, Cheng Har; Lee, Daphne S C; Wong, Tien Y; Hooning, Maartje J; Martens, John W M; Collée, J Margriet; van Deurzen, Carolien H M; Hopper, John L; Southey, Melissa C; Tsimiklis, Helen; Kapuscinski, Miroslav K; Shen, Chen-Yang; Wu, Pei-Ei; Yu, Jyh-Cherng; Chen, Shou-Tung; Alnæs, Grethe Grenaker; Borresen-Dale, Anne-Lise; Giles, Graham G; Milne, Roger L; McLean, Catriona; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Hartman, Mikael; Miao, Hui; Buhari, Shaik Ahmad Bin Syed; Teo, Yik Ying; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Simard, Jacques; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Brauch, Hiltrud; Brüning, Thomas; Koto, Yon-Dschun; Radice, Paolo; Peterlongo, Paolo; Bonanni, Bernardo; Volorio, Sara; Dörk, Thilo; Bogdanova, Natalia V; Helbig, Sonja; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Van Asperen, Christi J; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Slager, Susan; Toland, Amanda E; Ambrosone, Christine B; Yannoukakos, Drakoulis; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Hamann, Ute; Torres, Diana; Zheng, Wei; Long, Jirong; Anton-Culver, Hoda; Neuhausen, Susan L; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Alvarez, Nuria; Herrero, Daniel; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; de Santiago, Ines; Carroll, Jason; Caldas, Carlos; Brown, Melissa A; Lupien, Mathieu; Kristensen, Vessela N; Pharoah, Paul D P; Chenevix-Trench, Georgia; French, Juliet D; Easton, Douglas F; Dunning, Alison M

    2014-09-23

    GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.

  13. Association between the European GWAS-identified susceptibility locus at chromosome 4p16 and the risk of atrial septal defect: a case-control study in Southwest China and a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Li Zhao

    Full Text Available Atrial septal defect (ASD is the third most frequent type of congenital heart anomaly, featuring shunting of blood between the two atria. Gene-environment interaction remains to be an acknowledged cause for ASD occurrence. A recent European genome-wide association study (GWAS of congenital heart disease (CHD identified 3 susceptibility SNPs at chromosome 4p16 associated with ASD: rs870142, rs16835979 and rs6824295. A Chinese-GWAS of CHD conducted in the corresponding period did not reveal the 3 susceptibility SNPs, but reported 2 different risk SNPs: rs2474937 and rs1531070. Therefore, we aimed to investigate the associations between the 3 European GWAS-identified susceptibility SNPs and ASD risk in the Han population in southwest China. Additionally, to increase the robustness of our current analysis, we conducted a meta-analysis combining published studies and our current case-control study. We performed association, linkage disequilibrium, and haplotype analysis among the 3 SNPs in 190 ASD cases and 225 age-, sex-, and ethnicity-matched healthy controls. Genotype and allele frequencies among the 3 SNPs showed statistically significant differences between the cases and controls. Our study found that individuals carrying the allele T of rs870142, the allele A of rs16835979, and the allele T of rs6824295 had a respective 50.1% (odds ratio (OR = 1.501, 95% confidence interval (CI = 1.122-2.009, PFDR-BH = 0.018, 48.5% (OR = 1.485, 95%CI = 1.109-1.987, PFDR-BH = 0.012, and 38.6% (OR = 1.386, 95%CI = 1.042-1.844, PFDR-BH = 0.025 increased risk to develop ASD than wild-type allele carriers in our study cohort. In the haplotype analysis, we identified a disease-risk haplotype (TAT (OR = 1.540, 95%CI = 1.030-2.380, PFDR-BH = 0.016. Our meta-analysis also showed that the investigated SNP was associated with ASD risk (combined OR (95%CI = 1.35 (1.24-1.46, P < 0.00001. Our study provides compelling evidence to motivate better understanding of the etiology

  14. Comprehensive SNP scan of DNA repair and DNA damage response genes reveal multiple susceptibility loci conferring risk to tobacco associated leukoplakia and oral cancer.

    Science.gov (United States)

    Mondal, Pinaki; Datta, Sayantan; Maiti, Guru Prasad; Baral, Aradhita; Jha, Ganga Nath; Panda, Chinmay Kumar; Chowdhury, Shantanu; Ghosh, Saurabh; Roy, Bidyut; Roychoudhury, Susanta

    2013-01-01

    Polymorphic variants of DNA repair and damage response genes play major role in carcinogenesis. These variants are suspected as predisposition factors to Oral Squamous Cell Carcinoma (OSCC). For identification of susceptible variants affecting OSCC development in Indian population, the "maximally informative" method of SNP selection from HapMap data to non-HapMap populations was applied. Three hundred twenty-five SNPs from 11 key genes involved in double strand break repair, mismatch repair and DNA damage response pathways were genotyped on a total of 373 OSCC, 253 leukoplakia and 535 unrelated control individuals. The significantly associated SNPs were validated in an additional cohort of 144 OSCC patients and 160 controls. The rs12515548 of MSH3 showed significant association with OSCC both in the discovery and validation phases (discovery P-value: 1.43E-05, replication P-value: 4.84E-03). Two SNPs (rs12360870 of MRE11A, P-value: 2.37E-07 and rs7003908 of PRKDC, P-value: 7.99E-05) were found to be significantly associated only with leukoplakia. Stratification of subjects based on amount of tobacco consumption identified SNPs that were associated with either high or low tobacco exposed group. The study reveals a synergism between associated SNPs and lifestyle factors in predisposition to OSCC and leukoplakia.

  15. Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy

    DEFF Research Database (Denmark)

    Kamiyama, Masumi; Kobayashi, Masaaki; Araki, Shin-ichi

    2007-01-01

    Using a large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese type 2 diabetic patients, we have identified a gene encoding neurocalcin delta (NCALD) as a candidate for a susceptibility gene to diabetic nephropathy; the landmark SNP was found in the 3' UTR...... of NCALD (rs1131863: exon 4 +1340 A vs. G, P = 0.00004, odds ratio = 1.59, 95% CI 1.27-1.98). We also discovered two other SNPs in exon 4 of this gene (+999 T/A, +1307 A/G) that showed absolute linkage disequilibrium to the landmark SNP. Subsequent in vitro functional analysis revealed that synthetic m...... in cultured renal proximal tubular epithelial cells. We also identified the association of the landmark SNP with the progression of diabetic nephropathy in a 8-year prospective study (A vs. G, P = 0.03, odds ratio = 1.91, 95% CI 1.07-3.42). These results suggest that the NCALD gene is a likely candidate...

  16. Structural and dynamical insights on HLA-DR2 complexes that confer susceptibility to multiple sclerosis in Sardinia: a molecular dynamics simulation study.

    Directory of Open Access Journals (Sweden)

    Amit Kumar

    Full Text Available Sardinia is a major Island in the Mediterranean with a high incidence of multiple sclerosis, a chronic autoimmune inflammatory disease of the central nervous system. Disease susceptibility in Sardinian population has been associated with five alleles of major histocompatibility complex (MHC class II DRB1 gene. We performed 120 ns of molecular dynamics simulation on one predisposing and one protective alleles, unbound and in complex with the two relevant peptides: Myelin Basic Protein and Epstein Barr Virus derived peptide. In particular we focused on the MHC peptide binding groove dynamics. The predisposing allele was found to form a stable complex with both the peptides, while the protective allele displayed stability only when bound with myelin peptide. The local flexibility of the MHC was probed dividing the binding groove into four compartments covering the well known peptide anchoring pockets. The predisposing allele in the first half cleft exhibits a narrower and more rigid groove conformation in the presence of myelin peptide. The protective allele shows a similar behavior, while in the second half cleft it displays a narrower and more flexible groove conformation in the presence of viral peptide. We further characterized these dynamical differences by evaluating H-bonds, hydrophobic and stacking interaction networks, finding striking similarities with super-type patterns emerging in other autoimmune diseases. The protective allele shows a defined preferential binding to myelin peptide, as confirmed by binding free energy calculations. All together, we believe the presented molecular analysis could help to design experimental assays, supports the molecular mimicry hypothesis and suggests that propensity to multiple sclerosis in Sardinia could be partly linked to distinct peptide-MHC interaction and binding characteristics of the antigen presentation mechanism.

  17. Structural and Dynamical Insights on HLA-DR2 Complexes That Confer Susceptibility to Multiple Sclerosis in Sardinia: A Molecular Dynamics Simulation Study

    Science.gov (United States)

    Kumar, Amit; Cocco, Eleonora; Atzori, Luigi; Marrosu, Maria Giovanna; Pieroni, Enrico

    2013-01-01

    Sardinia is a major Island in the Mediterranean with a high incidence of multiple sclerosis, a chronic autoimmune inflammatory disease of the central nervous system. Disease susceptibility in Sardinian population has been associated with five alleles of major histocompatibility complex (MHC) class II DRB1 gene. We performed 120 ns of molecular dynamics simulation on one predisposing and one protective alleles, unbound and in complex with the two relevant peptides: Myelin Basic Protein and Epstein Barr Virus derived peptide. In particular we focused on the MHC peptide binding groove dynamics. The predisposing allele was found to form a stable complex with both the peptides, while the protective allele displayed stability only when bound with myelin peptide. The local flexibility of the MHC was probed dividing the binding groove into four compartments covering the well known peptide anchoring pockets. The predisposing allele in the first half cleft exhibits a narrower and more rigid groove conformation in the presence of myelin peptide. The protective allele shows a similar behavior, while in the second half cleft it displays a narrower and more flexible groove conformation in the presence of viral peptide. We further characterized these dynamical differences by evaluating H-bonds, hydrophobic and stacking interaction networks, finding striking similarities with super-type patterns emerging in other autoimmune diseases. The protective allele shows a defined preferential binding to myelin peptide, as confirmed by binding free energy calculations. All together, we believe the presented molecular analysis could help to design experimental assays, supports the molecular mimicry hypothesis and suggests that propensity to multiple sclerosis in Sardinia could be partly linked to distinct peptide-MHC interaction and binding characteristics of the antigen presentation mechanism. PMID:23555757

  18. StCDPK5 confers resistance to late blight pathogen but increases susceptibility to early blight pathogen in potato via reactive oxygen species burst.

    Science.gov (United States)

    Kobayashi, Michie; Yoshioka, Miki; Asai, Shuta; Nomura, Hironari; Kuchimura, Kazuo; Mori, Hitoshi; Doke, Noriyuki; Yoshioka, Hirofumi

    2012-10-01

    • Potato (Solanum tuberosum) calcium-dependent protein kinase (StCDPK5) has been shown to phosphorylate the N-terminal region of plasma membrane RBOH (respiratory burst oxidase homolog) proteins, and participate in StRBOHB-mediated reactive oxygen species (ROS) burst. The constitutively active form, StCDPK5VK, provides a useful tool for gain-of-function analysis of RBOH in defense responses. • StCDPK5- and StCDPK5VK-green fluorescent protein fusion proteins were predominantly targeted to the plasma membrane, and conditional expression of StCDPK5VK activated StRBOHA-D. The interaction was confirmed by bimolecular fluorescence complementation assay. We generated transgenic potato plants containing StCDPK5VK under the control of a pathogen-inducible promoter to investigate the role of ROS burst on defense responses to blight pathogens. • Virulent isolates of the late blight pathogen Phytophthora infestans and the early blight pathogen Alternaria solani induced hypersensitive response-like cell death accompanied by ROS production at the infection sites of transgenic plants. Transgenic plants showed resistance to the near-obligate hemibiotrophic pathogen P. infestans and, by contrast, increased susceptibility to the necrotrophic pathogen A. solani. • These results indicate that RBOH-dependent ROS contribute to basal defense against near-obligate pathogens, but have a negative role in resistance or have a positive role in expansion of disease lesions caused by necrotrophic pathogens. © 2012 The Authors. New Phytologist © 2012 New Phytologist Trust.

  19. Identification of New World Quails Susceptible to Infection with Avian Leukosis Virus Subgroup J.

    Science.gov (United States)

    Plachý, Jiří; Reinišová, Markéta; Kučerová, Dana; Šenigl, Filip; Stepanets, Volodymyr; Hron, Tomáš; Trejbalová, Kateřina; Elleder, Daniel; Hejnar, Jiří

    2017-02-01

    The J subgroup of avian leukosis virus (ALV-J) infects domestic chickens, jungle fowl, and turkeys. This virus enters the host cell through a receptor encoded by the tvj locus and identified as Na(+)/H(+) exchanger 1. The resistance to avian leukosis virus subgroup J in a great majority of galliform species has been explained by deletions or substitutions of the critical tryptophan 38 in the first extracellular loop of Na(+)/H(+) exchanger 1. Because there are concerns of transspecies virus transmission, we studied natural polymorphisms and susceptibility/resistance in wild galliforms and found the presence of tryptophan 38 in four species of New World quails. The embryo fibroblasts of New World quails are susceptible to infection with avian leukosis virus subgroup J, and the cloned Na(+)/H(+) exchanger 1 confers susceptibility on the otherwise resistant host. New World quails are also susceptible to new avian leukosis virus subgroup J variants but resistant to subgroups A and B and weakly susceptible to subgroups C and D of avian sarcoma/leukosis virus due to obvious defects of the respective receptors. Our results suggest that the avian leukosis virus subgroup J could be transmitted to New World quails and establish a natural reservoir of circulating virus with a potential for further evolution.

  20. Diabetes mellitus tipo 1: multifatores que conferem suscetibilidade à patogenia auto-imune = Type 1 diabetes mellitus: multifactors that confer susceptibility to the autoimmune pathogenesis

    Directory of Open Access Journals (Sweden)

    Staub, Henrique Luiz

    2007-01-01

    Full Text Available Objetivos: revisar dados de literatura concernentes aos fatores que conferem suscetibilidade à patogenia auto-imune do diabetes mellitus tipo 1. Fonte de dados: revisão de artigos especializados no assunto publicados em bancos de dados nacionais e internacionais (SCIELO, LILACS e PUBMED. Síntese de dados: a etiopatogenia do diabetes mellitus tipo 1 está associada a fatores inflamatórios, genéticos e ambientais. Nesta revisão, abordamos o papel da auto-imunidade humoral e celular que culmina com a disfunção das células-beta produtoras de insulina. A precocidade da presença de alguns autoanticorpos como anti-ilhotas pancreáticas, antiinsulina e anti-ácido glutâmico descarboxilase é uma característica importante nesta patologia. Os diversos fatores genéticos associados ao deflagramento do diabetes mellitus tipo 1, sobretudo os associados ao sistema de antígenos leucocitários humanos, acabam por potencializar a apresentação de antígenos das ilhotas para o sistema imune. Por fim, fatores ambientais como exposição viral também contribuem para a quebra de tolerância imunológica observada nesses pacientes. Conclusões: o diabetes mellitus tipo 1 é uma entidade de etiopatogenia altamente complexa. Diversos fatores genéticos e ambientais potencializam os mecanismos de auto-imunidade humoral e celular que levam à insulite. O risco de hipoglicemia severa observada com o tratamento insulínico e as complicações crônicas do diabetes mellitus tipo 1 justificam pesquisas contínuas em relação à etiopatogenia desta entidade, o que contribuirá para abordagens terapêuticas mais eficazes. Aims: To review the literature data concerning the factors which confer susceptibilitiy to the autoimmune pathogenesis of type I diabetes mellitus. Source of data: Review of specific articles on the issue published in national and in-ternational databases (SCIELO, LILACS, PUBMED. Summary of the findings: The etiopathogenesis of type I diabetes

  1. Effects of single nucleotide polymorphisms 869 T/C and 915 G/C in the exon 1 locus of transforming growth factor-β1 gene on chronic obstructive pulmonary disease susceptibility in Chinese

    Institute of Scientific and Technical Information of China (English)

    LIU Dai-shun; LI Xiao-ou; YING Bin-wu; CHEN Lei; WANG Tao; XU Dan; WEN Fu-qiang

    2010-01-01

    Background The main risk factor for chronic obstructive pulmonary disease (COPD) is cigarette smoking. However, only 10%-20% of chronic heavy smokers develop systematic COPD. We hypothesized that the inheritance of gene polymorphisms could influence the development of COPD, which was investigated by studying two single nucleotide polymorphisms (SNP) in exon 1 of the transforming growth factor-β1 (TGF-β1) gene.Methods We enrolled 219 patients with COPD as the research group and 148 healthy people as the control group, all of whom were Chinese Han people. The polymorphisms of the TGF-β1 gene, 869T/C and 915G/C, were analyzed using the method of amplification refractory mutation system-polymerase chain reaction (ARMS-PCR).Results The occurrence of the TGF-β1 gene 869T/C polymorphism in patients with COPD was significantly different from the control group (P 0.05).Conclusions The polymorphism 869T/C in TGF-β1 gene has a significant association with disease occurrence in COPD patients and the C allele might be a risk factor. The homozygous wild-type CC of 869T/C on TGFβ1 could be a predisposing factor in COPD and those who carry the C allele might have particularly susceptibility to developing COPD.

  2. Identification of Orch3, a locus controlling dominant resistance to autoimmune orchitis, as kinesin family member 1C.

    Directory of Open Access Journals (Sweden)

    Roxana del Rio

    Full Text Available Experimental autoimmune orchitis (EAO, the principal model of non-infectious testicular inflammatory disease, can be induced in susceptible mouse strains by immunization with autologous testicular homogenate and appropriate adjuvants. As previously established, the genome of DBA/2J mice encodes genes that are capable of conferring dominant resistance to EAO, while the genome of BALB/cByJ mice does not and they are therefore susceptible to EAO. In a genome scan, we previously identified Orch3 as the major quantitative trait locus controlling dominant resistance to EAO and mapped it to chromosome 11. Here, by utilizing a forward genetic approach, we identified kinesin family member 1C (Kif1c as a positional candidate for Orch3 and, using a transgenic approach, demonstrated that Kif1c is Orch3. Mechanistically, we showed that the resistant Kif1c(D2 allele leads to a reduced antigen-specific T cell proliferative response as a consequence of decreased MHC class II expression by antigen presenting cells, and that the L(578 → P(578 and S(1027 → P(1027 polymorphisms distinguishing the BALB/cByJ and DBA/2J alleles, respectively, can play a role in transcriptional regulation. These findings may provide mechanistic insight into how polymorphism in other kinesins such as KIF21B and KIF5A influence susceptibility and resistance to human autoimmune diseases.

  3. Comparative Genomic Analyses of the Human NPHP1 Locus Reveal Complex Genomic Architecture and Its Regional Evolution in Primates.

    Directory of Open Access Journals (Sweden)

    Bo Yuan

    2015-12-01

    Full Text Available Many loci in the human genome harbor complex genomic structures that can result in susceptibility to genomic rearrangements leading to various genomic disorders. Nephronophthisis 1 (NPHP1, MIM# 256100 is an autosomal recessive disorder that can be caused by defects of NPHP1; the gene maps within the human 2q13 region where low copy repeats (LCRs are abundant. Loss of function of NPHP1 is responsible for approximately 85% of the NPHP1 cases-about 80% of such individuals carry a large recurrent homozygous NPHP1 deletion that occurs via nonallelic homologous recombination (NAHR between two flanking directly oriented ~45 kb LCRs. Published data revealed a non-pathogenic inversion polymorphism involving the NPHP1 gene flanked by two inverted ~358 kb LCRs. Using optical mapping and array-comparative genomic hybridization, we identified three potential novel structural variant (SV haplotypes at the NPHP1 locus that may protect a haploid genome from the NPHP1 deletion. Inter-species comparative genomic analyses among primate genomes revealed massive genomic changes during evolution. The aggregated data suggest that dynamic genomic rearrangements occurred historically within the NPHP1 locus and generated SV haplotypes observed in the human population today, which may confer differential susceptibility to genomic instability and the NPHP1 deletion within a personal genome. Our study documents diverse SV haplotypes at a complex LCR-laden human genomic region. Comparative analyses provide a model for how this complex region arose during primate evolution, and studies among humans suggest that intra-species polymorphism may potentially modulate an individual's susceptibility to acquiring disease-associated alleles.

  4. Comparative sequence analysis of the potato cyst nematode resistance locus H1 reveals a major lack of co-linearity between three haplotypes in potato (Solanum tuberosum ssp.).

    Science.gov (United States)

    Finkers-Tomczak, Anna; Bakker, Erin; de Boer, Jan; van der Vossen, Edwin; Achenbach, Ute; Golas, Tomasz; Suryaningrat, Suwardi; Smant, Geert; Bakker, Jaap; Goverse, Aska

    2011-02-01

    The H1 locus confers resistance to the potato cyst nematode Globodera rostochiensis pathotypes 1 and 4. It is positioned at the distal end of chromosome V of the diploid Solanum tuberosum genotype SH83-92-488 (SH) on an introgression segment derived from S. tuberosum ssp. andigena. Markers from a high-resolution genetic map of the H1 locus (Bakker et al. in Theor Appl Genet 109:146-152, 2004) were used to screen a BAC library to construct a physical map covering a 341-kb region of the resistant haplotype coming from SH. For comparison, physical maps were also generated of the two haplotypes from the diploid susceptible genotype RH89-039-16 (S. tuberosum ssp. tuberosum/S. phureja), spanning syntenic regions of 700 and 319 kb. Gene predictions on the genomic segments resulted in the identification of a large cluster consisting of variable numbers of the CC-NB-LRR type of R genes for each haplotype. Furthermore, the regions were interspersed with numerous transposable elements and genes coding for an extensin-like protein and an amino acid transporter. Comparative analysis revealed a major lack of gene order conservation in the sequences of the three closely related haplotypes. Our data provide insight in the evolutionary mechanisms shaping the H1 locus and will facilitate the map-based cloning of the H1 resistance gene.

  5. Eliana Machado, Locus Brasilis

    OpenAIRE

    Ramos, Domingo

    2013-01-01

    Locus Brasilis es un complejo libro de la poeta brasileña y trilingüe Eliana Machado, que actualmente radica en Europa y por primera vez publica en el Perú. El volumen, el segundo de la autora luego de Blanco en el blanco, que apareció en Sao Paulo, consta de tres partes bien definidas, que corresponden a los tres reinos de la naturaleza. En poesía esto se traslada al hombre con sus respectivos correlatos del animal como ser destructivo, pero también conciliador y hasta protector de un mundo ...

  6. Correlation between interleukin-18 promoter -607C/A polymorphism and susceptibility to ischemic stroke

    Directory of Open Access Journals (Sweden)

    Jian-xia Lu

    2013-06-01

    Full Text Available Single nucleotide polymorphisms in the promoter region of interleukin-18 (IL-18, an inflammatory cytokine, have been linked to susceptibility to many diseases, including cancer and immune dysfunction. Here, we explored the potential association between the IL-18 -607C/A (rs1946518 promoter region polymorphism and susceptibility to ischemic stroke (IS. This locus was amplified from peripheral blood samples of 386 IS patients (cases and 364 healthy individuals (controls by the polymerase chain reaction with sequence-specific primers. Significant differences were observed by the χ2 test in the -607C/A (rs1946518 genotype and allele frequencies between cases and controls (P < 0.05. Furthermore, after excluding for age, gender, smoking status, and hypertension, logistic regression indicated that IS susceptibility of -607C carriers increased 1.6 times (OR = 1.601, 95%CI = 1.148-2.233, P = 0.006 compared to -607A carriers. Additionally, similar increases in IS risk were noted for male patients or patients less than 65 years old. In conclusion, IL-18 -607C/A (rs1946518 promoter polymorphism is associated with IS susceptibility, and the C allele may confer increased IS risk.

  7. Assessing SNP-SNP interactions among DNA repair, modification and metabolism related pathway genes in breast cancer susceptibility.

    Directory of Open Access Journals (Sweden)

    Yadav Sapkota

    Full Text Available Genome-wide association studies (GWASs have identified low-penetrance common variants (i.e., single nucleotide polymorphisms, SNPs associated with breast cancer susceptibility. Although GWASs are primarily focused on single-locus effects, gene-gene interactions (i.e., epistasis are also assumed to contribute to the genetic risks for complex diseases including breast cancer. While it has been hypothesized that moderately ranked (P value based weak single-locus effects in GWASs could potentially harbor valuable information for evaluating epistasis, we lack systematic efforts to investigate SNPs showing consistent associations with weak statistical significance across independent discovery and replication stages. The objectives of this study were i to select SNPs showing single-locus effects with weak statistical significance for breast cancer in a GWAS and/or candidate-gene studies; ii to replicate these SNPs in an independent set of breast cancer cases and controls; and iii to explore their potential SNP-SNP interactions contributing to breast cancer susceptibility. A total of 17 SNPs related to DNA repair, modification and metabolism pathway genes were selected since these pathways offer a priori knowledge for potential epistatic interactions and an overall role in breast carcinogenesis. The study design included predominantly Caucasian women (2,795 cases and 4,505 controls from Alberta, Canada. We observed two two-way SNP-SNP interactions (APEX1-rs1130409 and RPAP1-rs2297381; MLH1-rs1799977 and MDM2-rs769412 in logistic regression that conferred elevated risks for breast cancer (P(interaction<7.3 × 10(-3. Logic regression identified an interaction involving four SNPs (MBD2-rs4041245, MLH1-rs1799977, MDM2-rs769412, BRCA2-rs1799943 (P(permutation = 2.4 × 10(-3. SNPs involved in SNP-SNP interactions also showed single-locus effects with weak statistical significance, while BRCA2-rs1799943 showed stronger statistical significance (P

  8. Identification of a Major Locus for Paget's Disease on Chromosome 10p13 in Families of British Descent

    National Research Council Canada - National Science Library

    Lucas, Gavin JA; Riches, Phillip L; Hocking, Lynne J; Cundy, Tim; Nicholson, Geoff C; Walsh, John P; Ralston, Stuart H

    2008-01-01

    .... A major susceptibility locus for PDB was identified on chromosome 10p13 by a genome‐wide linkage scan in families of British descent, which accounted for the vast majority of cases not caused by SQSTM1 mutations. Introduction...

  9. Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus

    DEFF Research Database (Denmark)

    von Kampen, Oliver; Buch, Stephan; Nothnagel, Michael

    2013-01-01

    The sterolin locus (ABCG5/ABCG8) confers susceptibility for cholesterol gallstone disease in humans. Both the responsible variant and the molecular mechanism causing an increased incidence of gallstones in these patients have as yet not been identified. Genetic mapping utilized patient samples from...... or allelic splicing of the ABCG5 and ABCG8 transcripts in human liver limited the search to coding single nucleotide polymorphisms. Subsequent mutation detection and genotyping yielded two disease-associated variants: ABCG5-R50C (P = 4.94 × 10(-9) ) and ABCG8-D19H (P = 1.74 × 10(-10) ) in high pairwise...... linkage disequilibrium (r(2) = 0.95). [(3) H]-cholesterol export assays of allelic constructs harboring these genetic candidate variants demonstrated increased transport activity (3.2-fold, P = 0.003) only for the ABCG8-19H variant, which was also superior in nested logistic regression models in German (P...

  10. Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

    NARCIS (Netherlands)

    M. Ghoussaini (Maya); S.L. Edwards (Stacey); K. Michailidou (Kyriaki); S. Nord (Silje); R. Cowper-Sal-lari (Richard); K. Desai (Kinjal); S. Kar (Siddhartha); K.M. Hillman (Kristine); S. Kaufmann (Susanne); D.M. Glubb (Dylan); J. Beesley (Jonathan); J. Dennis (Joe); M.K. Bolla (Manjeet); Q. Wang (Qing); E. Dicks (Ed); Q. Guo (Qi); M.K. Schmidt (Marjanka); M. Shah (Mitul); R.N. Luben (Robert); J. Brown (Judith); K. Czene (Kamila); H. Darabi (Hatef); M. Eriksson (Mats); D. Klevebring (Daniel); S.E. Bojesen (Stig); B.G. Nordestgaard (Børge); S.F. Nielsen (Sune); H. Flyger (Henrik); D. Lambrechts (Diether); B. Thienpont (Bernard); P. Neven (Patrick); H. Wildiers (Hans); A. Broeks (Annegien); L.J. van 't Veer (Laura); E.J.T. Rutgers (Emiel); F.J. Couch (Fergus); J.E. Olson (Janet); B. Hallberg (Boubou); C. Vachon (Celine); J. Chang-Claude (Jenny); A. Rudolph (Anja); P. Seibold (Petra); D. Flesch-Janys (Dieter); J. Peto (Julian); I. dos Santos Silva (Isabel); L.J. Gibson (Lorna); H. Nevanlinna (Heli); T.A. Muranen (Taru); K. Aittomäki (Kristiina); C. Blomqvist (Carl); P. Hall (Per); J. Li (Jingmei); J. Liu (Jianjun); M.K. Humphreys (Manjeet); D. Kang (Daehee); J.-Y. Choi (J.); S.K. Park (Sue); D-Y. Noh (Dong-Young); K. Matsuo (Keitaro); H. Ito (Hidemi); H. Iwata (Hisato); Y. Yatabe (Yasushi); P. Guénel (Pascal); T. Truong (Thérèse); F. Menegaux (Florence); M. Sanchez (Marie); B. Burwinkel (Barbara); F. Marme (Federick); A. Schneeweiss (Andreas); C. Sohn (Christof); A.H. Wu (Anna H.); C.-C. Tseng (Chiu-Chen); D. Van Den Berg (David); D.O. Stram (Daniel O.); J. Benítez (Javier); M.P. Zamora (Pilar); J.I.A. Perez (Jose Ignacio Arias); P. Menéndez (Primitiva); X.-O. Shu (Xiao-Ou); W. Lu (Wei); Y. Gao; Q. Cai (Qiuyin); A. Cox (Angela); S.S. Cross (Simon); M.W.R. Reed (Malcolm); I.L. Andrulis (Irene); J.A. Knight (Julia); G. Glendon (Gord); S. Tchatchou (Sandrine); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); N. Miller (Nicola); C.A. Haiman (Christopher); B.E. Henderson (Brian); F.R. Schumacher (Fredrick); L. Le Marchand (Loic); A. Lindblom (Annika); S. Margolin (Sara); S.-H. Teo; C.H. Yip (Cheng Har); D.S.C. Lee (Daphne S.C.); T.Y. Wong (Tien Y.); M.J. Hooning (Maartje); J.W.M. Martens (John W. M.); J.M. Collee (Margriet); C.H.M. van Deurzen (Carolien); J.L. Hopper (John); M.C. Southey (Melissa); H. Tsimiklis (Helen); M.K. Kapuscinski (Miroslav K.); C-Y. Shen (Chen-Yang); P.-E. Wu (Pei-Ei); J-C. Yu (Jyh-Cherng); S.-T. Chen; G.G. Alnæs (Grethe Grenaker); A.-L. Borresen-Dale (Anne-Lise); G.G. Giles (Graham); R.L. Milne (Roger); C.A. McLean (Catriona Ann); K.R. Muir (K.); A. Lophatananon (Artitaya); S. Stewart-Brown (Sarah); P. Siriwanarangsan (Pornthep); M. Hartman (Mikael); X. Miao; S.A.B.S. Buhari (Shaik Ahmad Bin Syed); Y.Y. Teo (Yik Ying); P.A. Fasching (Peter); L. Haeberle (Lothar); A.B. Ekici (Arif); M.W. Beckmann (Matthias); H. Brenner (Hermann); A.K. Dieffenbach (Aida Karina); V. Arndt (Volker); C. Stegmaier (Christa); A.J. Swerdlow (Anthony ); A. Ashworth (Alan); N. Orr (Nick); M. Schoemaker (Minouk); M. García-Closas (Montserrat); J.D. Figueroa (Jonine); S.J. Chanock (Stephen); J. Lissowska (Jolanta); J. Simard (Jacques); M.S. Goldberg (Mark); F. Labrèche (France); M. Dumont (Martine); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); H. Brauch (Hiltrud); T. Brüning (Thomas); Y.-D. Koto (Yon-Dschun); P. Radice (Paolo); P. Peterlongo (Paolo); B. Bonnani (Bernardo); S. Volorio (Sara); T. Dörk (Thilo); N.V. Bogdanova (Natalia); S. Helbig (Sonja); A. Mannermaa (Arto); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J.M. Hartikainen (J.); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); C.M. Seynaeve (Caroline); C.J. van Asperen (Christi); A. Jakubowska (Anna); J. Lubinski (Jan); K. Jaworska-Bieniek (Katarzyna); K. Durda (Katarzyna); S. Slager (Susan); A.E. Toland (Amanda); C.B. Ambrosone (Christine); D. Yannoukakos (Drakoulis); S. Sangrajrang (Suleeporn); V. Gaborieau (Valerie); P. Brennan (Paul); J.D. McKay (James); U. Hamann (Ute); D. Torres (Diana); W. Zheng (Wei); J. Long (Jirong); H. Anton-Culver (Hoda); S.L. Neuhausen (Susan); C. Luccarini (Craig); C. Baynes (Caroline); S. Ahmed (Shahana); M. Maranian (Melanie); S. Healey (Sue); A. González-Neira (Anna); G. Pita (G.); M.R. Alonso (M Rosario); N. Álvarez (Nuria); D. Herrero (Daniel); D.C. Tessier (Daniel C.); D. Vincent (Daniel); F. Bacot (Francois); I. de Santiago (Ines); J. Carroll (Jason); C. Caldas (Carlos); M. Brown (Melissa); M. Lupien (Mathieu); V. Kristensen (Vessela); P.D.P. Pharoah (Paul); G. Chenevix-Trench (Georgia); J.D. French (Juliet); D.F. Easton (Douglas); A.M. Dunning (Alison); P. Webb (Penny); A. De Fazio (Anna)

    2014-01-01

    textabstractGWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Geno

  11. Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

    DEFF Research Database (Denmark)

    Ghoussaini, Maya; Edwards, Stacey L; Michailidou, Kyriaki

    2014-01-01

    GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Proje...

  12. Nostradamus conference

    CERN Document Server

    Rössler, Otto; Snášel, Václav; Abraham, Ajith; Corchado, Emilio; Nostradamus: Modern Methods of Prediction, Modeling and Analysis of Nonlinear Systems

    2013-01-01

    This proceeding book of Nostradamus conference (http://nostradamus-conference.org) contains accepted papers presented at this event in 2012. Nostradamus conference was held in the one of the biggest and historic city of Ostrava (the Czech Republic, http://www.ostrava.cz/en), in September 2012. Conference topics are focused on classical as well as modern methods for prediction of dynamical systems with applications in science, engineering and economy. Topics are (but not limited to): prediction by classical and novel methods, predictive control, deterministic chaos and its control, complex systems, modelling and prediction of its dynamics and much more.

  13. Consensus conferences

    DEFF Research Database (Denmark)

    Nielsen, Annika Porsborg; Lassen, Jesper

    Our results point to significant national variation both in terms of the perceived aim of consensus conferences, expectations to conference outcomes, conceptions of the roles of lay people and experts, and in terms of the way in which the role of public deliberation is interpreted. Interestingly...

  14. Expression of the Blood-Group-Related Gene B4galnt2 Alters Susceptibility to Salmonella Infection.

    Directory of Open Access Journals (Sweden)

    Philipp Rausch

    2015-07-01

    Full Text Available Glycans play important roles in host-microbe interactions. Tissue-specific expression patterns of the blood group glycosyltransferase β-1,4-N-acetylgalactosaminyltransferase 2 (B4galnt2 are variable in wild mouse populations, and loss of B4galnt2 expression is associated with altered intestinal microbiota. We hypothesized that variation in B4galnt2 expression alters susceptibility to intestinal pathogens. To test this, we challenged mice genetically engineered to express different B4galnt2 tissue-specific patterns with a Salmonella Typhimurium infection model. We found B4galnt2 intestinal expression was strongly associated with bacterial community composition and increased Salmonella susceptibility as evidenced by increased intestinal inflammatory cytokines and infiltrating immune cells. Fecal transfer experiments demonstrated a crucial role of the B4galnt2-dependent microbiota in conferring susceptibility to intestinal inflammation, while epithelial B4galnt2 expression facilitated epithelial invasion of S. Typhimurium. These data support a critical role for B4galnt2 in gastrointestinal infections. We speculate that B4galnt2-specific differences in host susceptibility to intestinal pathogens underlie the strong signatures of balancing selection observed at the B4galnt2 locus in wild mouse populations.

  15. Expression of the Blood-Group-Related Gene B4galnt2 Alters Susceptibility to Salmonella Infection.

    Science.gov (United States)

    Rausch, Philipp; Steck, Natalie; Suwandi, Abdulhadi; Seidel, Janice A; Künzel, Sven; Bhullar, Kirandeep; Basic, Marijana; Bleich, Andre; Johnsen, Jill M; Vallance, Bruce A; Baines, John F; Grassl, Guntram A

    2015-07-01

    Glycans play important roles in host-microbe interactions. Tissue-specific expression patterns of the blood group glycosyltransferase β-1,4-N-acetylgalactosaminyltransferase 2 (B4galnt2) are variable in wild mouse populations, and loss of B4galnt2 expression is associated with altered intestinal microbiota. We hypothesized that variation in B4galnt2 expression alters susceptibility to intestinal pathogens. To test this, we challenged mice genetically engineered to express different B4galnt2 tissue-specific patterns with a Salmonella Typhimurium infection model. We found B4galnt2 intestinal expression was strongly associated with bacterial community composition and increased Salmonella susceptibility as evidenced by increased intestinal inflammatory cytokines and infiltrating immune cells. Fecal transfer experiments demonstrated a crucial role of the B4galnt2-dependent microbiota in conferring susceptibility to intestinal inflammation, while epithelial B4galnt2 expression facilitated epithelial invasion of S. Typhimurium. These data support a critical role for B4galnt2 in gastrointestinal infections. We speculate that B4galnt2-specific differences in host susceptibility to intestinal pathogens underlie the strong signatures of balancing selection observed at the B4galnt2 locus in wild mouse populations.

  16. AZT-related mutation Lys70Arg in reverse transcriptase of human immunodeficiency virus type 1 confers decrease in susceptibility to ddATP in in vitro RT inhibition assay.

    Science.gov (United States)

    Sharma, P L; Chatis, P A; Dogon, A L; Mayers, D L; McCutchan, F E; Page, C; Crumpacker, C S

    1996-09-15

    The genetic basis for didanosine (ddl) resistance in human immunodeficiency virus (HIV-1) has previously been shown to be commonly associated with a Leu to Val change at codon 74 in the HIV-1 RT gene. In this study sequential viral isolates were analyzed from five patients with prior zidovudine (AZT) use who received 6 to 16 months of ddl therapy. Following ddl therapy, viral isolates exhibited an increased AZT susceptibility and decreased ddl susceptibility. Sequence and nested PCR analysis of the HIV-1 RT gene revealed that two viral isolates contained the Leu to Val change at codon 74, and three other isolates with reduced susceptibility to ddl each contained changes at codons 65, 70, and 72. Site-directed mutagenesis was employed to insert specific mutations in RT gene of proviral clone pNL4-3. Analysis of virion-associated reverse transcriptase activity indicated that the Lys70Arg mutation resulted in an enzyme with 2- to 4-fold decreased susceptibility to ddATP. Statistical analysis of the inhibitory concentration for RT activity between pNL4-3 and mutant Lys70Arg viruses obtained in three independent RT inhibition assays was significant (P = 0.05) by student t test paired analysis. Drug susceptibility assays on the virus with Lys70Arg mutation showed a marginal decrease in susceptibility to ddl (1.5- to 2-fold) and about 4- to 6-fold decrease in susceptibility to AZT. Mutations Lys65Glu and Arg72Ser resulted in an impaired RT with greatly diminished functional RT activity. The AZT-associated Lys70Arg mutation results in an RT enzyme with decreased susceptibility to ddATP.

  17. Susceptibility loci associated with specific and shared subtypes of lymphoid malignancies.

    Directory of Open Access Journals (Sweden)

    Joseph Vijai

    Full Text Available The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM subtypes. SNPs in this region included rs12289961 near LPXN, (P(LYM = 3.89×10(-8, OR = 1.29 and rs948562 (P(LYM = 5.85×10(-7, OR = 1.29. A SNP in a novel non-HLA region on 6p23 (rs707824, P(NHL = 5.72×10(-7 was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (P(FL = 2.69×10(-12, OR = 1.93. Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy.

  18. Coherent states and geodesics cut locus and conjugate locus

    CERN Document Server

    Berceanu, S

    1997-01-01

    The intimate relationship between coherent states and geodesics is pointed out. For homogenous manifolds on which the exponential from the Lie algebra to the Lie group equals the geodesic exponential, and in particular for symmetric spaces, it is proved that the cut locus of the point $0$ is equal to the set of coherent vectors orthogonal to $\\vert 0>$. A simple method to calculate the conjugate locus in Hermitian symmetric spaces with significance in the coherent state approach is presented. The results are illustrated on the complex Grassmann manifold.

  19. 新疆维吾尔族和汉族早发性乳腺癌中乳腺癌易感基因1相互作用蛋白1基因外显子共有突变位点的分析%Analysis on common mutation locus of breast cancer susceptibility gene 1 associated C terminal helicase 1 gene in exon of the early onset breast cancer patients of Uygur and Han nationalities in Xinjiang

    Institute of Scientific and Technical Information of China (English)

    马斌; 杨乐; 吴军; 马斌林

    2015-01-01

    目的 检测新疆地区维吾尔族(简称维族)和汉族妇女早发性乳腺癌患者乳腺癌易感基因1相互作用蛋白1(BACH1)基因外显子突变情况,探讨维、汉族共有的突变位点与临床病理特征的相关性.方法 直接测序法检测新疆地区维吾尔族与汉族妇女早发性乳腺癌(年龄30 ~ 40岁,各80例)BACHI基因外显子区域的突变情况.结果 (1)维族、汉族共检测出4个共有的突变位点,包括2个错义突变、2个同义突变,分别位于外显子(EXON)6、EXON19和EXON20.Polyphen和SIFT软件预测蛋白质功能,结果表明维、汉早发性乳腺癌患者共有的突变位点rs4986764可能为有害突变,可能影响BACH1蛋白质的功能.(2)在汉族人群中,c.587A→G、rs4986765、rs49867654、rs4986763位点的野生型与突变型在三阴性、非三阴性乳腺癌中的差异均无统计学意义(P>0.05).但rs49867654、rs4986763位点的野生型与突变型在组织学分级Ⅰ+Ⅱ、Ⅲ级中的差异有统计学意义(P<0.05),与野生型基因型比较,突变型基因型可降低病理组织学分级[比值比(OR)=0.063、0.015].在维族人群中,上述3个位点的野生型与突变型在三阴性、非三阴性乳腺癌及组织学分级Ⅰ+Ⅱ、Ⅲ级中的差异均无统计学意义(P>0.05).结论 在汉族人群中,rs49867654、rs4986763位点的突变型基因型可降低病理组织学分级,但在维族人群中未见统计学差异.%Objective Detect the state of common mutation locus of breast cancer susceptibility gene 1 (BRCA1) associated C terminal helicase 1 (BACH1) gene in exon of the early onset breast cancer women patients of Uygur and Han nationalities in Xinjiang region and discuss the correlation between common mutation locus of Uygur and Han nationalities and clinicopathologic features.Methods Detect the state of mutation of BACH1 gene in exon of the early onset breast cancer women patients of Uygur and Han nationalities in Xinjiang region (aged 30

  20. [Study on preferred retinal locus].

    Science.gov (United States)

    Dai, Bing-Fa; Hu, Jian-Min; Xu, Duan-Lian

    2012-03-01

    Preferred retinal locus (PRL) is always found in the age-related macular degeneration and other macular damages in patients with low vision, and it is a very important anatomic position in patients with central vision impairment to achieve the rehabilitation. In recent years, the training of preferred retinal locus (PRL) has become a research hotspot of low vision rehabilitation, it can clearly improve functional vision and quality of life. The authors reviewed relevant literatures, and summarized the definition, position, characteristics, training and clinical implications of the PRL.

  1. Searching for a Schizophrenia Susceptibility Gene in the 22q11 Region

    Institute of Scientific and Technical Information of China (English)

    LIN XIE; GUI-ZHI JU; SHU-ZHENG LIU; JIE-PING SHI; YA-QIN YU; JUN WEI

    2005-01-01

    Objective To investigate a genetic association for schizophrenia within chromosome 22q11 in a Chinese Han population. Methods The PCR-based restriction fragment length polymorphism (PCR-RFLP) analysis was used to detect three single nucleotide polymorphisms (SNPs), rs165655 (A/G base change) and rs165815 (C/T base change) present in the ARVCF (armadillo repeat gene deletion in velocardiofacial syndrome) locus, and rs756656 (A/C base change) in the LOC128979 (expressed sequence tags, EST) locus, among 100 Chinese family trios consisting of fathers, mothers and affected offspring with schizophrenia. Genotype data were analyzed by using linkage disequilibrium (LD) methods including haplotype relative risk (HRR) analysis, transmission disequilibrium test (TDT) and haplotype transmission analysis. Results The genotype frequency distributions of three SNPs were all in Hardy-Weinberg equilibrium (P>0.05). Both the HRR and the TDT analysis showed that rs165815 was associated with schizophrenia (χ2=6.447, df=1, P=0.011 and χ2=6.313, df=1, P=0.012, respectively), whereas the other two SNPs did not show any allelic association. The haplotype transmission analysis showed a biased transmission for the rs165655-rs165815 haplotype system (χ2=17.224, df=3, P=0.0006) and for the rs756656- rs165655-rs165815 hapoltype system (χ2=20.965, df=7, P=0.0038). Conclusion Either the ARVCF gene itself or a nearby locus may confer susceptibility to schizophrenia in a Chinese Han population.

  2. Mendel conference

    CERN Document Server

    2015-01-01

    This book is a collection of selected accepted papers of Mendel conference that has been held in Brno, Czech Republic in June 2015. The book contents three chapters which represent recent advances in soft computing including intelligent image processing and bio-inspired robotics.: Chapter 1: Evolutionary Computing, and Swarm intelligence, Chapter 2: Neural Networks, Self-organization, and Machine Learning, and Chapter3: Intelligent Image Processing, and Bio-inspired Robotics. The Mendel conference was established in 1995, and it carries the name of the scientist and Augustinian priest Gregor J. Mendel who discovered the famous Laws of Heredity. In 2015 we are commemorating 150 years since Mendel's lectures, which he presented in Brno on February and March 1865. The main aim of the conference was to create a periodical possibility for students, academics and researchers to exchange their ideas and novel research methods.  .

  3. Conference Notification

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    Roskill Information Services and Metal Events Ltd areorganizing the 2nd International Rare Earths Conference,which will be held at the Conrad Hotel in Hong Kong onFebruary 28 to March 2 2006.The program is structured tocover all the main aspects of the rare earths industry,including development of Chinese rare earth industry; trendsin rare earths demand; potential constraints on supply;research on potential capacity of rare earths supply chain.Global rare earths consumers will attend the conference.Registra...

  4. Locus of Control and Interpersonal Attraction.

    Science.gov (United States)

    Fagan, M. Michael

    1980-01-01

    The role of locus of control in interpersonal attraction was examined by administering 1) the Nowicki-Strickland Locus of Control Scale and 2) a sociometric test of friendship to 200 eighth graders. (CM)

  5. Conference Report: CAQD Conference 2013

    Directory of Open Access Journals (Sweden)

    Christina Silver

    2013-05-01

    Full Text Available Nestled on the banks of the river Lahn in central Germany, the 15th CAQD conference was held at Marburg. A beautiful provincial town, it is one of very few that was spared the bombings of WWII; now providing the perfect backdrop for meeting to discuss developments in qualitative technology. This was the second international conference in the series with more than 140 delegates from 14 countries, including: Canada, Brazil, Portugal, the UK, as well as Germany. Hosted by MAGMA, the Marburg Research Group for Methodology and Evaluation, in partnership with Philipps-University Marburg, CAQD prioritizes a user-focus which balances practical and methodological workshops with conference presentations. URN: http://nbn-resolving.de/urn:nbn:de:0114-fqs1302249

  6. Conference Hopes

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Annual conference outlines tasks for 2010 to solidify China’s economic recovery through rational investment and increasing consumptionc hina will adhere to a consistent and stable economic strategy, putting in place a proactive fiscal policy and an accommodative monetary policy for the 2010 fiscal year-the macro-economic course mapped out during China’s Central

  7. Conference proceedings

    African Journals Online (AJOL)

    abp

    2015-08-07

    Aug 7, 2015 ... African epidemiological association and 1st conference of the Cameroon society of ... International Reference Centre (CIRCB) for research on HIV/AIDS prevention and .... interests (third line regimens, clinical trials and HIV functional cure). ... sharing. Regarding Mycobacterium Tuberculosis, the efficacy of.

  8. A schizophrenia-associated HLA locus affects thalamus volume and asymmetry

    NARCIS (Netherlands)

    Brucato, N.; Guadalupe, T.; Franke, B.; Fisher, S.E.; Francks, C.

    2015-01-01

    Genes of the Major Histocompatibility Complex (MHC) have recently been shown to have neuronal functions in the thalamus and hippocampus. Common genetic variants in the Human Leukocyte Antigens (HLA) region, human homologue of the MHC locus, are associated with small effects on susceptibility to

  9. Investigation of rheumatoid arthritis susceptibility loci in juvenile idiopathic arthritis confirms high degree of overlap

    Science.gov (United States)

    Hinks, Anne; Cobb, Joanna; Sudman, Marc; Eyre, Stephen; Martin, Paul; Flynn, Edward; Packham, Jonathon; Barton, Anne; Worthington, Jane; Langefeld, Carl D; Glass, David N; Thompson, Susan D; Thomson, Wendy

    2012-01-01

    Objectives Rheumatoid arthritis (RA) shares some similar clinical and pathological features with juvenile idiopathic arthritis (JIA); indeed, the strategy of investigating whether RA susceptibility loci also confer susceptibility to JIA has already proved highly successful in identifying novel JIA loci. A plethora of newly validated RA loci has been reported in the past year. Therefore, the aim of this study was to investigate these single nucleotide polymorphisms (SNP) to determine if they were also associated with JIA. Methods Thirty-four SNP that showed validated association with RA and had not been investigated previously in the UK JIA cohort were genotyped in JIA cases (n=1242), healthy controls (n=4281), and data were extracted for approximately 5380 UK Caucasian controls from the Wellcome Trust Case–Control Consortium 2. Genotype and allele frequencies were compared between cases with JIA and controls using PLINK. A replication cohort of 813 JIA cases and 3058 controls from the USA was available for validation of any significant findings. Results Thirteen SNP showed significant association (p<0.05) with JIA and for all but one the direction of association was the same as in RA. Of the eight loci that were tested, three showed significant association in the US cohort. Conclusions A novel JIA susceptibility locus was identified, CD247, which represents another JIA susceptibility gene whose protein product is important in T-cell activation and signalling. The authors have also confirmed association of the PTPN2 and IL2RA genes with JIA, both reaching genome-wide significance in the combined analysis. PMID:22294642

  10. SIGEF Conference

    CERN Document Server

    Terceño-Gómez, Antonio; Ferrer-Comalat, Joan; Merigó-Lindahl, José; Linares-Mustarós, Salvador

    2015-01-01

    This book is a collection of selected papers presented at the SIGEF conference, held at the Faculty of Economics and Business of the University of Girona (Spain), 06-08 July, 2015. This edition of the conference has been presented with the slogan “Scientific methods for the treatment of uncertainty in social sciences”. There are different ways for dealing with uncertainty in management. The book focuses on soft computing theories and their role in assessing uncertainty in a complex world. It gives a comprehensive overview of quantitative management topics and discusses some of the most recent developments in all the areas of business and management in soft computing including Decision Making, Expert Systems and Forgotten Effects Theory, Forecasting Models, Fuzzy Logic and Fuzzy Sets, Modelling and Simulation Techniques, Neural Networks and Genetic Algorithms and Optimization and Control. The book might be of great interest for anyone working in the area of management and business economics and might be es...

  11. Conference information

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    @@ Thermag Ⅳ- The 4th International Conference on Magnetic Refrigeration at Room Temperature of IIR Refrigeration technology is widely used today. However, traditional vapor compression/expansion refrigeration technology has some disadvantages, such as low conversion efficiency of vapor compressor, and emission of the ozonosphere depletion gas and greenhouse effect gas, etc. Magnetic refrigeration is a new cooling technology with huge potential application prospect, characterized by high efficiency, energy saving and environmental friendly.

  12. Speaking rate effects on locus equation slope

    Science.gov (United States)

    Berry, Jeff; Weismer, Gary

    2013-01-01

    A locus equation describes a 1st order regression fit to a scatter of vowel steady-state frequency values predicting vowel onset frequency values. Locus equation coefficients are often interpreted as indices of coarticulation. Speaking rate variations with a constant consonant–vowel form are thought to induce changes in the degree of coarticulation. In the current work, the hypothesis that locus slope is a transparent index of coarticulation is examined through the analysis of acoustic samples of large-scale, nearly continuous variations in speaking rate. Following the methodological conventions for locus equation derivation, data pooled across ten vowels yield locus equation slopes that are mostly consistent with the hypothesis that locus equations vary systematically with coarticulation. Comparable analyses between different four-vowel pools reveal variations in the locus slope range and changes in locus slope sensitivity to rate change. Analyses across rate but within vowels are substantially less consistent with the locus hypothesis. Taken together, these findings suggest that the practice of vowel pooling exerts a non-negligible influence on locus outcomes. Results are discussed within the context of articulatory accounts of locus equations and the effects of speaking rate change. PMID:24535890

  13. A novel stroke locus identified in a northern Sweden pedigree

    DEFF Research Database (Denmark)

    Janunger, T.; Nilsson-Ardnor, S.; Wiklund, P.-G.

    2009-01-01

    OBJECTIVES: The population of northern Sweden is characterized by reduced genetic diversity and a high incidence of stroke. We sought to reduce genetic variation further, using genealogic analysis in a set of nuclear families affected by stroke, and we subsequently performed a genome-wide scan...... to identify novel stroke susceptibility loci. METHODS: Through genealogy, 7 nuclear families with a common ancestor, connected over 8 generations, were identified. A genome-wide scan using 449 microsatellite markers was performed with subsequent haplotype analyses. RESULTS: A maximum allele-sharing lod score...... of 4.81 on chromosome 9q31-q33 was detected. Haplotype analysis identified a common 2.2-megabase interval in the chromosomal region in 4 of the nuclear families, where an overrepresentation of intracerebral hemorrhage was observed. CONCLUSIONS: We have identified a novel susceptibility locus for stroke...

  14. Susceptibility to Infectious Diseases Based on Antimicrobial Peptide Production▿

    Science.gov (United States)

    Rivas-Santiago, Bruno; Serrano, Carmen J.; Enciso-Moreno, J. Antonio

    2009-01-01

    In the last few years, the great impact of antimicrobial peptides on infectious disease susceptibility and natural resistance has been reported. In some cases, susceptibility to diseases is related to antimicrobial peptide polymorphisms and gene copy numbers, but for the vast majority of infectious diseases, these phenomena need to be elucidated. This review is focused on the current knowledge about susceptibility and resistance conferred by genetic variations in antimicrobial peptide expression in infectious diseases. PMID:19703980

  15. Susceptibility to infectious diseases based on antimicrobial peptide production.

    Science.gov (United States)

    Rivas-Santiago, Bruno; Serrano, Carmen J; Enciso-Moreno, J Antonio

    2009-11-01

    In the last few years, the great impact of antimicrobial peptides on infectious disease susceptibility and natural resistance has been reported. In some cases, susceptibility to diseases is related to antimicrobial peptide polymorphisms and gene copy numbers, but for the vast majority of infectious diseases, these phenomena need to be elucidated. This review is focused on the current knowledge about susceptibility and resistance conferred by genetic variations in antimicrobial peptide expression in infectious diseases.

  16. A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups

    DEFF Research Database (Denmark)

    Londono, Douglas; Kou, Ikuyo; Johnson, Todd A

    2014-01-01

    BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a common rotational deformity of the spine that presents in children worldwide, yet its etiology is poorly understood. Recent genome-wide association studies (GWAS) have identified a few candidate risk loci. One locus near the chromosome 10q24...... the International Consortium for Scoliosis Genetics (ICSG). METHODS: Here, we report the first ICSG study, a meta-analysis of the LBX1 locus in six Asian and three non-Asian cohorts. RESULTS: We find significant evidence for association of this locus with AIS susceptibility in all nine cohorts. Results for seven...

  17. Electoral Susceptibility

    CERN Document Server

    Levine, G C; Cerise, J E

    2012-01-01

    In the United States electoral system, a candidate is elected indirectly by winning a majority of electoral votes cast by individual states, the election usually being decided by the votes cast by a small number of "swing states" where the two candidates historically have roughly equal probabilities of winning. The effective value of a swing state in deciding the election is determined not only by the number of its electoral votes but by the frequency of its appearance in the set of winning partitions of the electoral college. Since the electoral vote values of swing states are not identical, the presence or absence of a state in a winning partition is generally correlated with the frequency of appearance of other states and, hence, their effective values. We quantify the effective value of states by an {\\sl electoral susceptibility}, $\\chi_j$, the variation of the winning probability with the "cost" of changing the probability of winning state $j$. We study $\\chi_j$ for realistic data accumulated for the 201...

  18. Development of a locus-specific, co-dominant SCAR marker for assisted-selection of the Sw-5 (Tospovirus resistance) gene cluster in a wide range of tomato accessions

    NARCIS (Netherlands)

    Dianese, E.C.; Fonseca, M.E.N.; Goldbach, R.W.; Kormelink, R.J.M.; Inoue-Nagata, A.K.; Resende, de R.O.; Boiteux, L.S.

    2010-01-01

    The best levels of broad-spectrum Tospovirus resistance reported in tomatoes thus far are conferred by the Sw-5 locus. This locus contains at least five paralogues (denoted Sw-5a through Sw-5e), of which Sw-5b represents the actual resistance gene. Here we evaluated a panel of seven PCR primer pairs

  19. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

    DEFF Research Database (Denmark)

    Orr, Nick; Dudbridge, Frank; Dryden, Nicola

    2015-01-01

    We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further...

  20. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

    NARCIS (Netherlands)

    N. Orr (Nick); F. Dudbridge (Frank); N. Dryden (Nicola); S. Maguire (Sarah); D. Novo (Daniela); E. Perrakis (Eleni); N. Johnson (Nichola); M. Ghoussaini (Maya); J. Hopper (John); M.C. Southey (Melissa); C. Apicella (Carmel); J. Stone (Jennifer); M.K. Schmidt (Marjanka); A. Broeks (Annegien); L.J. van 't Veer (Laura); F.B.L. Hogervorst (Frans); P.A. Fasching (Peter); L. Haeberle (Lothar); A.B. Ekici (Arif); M.W. Beckmann (Matthias W.); L.J. Gibson (Lorna); A. Aitken; H. Warren (Helen); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); N. Miller (Nicola); B. Burwinkel (Barbara); F. Marme (Federick); A. Schneeweiss (Andreas); C. Sohn (Chistof); P. Guénel (Pascal); T. Truong (Thérèse); E. Cordina-Duverger (Emilie); M. Sanchez (Marie); S.E. Bojesen (Stig); B.G. Nordestgaard (Børge); S.F. Nielsen (Sune); H. Flyger (Henrik); J. Benítez (Javier); M.P. Zamora (Pilar); J.I.A. Perez (Jose Ignacio Arias); P. Menéndez (Primitiva); H. Anton-Culver (Hoda); S.L. Neuhausen (Susan); H. Brenner (Hermann); A.K. Dieffenbach (Aida Karina); V. Arndt (Volker); C. Stegmaier (Christa); U. Hamann (Ute); H. Brauch (Hiltrud); C. Justenhoven (Christina); T. Brüning (Thomas); Y.-D. Ko (Yon-Dschun); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); C. Blomqvist (Carl); S. Khan (Sofia); N.V. Bogdanova (Natalia); T. Dörk (Thilo); A. Lindblom (Annika); S. Margolin (Sara); A. Mannermaa (Arto); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J.M. Hartikainen (J.); G. Chenevix-Trench (Georgia); J. Beesley (Jonathan); D. Lambrechts (Diether); M. Moisse (Matthieu); O.A.M. Floris; B. Beuselinck (B.); J. Chang-Claude (Jenny); A. Rudolph (Anja); P. Seibold (Petra); D. Flesch-Janys (Dieter); P. Radice (Paolo); P. Peterlongo (Paolo); B. Peissel (Bernard); V. Pensotti (Valeria); F.J. Couch (Fergus); J.E. Olson (Janet); S. Slettedahl (Seth); C. Vachon (Celine); G.G. Giles (Graham G.); R.L. Milne (Roger L.); C.A. McLean (Catriona Ann); C.A. Haiman (Christopher); B.E. Henderson (Brian); F.R. Schumacher (Fredrick); L. Le Marchand (Loic); J. Simard (Jacques); M.S. Goldberg (Mark); F. Labrèche (France); M. Dumont (Martine); V. Kristensen (Vessela); G.G. Alnæs (Grethe Grenaker); S. Nord (Silje); A.-L. Borresen-Dale (Anne-Lise); W. Zheng (Wei); S.L. Deming-Halverson (Sandra); M. Shrubsole (Martha); J. Long (Jirong); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); I.L. Andrulis (Irene); J.A. Knight (Julia); G. Glendon (Gord); S. Tchatchou (Sandrine); P. Devilee (Peter); R.A.E.M. Tollenaar (Robertus A. E. M.); C.M. Seynaeve (Caroline); C.J. van Asperen (Christi); M. García-Closas (Montserrat); J.D. Figueroa (Jonine); S.J. Chanock (Stephen); J. Lissowska (Jolanta); K. Czene (Kamila); H. Darabi (Hatef); M. Eriksson (Mikael); D. Klevebring (Daniel); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); C.H.M. van Deurzen (Carolien); M. Kriege (Mieke); P. Hall (Per); J. Li (Jingmei); J. Liu (Jianjun); M.K. Humphreys (Manjeet); A. Cox (Angela); S.S. Cross (Simon); M.W.R. Reed (Malcolm); P.D.P. Pharoah (Paul); A.M. Dunning (Alison); M. Shah (Mitul); B. Perkins (Barbara); A. Jakubowska (Anna); J. Lubinski (Jan); K. Jaworska-Bieniek (Katarzyna); K. Durda (Katarzyna); A. Ashworth (Alan); A.J. Swerdlow (Anthony ); M. Jones (Michael); M. Schoemaker (Minouk); A. Meindl (Alfons); R.K. Schmutzler (Rita); C. Olswold (Curtis); S. Slager (Susan); A.E. Toland (Amanda); D. Yannoukakos (Drakoulis); K.R. Muir (K.); A. Lophatananon (Artitaya); S. Stewart-Brown (Sarah); P. Siriwanarangsan (Pornthep); K. Matsuo (Keitaro); H. Ito (Hidema); H. Iwata (Hisato); J. Ishiguro (Junko); A.H. Wu (Anna H.); C.-C. Tseng (Chiu-chen); D. Van Den Berg (David); D.O. Stram (Daniel O.); S.-H. Teo; C.H. Yip (Cheng Har); P. Kang (Peter); M.K. Ikram (Kamran); X.-O. Shu (Xiao-Ou); W. Lu (Wei); Y. Gao; H. Cai (Hui); D. Kang (Daehee); J.-Y. Choi (J.); S.K. Park (Sue); D-Y. Noh (Dong-Young); J.M. Hartman (Joost); X. Miao; W.-Y. Lim (Wei-Yen); S.C. Lee (Soo Chin); S. Sangrajrang (Suleeporn); V. Gaborieau (Valerie); P. Brennan (Paul); J.D. McKay (James); P.-E. Wu (Pei-Ei); M.-F. Hou (Ming-Feng); J-C. Yu (Jyh-Cherng); C-Y. Shen (Chen-Yang); W.J. Blot (William); Q. Cai (Qiuyin); L.B. Signorello (Lisa B.); C. Luccarini (Craig); C. Bayes (Caroline); S. Ahmed (Shahana); M. Maranian (Melanie); S. Healey (Sue); A. González-Neira (Anna); G. Pita (G.); M. Rosario Alonso; N. Álvarez (Nuria); D. Herrero (Daniel); D.C. Tessier (Daniel C.); D. Vincent (Daniel); F. Bacot (Francois); D. Hunter (David); S. Lindstrom (Stephen); J. Dennis (Joe); K. Michailidou (Kyriaki); M.K. Bolla (Manjeet); D.F. Easton (Douglas); I. dos Santos Silva (Isabel); O. Fletcher (Olivia); J. Peto (Julian)

    2015-01-01

    textabstractWe recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and

  1. "Population structure of drug-susceptible,-resistant and ESBL-producing Escherichia coli from community-acquired urinary tract"

    DEFF Research Database (Denmark)

    Hertz, Frederik Boëtius; Nielsen, Jesper Boye; Schønning, Kristian;

    2016-01-01

    , from non-hospitalized patients to describe the genetic kinship between resistant and susceptible isolates. We studied the populations by use of multi-locus sequence typing (MLST) and abbreviated-multi locus variable number of tandem repeat analysis (a-MLVA). Urine samples submitted for testing...

  2. Conference Proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Riveros, P. A.; Dutrizac, J. E. [Natural Resources Canada, Ottawa, ON (Canada)] [eds.

    2001-07-01

    This workshop is part of a continuing series of joint workshops organized by CANMET of Natural Resources Canada and the Research Directorate-General of the European Commission in the areas of sustainable metallurgical processing, recycling and environmental protection. The program presented at this conference also benefited from the organizational support of the Canadian Association of Recycling Industries. Over the past twenty years these workshops served as a valuable forum for the discussion of the technological issues associated with metallurgical processing, recycling and compliance with environmental regulations within the framework of sustainable development. The program this year was organized in five sessions. A total of 32 papers were presented. Session One emphasized the international dimension of modern research as illustrated by the Intelligent Manufacturing System (MIS) program. Session Two dealt with recycling, with special attention to the recycling of plastics and construction materials. Session Three was devoted to highlighting European efforts to treat chromium-bearing solutions or to find alternatives to chromium salts in surface treatment operations. Session Four emphasized primary and secondary zinc processing and the importance of energy conservation. The final session reviewed waste management practices and the utilization of waste materials. Opening addresses by representatives of the sponsoring organizations and a list of conference attendees and their affiliations are also included.

  3. NATO Conference

    CERN Document Server

    Lynn, W

    1975-01-01

    The contents of this volume involve selection, emendation and up-dating of papers presented at the NATO Conference "Mathe­ matical Analysis of Decision problems in Ecology" in Istanbul, Turkey, July 9-13, 1973. It was sponsored by the System Sciences Division of NATO directed by Dr. B. Bayraktar with local arrange­ ments administered by Dr. Ilhami Karayalcin, professor of the Department of Industrial Engineering at the Technical University of Istanbul. It was organized by A. Charnes, University professor across the University of Texas System, and Walter R.Lynn, Di­ rector of the School of Civil and Environmental Engineering at Cornell Unjversity. The objective of the conference was to bring together a group of leading researchers from the major sciences involved in eco­ logical problems and to present the current state of progress in research of a mathematical nature which might assist in the solu­ tion of these problems. Although their presentations are not herein recorded, the key­ note address of Dr....

  4. EGC Conferences

    CERN Document Server

    Ritschard, Gilbert; Pinaud, Bruno; Venturini, Gilles; Zighed, Djamel; Advances in Knowledge Discovery and Management

    This book is a collection of representative and novel works done in Data Mining, Knowledge Discovery, Clustering and Classification that were originally presented in French at the EGC'2012 Conference held in Bordeaux, France, on January 2012. This conference was the 12th edition of this event, which takes place each year and which is now successful and well-known in the French-speaking community. This community was structured in 2003 by the foundation of the French-speaking EGC society (EGC in French stands for ``Extraction et Gestion des Connaissances'' and means ``Knowledge Discovery and Management'', or KDM). This book is intended to be read by all researchers interested in these fields, including PhD or MSc students, and researchers from public or private laboratories. It concerns both theoretical and practical aspects of KDM. The book is structured in two parts called ``Knowledge Discovery and Data Mining'' and ``Classification and Feature Extraction or Selection''. The first part (6 chapters) deals with...

  5. ADAM33, a new candidate for psoriasis susceptibility.

    Directory of Open Access Journals (Sweden)

    Fabienne Lesueur

    Full Text Available Psoriasis is a chronic skin disorder with multifactorial etiology. In a recent study, we reported results of a genome-wide scan on 46 French extended families presenting with plaque psoriasis. In addition to unambiguous linkage to the major susceptibility locus PSORS1 on Chromosome 6p21, we provided evidence for a susceptibility locus on Chromosome 20p13. To follow up this novel psoriasis susceptibility locus we used a family-based association test (FBAT for an association scan over the 17 Mb candidate region. A total of 85 uncorrelated SNP markers located in 65 genes of the region were initially investigated in the same set of large families used for the genome wide search, which consisted of 295 nuclear families. When positive association was obtained for a SNP, candidate genes nearby were explored more in detail using a denser set of SNPs. Thus, the gene ADAM33 was found to be significantly associated with psoriasis in this family set (The best association was on a 3-SNP haplotype P = 0.00004, based on 1,000,000 permutations. This association was independent of PSORS1. ADAM33 has been previously associated with asthma, which demonstrates that immune system diseases may be controlled by common susceptibility genes with general effects on dermal inflammation and immunity. The identification of ADAM33 as a psoriasis susceptibility gene identified by positional cloning in an outbred population should provide insights into the pathogenesis and natural history of this common disease.

  6. Investigation of Caucasian rheumatoid arthritis susceptibility loci in African patients with the same disease

    Science.gov (United States)

    2012-01-01

    Introduction The largest genetic risk to develop rheumatoid arthritis (RA) arises from a group of alleles of the HLA DRB1 locus ('shared epitope', SE). Over 30 non-HLA single nucleotide polymorphisms (SNPs) predisposing to disease have been identified in Caucasians, but they have never been investigated in West/Central Africa. We previously reported a lower prevalence of the SE in RA patients in Cameroon compared to European patients and aimed in the present study to investigate the contribution of Caucasian non-HLA RA SNPs to disease susceptibility in Black Africans. Methods RA cases and controls from Cameroon were genotyped for Caucasian RA susceptibility SNPs using Sequenom MassArray technology. Genotype data were also available for 5024 UK cases and 4281 UK controls and for 119 Yoruba individuals in Ibadan, Nigeria (YRI, HapMap). A Caucasian aggregate genetic-risk score (GRS) was calculated as the sum of the weighted risk-allele counts. Results After genotyping quality control procedures were performed, data on 28 Caucasian non-HLA susceptibility SNPs were available in 43 Cameroonian RA cases and 44 controls. The minor allele frequencies (MAF) were tightly correlated between Cameroonian controls and YRI individuals (correlation coefficient 93.8%, p = 1.7E-13), and they were pooled together. There was no correlation between MAF of UK and African controls; 13 markers differed by more than 20%. The MAF for markers at PTPN22, IL2RA, FCGR2A and IL2/IL21 was below 2% in Africans. The GRS showed a strong association with RA in the UK. However, the GRS did not predict RA in Africans (OR = 0.71, 95% CI 0.29 - 1.74, p = 0.456). Random sampling from the UK cohort showed that this difference in association is unlikely to be explained by small sample size or chance, but is statistically significant with p<0.001. Conclusions The MAFs of non-HLA Caucasian RA susceptibility SNPs are different between Caucasians and Africans, and several polymorphisms are barely detectable in

  7. MUSME Conference

    CERN Document Server

    Martinez, Eusebio

    2015-01-01

    This volume contains the Proceedings of MUSME 2014, held at Huatulco in Oaxaca, Mexico, October 2014. Topics include analysis and synthesis of mechanisms; dynamics of multibody systems; design algorithms for mechatronic systems; simulation procedures and results; prototypes and their performance; robots and micromachines; experimental validations; theory of mechatronic simulation; mechatronic systems; and control of mechatronic systems. The MUSME symposium on Multibody Systems and Mechatronics was held under the auspices of IFToMM, the International Federation for Promotion of Mechanism and Machine Science, and FeIbIM, the Iberoamerican Federation of Mechanical Engineering. Since the first symposium in 2002, MUSME events have been characterised by the way they stimulate the integration between the various mechatronics and multibody systems dynamics disciplines, present a forum for facilitating contacts among researchers and students mainly in South American countries, and serve as a joint conference for the ...

  8. TMEM187-IRAK1 Polymorphisms Associated with Rheumatoid Arthritis Susceptibility in Tunisian and French Female Populations: Influence of Geographic Origin

    Science.gov (United States)

    Lambert, Nathalie; Auger, Isabelle; Roudier, Jean; Sénéchal, Audrey; Geneviève, David; Lefranc, Gérard; Mrenda, Bakridine M'Madi; Benedito, Cécilia; Pardoux, Etienne; Gagez, Anne-Laure; Jorgensen, Christian; Mahjoub, Touhami

    2017-01-01

    Polymorphisms have been identified in the Xq28 locus as risk loci for rheumatoid arthritis (RA). Here, we investigated the association between three polymorphisms in the Xq28 region containing TMEM187 and IRAK1 (rs13397, rs1059703, and rs1059702) in two unstudied populations: Tunisian and French. The rs13397 G and rs1059703 T major alleles were significantly increased in RA patients (n = 408) compared with age-matched controls (n = 471) in both Tunisian and French women. These results were confirmed by a meta-analysis replication study including two independent Greek and Korean cohorts. The rs1059702 C major allele was significantly associated with RA, only with French women. In the French population, the GTC haplotype displayed a protective effect against RA, while the ATC, GCC, and GTT haplotypes conferred significant risk for RA. No association for these haplotypes was found in the Tunisian population. Our results replicated for the first time the association of the three Xq28 polymorphisms with RA risk in Tunisian and French populations and suggested that RA susceptibility is associated with TMEM187-IRAK1 polymorphisms in women. Our data further support the involvement of X chromosome in RA susceptibility and evidence ethnicities differences that might be explained by differences in the frequencies of SE HLA-DRB1 alleles between both populations. PMID:28271077

  9. Linkage disequilibrium at the APA insecticidal seed protein locus of common bean (Phaseolus vulgaris L.).

    Science.gov (United States)

    Blair, Matthew W; Prieto, Sergio; Díaz, Lucy M; Buendía, Héctor F; Cardona, César

    2010-04-29

    An interesting seed protein family with a role in preventing insect herbivory is the multi-gene, APA family encoding the alpha-amylase inhibitor, phytohemagglutinin and arcelin proteins of common bean (Phaseolus vulgaris). Variability for this gene family exists and has been exploited to breed for insect resistance. For example, the arcelin locus has been successfully transferred from wild to cultivated common bean genotypes to provide resistance against the bruchid species Zabrotes subfasciatus although the process has been hampered by a lack of genetic tools for and understanding about the locus. In this study, we analyzed linkage disequilibrium (LD) between microsatellite markers at the APA locus and bruchid resistance in a germplasm survey of 105 resistant and susceptible genotypes and compared this with LD in other parts of the genome. Microsatellite allele diversity was found to vary with each of the eight APA-linked markers analyzed, and two markers within the APA locus were found to be diagnostic for bruchid resistance or susceptibility and for the different arcelin alleles inherited from the wild accessions. Arc1 was found to provide higher levels of resistance than Arc5 and the markers in the APA locus were highly associated with resistance showing that introgression of this gene-family from wild beans provides resistance in cultivated beans. LD around the APA locus was found to be intermediate compared to other regions of the genome and the highest LD was found within the APA locus itself for example between the markers PV-atct001 and PV-ag004. We found the APA locus to be an important genetic determinant of bruchid resistance and also found that LD existed mostly within the APA locus but not beyond it. Moderate LD was also found for some other regions of the genome perhaps related to domestication genes. The LD pattern may reflect the introgression of arcelin from the wild into the cultivated background through breeding. LD and association studies for

  10. Linkage disequilibrium at the APA insecticidal seed protein locus of common bean (Phaseolus vulgaris L.

    Directory of Open Access Journals (Sweden)

    Buendía Héctor F

    2010-04-01

    Full Text Available Abstract Background An interesting seed protein family with a role in preventing insect herbivory is the multi-gene, APA family encoding the α-amylase inhibitor, phytohemagglutinin and arcelin proteins of common bean (Phaseolus vulgaris. Variability for this gene family exists and has been exploited to breed for insect resistance. For example, the arcelin locus has been successfully transferred from wild to cultivated common bean genotypes to provide resistance against the bruchid species Zabrotes subfasciatus although the process has been hampered by a lack of genetic tools for and understanding about the locus. In this study, we analyzed linkage disequilibrium (LD between microsatellite markers at the APA locus and bruchid resistance in a germplasm survey of 105 resistant and susceptible genotypes and compared this with LD in other parts of the genome. Results Microsatellite allele diversity was found to vary with each of the eight APA-linked markers analyzed, and two markers within the APA locus were found to be diagnostic for bruchid resistance or susceptibility and for the different arcelin alleles inherited from the wild accessions. Arc1 was found to provide higher levels of resistance than Arc5 and the markers in the APA locus were highly associated with resistance showing that introgression of this gene-family from wild beans provides resistance in cultivated beans. LD around the APA locus was found to be intermediate compared to other regions of the genome and the highest LD was found within the APA locus itself for example between the markers PV-atct001 and PV-ag004. Conclusions We found the APA locus to be an important genetic determinant of bruchid resistance and also found that LD existed mostly within the APA locus but not beyond it. Moderate LD was also found for some other regions of the genome perhaps related to domestication genes. The LD pattern may reflect the introgression of arcelin from the wild into the cultivated

  11. Direct visualization of the highly polymorphic RNU2 locus in proximity to the BRCA1 gene.

    Directory of Open Access Journals (Sweden)

    Chloé Tessereau

    Full Text Available Although the breast cancer susceptibility gene BRCA1 is one of the most extensively characterized genetic loci, much less is known about its upstream variable number tandem repeat element, the RNU2 locus. RNU2 encodes the U2 small nuclear RNA, an essential splicing element, but this locus is missing from the human genome assembly due to the inherent difficulty in the assembly of repetitive sequences. To fill the gap between RNU2 and BRCA1, we have reconstructed the physical map of this region by re-examining genomic clone sequences of public databases, which allowed us to precisely localize the RNU2 array 124 kb telomeric to BRCA1. We measured by performing FISH analyses on combed DNA for the first time the exact number of repeats carried by each of the two alleles in 41 individuals and found a range of 6-82 copies and a level of heterozygosity of 98%. The precise localisation of the RNU2 locus in the genome reference assembly and the implementation of a new technical tool to study it will make the detailed exploration of this locus possible. This recently neglected macrosatellite could be valuable for evaluating the potential role of structural variations in disease due to its location next to a major cancer susceptibility gene.

  12. A dominant chromatin opening activity in 5' hypersensitive site 3 of the human β-globin locus control region.

    NARCIS (Netherlands)

    J. Ellis (James); K.C. Tan-Un; A. Harper; D. Michalovich (David); P.J. Fraser (Peter); N. Yannoutsos (Nikos); F.G. Grosveld (Frank)

    1996-01-01

    textabstractSingle-copy human beta-globin transgenes are very susceptible to suppression by position effects of surrounding closed chromatin. However, these position effects are overcome by a 20 kbp DNA fragment containing the locus control region (LCR). Here we show that the 6.5 kbp microlocus LCR

  13. EL LOCUS DE DISTRIBUCION COMO COROLARIO DEL LOCUS DE CONTROL

    Directory of Open Access Journals (Sweden)

    Luisa Mayoral

    2009-01-01

    Full Text Available Este es un artículo científico acerca del Locus de Distribución, surgido de un estudio realizado con una población de docentes y alumnos universitarios. Respecto de los primeros, se ha indagado acerca de las atribuciones que se realizaban en torno a las recompensas y sanciones, que ellos distribuían a sus alumnos. Respecto de los segundos, se ha buscado determinar la valoración que estos realizaban de sus profesores, en términos de aquellas atribuciones. Para ello, se utilizaron dos paradigmas clásicamente empleados para verificar la existencia de una norma: el paradigma de la autopresentación (docentes, y el paradigma de los juicios (alumnos. La cuestión planteada fue determinar si en el caso de los comportamientos distributivos de refuerzos, las causas se atribuían a variables externas -en particular a los receptores de esos refuerzos- y si esas formas de atribución eran conocidas y valoradas o no, por los alumnos. De los resultados, surgió la confirmación de nuestra hipótesis de explicaciones externas en materia de comportamientos distributivos de sanciones en el ámbito de la docencia y la valoración positiva de estas atribuciones por los alumnos.

  14. Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii.

    Directory of Open Access Journals (Sweden)

    Kimberly M Cirelli

    2014-03-01

    Full Text Available Toxoplasma gondii is an intracellular parasite that infects a wide range of warm-blooded species. Rats vary in their susceptibility to this parasite. The Toxo1 locus conferring Toxoplasma resistance in rats was previously mapped to a region of chromosome 10 containing Nlrp1. This gene encodes an inflammasome sensor controlling macrophage sensitivity to anthrax lethal toxin (LT induced rapid cell death (pyroptosis. We show here that rat strain differences in Toxoplasma infected macrophage sensitivity to pyroptosis, IL-1β/IL-18 processing, and inhibition of parasite proliferation are perfectly correlated with NLRP1 sequence, while inversely correlated with sensitivity to anthrax LT-induced cell death. Using recombinant inbred rats, SNP analyses and whole transcriptome gene expression studies, we narrowed the candidate genes for control of Toxoplasma-mediated rat macrophage pyroptosis to four genes, one of which was Nlrp1. Knockdown of Nlrp1 in pyroptosis-sensitive macrophages resulted in higher parasite replication and protection from cell death. Reciprocally, overexpression of the NLRP1 variant from Toxoplasma-sensitive macrophages in pyroptosis-resistant cells led to sensitization of these resistant macrophages. Our findings reveal Toxoplasma as a novel activator of the NLRP1 inflammasome in rat macrophages.

  15. Statistical evaluation of multiple-locus linkage data in experimental species and its relevance to human studies: Application to nonobese diabetic (NOD) mouse and human insulin-dependent diabetes mellitus (IDDM)

    Energy Technology Data Exchange (ETDEWEB)

    Risch, N. (Yale Univ. School of Medicine, New Haven, CT (United States)); Ghosh, S.; Todd, J.A.

    1993-09-01

    Common, familial human disorders generally do not follow Mendelian inheritance patterns, presumably because multiple loci are involved in disease susceptibility. One approach to mapping genes for such traits in humans is to first study an analogous form in an animal model, such as mouse, by using inbred strains and backcross experiments. Here the authors describe methodology for analyzing multiple-locus linkage data from such experimental backcrosses, particularly in light of multilocus genetic models, including the effects of epistasis. They illustrate these methods by using data from backcrosses involving nonobese diabetic mouse, which serves as an animal model for human insulin-dependent diabetes mellitus. They show that it is likely that a minimum of nine loci contribute to susceptibility, with strong epistasis effects among these loci. Three of the loci actually confer a protective effect in the homozygote, compared with the heterozygote. Further, they discuss the relevance of these studies for analogous studies of the human form of the trait. Specifically, they show that the magnitude of the gene effect in the experimental backcross is likely to correlate only weakly, at best, with the expected magnitude of effect for a human form, because in humans the gene effect will depend more heavily on disease allele frequencies than on the observed penetrance ratios; such allele frequencies are unpredictable. Hence, the major benefit from animal studies may be a better understanding of the disease process itself, rather than identification of cells through comparison mapping in humans by using regions of homology. 12 refs., 7 tabs.

  16. Translocations affecting human immunoglobulin heavy chain locus

    Directory of Open Access Journals (Sweden)

    Sklyar I. V.

    2014-03-01

    Full Text Available Translocations involving human immunoglobulin heavy chain (IGH locus are implicated in different leukaemias and lymphomas, including multiple myeloma, mantle cell lymphoma, Burkitt’s lymphoma and diffuse large B cell lymphoma. We have analysed published data and identified eleven breakpoint cluster regions (bcr related to these cancers within the IgH locus. These ~1 kbp bcrs are specific for one or several types of blood cancer. Our findings could help devise PCR-based assays to detect cancer-related translocations, to identify the mechanisms of translocations and to help in the research of potential translocation partners of the immunoglobulin locus at different stages of B-cell differentiation.

  17. Fitness penalty in susceptible host is associated with virulence of Soybean mosaic virus on Rsv1-genotype soybean: a consequence of perturbation of HC-Pro and not P3.

    Science.gov (United States)

    Khatabi, B; Wen, R-H; Hajimorad, M R

    2013-12-01

    The multigenic Rsv1 locus in the soybean plant introduction (PI) 'PI96983' confers extreme resistance against the majority of Soybean mosaic virus (SMV) strains, including SMV-N, but not SMV-G7 and SMV-G7d. In contrast, in susceptible soybean cultivars lacking a functional Rsv1 locus, such as 'Williams82' (rsv1), SMV-N induces severe disease symptoms and accumulates to a high level, whereas both SMV-G7 and SMV-G7d induce mild symptoms and accumulate to a significantly lower level. Gain of virulence by SMV-N on Rsv1-genotype soybean requires concurrent mutations in both the helper-component proteinase (HC-Pro) and P3 cistrons. This is because of the presence of at least two resistance (R) genes, probably belonging to the nucleotide-binding leucine-rich repeat (NB-LRR) class, within the Rsv1 locus, independently mediating the recognition of HC-Pro or P3. In this study, we show that the majority of experimentally evolved mutational pathways that disrupt the avirulence functions of SMV-N on Rsv1-genotype soybean also result in mild symptoms and reduced accumulation, relative to parental SMV-N, in Williams82 (rsv1). Furthermore, the evaluation of SMV-N-derived HC-Pro and P3 chimeras, containing homologous sequences from virulent SMV-G7 or SMV-G7d strains, as well as SMV-N-derived variants containing HC-Pro or P3 point mutation(s) associated with gain of virulence, reveals a direct correlation between the perturbation of HC-Pro and a fitness penalty in Williams82 (rsv1). Collectively, these data demonstrate that gain of virulence by SMV on Rsv1-genotype soybean results in fitness loss in a previously susceptible soybean genotype, this being a consequence of mutations in HC-Pro, but not in P3.

  18. Conference this! Lead Pipers compare conference experiences

    Directory of Open Access Journals (Sweden)

    Editorial Board

    2010-04-01

    Full Text Available As library travel budgets are increasingly slashed around the country, it’s a tough time for conference-going. In this group post, we compare notes about the conferences we’ve attended, which have been our favorites, and why. We hope this will generate creative ideas on good conferences (online or in-person to look forward to, and maybe offer [...

  19. Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility

    NARCIS (Netherlands)

    Astuti, Dewi; Morris, Mark R.; Cooper, Wendy N.; Staals, Raymond H. J.; Wake, Naomi C.; Fews, Graham A.; Gill, Harmeet; Gentle, Dean; Shuib, Salwati; Ricketts, Christopher J.; Cole, Trevor; van Essen, Anthonie J.; van Lingen, Richard A.; Neri, Giovanni; Opitz, John M.; Rump, Patrick; Stolte-Dijkstra, Irene; Mueller, Ferenc; Pruijn, Ger J. M.; Latif, Farida; Maher, Eamonn R.

    2012-01-01

    Perlman syndrome is a congenital overgrowth syndrome inherited in an autosomal recessive manner that is associated with Wilms tumor susceptibility. We mapped a previously unknown susceptibility locus to 2q37.1 and identified germline mutations in DIS3L2, a homolog of the Schizosaccharomyces pombe di

  20. Locus of control and decision to abort.

    Science.gov (United States)

    Dixon, P N; Strano, D A; Willingham, W

    1984-04-01

    The relationship of locus of control to deciding on an abortion was investigated by administering Rotter's Locus of Control Scale to 118 women immediately prior to abortion and 2 weeks and 3 months following abortion. Subjects' scores were compared across the 3 time periods, and the abortion group's pretest scores were compared with those of a nonpregnant control, group. As hypothesized, the aborting group scored significantly more internal than the general population but no differences in locus of control were found across the 3 time period. The length of delay in deciding to abort an unwanted pregnancy following confirmation was also assessed. Women seeking 1st trimester abortions were divided into internal and external groups on the Rotter Scale and the lengths of delay were compared. The hypothesis that external scores would delay the decision longer than internal ones was confirmed. The results confirm characteristics of the locus of control construct and add information about personality characteristics of women undergoing abortion.

  1. Search, Effort, and Locus of Control

    OpenAIRE

    McGee, Andrew; McGee, Peter

    2011-01-01

    We test the hypothesis that locus of control – one's perception of control over events in life – influences search by affecting beliefs about the efficacy of search effort in a laboratory experiment. We find that reservation offers and effort are increasing in the belief that one's efforts influence outcomes when subjects exert effort without knowing how effort influences the generation of offers but are unrelated to locus of control beliefs when subjects are informed about the relationship b...

  2. Culture, gender and locus of control

    DEFF Research Database (Denmark)

    Ottsen, Christina Lundsgaard; Johannessen, Kim Berg; Berntsen, Dorthe

    The current study is a cross-cultural comparison between the Middle East and Scandinavia. Two societies that offer a unique opportunity to examine gender differences in personal goals and how goals are affected by locus of control.......The current study is a cross-cultural comparison between the Middle East and Scandinavia. Two societies that offer a unique opportunity to examine gender differences in personal goals and how goals are affected by locus of control....

  3. 76 FR 64083 - Reliability Technical Conference; Notice of Technical Conference

    Science.gov (United States)

    2011-10-17

    ... Energy Regulatory Commission Reliability Technical Conference; Notice of Technical Conference Take notice that the Federal Energy Regulatory Commission will hold a Technical Conference on Tuesday, November 29... addressing risks to reliability that were identified in earlier Commission technical conferences....

  4. Introgression of ivermectin resistance genes into a susceptible Haemonchus contortus strain by multiple backcrossing.

    Science.gov (United States)

    Redman, Elizabeth; Sargison, Neil; Whitelaw, Fiona; Jackson, Frank; Morrison, Alison; Bartley, David Jon; Gilleard, John Stuart

    2012-02-01

    Anthelmintic drug resistance in livestock parasites is already widespread and in recent years there has been an increasing level of anthelmintic drug selection pressure applied to parasitic nematode populations in humans leading to concerns regarding the emergence of resistance. However, most parasitic nematodes, particularly those of humans, are difficult experimental subjects making mechanistic studies of drug resistance extremely difficult. The small ruminant parasitic nematode Haemonchus contortus is a more amenable model system to study many aspects of parasite biology and investigate the basic mechanisms and genetics of anthelmintic drug resistance. Here we report the successful introgression of ivermectin resistance genes from two independent ivermectin resistant strains, MHco4(WRS) and MHco10(CAVR), into the susceptible genome reference strain MHco3(ISE) using a backcrossing approach. A panel of microsatellite markers were used to monitor the procedure. We demonstrated that after four rounds of backcrossing, worms that were phenotypically resistant to ivermectin had a similar genetic background to the susceptible reference strain based on the bulk genotyping with 18 microsatellite loci and individual genotyping with a sub-panel of 9 microsatellite loci. In addition, a single marker, Hcms8a20, showed evidence of genetic linkage to an ivermectin resistance-conferring locus providing a starting point for more detailed studies of this genomic region to identify the causal mutation(s). This work presents a novel genetic approach to study anthelmintic resistance and provides a "proof-of-concept" of the use of forward genetics in an important model strongylid parasite of relevance to human hookworms. The resulting strains provide valuable resources for candidate gene studies, whole genome approaches and for further genetic analysis to identify ivermectin resistance loci.

  5. Introgression of ivermectin resistance genes into a susceptible Haemonchus contortus strain by multiple backcrossing.

    Directory of Open Access Journals (Sweden)

    Elizabeth Redman

    2012-02-01

    Full Text Available Anthelmintic drug resistance in livestock parasites is already widespread and in recent years there has been an increasing level of anthelmintic drug selection pressure applied to parasitic nematode populations in humans leading to concerns regarding the emergence of resistance. However, most parasitic nematodes, particularly those of humans, are difficult experimental subjects making mechanistic studies of drug resistance extremely difficult. The small ruminant parasitic nematode Haemonchus contortus is a more amenable model system to study many aspects of parasite biology and investigate the basic mechanisms and genetics of anthelmintic drug resistance. Here we report the successful introgression of ivermectin resistance genes from two independent ivermectin resistant strains, MHco4(WRS and MHco10(CAVR, into the susceptible genome reference strain MHco3(ISE using a backcrossing approach. A panel of microsatellite markers were used to monitor the procedure. We demonstrated that after four rounds of backcrossing, worms that were phenotypically resistant to ivermectin had a similar genetic background to the susceptible reference strain based on the bulk genotyping with 18 microsatellite loci and individual genotyping with a sub-panel of 9 microsatellite loci. In addition, a single marker, Hcms8a20, showed evidence of genetic linkage to an ivermectin resistance-conferring locus providing a starting point for more detailed studies of this genomic region to identify the causal mutation(s. This work presents a novel genetic approach to study anthelmintic resistance and provides a "proof-of-concept" of the use of forward genetics in an important model strongylid parasite of relevance to human hookworms. The resulting strains provide valuable resources for candidate gene studies, whole genome approaches and for further genetic analysis to identify ivermectin resistance loci.

  6. Identification of QTLs conferring resistance to downy mildew in legacy cultivars of lettuce.

    Science.gov (United States)

    Simko, Ivan; Atallah, Amy J; Ochoa, Oswaldo E; Antonise, Rudie; Galeano, Carlos H; Truco, Maria Jose; Michelmore, Richard W

    2013-10-07

    Many cultivars of lettuce (Lactuca sativa L.), the most popular leafy vegetable, are susceptible to downy mildew disease caused by Bremia lactucae. Cultivars Iceberg and Grand Rapids that were released in the 18th and 19th centuries, respectively, have high levels of quantitative resistance to downy mildew. We developed a population of recombinant inbred lines (RILs) originating from a cross between these two legacy cultivars, constructed a linkage map, and identified two QTLs for resistance on linkage groups 2 (qDM2.1) and 5 (qDM5.1) that determined resistance under field conditions in California and the Netherlands. The same QTLs determined delayed sporulation at the seedling stage in laboratory experiments. Alleles conferring elevated resistance at both QTLs originate from cultivar Iceberg. An additional QTL on linkage group 9 (qDM9.1) was detected through simultaneous analysis of all experiments with mixed-model approach. Alleles for elevated resistance at this locus originate from cultivar Grand Rapids.

  7. Resistance to Downy Mildew in Lettuce 'La Brillante' is Conferred by Dm50 Gene and Multiple QTL.

    Science.gov (United States)

    Simko, Ivan; Ochoa, Oswaldo E; Pel, Mathieu A; Tsuchida, Cayla; Font I Forcada, Carolina; Hayes, Ryan J; Truco, Maria-Jose; Antonise, Rudie; Galeano, Carlos H; Michelmore, Richard W

    2015-09-01

    Many cultivars of lettuce (Lactuca sativa L.) are susceptible to downy mildew, a nearly globally ubiquitous disease caused by Bremia lactucae. We previously determined that Batavia type cultivar 'La Brillante' has a high level of field resistance to the disease in California. Testing of a mapping population developed from a cross between 'Salinas 88' and La Brillante in multiple field and laboratory experiments revealed that at least five loci conferred resistance in La Brillante. The presence of a new dominant resistance gene (designated Dm50) that confers complete resistance to specific isolates was detected in laboratory tests of seedlings inoculated with multiple diverse isolates. Dm50 is located in the major resistance cluster on linkage group 2 that contains at least eight major, dominant Dm genes conferring resistance to downy mildew. However, this Dm gene is ineffective against the isolates of B. lactucae prevalent in the field in California and the Netherlands. A quantitative trait locus (QTL) located at the Dm50 chromosomal region (qDM2.2) was detected, though, when the amount of disease was evaluated a month before plants reached harvest maturity. Four additional QTL for resistance to B. lactucae were identified on linkage groups 4 (qDM4.1 and qDM4.2), 7 (qDM7.1), and 9 (qDM9.2). The largest effect was associated with qDM7.1 (up to 32.9% of the total phenotypic variance) that determined resistance in multiple field experiments. Markers identified in the present study will facilitate introduction of these resistance loci into commercial cultivars of lettuce.

  8. LRRK2 and RIPK2 variants in the NOD 2-mediated signaling pathway are associated with susceptibility to Mycobacterium leprae in Indian populations.

    Directory of Open Access Journals (Sweden)

    Patrick Marcinek

    Full Text Available In recent years, genome wide association studies have discovered a large number of gene loci that play a functional role in innate and adaptive immune pathways associated with leprosy susceptibility. The immunological control of intracellular bacteria M. leprae is modulated by NOD2-mediated signaling of Th1 responses. In this study, we investigated 211 clinically classified leprosy patients and 230 ethnically matched controls in Indian population by genotyping four variants in NOD2 (rs9302752A/G, LRRK2 (rs1873613A/G, RIPK2 (rs40457A/G and rs42490G/A. The LRRK2 locus is associated with leprosy outcome. The LRRK2 rs1873613A minor allele and respective rs1873613AA genotypes were significantly associated with an increased risk whereas the LRRK2 rs1873613G major allele and rs1873613GG genotypes confer protection in paucibacillary and leprosy patients. The reconstructed GA haplotypes from RIPK2 rs40457A/G and rs42490G/A variants was observed to contribute towards increased risk whereas haplotypes AA was observed to confer protective role. Our results indicate that a possible shared mechanisms underlying the development of these two clinical forms of the disease as hypothesized. Our findings confirm and validates the role of gene variants involved in NOD2-mediated signalling pathways that play a role in immunological control of intracellular bacteria M. leprae.

  9. Fake/Bogus Conferences

    DEFF Research Database (Denmark)

    Asadi, Amin; Rahbar, Nader; Rezvani, Mohammad Javad

    2017-01-01

    The main objective of the present paper is to introduce some features of fake/bogus conferences and some viable approaches to differentiate them from the real ones. These fake/bogus conferences introduce themselves as international conferences, which are multidisciplinary and indexed in major sci...... scientific digital libraries. Furthermore, most of the fake/bogus conference holders offer publishing the accepted papers in ISI journals and use other techniques in their advertisement e-mails....

  10. The murine Th2 locus undergoes epigenetic modification in the thymus during fetal and postnatal ontogeny.

    Directory of Open Access Journals (Sweden)

    Momoko Yoshimoto

    Full Text Available Epigenetic modifications play a central role in the differentiation and function of immune cells in adult animals. Developmentally regulated epigenetic patterns also appear to contribute to the ontogeny of the immune system. We show here that the epigenetic profile of the T-helper (Th 2 locus undergoes changes in T lineage cells beginning in mid-gestation and extending throughout the first week of life. In particular, regulatory regions of the Th2 locus are largely methylated at CpG residues among fetal liver common lymphoid progenitor cells. The locus subsequently becomes highly hypomethylated among the downstream progeny of these cells within the fetal thymus. This hypomethylated state is preserved until birth when the locus becomes rapidly re-methylated, achieving adult-like status by 3-6 days post birth. Notably, the capacity for rapid, high level Th2 cytokine production is lost in parallel with this re-methylation. In vitro organ culture and in vivo transplantation experiments indicate that signals from the adult environment are required to achieve the postnatal methylated state. Together, these findings indicate that the Th2 bias of neonates may be conferred, in part, by an epigenetic profile inherited from fetal life. However, the fetal program is rapidly terminated post birth by the development of signals leading to the acquisition of adult-like epigenetic patterns.

  11. Genetic susceptibility to non-necrotizing erysipelas/cellulitis.

    Directory of Open Access Journals (Sweden)

    Katariina Hannula-Jouppi

    Full Text Available BACKGROUND: Bacterial non-necrotizing erysipelas and cellulitis are often recurring, diffusely spreading infections of the skin and subcutaneous tissues caused most commonly by streptococci. Host genetic factors influence infection susceptibility but no extensive studies on the genetic determinants of human erysipelas exist. METHODS: We performed genome-wide linkage with the 10,000 variant Human Mapping Array (HMA10K array on 52 Finnish families with multiple erysipelas cases followed by microsatellite fine mapping of suggestive linkage peaks. A scan with the HMA250K array was subsequently performed with a subset of cases and controls. RESULTS: Significant linkage was found at 9q34 (nonparametric multipoint linkage score (NPL(all 3.84, p=0.026, which is syntenic to a quantitative trait locus for susceptibility to group A streptococci infections on chromosome 2 in mouse. Sequencing of candidate genes in the 9q34 region did not conclusively associate any to erysipelas/cellulitis susceptibility. Suggestive linkage (NPL(all>3.0 was found at three loci: 3q22-24, 21q22, and 22q13. A subsequent denser genome scan with the HMA250K array supported the 3q22 locus, in which several SNPs in the promoter of AGTR1 (Angiotensin II receptor type I suggestively associated with erysipelas/cellulitis susceptibility. CONCLUSIONS: Specific host genetic factors may cause erysipelas/cellulitis susceptibility in humans.

  12. Dissecting the Genetic Susceptibility to Graves' Disease in a Cohort of Patients of Italian Origin.

    Science.gov (United States)

    Lombardi, Angela; Menconi, Francesca; Greenberg, David; Concepcion, Erlinda; Leo, Marenza; Rocchi, Roberto; Marinó, Michele; Keddache, Mehdi; Tomer, Yaron

    2016-01-01

    Graves' disease (GD) is an autoimmune oligogenic disorder with a strong hereditary component. Several GD susceptibility genes have been identified and confirmed during the last two decades. However, there are very few studies that evaluated susceptibility genes for GD in specific geographic subsets. Previously, we mapped a new locus on chromosome 3q that was unique to GD families of Italian origin. In the present study, we used association analysis of single-nucleotide polymorphism (SNPs) at the 3q locus in a cohort of GD patients of Italian origin in order to prioritize the best candidates among the known genes in this locus to choose the one(s) best supported by the association. DNA samples were genotyped using the Illumina GoldenGate genotyping assay analyzing 690 SNP in the linked 3q locus covering all 124 linkage disequilibrium blocks in this locus. Candidate non-HLA (human-leukocyte-antigen) genes previously reported to be associated with GD and/or other autoimmune disorders were analyzed separately. Three SNPs in the 3q locus showed a nominal association (p < 0.05): rs13097181, rs763313, and rs6792646. Albeit these could not be further validated by multiple comparison correction, we were prioritizing candidate genes at a locus already known to harbor a GD-related gene, not hypothesis testing. Moreover, we found significant associations with the thyroid-stimulating hormone receptor (TSHR) gene, the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene, and the thyroglobulin (TG) gene. In conclusion, we identified three SNPs on chromosome 3q that may map a new GD susceptibility gene in this region which is unique to the Italian population. Furthermore, we confirmed that the TSHR, the CTLA-4, and the TG genes are associated with GD in Italians. Our findings highlight the influence of ethnicity and geographic variations on the genetic susceptibility to GD.

  13. Stage-specific hypermutability of the regA locus of Volvox, a gene regulating the germ-soma dichotomy

    Energy Technology Data Exchange (ETDEWEB)

    Kirk, D.L.; Baran, G.J.; Harper, J.F.; Huskey, R.J.; Huson, K.S.; Zagris, N.

    1987-01-16

    Mutation at the regA locus confers on somatic cells of Volvox (which otherwise undergo programmed death) ability to redifferentiate as reproductive cells. Stable mutations at the regA locus, but not at other loci, were induced at high frequency when embryos at one particular stage were exposed to either UV irradiation, novobiocin, nalidixic acid, bleomycin, 4-hydroxyaminoquinoline-1-oxide, 5-bromodeoxyuridine, or 5-fluorouracil. All treatments led to some mutations that were not expressed until the second generation after treatment. The sensitive period was after somatic and reproductive cells of the next generation had been set apart, but before they had undergone cytodifferentiation. Hypermutability occurs in presumptive reproductive cells (in which regA is normally not expressed) somewhat before regA normally acts in somatic cells. We postulate that hypermutability of regA in the reproductive cells at this time reflects a change of state that the locus undergoes as it is inactivated.

  14. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Kenna, Kevin P; van Doormaal, Perry T C; Dekker, Annelot M; Ticozzi, Nicola; Kenna, Brendan J; Diekstra, Frank P; van Rheenen, Wouter; van Eijk, Kristel R; Jones, Ashley R; Keagle, Pamela; Shatunov, Aleksey; Sproviero, William; Smith, Bradley N; van Es, Michael A; Topp, Simon D; Kenna, Aoife; Miller, Jack W; Fallini, Claudia; Tiloca, Cinzia; McLaughlin, Russell L; Vance, Caroline; Troakes, Claire; Colombrita, Claudia; Mora, Gabriele; Calvo, Andrea; Verde, Federico; Al-Sarraj, Safa; King, Andrew; Calini, Daniela; de Belleroche, Jacqueline; Baas, Frank; van der Kooi, Anneke J; de Visser, Marianne; Ten Asbroek, Anneloor L M A; Sapp, Peter C; McKenna-Yasek, Diane; Polak, Meraida; Asress, Seneshaw; Muñoz-Blanco, José Luis; Strom, Tim M; Meitinger, Thomas; Morrison, Karen E; Lauria, Giuseppe; Williams, Kelly L; Leigh, P Nigel; Nicholson, Garth A; Blair, Ian P; Leblond, Claire S; Dion, Patrick A; Rouleau, Guy A; Pall, Hardev; Shaw, Pamela J; Turner, Martin R; Talbot, Kevin; Taroni, Franco; Boylan, Kevin B; Van Blitterswijk, Marka; Rademakers, Rosa; Esteban-Pérez, Jesús; García-Redondo, Alberto; Van Damme, Phillip; Robberecht, Wim; Chio, Adriano; Gellera, Cinzia; Drepper, Carsten; Sendtner, Michael; Ratti, Antonia; Glass, Jonathan D; Mora, Jesús S; Basak, Nazli A; Hardiman, Orla; Ludolph, Albert C; Andersen, Peter M; Weishaupt, Jochen H; Brown, Robert H; Al-Chalabi, Ammar; Silani, Vincenzo; Shaw, Christopher E; van den Berg, Leonard H; Veldink, Jan H; Landers, John E

    2016-01-01

    To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a

  15. Loss of ATRX Does Not Confer Susceptibility to Osteoarthritis

    OpenAIRE

    Solomon, Lauren A.; Russell, Bailey A.; David Makar; Bérubé, Nathalie G.; Frank Beier

    2013-01-01

    The chromatin remodelling protein ATRX is associated with the rare genetic disorder ATR-X syndrome. This syndrome includes developmental delay, cognitive impairment, and a variety of skeletal deformities. ATRX plays a role in several basic chromatin-mediated cellular events including DNA replication, telomere stability, gene transcription, and chromosome congression and cohesion during cell division. We have used a loss-of-function approach to directly investigate the role of Atrx in the adul...

  16. TRPM2 SNP genotype previously associated with susceptibility to Rhodococcus equi pneumonia in Quarter Horse foals displays differential gene expression identified using RNA-Seq.

    Science.gov (United States)

    McQueen, Cole M; Whitfield-Cargile, Canaan M; Konganti, Kranti; Blodgett, Glenn P; Dindot, Scott V; Cohen, Noah D

    2016-12-05

    Rhodococcus equi (R. equi) is an intracellular bacterium that affects young foals and immuno-compromised individuals causing severe pneumonia. Currently, the genetic mechanisms that confer susceptibility and/or resistance to R. equi are not fully understood. Previously, using a SNP-based genome-wide association study, we identified a region on equine chromosome 26 associated with culture-confirmed clinical pneumonia. To better characterize this region and understand the function of the SNP located within TRPM2 that was associated with R. equi pneumonia, we performed RNA-Seq on 12 horses representing the 3 genotypic forms of this SNP. We identified differentially expressed genes in the innate immune response pathway when comparing homozygous A allele horses with the AB and BB horses. Isoform analyses of the RNA-Seq data predicted the existence of multiple transcripts and provided evidence of differential expression at the TRPM2 locus. This finding is consistent with previously demonstrated work in human cell lines in which isoform-specific expression of TRPM2 was critical for cell viability. This work demonstrates that SNPs in TRPM2 are associated with differences in gene expression, suggesting that modulation of expression of this innate immune gene contributes to susceptibility to R. equi pneumonia.

  17. International Conference on Physics

    CERN Document Server

    2016-01-01

    OMICS International, (conference series) the World Class Open Access Publisher and Scientific Event Organizer is hosting “International Conference on physics” which is going to be the biggest conference dedicated to Physics. The theme “Highlighting innovations and challenges in the field of Physics” and it features a three day conference addressing the major breakthroughs, challenges and the solutions adopted. The conference will be held during June 27-29, 2016 at New Orleans, USA. Will be published in: http://physics.conferenceseries.com/

  18. Locus heterogeneity in autosomal dominant spinocerebellar ataxia: Evidence for the existence of a fifth locus

    Energy Technology Data Exchange (ETDEWEB)

    Sarrazin, J.; Rouleau, G.A. [Montreal General Hospital, Quebec (Canada); Andermann, E. [Montreal Neurological Institute and Hospital, Quebec (Canada)] [and others

    1994-09-01

    The autosomal dominantly inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders. To date, four loci have been identified: the SCA-1 locus (on chromosome (chr) 6p), the SCA-2 locus (on chr 12q), the SCA-3/MJD locus (on chr 14q), and more recently an SCA-4 locus was described (chr 16q) in a Utah kindred. We have studied one large French Canadian kindred with four generations of living affected individuals segregating an autosomal dominant form of SCA. Linkage analysis using anonymous DNA markers which flank the four previously described loci significantly excludes the French Canadian kindred from the SCA-1, SCA-2, SCA-3/MJD and SCA-4 loci. Therefore a fifth, still unmapped, SCA locus remains to be identified.

  19. Facilitating Learning at Conferences

    DEFF Research Database (Denmark)

    Ravn, Ib; Elsborg, Steen

    2011-01-01

    and facilitate a variety of simple learning techniques at thirty one- and two-day conferences of up to 300 participants each. We present ten of these techniques and data evaluating them. We conclude that if conference organizers allocate a fraction of the total conference time to facilitated processes......The typical conference consists of a series of PowerPoint presentations that tend to render participants passive. Students of learning have long abandoned the transfer model that underlies such one-way communication. We propose an al-ternative theory of conferences that sees them as a forum...... for learning, mutual inspiration and human flourishing. We offer five design principles that specify how conferences may engage participants more and hence increase their learning. In the research-and-development effort reported here, our team collaborated with conference organizers in Denmark to introduce...

  20. The learning conference

    DEFF Research Database (Denmark)

    Ravn, Ib

    2007-01-01

    Purpose: To call attention to the fact that conferences for professionals rely on massive one-way communication and hence produce little learning for delegates. To introduce an alternative, the ?learning conference,? that involves delegates in fun and productive learning processes. Design....../methodology/approach: A typical full-day conference is analyzed. It has six hours of podium talk and twenty-five minutes for delegates to become involved. What model of learning can possibly lie behind this? The transfer model, which assumes learners to be empty vessels. An alternative view is that conference delegates...... are active professionals in search of inspiration, and they also want to share knowledge with their peers at the conference. A theory of the conference as a forum for mutual inspiration and human co-flourishing is proposed, as are four design principles for a learning conference: 1. Presentations must...

  1. Role of TRAV locus in low caries experience.

    Science.gov (United States)

    Briseño-Ruiz, Jessica; Shimizu, Takehiko; Deeley, Kathleen; Dizak, Piper M; Ruff, Timothy D; Faraco, Italo M; Poletta, Fernando A; Brancher, João A; Pecharki, Giovana D; Küchler, Erika C; Tannure, Patricia N; Lips, Andrea; Vieira, Thays C S; Patir, Asli; Koruyucu, Mine; Mereb, Juan C; Resick, Judith M; Brandon, Carla A; Letra, Ariadne; Silva, Renato M; Cooper, Margaret E; Seymen, Figen; Costa, Marcelo C; Granjeiro, José M; Trevilatto, Paula C; Orioli, Iêda M; Castilla, Eduardo E; Marazita, Mary L; Vieira, Alexandre R

    2013-09-01

    Caries is the most common chronic, multifactorial disease in the world today; and little is still known about the genetic factors influencing susceptibility. Our previous genome-wide linkage scan has identified five loci related to caries susceptibility: 5q13.3, 13q31.1, 14q11.2, 14q 24.3, and Xq27. In the present study, we fine mapped the 14q11.2 locus to identify genetic contributors to caries susceptibility. Four hundred seventy-seven subjects from 72 pedigrees with similar cultural and behavioral habits and limited access to dental care living in the Philippines were studied. An additional 387 DNA samples from unrelated individuals were used to determine allele frequencies. For replication purposes, a total of 1,446 independent subjects from four different populations were analyzed based on their caries experience (low versus high). Forty-eight markers in 14q11.2 were genotyped using TaqMan chemistry. Transmission disequilibrium test was used to detect over transmission of alleles in the Filipino families, and Chi-square, Fisher's exact and logistic regression were used to test for association between low caries experience and variant alleles in the replication data sets. We finally assessed the mRNA expression of TRAV4 in the saliva of 143 study subjects. In the Filipino families, statistically significant associations were found between low caries experience and markers in TRAV4. We were able to replicate these results in the populations studied that were characteristically from underserved areas. Direct sequencing of 22 subjects carrying the associated alleles detects one missense mutation (Y30R) that is predicted to be probably damaging. Finally, we observed higher expression in children and teenagers with low caries experience, correlating with specific alleles in TRAV4. Our results suggest that TRAV4 may have a role in protecting against caries.

  2. Systematic evaluation of genes and genetic variants associated with type 1 diabetes susceptibility

    DEFF Research Database (Denmark)

    Ram, Ramesh; Mehta, Munish; Nguyen, Tri Quang

    2016-01-01

    Genome-wide association studies have found >60 loci that confer genetic susceptibility to type 1 diabetes (T1D). Many of these are defined only by anonymous single nucleotide polymorphisms: the underlying causative genes, as well as the molecular bases by which they mediate susceptibility, are no...

  3. The Plasmid-Encoded Regulator Activates Factors Conferring Lysozyme Resistance on Enteropathogenic Escherichia coli Strains▿

    Science.gov (United States)

    Salinger, Nina; Kokona, Bashkim; Fairman, Robert; Okeke, Iruka N.

    2009-01-01

    We demonstrate that enhanced lysozyme resistance of enteropathogenic Escherichia coli requires the plasmid-encoded regulator, Per, and is mediated by factors outside the locus for enterocyte effacement. EspC, a Per-activated serine protease autotransporter protein, conferred enhanced resistance on nonpathogenic E. coli, and a second Per-regulated, espC-independent lysozyme resistance mechanism was identified. PMID:18997020

  4. The plasmid-encoded regulator activates factors conferring lysozyme resistance on enteropathogenic Escherichia coli strains.

    Science.gov (United States)

    Salinger, Nina; Kokona, Bashkim; Fairman, Robert; Okeke, Iruka N

    2009-01-01

    We demonstrate that enhanced lysozyme resistance of enteropathogenic Escherichia coli requires the plasmid-encoded regulator, Per, and is mediated by factors outside the locus for enterocyte effacement. EspC, a Per-activated serine protease autotransporter protein, conferred enhanced resistance on nonpathogenic E. coli, and a second Per-regulated, espC-independent lysozyme resistance mechanism was identified.

  5. Serine/threonine kinase gene Stpk-V, a key member of powdery mildew resistance gene Pm21, confers powdery mildew resistance in wheat.

    Science.gov (United States)

    Cao, Aizhong; Xing, Liping; Wang, Xiaoyun; Yang, Xueming; Wang, Wei; Sun, Yulei; Qian, Chen; Ni, Jinlong; Chen, Yaping; Liu, Dajun; Wang, Xiue; Chen, Peidu

    2011-05-10

    Powdery mildew resistance gene Pm21, located on the chromosome 6V short arm of Haynaldia villosa and transferred to wheat as a 6VS·6AL translocation (T6VS·6AL), confers durable and broad-spectrum resistance to wheat powdery mildew. Pm21 has become a key gene resource for powdery mildew resistance breeding all over the world. In China, 12 wheat varieties containing Pm21 have been planted on more than 3.4 million hectares since 2002. Pm21 has been intractable to molecular genetic mapping because the 6VS does not pair and recombine with the 6AS. Moreover, all known accessions of H. villosa are immune to powdery mildew fungus. Pm21 is still defined by cytogenetics as a locus. In the present study, a putative serine and threonine protein kinase gene Stpk-V was cloned and characterized with an integrative strategy of molecular and cytogenetic techniques. Stpk-V is located on the Pm21 locus. The results of a single cell transient expression assay showed that Stpk-V could decrease the haustorium index dramatically. After the Stpk-V was transformed into a susceptible wheat variety Yangmai158, the characterized transgenic plants showed high and broad-spectrum powdery mildew resistance similar to T6VS·6AL. Silencing of the Stpk-V by virus-induced gene silencing in both T6VS·6AL and H. villosa resulted in their increased susceptibility. Stpk-V could be induced by Bgt and exogenous H(2)O(2), but it also mediated the increase of endogenous H(2)O(2), leading to cell death and plant resistance when the plant was attacked by Bgt.

  6. Arabidopsis thaliana resistance to fusarium oxysporum 2 implicates tyrosine-sulfated peptide signaling in susceptibility and resistance to root infection.

    Directory of Open Access Journals (Sweden)

    Yunping Shen

    2013-05-01

    Full Text Available In the plant Arabidopsis thaliana, multiple quantitative trait loci (QTLs, including RFO2, account for the strong resistance of accession Columbia-0 (Col-0 and relative susceptibility of Taynuilt-0 (Ty-0 to the vascular wilt fungus Fusarium oxysporum forma specialis matthioli. We find that RFO2 corresponds to diversity in receptor-like protein (RLP genes. In Col-0, there is a tandem pair of RLP genes: RFO2/At1g17250 confers resistance while RLP2 does not. In Ty-0, the highly diverged RFO2 locus has one RLP gene conferring weaker resistance. While the endogenous RFO2 makes a modest contribution to resistance, transgenic RFO2 provides strong pathogen-specific resistance. The extracellular leucine-rich repeats (eLRRs in RFO2 and RLP2 are interchangeable for resistance and remarkably similar to eLRRs in the receptor-like kinase PSY1R, which perceives tyrosine-sulfated peptide PSY1. Reduced infection in psy1r and mutants of related phytosulfokine (PSK receptor genes PSKR1 and PSKR2 shows that tyrosine-sulfated peptide signaling promotes susceptibility. The related eLRRs in RFO2 and PSY1R are not interchangeable; and expression of the RLP nPcR, in which eLRRs in RFO2 are replaced with eLRRs in PSY1R, results in constitutive resistance. Counterintuitively, PSY1 signaling suppresses nPcR because psy1r nPcR is lethal. The fact that PSK signaling does not similarly affect nPcR argues that PSY1 signaling directly downregulates the expression of nPcR. Our results support a speculative but intriguing model to explain RFO2's role in resistance. We propose that F. oxysporum produces an effector that inhibits the normal negative feedback regulation of PSY1R, which stabilizes PSY1 signaling and induces susceptibility. However, RFO2, acting as a decoy receptor for PSY1R, is also stabilized by the effector and instead induces host immunity. Overall, the quantitative resistance of RFO2 is reminiscent of the better-studied monogenic resistance traits.

  7. International Cryocooler Conference

    CERN Document Server

    Cryocoolers 13

    2005-01-01

    This is the 13th volume in the conference series. Over the years the International Cryocoolers Conference has become the preeminent worldwide conference for the presentation of the latest developments and test experiences with cryocoolers. The typical applications of this technology include cooling space and terrestrial infrared focal plane arrays, space x-ray detectors, medical applications, and a growing number of high-temperature super-capacitor applications.

  8. Expectations for Cancun Conference

    Institute of Scientific and Technical Information of China (English)

    DING ZHITAO

    2010-01-01

    Compared with the great hopes raised by the Copenhagen Climate Conference in 2009, the 2010 UN Climate Change Conference in Cancun aroused fewer expectations. However, the international community is still waiting for a positive outcome that will benefit humankind as a whole. The Cancun conference is another important opportunity for all the participants to advance the Bali Road Map negotiations after last year's meeting in Copenhagen, which failed to reach a legally binding treaty for the years beyond 2012.

  9. A suppressor locus for MODY3-diabetes

    Science.gov (United States)

    Garcia-Gonzalez, Miguel A.; Carette, Claire; Bagattin, Alessia; Chiral, Magali; Makinistoglu, Munevver Parla; Garbay, Serge; Prévost, Géraldine; Madaras, Cécile; Hérault, Yann; Leibovici, Michel; Pontoglio, Marco

    2016-01-01

    Maturity Onset Diabetes of the Young type 3 (MODY3), linked to mutations in the transcription factor HNF1A, is the most prevalent form of monogenic diabetes mellitus. HNF1alpha-deficiency leads to defective insulin secretion via a molecular mechanism that is still not completely understood. Moreover, in MODY3 patients the severity of insulin secretion can be extremely variable even in the same kindred, indicating that modifier genes may control the onset of the disease. With the use of a mouse model for HNF1alpha-deficiency, we show here that specific genetic backgrounds (C3H and CBA) carry a powerful genetic suppressor of diabetes. A genome scan analysis led to the identification of a major suppressor locus on chromosome 3 (Moda1). Moda1 locus contains 11 genes with non-synonymous SNPs that significantly interacts with other loci on chromosomes 4, 11 and 18. Mechanistically, the absence of HNF1alpha in diabetic-prone (sensitive) strains leads to postnatal defective islets growth that is remarkably restored in resistant strains. Our findings are relevant to human genetics since Moda1 is syntenic with a human locus identified by genome wide association studies of fasting glycemia in patients. Most importantly, our results show that a single genetic locus can completely suppress diabetes in Hnf1a-deficiency. PMID:27667715

  10. Locus of Equity and Brand Extension

    NARCIS (Netherlands)

    S.M.J. van Osselaer (Stijn); J.W. Alba (Joseph)

    2003-01-01

    textabstractPrevailing wisdom assumes that brand equity increases when a brand touts its desirable attributes. We report conditions under which the use of attribute information to promote a product can shift the locus of equity from brand to attribute, thereby reducing the attractiveness of extensio

  11. Locus of Equity and Brand Extension

    NARCIS (Netherlands)

    S.M.J. van Osselaer (Stijn); J.W. Alba (Joseph)

    2003-01-01

    textabstractPrevailing wisdom assumes that brand equity increases when a brand touts its desirable attributes. We report conditions under which the use of attribute information to promote a product can shift the locus of equity from brand to attribute, thereby reducing the attractiveness of extensio

  12. Conference proceedings ISES 2014

    DEFF Research Database (Denmark)

    Christensen, Janne Winther; Peerstrup Ahrendt, Line; Malmkvist, Jens

    The 10th Internatinal Equitation Science Conference is held i Denmark from August 6th - 9th 2014. This book of proceedings contaions abstracts of 35 oral and 57 poster presentations within the conference themes Equine Stress, Learning and Training as well as free papers.......The 10th Internatinal Equitation Science Conference is held i Denmark from August 6th - 9th 2014. This book of proceedings contaions abstracts of 35 oral and 57 poster presentations within the conference themes Equine Stress, Learning and Training as well as free papers....

  13. Development of a locus-specific, co-dominant SCAR marker for assisted-selection of the Sw-5 (Tospovirus resistance) gene cluster in a wide range of tomato accessions

    OpenAIRE

    DIANESE, E. de C.; Fonseca, M.E.N.; Goldbach, R W; Kormelink, R.J.M.; Inoue-Nagata, A.K.; Resende, MR; BOITEUX, L. S.

    2010-01-01

    The best levels of broad-spectrum Tospovirus resistance reported in tomatoes thus far are conferred by the Sw-5 locus. This locus contains at least five paralogues (denoted Sw-5a through Sw-5e), of which Sw-5b represents the actual resistance gene. Here we evaluated a panel of seven PCR primer pairs matching different sequences within a genomic region spanning the Sw-5a and Sw-5b gene cluster. Primer efficiency evaluation was done employing tomato isolines with and without the Sw-5 locus. One...

  14. Replication Study and Meta-Analysis in European Samples Supports Association of the 3p21.1 Locus with Bipolar Disorder

    DEFF Research Database (Denmark)

    Vassos, Evangelos; Steinberg, Stacy; Cichon, Sven

    2012-01-01

    Common genetic polymorphisms at chromosome 3p21.1, including rs2251219 in polybromo 1 (PBRM1), have been implicated in susceptibility to bipolar affective disorder (BP) through genome-wide association studies. Subsequent studies have suggested that this is also a risk locus for other psychiatric ...

  15. Second international conference on isotopes. Conference proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Hardy, C.J. [ed.

    1997-10-01

    The Second International Conference on Isotopes (2ICI) was hosted by the Australian Nuclear Association in Sydney, NSW, Australia. The Theme of the Second Conference: Isotopes for Industry, Health and a Better Environment recognizes that isotopes have been used in these fields successfully for many years and offer prospects for increasing use in the future. The worldwide interest in the use of research reactors and accelerators and in applications of stable and radioactive isotopes, isotopic techniques and radiation in industry, agriculture, medicine, environmental studies and research in general, was considered. Other radiation issues including radiation protection and safety were also addressed. International and national overviews and subject reviews invited from leading experts were included to introduce the program of technical sessions. The invited papers were supported by contributions accepted from participants for oral and poster presentation. A Technical Exhibition was held in association with the Conference. This volume contains the full text or extended abstracts of papers number 61- to number 114

  16. Gpr177, a novel locus for bone-mineral-density and osteoporosis, regulates osteogenesis and chondrogenesis in skeletal development

    OpenAIRE

    Maruyama, Takamitsu; Jiang, Ming; Hsu, Wei

    2013-01-01

    Human genetic analysis has recently identified Gpr177 as a susceptibility locus for bone-mineral-density and osteoporosis. Determining the unknown function of this gene is therefore extremely important to further our knowledge base of skeletal development and disease. The protein encoded by Gpr177 exhibits an ability to modulate the trafficking of Wnt similar to the Drosophila Wls/Evi/Srt. Because of a critical role in Wnt regulation, Gpr177 might be required for several key steps of skeletog...

  17. Self-Esteem, Locus of Control, and Student Achievement.

    Science.gov (United States)

    Sterbin, Allan; Rakow, Ernest

    The direct effects of locus of control and self-esteem on standardized test scores were studied. The relationships among the standardized test scores and measures of locus of control and self-esteem for 12,260 students from the National Education Longitudinal Study 1994 database were examined, using the same definition of locus of control and…

  18. Radiation`96. Conference handbook

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-12-31

    The conference program includes eight invited lectures which cover a range of contemporary topics in radiation science and technology. In addition, thirty-two oral papers were presented, along with forty-five posters. The conference handbook contains one-page precis or extended abstracts of all presentations, and is a substantial compendium of current radiation research in Australia.

  19. Expectations for Cancun Conference

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Compared with the great hopes raised by the Copenhagen Climate Conference in 2009, the 2010 UN Climate Change Conference in Cancun aroused fewer expectations. However, the international community is still waiting for a positive outcome that will benefit humankind as a whole.

  20. Evaluation of single and double-locus real-time PCR assays for methicillin-resistant Staphylococcus aureus (MRSA surveillance

    Directory of Open Access Journals (Sweden)

    Arielly Haya

    2010-04-01

    Full Text Available Abstract Background Methicillin-resistant Staphylococcus aureus (MRSA is a human pathogen, representing an infection control challenge. Conventional MRSA screening takes up to three days, therefore development of rapid detection is essential. Real time-PCR (rt-PCR is the fastest method fulfilling this task. All currently published or commercially available rt-PCR MRSA assays relay on single or double-locus detection. Double-locus assays are based on simultaneous detection of mecA gene and a S. aureus-specific gene. Such assays cannot be applied on clinical samples, which often contain both coagulase-negative staphylococci (CoNS and S. aureus, either of which can carry mecA. Single-locus assays are based on detection of the staphylococcal cassette chromosome mec (SCCmec element and the S. aureus-specific orfX gene, assuming that it is equivalent to mecA detection. Findings Parallel evaluation of several published single and double-locus rt-PCR MRSA assays of 150 pure culture strains, followed by analysis of 460 swab-derived clinical samples which included standard identification, susceptibility testing, followed by PCR detection of staphylococcal suspected isolates and in-PCR mixed bacterial populations analysis indicated the following findings. Pure cultures analysis indicated that one of the single-locus assay had very high prevalence of false positives (Positive predictive value = 77.8% and was excluded from further analysis. Analysis of 460 swab-derived samples indicated that the second single-locus assay misidentified 16 out of 219 MRSA's and 13 out of 90 methicillin-sensitive S. aureus's (MSSA were misidentified as MRSA's. The double-locus detection assay misidentified 55 out of 90 MSSA's. 46 MSSA containing samples were misidentified as MRSA and 9 as other than S. aureus ending with low positive predicted value ( Conclusion The results indicate that high prevalence of false-positive and false-negative reactions occurs in such assays.

  1. CD33 Alzheimer’s disease locus: Altered monocyte function and amyloid biology

    Science.gov (United States)

    Bradshaw, Elizabeth M; Chibnik, Lori B; Keenan, Brendan T; Ottoboni, Linda; Raj, Towfique; Tang, Anna; Rosenkrantz, Laura L; Imboywa, Selina; Lee, Michelle; Von Korff, Alina; Morris, Martha C; Evans, Denis A; Johnson, Keith; Sperling, Reisa A; Schneider, Julie A; Bennett, David A; De Jager, Philip L

    2013-01-01

    In our functional dissection of the CD33 Alzheimer’s disease susceptibility locus, we find that the rs3865444C risk allele is associated with greater cell surface expression of CD33 in monocytes (t50 = 10.06, pjoint=1.3×10–13) of young and older individuals. It is also associated with (1) diminished internalization of Aβ42) (2) accumulation of neuritic amyloid pathology and fibrillar amyloid on in vivo imaging and (3), increased numbers of activated human microglia. PMID:23708142

  2. 3rd Cryocooler Conference

    CERN Document Server

    Louie, Berverly; McCarthy, Sandy

    1985-01-01

    Cryocoolers 3 documents the output of the Third Cryocooler Conference, held at the National Bureau of Standards, Boulder, Colorado, on September 17-18, 1984. About 140 people from 10 countries attended the conference representing industry, government, and academia. A total of 26 papers were presented orally at the conference and all appear in written form in the proceedings. The focus of this conference was on small cryocoolers in the temperature range of 4 - 80 K. Mechanical and nonmechanical types are discussed in the various papers. Applications of these small cryocoolers include the cooling of infrared detectors, cryopumps, small superconducting devices and magnets, and electronic devices. The conference proceedings reproduced here was published by the National Bureau of Standards in Boulder, Colorado as NBS Special Publication #698.

  3. MR susceptibility imaging

    Science.gov (United States)

    Duyn, Jeff

    2013-04-01

    This work reviews recent developments in the use of magnetic susceptibility contrast for human MRI, with a focus on the study of brain anatomy. The increase in susceptibility contrast with modern high field scanners has led to novel applications and insights into the sources and mechanism contributing to this contrast in brain tissues. Dedicated experiments have demonstrated that in most of healthy brain, iron and myelin dominate tissue susceptibility variations, although their relative contribution varies substantially. Local variations in these compounds can affect both amplitude and frequency of the MRI signal. In white matter, the myelin sheath introduces an anisotropic susceptibility that has distinct effects on the water compartments inside the axons, between the myelin sheath, and the axonal space, and renders their signals dependent on the angle between the axon and the magnetic field. This offers opportunities to derive tissue properties specific to these cellular compartments.

  4. Susceptibility genes in movement disorders.

    Science.gov (United States)

    Scholz, Sonja; Singleton, Andrew

    2008-05-15

    During the last years, remarkable progress in our understanding of molecular genetic mechanisms underlying movement disorders has been achieved. The successes of linkage studies, followed by positional cloning, have dominated the last decade and several genes underlying monogenic disorders have been discovered. The pathobiological understanding garnered from these mutations has laid the foundation for much of the search for genetic loci that confer risk for, rather than cause, disease. With the introduction of whole genome association studies as a novel tool to investigate genetic variation underlying common, complex diseases, a new era in neurogenomics has just begun. As the field rapidly moves forward several new challenges and critical questions in clinical care have to be addressed. In this review, we summarize recent advances in the discovery of susceptibility loci underlying major movement disorders, explain the newest methodologies and tools employed for finding and characterizing genes and discuss how insights into the molecular genetic basis of neurological disorders will impact therapeutic concepts in patient care.

  5. Second international conference on isotopes. Conference proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Hardy, C.J. [ed.

    1997-10-01

    The Second International Conference on Isotopes (2ICI) was hosted by the Australian Nuclear Association in Sydney, NSW, Australia. The Theme of the Second Conference: Isotopes for Industry, Health and a Better Environment recognizes that isotopes have been used in these fields successfully for many years and offer prospects for increasing use in the future. The worldwide interest in the use of research reactors and accelerators and in applications of stable and radioactive isotopes, isotopic techniques and radiation in industry, agriculture, medicine, environmental studies and research in general, was considered. Other radiation issues including radiation protection and safety were also addressed. International and national overviews and subject reviews invited from leading experts were included to introduce the program of technical sessions. The invited papers were supported by contributions accepted from participants for oral and poster presentation. A Technical Exhibition was held in association with the Conference. This volume contains the foreword, technical program, the author index and of the papers (1-60) presented at the conference.

  6. A locus regulating bronchial hyperresponsiveness maps to chromosome 5q

    Energy Technology Data Exchange (ETDEWEB)

    Levitt, R.C.; Meyers, D.A. [Johns Hopkins Medical Institutions, Baltimore, MD (United States); Bleecker, E.R. [Univ. of Maryland, Baltimore, MD (United States)] [and others

    1994-09-01

    Bronchial hyperresponsiveness (BHR) is one of the hallmarks of asthma. BHR correlates well with asthmatic symptoms and the response to treatment. Moreover, BHR appears to be closely related to airways inflammation. Numerous studies have demonstrated a familial aggregation; however, this phenotype is not likely inherited as a simple Mendelian trait. BHR is also closely associated with total serum IgE levels, as are allergy and asthma. We studied 92 families from Northern Holland ascertained through a parent with asthma who were originally studied between 1962-1970. Since there are a number of candidate genes on chromosome 5q potentially important in producing BHR, families were genotyped for markers in this region. These genes regulate IgE production and the cellular elements that are likely involved in inflammation associated with BHR, allergy and asthma. They include IL-4, IL-3, IL-5, IL-9, IL-12, IL-13 and GM-CSF. Linkage of BHR with markers on 5q was tested using a model free sib-pair method. The data suggest a locus for BHR maps near the cytokine gene cluster on 5q. This region appears critical in producing susceptibility to BHR and possibly to asthma.

  7. Schizophrenia susceptibility genes on chromosome 13q32

    Institute of Scientific and Technical Information of China (English)

    胡颖; 许琪; 鞠桂芝; 刘树铮; 史杰萍; 于雅琴; 尉军

    2004-01-01

    @@Schizophrenia is a complex mental disorder affecting approximately 1% of the general population worldwide.1 It has a high incidence in the general population, a poor prognosis and a poor outcome, in that it has become a major social problem. Family, twin, and adoption studies have clearly shown that a genetic component is quite likely to play an important role in determining susceptibility to schizophrenia. The genome-wide scan indicates that several chromosomal regions are linked to schizophrenia, some of which have been replicated independently including 6p21-24, 8p21-22, 13q14-33 and 22q11-12.2,3 This study was designed to detect two single nucleotide polymorphisms (SNPs) located in the 13q14-33 region, rs188608 at the STK24 locus and rs2892679 at the GPC6 locus, among Chinese population.

  8. Grapevine powdery mildew resistance and susceptibility loci identified on a high-resolution SNP map.

    Science.gov (United States)

    Barba, Paola; Cadle-Davidson, Lance; Harriman, James; Glaubitz, Jeffrey C; Brooks, Siraprapa; Hyma, Katie; Reisch, Bruce

    2014-01-01

    Improved efficacy and durability of powdery mildew resistance can be enhanced via knowledge of the genetics of resistance and susceptibility coupled with the development of high-resolution maps to facilitate the stacking of multiple resistance genes and other desirable traits. We studied the inheritance of powdery mildew (Erysiphe necator) resistance and susceptibility of wild Vitis rupestris B38 and cultivated V. vinifera 'Chardonnay', finding evidence for quantitative variation. Molecular markers were identified using genotyping-by-sequencing, resulting in 16,833 single nucleotide polymorphisms (SNPs) based on alignment to the V. vinifera 'PN40024' reference genome sequence. With an average density of 36 SNPs/Mbp and uniform coverage of the genome, this 17K set was used to identify 11 SNPs on chromosome 7 associated with a resistance locus from V. rupestris B38 and ten SNPs on chromosome 9 associated with a locus for susceptibility from 'Chardonnay' using single marker association and linkage disequilibrium analysis. Linkage maps for V. rupestris B38 (1,146 SNPs) and 'Chardonnay' (1,215 SNPs) were constructed and used to corroborate the 'Chardonnay' locus named Sen1 (Susceptibility to Erysiphe necator 1), providing the first insight into the genetics of susceptibility to powdery mildew from V. vinifera. The identification of markers associated with a susceptibility locus in a V. vinifera background can be used for negative selection among breeding progenies. This work improves our understanding of the nature of powdery mildew resistance in V. rupestris B38 and 'Chardonnay', while applying next-generation sequencing tools to advance grapevine genomics and breeding.

  9. Health Psychological Constructs as Predictors of Doping Susceptibility in Adolescent Athletes

    Science.gov (United States)

    Blank, Cornelia; Schobersberger, Wolfgang; Leichtfried, Veronika; Duschek, Stefan

    2016-01-01

    Background Doping is a highly relevant problem in sport, even in adolescent athletes. Knowledge of the psychological factors that influence doping susceptibility in young elite athletes remains sparse. Objectives This study investigated the predictive potential of different health-psychological constructs and well-being on doping susceptibility. The main hypotheses to be tested were positive associations of fear of failure, external locus of control, and ego-oriented goal orientation as well as negative associations of confidence of success, task orientation, internal locus of control, and performance motivation with doping susceptibility. Low levels of well-being are furthermore expected to be associated with doping susceptibility. Methods Within this cross-sectional study, 1,265 Austrian junior athletes aged between 14 and 19 years responded to a paper-pencil questionnaire. Results Performance motivation was a negative, while depressive mood, self-esteem, fear of failure and ego-oriented goal orientation were positive predictors of doping susceptibility. In addition, participants who were offered performance enhancing substances in the past were particularly susceptible to doping. Conclusions The study corroborates the predictive value of classical psychological constructs in doping research, initially analyzed in view of adult athletes, also for adolescents’ doping susceptibility. PMID:28144408

  10. Talking Curves at the Montreaux+5 Conference

    DEFF Research Database (Denmark)

    Leander, Anna

    in armed conflicts”. To this end the MD spells out “pertinent legal obligations” (on four pages and a small paragraph) but also “best practices” (on eleven full pages). The Montreux+5 Conference celebrated the document’s fifth anniversary. The party was held to review the MD but also to promote it. Invited...... were the signatory states, non-signatory states, but also assorted companies, NGOs and academics (including myself) susceptible of having a view on the topic. I want to tell the political tale of how talking in curves around the MD at the Montreux+5 “translated” security in plural, non...

  11. Conference Report: Wyoming Invitational Conference on Instructional Applications of Computers.

    Science.gov (United States)

    Kansky, Bob

    This report: (1) describes the organization of an invitational conference aimed at gathering direction from classroom teachers regarding instructional applications of computers; (2) provides copies of all materials used in organizing such a conference; and (3) reports the results of the conference in terms of conference products (resolutions,…

  12. Human genetic susceptibility and infection with Leishmania peruviana

    Energy Technology Data Exchange (ETDEWEB)

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

    1995-11-01

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

  13. Genome-wide association study identifies a novel canine glaucoma locus.

    Science.gov (United States)

    Ahonen, Saija J; Pietilä, Elina; Mellersh, Cathryn S; Tiira, Katriina; Hansen, Liz; Johnson, Gary S; Lohi, Hannes

    2013-01-01

    Glaucoma is an optic neuropathy and one of the leading causes of blindness. Its hereditary forms are classified into primary closed-angle (PCAG), primary open-angle (POAG) and primary congenital glaucoma (PCG). Although many loci have been mapped in human, only a few genes have been identified that are associated with the development of glaucoma and the genetic basis of the disease remains poorly understood. Glaucoma has also been described in many dog breeds, including Dandie Dinmont Terriers (DDT) in which it is a late-onset (>7 years) disease. We designed clinical and genetic studies to better define the clinical features of glaucoma in the DDT and to identify the genetic cause. Clinical diagnosis was based on ophthalmic examinations of the affected dogs and 18 additionally investigated unaffected DDTs. We collected DNA from over 400 DTTs and a genome wide association study was performed in a cohort of 23 affected and 23 controls, followed by a fine mapping, a replication study and candidate gene sequencing. The clinical study suggested that ocular abnormalities including abnormal iridocorneal angles and pectinate ligament dysplasia are common (50% and 72%, respectively) in the breed and the disease resembles human PCAG. The genetic study identified a novel 9.5 Mb locus on canine chromosome 8 including the 1.6 Mb best associated region (p = 1.63 × 10(-10), OR = 32 for homozygosity). Mutation screening in five candidate genes did not reveal any causative variants. This study indicates that although ocular abnormalities are common in DDTs, the genetic risk for glaucoma is conferred by a novel locus on CFA8. The canine locus shares synteny to a region in human chromosome 14q, which harbors several loci associated with POAG and PCG. Our study reveals a new locus for canine glaucoma and ongoing molecular studies will likely help to understand the genetic etiology of the disease.

  14. Genome-wide association study identifies a novel canine glaucoma locus.

    Directory of Open Access Journals (Sweden)

    Saija J Ahonen

    Full Text Available Glaucoma is an optic neuropathy and one of the leading causes of blindness. Its hereditary forms are classified into primary closed-angle (PCAG, primary open-angle (POAG and primary congenital glaucoma (PCG. Although many loci have been mapped in human, only a few genes have been identified that are associated with the development of glaucoma and the genetic basis of the disease remains poorly understood. Glaucoma has also been described in many dog breeds, including Dandie Dinmont Terriers (DDT in which it is a late-onset (>7 years disease. We designed clinical and genetic studies to better define the clinical features of glaucoma in the DDT and to identify the genetic cause. Clinical diagnosis was based on ophthalmic examinations of the affected dogs and 18 additionally investigated unaffected DDTs. We collected DNA from over 400 DTTs and a genome wide association study was performed in a cohort of 23 affected and 23 controls, followed by a fine mapping, a replication study and candidate gene sequencing. The clinical study suggested that ocular abnormalities including abnormal iridocorneal angles and pectinate ligament dysplasia are common (50% and 72%, respectively in the breed and the disease resembles human PCAG. The genetic study identified a novel 9.5 Mb locus on canine chromosome 8 including the 1.6 Mb best associated region (p = 1.63 × 10(-10, OR = 32 for homozygosity. Mutation screening in five candidate genes did not reveal any causative variants. This study indicates that although ocular abnormalities are common in DDTs, the genetic risk for glaucoma is conferred by a novel locus on CFA8. The canine locus shares synteny to a region in human chromosome 14q, which harbors several loci associated with POAG and PCG. Our study reveals a new locus for canine glaucoma and ongoing molecular studies will likely help to understand the genetic etiology of the disease.

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

    Directory of Open Access Journals (Sweden)

    Morten Herlin

    2014-07-01

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

  16. Evidence for a chromosome 22q susceptibility locus for some schizophrenics

    Energy Technology Data Exchange (ETDEWEB)

    Pulver, A.E.; Wolyniec, P.; Nestadt, G. [Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)] [and others

    1994-09-01

    Recent reports from linkage studies suggests that in some families there may be a gene associated with schizophrenia on chromosome 22q. Given the probable heterogeneity of schizophrenia, further exploration of this region was undertaken. The region was examined for candidate genes and diseases reported to have some psychiatric manifestations. Studies were initiated to examine the the potential phenotypic and molecular similarity between schizophrenia and velo-cardio-facial syndrome (VCFS), a syndrome associated with an interstitial deletion of 22q11.2. Phenotypic expression: (1) psychiatric evaluations of VCFS patients and their relatives found a high rate of DSM III-R schizophrenia in the patients and of psychotic illness in their 2nd and 3rd degree relatives. (2) 160 schizophrenic patients from the Maryland Epidemiology Sample (MES) were evaluated for the presence of typical facies seen in VCFS. Rating a 5-point scale, {open_quotes}5{close_quotes} being most likely, 15 (9.4%) were rated {open_quotes}5{close_quotes} and 27 (16.9%) were rated {open_quotes}4{close_quotes} for the VCFS-like facial features. Molecular characteristics: fluorescent in situ hybridization methods (FISH) identified 3 schizophrenics among 60 in the MES with the microdeletion of probe sc11.lab commonly deleted in VCFS subjects. This work provides a model for the mapping of complex phenotypes such schizophrenia using both genetic and epidemiological methods.

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

    NARCIS (Netherlands)

    Schaefer, A.S.; Richter, G.M.; Groessner-Schreiber, B.; Noack, D.; Nothnagel, M.; El Mokhtari, N.E.; Loos, B.G.; Jepsen, S.; Schreiber, S.

    2009-01-01

    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

  18. Genome-wide association study identifies ZFHX1B as a susceptibility locus for severe myopia.

    Science.gov (United States)

    Khor, Chiea Chuen; Miyake, Masahiro; Chen, Li Jia; Shi, Yi; Barathi, Veluchamy A; Qiao, Fan; Nakata, Isao; Yamashiro, Kenji; Zhou, Xin; Tam, Pancy O S; Cheng, Ching-Yu; Tai, E Shyong; Vithana, Eranga N; Aung, Tin; Teo, Yik-Ying; Wong, Tien-Yin; Moriyama, Muka; Ohno-Matsui, Kyoko; Mochizuki, Manabu; Matsuda, Fumihiko; Yong, Rita Y Y; Yap, Eric P H; Yang, Zhenglin; Pang, Chi Pui; Saw, Seang-Mei; Yoshimura, Nagahisa

    2013-12-20

    Severe myopia (defined as spherical equivalent retinal pigmented epithelium. In an experimental mouse model for myopia, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for Zfhx1b and Sntb1. These new data advance our understanding of the molecular pathogenesis of severe myopia.

  19. Allelic expression analysis of the osteoarthritis susceptibility locus that maps to MICAL3

    Directory of Open Access Journals (Sweden)

    Ratnayake Madhushika

    2012-03-01

    Full Text Available Abstract Background A genome-wide association scan with subsequent replication study that involved over 67,000 individuals of European ancestry has produced evidence of association of single nucleotide polymorphism rs2277831 to primary osteoarthritis (OA with a P-value of 2.9 × 10-5. rs2277831, an A/G transition, is located in an intron of MICAL3. This gene is located on chromosome 22q11.21 and the association signal encompasses two additional genes, BCL2L13 and BID. It is becoming increasingly apparent that many common complex traits are mediated by cis-acting regulatory polymorphisms that influence, in a tissue-specific manner, gene expression or transcript stability. Methods We used total and allelic expression analysis to assess whether the OA association to rs2277831 is mediated by an influence on MICAL3, BCL2L13 or BID expression. Using RNA extracted from joint tissues of 60 patients who had undergone elective joint replacement surgery, we assessed whether rs2277831 correlated with allelic expression of either of the three genes by: 1 measuring the expression of each gene by quantitative PCR and then stratifying the data by genotype at rs2277831 and 2 accurately discriminating and quantifying the mRNA synthesised from the alleles of OA patients using allelic-quantitative PCR. Results We found no evidence for a correlation between gene expression and genotype at rs2277831, with P-values of 0.09 for BCL2L13, 0.07 for BID and 0.33 for MICAL3. In the allelic expression analysis we observed several examples of significant (p BCL2L13 (P = 0.004, 2.09 at BID (P = 0.001 and the most extreme case being at MICAL3, with an allelic expression ratio of 5.47 (P = 0.001. However, there was no correlation observed between the pattern of allelic expression and the genotype at rs2277831. Conclusions In the tissues that we have studied, our data do not support our hypothesis that the association between rs2277831 and OA is due to the effect this SNP has on MICAL3, BCL2L13 or BID gene expression. Instead, our data point towards other functional effects accounting for the OA associated signal.

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

    NARCIS (Netherlands)

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

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

  1. The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway

    NARCIS (Netherlands)

    t Hart, L.M.; Fritsche, A.; Nijpels, G.; van Leeuwen, N.; Donnelly, L.A.; Dekker, J.M.; Alssema, M.; Fadista, J.; Carlotti, F.; Gjesing, A.P.; Palmer, C.N.; van Haeften, T.W.; Herzberg-Schafer, S.A.; Simonis-Bik, A.M.; Houwing-Duistermaat, J.J.; Helmer, Q.; Deelen, J.; Guigas, B.; Hansen, T.; Machicao, F.; Willemsen, G.; Heine, R.J.; Kramer, M.H.; Holst, J.J.; de Koning, E.J.; Haring, H.U.; Pedersen, O.; Groop, L.; de Geus, E.J.; Slagboom, P.E.; Boomsma, D.I.; Eekhoff, E.M.; Pearson, E.R.; Diamant, M.

    2013-01-01

    The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances beta-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2

  2. Genome-wide pathway analysis identifies oxidative stress related gene MSRA as rheumatoid arthritis susceptibility locus

    NARCIS (Netherlands)

    Martin, Jose Ezequiel; Alizadeh, Behrooz Z.; Gonzalez-Gay, Miguel A.; Balsa, Alejandro; Pascual-Salcedo, Dora; Fernandez-Gutierrez, Benjamín; Raya, Enrique

    2010-01-01

    Objective: Genome-wide association studies (GWASs) carried out in rheumatoid arthritis (RA) have led to the discovery of several genetic associations with this disease. Still, the current associated genetic variations can explain only part of the genetic risk involved in RA, and it is well recognise

  3. A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22

    NARCIS (Netherlands)

    J.M. Kerkhof (Hanneke); R.J. Lories (Rik); I. Meulenbelt (Ingrid); I. Jonsdottir (Ingileif); A.M. Valdes (Ana Maria); P.P. Arp (Pascal); T. Ingvarsson (Torvaldur); M. Jhamai (Mila); H. Jonsson (Helgi); L. Stolk (Lisette); G. Thorleifsson (Gudmar); G. Zhai (Guangju); F. Zhang (Feng); Y. Zhu (Yicheng); R. van der Breggen (Ruud); M. Doherty (Michael); D. Felson; A. Gonzalez (Antonio); B.V. Halldorsson (Bjarni); D.J. Hart (Deborah); V.B. Hauksson (Valdimar); A. Hofman (Albert); J.P.A. Ioannidis (John); M. Kloppenburg (Margreet); N.E. Lane (Nancy); J. Loughlin (John); F.P. Luyten (Frank); M.C. Nevitt (Michael); N. Parimi (Neeta); H.A.P. Pols (Huib); F. Rivadeneira Ramirez (Fernando); E. Slagboom (Eline); U. Styrkarsdottir (Unnur); A. Tsezou (Aspasia); T. van de Putte (Tom); J. Zmuda (Joseph); T.D. Spector (Timothy); J-A. Zwart (John-Anker); A.G. Uitterlinden (André); J.B.J. van Meurs (Joyce); A.J. Carr (Andrew Jonathan)

    2010-01-01

    markdownabstract__Objective__ To identify novel genes involved in osteoarthritis (OA), by means of a genome-wide association study. Methods. We tested 500,510 single-nucleotide polymorphisms (SNPs) in 1,341 Dutch Caucasian OA cases and 3,496 Dutch Caucasian controls. SNPs associated with at least 2

  4. Mutation at the Evi1 locus in Junbo mice causes susceptibility to otitis media.

    Directory of Open Access Journals (Sweden)

    Nicholas Parkinson

    2006-10-01

    Full Text Available Otitis media (OM, inflammation of the middle ear, remains the most common cause of hearing impairment in children. It is also the most common cause of surgery in children in the developed world. There is evidence from studies of the human population and mouse models that there is a significant genetic component predisposing to OM, yet nothing is known about the underlying genetic pathways involved in humans. We identified an N-ethyl-N-nitrosourea-induced dominant mouse mutant Junbo with hearing loss due to chronic suppurative OM and otorrhea. This develops from acute OM that arises spontaneously in the postnatal period, with the age of onset and early severity dependent on the microbiological status of the mice and their air quality. We have identified the causal mutation, a missense change in the C-terminal zinc finger region of the transcription factor Evi1. This protein is expressed in middle ear basal epithelial cells, fibroblasts, and neutrophil leukocytes at postnatal day 13 and 21 when inflammatory changes are underway. The identification and characterization of the Junbo mutant elaborates a novel role for Evi1 in mammalian disease and implicates a new pathway in genetic predisposition to OM.

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

    NARCIS (Netherlands)

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

    2012-01-01

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

  6. Multifactor dimensionality reduction reveals a three-locus epistatic interaction associated with susceptibility to pulmonary tuberculosis

    DEFF Research Database (Denmark)

    Collins, Ryan L; Hu, Ting; Wejse, Christian;

    2013-01-01

    for this problem. The goal of the present study was to apply MDR to mining high-order epistatic interactions in a population-based genetic study of tuberculosis (TB). Results The study used a previously published data set consisting of 19 candidate single-nucleotide polymorphisms (SNPs) in 321 pulmonary TB cases......Background Identifying high-order genetics associations with non-additive (i.e. epistatic) effects in population-based studies of common human diseases is a computational challenge. Multifactor dimensionality reduction (MDR) is a machine learning method that was designed specifically...... and 347 healthy controls from Guniea-Bissau in Africa. The ReliefF algorithm was applied first to generate a smaller set of the five most informative SNPs. MDR with 10-fold cross-validation was then applied to look at all possible combinations of two, three, four and five SNPs. The MDR model with the best...

  7. Mutation at the Evi1 locus in Junbo mice causes susceptibility to otitis media

    OpenAIRE

    Parkinson, N.; Hardisty-Hughes, R.E.; Tateossian, H.; Tsai, H. T.; Brooker, D.; Morse, S.; Lalane, Z.; Mackenzie, F.; Fray, M.; Glenister, P.; Woodward, A. M.; Polley, S.; Barbaric, I.; Dear, N.; Hough, T.A.

    2006-01-01

    Otitis media ( OM), inflammation of the middle ear, remains the most common cause of hearing impairment in children. It is also the most common cause of surgery in children in the developed world. There is evidence from studies of the human population and mouse models that there is a significant genetic component predisposing to OM, yet nothing is known about the underlying genetic pathways involved in humans. We identified an N-ethyl-N-nitrosourea-induced dominant mouse mutant Junbo with hea...

  8. Mutation at the Evi1 locus in Junbo mice causes susceptibility to otitis media.

    Science.gov (United States)

    Parkinson, Nicholas; Hardisty-Hughes, Rachel E; Tateossian, Hilda; Tsai, Hsun-Tien; Brooker, Debra; Morse, Sue; Lalane, Zuzanna; MacKenzie, Francesca; Fray, Martin; Glenister, Pete; Woodward, Anne-Marie; Polley, Sian; Barbaric, Ivana; Dear, Neil; Hough, Tertius A; Hunter, A Jackie; Cheeseman, Michael T; Brown, Steve D M

    2006-10-06

    Otitis media (OM), inflammation of the middle ear, remains the most common cause of hearing impairment in children. It is also the most common cause of surgery in children in the developed world. There is evidence from studies of the human population and mouse models that there is a significant genetic component predisposing to OM, yet nothing is known about the underlying genetic pathways involved in humans. We identified an N-ethyl-N-nitrosourea-induced dominant mouse mutant Junbo with hearing loss due to chronic suppurative OM and otorrhea. This develops from acute OM that arises spontaneously in the postnatal period, with the age of onset and early severity dependent on the microbiological status of the mice and their air quality. We have identified the causal mutation, a missense change in the C-terminal zinc finger region of the transcription factor Evi1. This protein is expressed in middle ear basal epithelial cells, fibroblasts, and neutrophil leukocytes at postnatal day 13 and 21 when inflammatory changes are underway. The identification and characterization of the Junbo mutant elaborates a novel role for Evi1 in mammalian disease and implicates a new pathway in genetic predisposition to OM.

  9. Mutation at the Evi1 Locus in Junbo Mice Causes Susceptibility to Otitis Media

    OpenAIRE

    Parkinson, N.; Hardisty-Hughes, R.E.; Tateossian, H.; Tsai, H. T.; Brooker, D.; Morse, S.; Lalane, Z.; Mackenzie, F.; Fray, M.; Glenister, P.; Woodward, A. M.; Polley, S.; Barbaric, I.; Dear, N.; Hough, T.A.

    2006-01-01

    Otitis media ( OM), inflammation of the middle ear, remains the most common cause of hearing impairment in children. It is also the most common cause of surgery in children in the developed world. There is evidence from studies of the human population and mouse models that there is a significant genetic component predisposing to OM, yet nothing is known about the underlying genetic pathways involved in humans. We identified an N-ethyl-N-nitrosourea-induced dominant mouse mutant Junbo with hea...

  10. Fine mapping of the barley chromosome 6H net form net blotch susceptibility locus

    Science.gov (United States)

    Net form net blotch (NFNB) caused by the necrotrophic fungal pathogen Pyrenophora teres f. teres (Ptt) is a destructive foliar disease of barley with the potential to cause significant yield loss in major production regions throughout the world. Characterization of diverse genetic resistances to thi...

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

    NARCIS (Netherlands)

    Schaefer, A.S.; Richter, G.M.; Groessner-Schreiber, B.; Noack, D.; Nothnagel, M.; El Mokhtari, N.E.; Loos, B.G.; Jepsen, S.; Schreiber, S.

    2009-01-01

    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

  12. Murine and human b locus pigmentation genes encode a glycoprotein (gp75) with catalase activity

    Energy Technology Data Exchange (ETDEWEB)

    Halaban, R.; Moellmann, G. (Yale Univ. School of Medicine, New Haven, CT (USA))

    1990-06-01

    Melanogenesis is regulated in large part by tyrosinase, and defective tyrosinase leads to albinism. The mechanisms for other pigmentation determinants (e.g., those operative in tyrosinase-positive albinism and in murine coat-color mutants) are not yet known. One murine pigmentation gene, the brown (b) locus, when mutated leads to a brown (b/b) or hypopigmentated (B{sup lt}/B{sup lt}) coat versus the wild-type black (B/B). The authors show that the b locus codes for a glycoprotein with the activity of a catalase (catalase B). Only the c locus protein is a tyrosinase. Because peroxides may be by-products of melanogenic activity and hydrogen peroxide in particular is known to destroy melanin precursors and melanin, they conclude that pigmentation is controlled not only by tyrosinase but also by a hydroperoxidase. The studies indicate that catalase B is identical with gp75, a known human melanosomal glycoprotein; that the b mutation is in a heme-associated domain; and that the B{sup lt} mutation renders the protein susceptible to rapid proteolytic degradation.

  13. THE PRIMER EXTENSION TECHNIQUE FOR THE POLYMORPHISM DETECTION AT OVINE PRN-P LOCUS

    Directory of Open Access Journals (Sweden)

    VIORICA COSIER

    2013-12-01

    Full Text Available Scrapie is a prionic illness with endemic character in many parts of the glob, and the control measures is difficult to apply because of the long incubation period, the lack of the preclinical manifestation and the existing tests for diagnostic in living animals. The Ppn-p locus is polymorphic with known variability at codon 136, 154, 171, which are associated with different sensibility in experimental and natural spongiform encephalopaties. General the possible combinations of the 5 amino acids encoded by the 3 different codons will determine the existence of 15 possible genotypes. To put in evidence those polymorphisms at the ovine Prn-p locus, several methods are developed but the most accurate assay is the direct sequencing of the gene and the primer extension technique. The purpose of this study was to determine the genotypes at Prp locus in 123 male of Tsurcana breed, Hateg ecotype, using primer extension technique (ABI 3130xl Genetic Analyzer and to establish the risk groups of the susceptibility at scrapie disease.

  14. The learning conference

    DEFF Research Database (Denmark)

    Ravn, Ib

    The typical one-day conference attended by managers or professionals in search of inspiration is packed with PowerPoint presentations and offers little opportunity for involvement or knowledge sharing. Behind the conventional conference format lurks the transfer model of learning, which finds...... little support amongst serious students of learning. The professional conference as a forum for knowledge sharing is in dire need of a new learning theory and a more enlightened practice. The notion of human flourishing is offered as basis for theory, and four simple design principles for the so......-called “learning conference” are proposed: People go to conferences to 1. get concise input, 2. interpret it in the light of their ongoing concerns, 3. talk about their current projects and 4. meet the other attendees and be inspired by them. Six practical techniques that induce attendees to do these things...

  15. Statewide Professional Development Conference

    Directory of Open Access Journals (Sweden)

    Paul V. Bredeson

    2000-02-01

    Full Text Available In an environment increasingly skeptical of the effectiveness of large-scale professional development activities, this study examines K-12 educators' reasons for participating and beliefs in the utility in a large-scale professional development conference. Pre- and post-conference surveys revealed that while financial support played a significant role in educators' ability to participate, they were drawn to the conference by the promise to learn substantive issues related to, in this case, performance assessment—what it means, how to implement it, and how to address community concerns. In spite of the conference's utility as a means to increase awareness of critical issues and to facilitate formal and informal learning, well conceived linkages to transfer new knowledge to the school and classroom were lacking.

  16. Tackling conference carbon footprints

    Science.gov (United States)

    Grozier, Jim

    2016-12-01

    In reply to Margaret Harris's Lateral Thoughts article "Putting my foot down", which discussed the challenges of attending a conference with a physical disability (October p76) and a subsequent letter by Anna Wood (November p18).

  17. The learning conference

    DEFF Research Database (Denmark)

    Ravn, Ib

    2007-01-01

    are described: Individual reflection, the buzz dyad, ?You have won two consultants, free of charge?, facilitated group work, the knowledge exchange, and lunch with gaffer tape. Originality/value: This paper introduces modern learning theory and techniques into an educational context which has resisted......Purpose: To call attention to the fact that conferences for professionals rely on massive one-way communication and hence produce little learning for delegates. To introduce an alternative, the ?learning conference,? that involves delegates in fun and productive learning processes. Design....../methodology/approach: A typical full-day conference is analyzed. It has six hours of podium talk and twenty-five minutes for delegates to become involved. What model of learning can possibly lie behind this? The transfer model, which assumes learners to be empty vessels. An alternative view is that conference delegates...

  18. The learning conference

    DEFF Research Database (Denmark)

    Ravn, Ib

    2007-01-01

    are described: Individual reflection, the buzz dyad, ?You have won two consultants, free of charge?, facilitated group work, the knowledge exchange, and lunch with gaffer tape. Originality/value: This paper introduces modern learning theory and techniques into an educational context which has resisted......Purpose: To call attention to the fact that conferences for professionals rely on massive one-way communication and hence produce little learning for delegates. To introduce an alternative, the ?learning conference,? that involves delegates in fun and productive learning processes. Design....../methodology/approach: A typical full-day conference is analyzed. It has six hours of podium talk and twenty-five minutes for delegates to become involved. What model of learning can possibly lie behind this? The transfer model, which assumes learners to be empty vessels. An alternative view is that conference delegates...

  19. DNA sequencing conference, 2

    Energy Technology Data Exchange (ETDEWEB)

    Cook-Deegan, R.M. [Georgetown Univ., Kennedy Inst. of Ethics, Washington, DC (United States); Venter, J.C. [National Inst. of Neurological Disorders and Strokes, Bethesda, MD (United States); Gilbert, W. [Harvard Univ., Cambridge, MA (United States); Mulligan, J. [Stanford Univ., CA (United States); Mansfield, B.K. [Oak Ridge National Lab., TN (United States)

    1991-06-19

    This conference focused on DNA sequencing, genetic linkage mapping, physical mapping, informatics and bioethics. Several were used to study this sequencing and mapping. This article also discusses computer hardware and software aiding in the mapping of genes.

  20. Ranking Operations Management Conferences

    NARCIS (Netherlands)

    Steenhuis, Harm-Jan; Bruijn, de Erik Joost; Gupta, Sushil; Laptaned, U.

    2007-01-01

    Several publications have appeared in the field of Operations Management which rank Operations Management related journals. Several ranking systems exist for journals based on , for example, perceived relevance and quality, citation, and author affiliation. Many academics also publish at conferences

  1. EVOLVE 2014 International Conference

    CERN Document Server

    Tantar, Emilia; Sun, Jian-Qiao; Zhang, Wei; Ding, Qian; Schütze, Oliver; Emmerich, Michael; Legrand, Pierrick; Moral, Pierre; Coello, Carlos

    2014-01-01

    This volume encloses research articles that were presented at the EVOLVE 2014 International Conference in Beijing, China, July 1–4, 2014.The book gathers contributions that emerged from the conference tracks, ranging from probability to set oriented numerics and evolutionary computation; all complemented by the bridging purpose of the conference, e.g. Complex Networks and Landscape Analysis, or by the more application oriented perspective. The novelty of the volume, when considering the EVOLVE series, comes from targeting also the practitioner’s view. This is supported by the Machine Learning Applied to Networks and Practical Aspects of Evolutionary Algorithms tracks, providing surveys on new application areas, as in the networking area and useful insights in the development of evolutionary techniques, from a practitioner’s perspective. Complementary to these directions, the conference tracks supporting the volume, follow on the individual advancements of the subareas constituting the scope of the confe...

  2. Multiphoton processes: conference proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Lambropoulos, P.; Smith, S.J. (eds.)

    1984-01-01

    The chapters of this volume represent the invited papers delivered at the conference. They are arranged according to thermatic proximity beginning with atoms and continuing with molecules and surfaces. Section headings include multiphoton processes in atoms, field fluctuations and collisions in multiphoton process, and multiphoton processes in molecules and surfaces. Abstracts of individual items from the conference were prepared separately for the data base. (GHT)

  3. 2nd SUMO Conference

    CERN Document Server

    Weber, Melanie

    2015-01-01

    This contributed volume contains the conference proceedings of the Simulation of Urban Mobility (SUMO) conference 2014, Berlin. The included research papers cover a wide range of topics in traffic planning and simulation, including open data, vehicular communication, e-mobility, urban mobility, multimodal traffic as well as usage approaches. The target audience primarily comprises researchers and experts in the field, but the book may also be beneficial for graduate students.  

  4. Conference scene: DGVS spring conference 2009.

    Science.gov (United States)

    Kolligs, Frank Thomas

    2009-10-01

    The 3rd annual DGVS Spring Conference of the German Society for Gastroenterology (Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten) was held at the Seminaris Campus Hotel in Berlin, Germany, on 8-9 May, 2009. The conference was organized by Roland Schmid and Matthias Ebert from the Technical University of Munich, Germany. The central theme of the meeting was 'translational gastrointestinal oncology: towards personalized medicine and individualized therapy'. The conference covered talks on markers for diagnosis, screening and surveillance of colorectal cancer, targets for molecular therapy, response prediction in clinical oncology, development and integration of molecular imaging in gastrointestinal oncology and translational research in clinical trial design. Owing to the broad array of topics and limitations of space, this article will focus on biomarkers, response prediction and the integration of biomarkers into clinical trials. Presentations mentioned in this summary were given by Matthias Ebert (Technical University of Munich, Germany), Esmeralda Heiden (Epigenomics, Berlin, Germany), Frank Kolligs (University of Munich, Germany), Florian Lordick (University of Heidelberg, Germany), Hans Jorgen Nielsen (University of Copenhagen, Denmark), Anke Reinacher-Schick (University of Bochum, Germany), Christoph Röcken (University of Berlin, Germany), Wolff Schmiegel (University of Bochum, Germany) and Thomas Seufferlein (University of Halle, Germany).

  5. Conference Report: The BPS Annual Conference 2004

    Directory of Open Access Journals (Sweden)

    Irina Roncaglia

    2004-05-01

    Full Text Available In this article I will review four papers presented at the British Psychological Society Annual Conference held this year in London held over a 3 day period. The Conference included a variety of scientific presentations and discussions through symposia, roundtable discussions, single papers and poster sessions. Although numerous papers took an experimental approach, few applied any type of qualitative methodology. The topics covered within the different psychological disciplines spanned from early childhood through old age; I have chosen four papers that covered a life course perspective and took into consideration clinical issues as well. The first paper discusses a grounded theory approach used to analyse a play therapy session between therapist and child. The second review reports some recent findings in the way the brains of people on the autistic spectrum disorder might function. The third paper discusses positive psychology and how such an emerging movement has influenced new research in the field. The last paper reviewed will discuss the issue of the ageing process, and I will present some arguments related to the useful application of qualitative methodologies within this area of research. In conclusion, I will highlight some personal reflections on the Conference and the need for a greater balance between qualitative and quantitative methodologies to be used in collaboration rather than as antagonists. URN: urn:nbn:de:0114-fqs0402176

  6. Can Pierce’s disease resistance introgressed into Vitis vinifera be translocated from a resistant rootstock to a susceptible scion?

    Science.gov (United States)

    The goal of this research is to evaluate the potential of a non-transgenic, PD-resistant Vitis vinifera selection used as an experimental rootstock to confer systemic resistance to PD-susceptible V. vinifera scions. Source of PD-susceptible plant material was the wine grape variety ‘Chardonnay’, kno...

  7. Dopamine D3 receptor gene locus: Association with schizophrenia, as well age of onset

    Energy Technology Data Exchange (ETDEWEB)

    Nimgsonkar, V.L.; Zhang, X.R.; Brar, J.S. [Univ. of Pittsburgh, PA (United States)] [and others

    1994-09-01

    Genetic factors are clearly involved in the etiology of schizophrenia, but their specific nature is unknown. If the genetic etiology is multifactorial or polygenic, the role of specific genes as susceptibility factors can be directly evaluated by examining allelic variation at these loci among cases in comparison with controls. Two studies have independently demonstrated an association of schizophrenia with homozygosity at the dopamine D3 receptor gene (D3RG) locus, using a biallelic polymorphism in the first exon of D3RG. These results are important because D3RG is a favored candidate gene. Three other studies have identified associations among sub-groups of patients, but the majority were negative. The present study involved patients with schizophrenia (DSM-III-R criteria) of Caucasian or African-American ethnicity (n=130). Two groups of controls, matched for ethnicity, were used: adults screened for schizophrenia (n=128) and unselected neonates (n=160). Multivariate analysis revealed an association between allele no. 1 homozygosity and schizophrenia in comparison with adult, but not neonatal controls. The association was most marked among Caucasian patients with a family history of schizophrenia (odds ratio 13.7, C.I. 1.8, 104.3). An association of the D3RG locus with age of onset (AOO) was also noted. The discrepancies in earlier studies may due to variations in control groups, differencies in mean AOO among different cohorts, or ethnic variations in susceptibility attributable to D3RG.

  8. Telomerase Reverse Transcriptase Locus Polymorphisms and Cancer Risk: A Field Synopsis and Meta-Analysis

    Science.gov (United States)

    Verdi, Daunia; Pooley, Karen A.; Landi, Maria T.; Egan, Kathleen M.; Baird, Duncan M.; Prescott, Jennifer; De Vivo, Immaculata; Nitti, Donato

    2012-01-01

    polymorphisms (TERT rs2736100, intergenic rs4635969, and CLPTM1L rs402710) was 41%. Strong evidence for lack of association was identified for five polymorphisms in three tumor types. Conclusions To our knowledge, this is the largest collection of data for associations between TERT locus polymorphisms and cancer risk. Our findings support the hypothesis that genetic variability in this genomic region can modulate cancer susceptibility in humans. PMID:22523397

  9. Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4.

    Directory of Open Access Journals (Sweden)

    Cécile Libioulle

    2007-04-01

    Full Text Available To identify novel susceptibility loci for Crohn disease (CD, we undertook a genome-wide association study with more than 300,000 SNPs characterized in 547 patients and 928 controls. We found three chromosome regions that provided evidence of disease association with p-values between 10(-6 and 10(-9. Two of these (IL23R on Chromosome 1 and CARD15 on Chromosome 16 correspond to genes previously reported to be associated with CD. In addition, a 250-kb region of Chromosome 5p13.1 was found to contain multiple markers with strongly suggestive evidence of disease association (including four markers with p < 10(-7. We replicated the results for 5p13.1 by studying 1,266 additional CD patients, 559 additional controls, and 428 trios. Significant evidence of association (p < 4 x 10(-4 was found in case/control comparisons with the replication data, while associated alleles were over-transmitted to affected offspring (p < 0.05, thus confirming that the 5p13.1 locus contributes to CD susceptibility. The CD-associated 250-kb region was saturated with 111 SNP markers. Haplotype analysis supports a complex locus architecture with multiple variants contributing to disease susceptibility. The novel 5p13.1 CD locus is contained within a 1.25-Mb gene desert. We present evidence that disease-associated alleles correlate with quantitative expression levels of the prostaglandin receptor EP4, PTGER4, the gene that resides closest to the associated region. Our results identify a major new susceptibility locus for CD, and suggest that genetic variants associated with disease risk at this locus could modulate cis-acting regulatory elements of PTGER4.

  10. Regulatory organization of the staphylococcal sae locus.

    Science.gov (United States)

    Adhikari, Rajan P; Novick, Richard P

    2008-03-01

    This paper describes an investigation of the complex internal regulatory circuitry of the staphylococcal sae locus and the impact of modifying this circuitry on the expression of external genes in the sae regulon. The sae locus contains four genes, the saeR and S two-component signalling module (TCS), and saeP and Q, two upstream genes of hitherto unknown function. It is expressed from two promoters, P(A)sae, which transcribes only the TCS, and P(C)sae, which transcribes the entire locus. A bursa aurealis (bursa) transposon insertion in saeP in a derivative of Staphylococcus aureus NCTC 8325 has a profound effect on sae function. It modifies the activity of the TCS, changing the expression of many genes in the sae regulon, even though transcription of the TCS (from P(A)sae) is not interrupted. Moreover, these effects are not due to disruption of saeP since an in-frame deletion in saeP has essentially no phenotype. The phenotype of S. aureus strain Newman is remarkably similar to that of the saeP : : bursa and this similarity is explained by an amino acid substitution in the Newman saeS gene that is predicted to modify profoundly the signalling function of the protein. This concurrence suggests that the saeP : : bursa insertion affects the signalling function of saeS, a suggestion that is supported by the ability of an saeQR clone, but not an saeR clone, to complement the effects of the saeP : : bursa insertion.

  11. Locus of control and online learning

    Directory of Open Access Journals (Sweden)

    Suretha Esterhuysen

    2004-10-01

    Full Text Available The integration of online learning in university courses is considered to be both inevitable and necessary. Thus there is an increasing need to raise awareness among educators and course designers about the critical issues impacting on online learning. The aim of this study, therefore, was to assess the differences between two groups of first-year Business Sciences learners (online and conventional learners in terms of biographic and demographic characteristics and locus of control. The study population consisted of 586 first-year learners of whom 185 completed the Locus of Control Inventory (LCI. The results show that the two groups of learners do not differ statistically significantly from each other with respect to locus of control. The findings and their implications are also discussed. Opsomming Die integrasie van aanlyn-leer in universiteitskursusse word beskou as sowel onafwendbaar as noodsaaklik. Daar is dus ’n toenemende behoefte om bewustheid onder opvoedkundiges en kursusontwerpers te kweek oor die kritiese aspekte wat ’n impak op aanlyn-leer het (Morgan, 1996. Daarom was die doel van hierdie ondersoek om die verskille tussen twee groepe eerstejaarleerders in Bestuurs- en Ekonomiese Wetenskap (aanlyn en konvensionele leerders te bepaal ten opsigte van biografiese en demografiese eienskappe en lokus van beheer. Die populasie het bestaan uit 586 eerstejaarleerders waarvan 185 die Lokus van Beheer Vraelys voltooi het. Die resultate toon dat die twee groepe leerders nie statisties beduidend van mekaar verskil het met betrekking tot lokus van beheer nie. Die bevindinge en implikasies word ook bespreek.

  12. Cut Locus Construction using Deformable Simplicial Complexes

    DEFF Research Database (Denmark)

    Misztal, Marek Krzysztof; Bærentzen, Jakob Andreas; Anton, François

    2011-01-01

    In this paper we present a method for appproximating cut loci for a given point p on Riemannian 2D manifolds, closely related to the notion of Voronoi diagrams. Our method finds the cut locus by advecting a front of points equally distant from p along the geodesics originating at p and finding...... the lines of self-intersections of the front in the parametric space. This becomes possible by using the deformable simplicial complexes (DSC, [1]) method for deformable interface tracking. DSC provide a simple collision detection mechanism, allows for interface topology control, and does not require...

  13. Genetic susceptibility of periodontitis

    NARCIS (Netherlands)

    Laine, M.L.; Crielaard, W.; Loos, B.G.

    2012-01-01

    In this systematic review, we explore and summarize the peer-reviewed literature on putative genetic risk factors for susceptibility to aggressive and chronic periodontitis. A comprehensive literature search on the PubMed database was performed using the keywords ‘periodontitis’ or ‘periodontal dise

  14. The genetics of feto-placental development: A study of acid phosphatase locus 1 and adenosine deaminase polymorphisms in a consecutive series of newborn infants

    Directory of Open Access Journals (Sweden)

    Bergamaschi Antonio

    2008-09-01

    Full Text Available Abstract Background Acid phosphatase locus 1 and adenosine deaminase locus 1 polymorphisms show cooperative effects on glucose metabolism and immunological functions. The recent observation of cooperation between the two systems on susceptibility to repeated spontaneous miscarriage prompted us to search for possible interactional effects between these genes and the correlation between birth weight and placental weight. Deviation from a balanced development of the feto-placental unit has been found to be associated with perinatal morbidity and mortality and with cardiovascular diseases in adulthood. Methods We examined 400 consecutive newborns from the Caucasian population of Rome. Birth weight, placental weight, and gestational length were registered. Acid phosphatase locus 1 and adenosine deaminase locus 1 phenotypes were determined by starch gel electrophoresis and correlation analysis was performed by SPSS programs. Informed verbal consent to participate in the study was obtained from the mothers. Results Highly significant differences in birth weight-placental weight correlations were observed among acid phosphatase locus 1 phenotypes (p = 0.005. The correlation between birth weight and placental weight was markedly elevated in subjects carrying acid phosphatase locus 1 phenotypes with medium-low F isoform concentration (A, CA and CB phenotypes compared to those carrying acid phosphatase locus 1 phenotypes with medium-high F isoform concentration (BA and B phenotypes (p = 0.002. Environmental and developmental variables were found to exert a significant effect on birth weight-placental weight correlation in subjects with medium-high F isoform concentrations, but only a marginal effect was observed in those with medium-low F isoform concentrations. The correlation between birth weight and placental weight is higher among carriers of the adenosine deaminase locus 1 allele*2, which is associated with low activity, than in homozygous adenosine

  15. Impact of locus of control on health message effectiveness.

    Science.gov (United States)

    Kong, Ying; Shen, Fuyuan

    2011-10-01

    This article examined how individuals' locus of control might moderate the effect of health message frames. An experiment was conducted whereby participants read either individual- or social-responsibility message frames after their locus of control was primed. Results indicated that messages presented in individual-responsibility frames were more persuasive when people were primed with internal locus of control, whereas social-responsibility framed appeals were more persuasive when people were primed with external locus of control. These results were found for individuals in both high and low cognitive load conditions. Theoretical and practical implications of the findings are discussed.

  16. Relationships between locus of control and paranormal beliefs.

    Science.gov (United States)

    Newby, Robert W; Davis, Jessica Boyette

    2004-06-01

    The present study investigated the associations between scores on paranormal beliefs, locus of control, and certain psychological processes such as affect and cognitions as measured by the Linguistic Inquiry and Word Count. Analysis yielded significant correlations between scores on Locus of Control and two subscales of Tobacyk's (1988) Revised Paranormal Beliefs Scale, New Age Philosophy and Traditional Paranormal Beliefs. A step-wise multiple regression analysis indicated that Locus of Control was significantly related to New Age Philosophy. Other correlations were found between Tobacyk's subscales, Locus of Control, and three processes measured by the Linguistic Inquiry and Word Count.

  17. 2nd Bozeman Conference

    CERN Document Server

    Lund, John

    1991-01-01

    This volume contains a collection of papers delivered by the partici­ pants at the second Conference on Computation and Control held at Mon­ tana State University in Bozeman, Montana from August 1-7, 1990. The conference, as well as this proceedings, attests to the vitality and cohesion between the control theorist and the numerical analyst that was adver­ tised by the first Conference on Computation and Control in 1988. The proceedings of that initial conference was published by Birkhiiuser Boston as the first volume of this same series entitled Computation and Control, Proceedings of the Bozeman Conference, Bozeman, Montana, 1988. Control theory and numerical analysis are both, by their very nature, interdisciplinary subjects as evidenced by their interaction with other fields of mathematics and engineering. While it is clear that new control or es­ timation algorithms and new feedback design methodologies will need to be implemented computationally, it is likewise clear that new problems in computation...

  18. Inside the CBF locus in Poaceae.

    Science.gov (United States)

    Tondelli, Alessandro; Francia, Enrico; Barabaschi, Delfina; Pasquariello, Marianna; Pecchioni, Nicola

    2011-01-01

    Several molecular evidences have been gathered in Poaceae that point out a central role of the CBF/DREB1 transcription factors in the signal transduction pathways leading to low-temperature tolerance, although to a quite different extent between crops originating from either temperate or tropical climates. A common feature of the CBF/DREB1 genes in Poaceae is their structural organization at the genome level in clusters of tandemly duplicated genes. In temperate cereals such as barley and wheat, expansion of specific multigene phylogenetic clades of CBFs that map at the Frost Resistance-2 locus has been exclusively observed. In addition, copy number variants of CBF genes between frost resistant and frost sensitive genotypes raise the question if multiple copies of the CBF/DREB1s are required to ensure freezing tolerance. On the other hand, in crops of tropical origin such as rice and maize, a smaller or less-responsive CBF regulon may have evolved, and different mechanisms might determine chilling tolerance. In this review, recent advances on the organization and diversity at the CBF cluster locus in the grasses are provided and discussed. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  19. Association of the GNAS Locus with Severe Malaria

    Science.gov (United States)

    Auburn, Sarah; Diakite, Mahamadou; Fry, Andrew E.; Ghansah, Anita; Campino, Susana; Richardson, Anna; Jallow, Muminatou; Sisay-Joof, Fatou; Pinder, Margaret; Griffiths, Michael J.; Peshu, Norbert; Williams, Thomas N.; Marsh, Kevin; Molyneux, Malcolm E.; Taylor, Terrie E.; Koram, Kwadwo A.; Oduro, Abraham R.; Rogers, William O.; Rockett, Kirk A.; Haldar, Kasturi; Kwiatkowski, Dominic P.

    2009-01-01

    Functional studies have demonstrated an interaction between the stimulatory G protein alpha subunit (G-alpha-s) and the malaria parasite at a cellular level. Obstruction of signal transduction via the erythrocyte G-alpha-s subunit reduced invasion by P.falciparum parasites. We sought to determine whether this signal pathway had an impact at the disease level by testing polymorphisms in the gene encoding G-alpha-s (GNAS) for association with severe malaria in a large multi-centre study encompassing family and case-control studies from The Gambia, Kenya and Malawi, and a case-control study from Ghana. We gained power to detect association using meta-analysis across the 7 studies, with an overall sample size approximating 4000 cases and 4000 controls. Out of 12 SNPs investigated in the 19kb GNAS region, 4 presented signals of association (P<0.05) with severe malaria. The strongest single locus association demonstrated an odds ratio of 1.13 (1.05-1.21), P=0.001. Three of the loci presenting significant associations were clustered at the 5-prime end of the GNAS gene. Accordingly, haplotypes constructed from these loci demonstrated significant associations with severe malaria (OR=0.88 (0.81-0.96), P=0.005; and OR=1.12 (1.03-1.20), P=0.005). The evidence presented here indicates that the influence of G-alpha-s on erythrocyte invasion efficacy may, indeed, alter individual susceptibility to disease. PMID:18951142

  20. The Shc locus regulates insulin signaling and adiposity in mammals

    Science.gov (United States)

    Tomilov, Alexey A.; Ramsey, Jon J.; Hagopian, Kevork; Giorgio, Marco; Kim, Kyoungmi M.; Lam, Adam; Migliaccio, Enrica; Lloyd, Kent C.; Berniakovich, Ina; Prolla, Tomas A.; Pelicci, PierGiuseppe; Cortopassi, Gino A.

    2014-01-01

    Summary Longevity of a p66Shc knockout strain (ShcP) was previously attributed to increased stress resistance and altered mitochondria. Microarrays of ShcP tissues indicated alterations in insulin signaling. Consistent with this observation, ShcP mice were more insulin sensitive and glucose tolerant at organismal and tissue levels, as was a novel p66Shc knockout (ShcL). Increasing and decreasing Shc expression in cell lines decreased and increased insulin sensitivity, respectively – consistent with p66Shc's function as a repressor of insulin signaling. However, differences between the two p66Shc knockout strains were also observed. ShcL mice were fatter and susceptible to fatty diets, and their fat was more insulin sensitive than controls. On the other hand, ShcP mice were leaner and resisted fatty diets, and their adipose was less insulin sensitive than controls. ShcL and ShcP strains are both highly inbred on the C57Bl/6 background, so we investigated gene expression at the Shc locus, which encodes three isoforms, p66, p52, and p46. Isoform p66 is absent in both strains; thus, the remaining difference to which to attribute the ‘lean’ phenotype is expression of the other two isoforms. ShcL mice have a precise deletion of p66Shc and normal expression of p52 and p46Shc isoforms in all tissues; thus, a simple deletion of p66Shc results in a ‘fat’ phenotype. However, ShcP mice in addition to p66Shc deletion have a fourfold increase in p46Shc expression in white fat. Thus, p46Shc overexpression in fat, rather than p66Shc deletion, is the likely cause of decreased adiposity and reduced insulin sensitivity in the fat of ShcP mice, which has implications for the longevity of the strain. PMID:21040401

  1. Genetic Susceptibility to Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Sanja Kovacic

    2012-01-01

    Full Text Available Atherosclerosis is a complex multifocal arterial disease involving interactions of multiple genetic and environmental factors. Advances in techniques of molecular genetics have revealed that genetic ground significantly influences susceptibility to atherosclerotic vascular diseases. Besides further investigations of monogenetic diseases, candidate genes, genetic polymorphisms, and susceptibility loci associated with atherosclerotic diseases have been identified in recent years, and their number is rapidly increasing. This paper discusses main genetic investigations fields associated with human atherosclerotic vascular diseases. The paper concludes with a discussion of the directions and implications of future genetic research in arteriosclerosis with an emphasis on prospective prediction from an early age of individuals who are predisposed to develop premature atherosclerosis as well as to facilitate the discovery of novel drug targets.

  2. 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.

  3. 5th ESCOM Conference

    DEFF Research Database (Denmark)

    Ridder, Hanne Mette Ochsner

    2003-01-01

    What happens when a music therapist participates in a conference of the European Society for the Cognitive Sciences of Music? Well, she seems to get a lot of inspiration and sees very interesting and useful research, - and sometimes she is astonished about which kind of research some people are i...... are investigating time and money in. In the following you will find thoughts and impressions from the conference where there were a huge number of presentations with a common theme on cognitive science of music, and here seen from a music therapeutic perspective....

  4. PHYSICS FOR HEALTH: CONFERENCE

    CERN Multimedia

    2016-01-01

    ICTR-PHE 2016 - International Conference on Translational Research in Radio-Oncology and Physics for Health -, co organized by CERN, aims at developing new strategies to better diagnose and treat cancer, by uniting biology and physics with clinics. Through the various sessions and symposia, the scientific programme offers the delegates the opportunity to discuss, in a friendly atmosphere, the latest progress in physics breakthroughs for health applications. The third edition of this conference took place at CICG (Centre International de Conférence Genève) from 15 to 19 Feb 2016.

  5. 78 FR 27963 - Reliability Technical Conference; Notice of Technical Conference

    Science.gov (United States)

    2013-05-13

    ... Energy Regulatory Commission Reliability Technical Conference; Notice of Technical Conference Take notice that the Federal Energy Regulatory Commission will hold a Technical Conference on Tuesday, July 9, 2013... to the webcast. The Capitol Connection provides technical support for webcasts and offers the...

  6. Potential linkage disequilibrium between schizophrenia and locus D22S278 on the long arm of chromosome 22

    Energy Technology Data Exchange (ETDEWEB)

    Moises, H.W.; Yang, L.; Havsteen, B. [Kiel Univ. (Germany)] [and others

    1995-10-09

    Locus D22S278 at 22q12 has been implicated in schizophrenia by sib-pair analysis. In order to replicate these results, we performed the transmission test for linkage disequilibrium (TDT) in 113 unrelated schizophrenic patients and their 226 parents. Evidence for potential linkage disequilibrium was obtained between schizophrenia and allele 243 of the marker AFM 182xd12 at the locus D22S278 (P = 0.02). The results of our study suggest a detectable oligogenic gene in a multigene system for schizophrenia closely linked to D22S278 on the long arm of chromosome 22. If confirmed by others, this finding could lead to the identification of a schizophrenia susceptibility gene. 12 refs., 1 tab.

  7. Functional expression of SCL/TAL1 interrupting locus (Stil) protects retinal dopaminergic cells from neurotoxin-induced degeneration.

    Science.gov (United States)

    Li, Jingling; Li, Ping; Carr, Aprell; Wang, Xiaokai; DeLaPaz, April; Sun, Lei; Lee, Eric; Tomei, Erika; Li, Lei

    2013-01-11

    We previously isolated a dominant mutation, night blindness b (nbb), which causes a late onset of retinal dopaminergic cell degeneration in zebrafish. In this study, we cloned the zebrafish nbb locus. Sequencing results revealed that nbb is a homolog of the vertebrate SCL/TAL1 interrupting locus (Stil). The Stil gene has been shown to play important roles in the regulation of vertebrate embryonic neural development and human cancer cell proliferation. In this study, we demonstrate that functional expression of Stil is also required for neural survival. In zebrafish, decreased expression of Stil resulted in increased toxic susceptibility of retinal dopaminergic cells to 6-hydroxydopamine. Increases in Stil-mediated Shh signaling transduction (i.e. by knocking down the Shh repressor Sufu) prevented dopaminergic cell death induced by neurotoxic insult. The data suggest that the oncogene Stil also plays important roles in neural protection.

  8. Turkish population data on the short tandem repeat locus TPOX

    DEFF Research Database (Denmark)

    Vural, B; Poda, M; Atlioglu, E;

    1998-01-01

    Allele and genotype frequencies were determined for the STR (short tandem repeat) locus TPOX in a random Turkish population sample of 200 individuals.......Allele and genotype frequencies were determined for the STR (short tandem repeat) locus TPOX in a random Turkish population sample of 200 individuals....

  9. Metacognition: As a Predictor of One's Academic Locus of Control

    Science.gov (United States)

    Arslan, Serhat; Akin, Ahmet

    2014-01-01

    The purpose of this study is to examine the effect of metacognition on one's academic locus of control. The study's sample group consists of 451 university students enrolled in various programs at Sakarya University, Turkey. In this study, the Metacognitive Awareness Inventory and the Academic Locus of Control Scale were used. The correlations and…

  10. Locus of Control, Attitudes toward Education, and Teaching Behaviors.

    Science.gov (United States)

    Kremer, Lya

    1982-01-01

    Tests 191 elementary school teachers in northern Israel for the relationships among locus of control, traditional and progressive educational attitudes, and related teaching behaviors. Finds external and internal locus of control explain the variance in traditional and progressive attitudes, respectively, and teaching behaviors. (Author/LC)

  11. The Cut Locus of a Torus of Revolution

    DEFF Research Database (Denmark)

    Gravesen, Jens; Markvorsen, Steen; Sinclair, Robert

    2005-01-01

    We determine the structure of the cut locus of a class of tori of revolution, which includes the standard tori in 3-dimensional Euclidean space.......We determine the structure of the cut locus of a class of tori of revolution, which includes the standard tori in 3-dimensional Euclidean space....

  12. Locus of control and investment in risky assets

    NARCIS (Netherlands)

    Salamanca, N.; de Grip, A.; Fouarge, D.; Montizaan, R.M.

    2013-01-01

    Using representative household panel data, we show that the investment behavior of households is related to the economic locus of control of household heads. A household's internal locus of control in economic issues is positively related to its decision to hold risky assets as well as its share of

  13. Locus of Control and Protection of Consumer Rights

    Directory of Open Access Journals (Sweden)

    Ivan Krastev

    2012-10-01

    Full Text Available This paper examines the influence of locus of control on the consumer behavior. Theoretical supposition is proven by analyzing empirical data from a study of 287 students. The methods assessed the capacity for defending personal and consumer rights, as well as the type of locus of control.

  14. Locus of Control in Underachieving and Achieving Gifted Students.

    Science.gov (United States)

    McClelland, Robert; And Others

    1991-01-01

    This study, with 87 underachieving and 77 achieving gifted students in grades 6-9, found that general locus of control measures did not differentiate between the 2 groups, that both scored significantly higher on positive internal than on negative internal locus of control, and that there were no gender or grade effects. (Author/DB)

  15. Locus of Control and Marital Stability: A Longitudinal Study.

    Science.gov (United States)

    Constantine, John A.; Bahr, Stephen J.

    1980-01-01

    Investigated relationship between locus of control and marital stability of young men. Factors derived from locus of control measures included leadership, personal, and fate scales. Results indicated the only significant difference was on the leadership scale between men remaining married and those who did not. (RC)

  16. Personality and Locus of Control among School Children

    Science.gov (United States)

    Pandya, Archana A.; Jogsan, Yogesh A.

    2013-01-01

    The main purpose of this investigation is to find out the sex differences in personality traits and locus of control among school children. A total 60 children (30 boys and 30 girls) were taken as a sample. The research tool for personality, children personality questionnaire was used, which was made by Cattell and Porter. Locus of control was…

  17. Is this Red Spot the Blue Spot (locus ceruleum)?

    Energy Technology Data Exchange (ETDEWEB)

    Choe, Won Sick; Lee, Yu Kyung; Lee, Min Kyung; Hwang, Kyung Hoon [Gachon University Gil Hospital, Incheon (Korea, Republic of)

    2010-06-15

    The authors report brain images of 18F-FDG-PET in a case of schizophrenia. The images showed strikingly increased bilateral uptake in the locus ceruleum. The locus ceruleum is called the blue spot and known to be a center of the norepinephrinergic system.

  18. Locus of Control in Underachieving and Achieving Gifted Students.

    Science.gov (United States)

    McClelland, Robert; And Others

    1991-01-01

    This study, with 87 underachieving and 77 achieving gifted students in grades 6-9, found that general locus of control measures did not differentiate between the 2 groups, that both scored significantly higher on positive internal than on negative internal locus of control, and that there were no gender or grade effects. (Author/DB)

  19. Physical Attractiveness, Locus of Control, Sex Role, and Conversational Assertiveness.

    Science.gov (United States)

    Campbell, Keith F.; And Others

    1990-01-01

    Analyzes the relationship among physical attractiveness, locus of control, sex role orientation, and assertiveness in undergraduate students. Reviews videotapes of mixed-sex student groups engaged in discussion. Finds an internal locus of control positively correlated with assertiveness. Uses a behavioral measure of assertiveness rather than…

  20. Sign Stability via Root Locus Analysis

    CERN Document Server

    Gibson, Travis E

    2015-01-01

    With the rise of network science old topics in ecology and economics are resurfacing. One such topic is structural stability (often referred to as qualitative stability or sign stability). A system is deemed structurally stable if the system remains stable for all possible parameter variations so long as the parameters do not change sign. This type of stability analysis is appealing when studying real systems as the underlying stability result only requires the scientist or engineer to know the sign of the parameters in the model and not the specific values. The necessary and sufficient conditions for qualitative stability however are opaque. In order to shed light on those conditions root locus analysis is employed. This technique allows us to illustrate the necessary conditions for qualitative stability.

  1. Cut Locus Construction using Deformable Simplicial Complexes

    DEFF Research Database (Denmark)

    Misztal, Marek Krzysztof; Bærentzen, Jakob Andreas; Anton, François;

    2011-01-01

    In this paper we present a method for appproximating cut loci for a given point p on Riemannian 2D manifolds, closely related to the notion of Voronoi diagrams. Our method finds the cut locus by advecting a front of points equally distant from p along the geodesics originating at p and finding...... the domain to have disk topology. We test our method for tori of revolution and compare our results to the benchmark ones from [2]. The method, however, is generic and can be easily adapted to construct cut loci for other manifolds of genera other than 1....... the lines of self-intersections of the front in the parametric space. This becomes possible by using the deformable simplicial complexes (DSC, [1]) method for deformable interface tracking. DSC provide a simple collision detection mechanism, allows for interface topology control, and does not require...

  2. International conference on string theory

    CERN Document Server

    2016-01-01

    The Strings conference is an annual event that brings the entire string theory community together. Since the 1980s, it has grown to be the largest and most important conference in the field. The aim is to review recent developments in string theory and to stimulate scientific exchanges among the participants. This is the second Strings conference organised in Beijing, after Strings 2006. Following the tradition, besides scientific talks, the conference will also include some public lectures open to a general audience.

  3. On the Conference Circuit.

    Science.gov (United States)

    Tyckoson, David A.

    1987-01-01

    Summarizes three conference presentations on the effects of the economic climate on academic libraries in Iowa. These presentations focused on the impact of austerity budgets on collection development, library services and personnel, and possible management approaches to retrenchment in these areas. (CLB)

  4. Metabolic Engineering X Conference

    Energy Technology Data Exchange (ETDEWEB)

    Flach, Evan [American Institute of Chemical Engineers

    2015-05-07

    The International Metabolic Engineering Society (IMES) and the Society for Biological Engineering (SBE), both technological communities of the American Institute of Chemical Engineers (AIChE), hosted the Metabolic Engineering X Conference (ME-X) on June 15-19, 2014 at the Westin Bayshore in Vancouver, British Columbia. It attracted 395 metabolic engineers from academia, industry and government from around the globe.

  5. CONFERENCE OF YOUNG SCIENTISTS

    Directory of Open Access Journals (Sweden)

    article editorial

    2008-01-01

    Full Text Available A conference of young scientists dedicated to the 245th anniversary of the Scientific Center of Children's Health was held on September 12, 2008.Speakers at the conference were young professionals working at SCCH of RAMS, Sechenov Moscow Medical Academy, Institute of Pediatric Hematology, Oncology, and Immunology. During the conference the poster session was held in which young scientists of the Centre took part. Presentations of participants were evaluated by the members of the Academic Council of SCCH, leading specialists of the Center. Gifts to the winners of the conference were provided by "Procter & Gamble".Winners and awardees:I place: Chistyakova V.P. - Clinical intern at SCCH of RAMS;II place: Gudkova E.Yu. - Researcher at the Department of Rheumatology of SCCH of RAMS;III place: Darmanyan A.S. - Researcher at the Department of diagnostics and rehabilitation treatment of SCCH of RAMS.Best poster paper: Plyakin V.A. - Researcher at Surgical Department NTSZD RAMS.Audience Award: Tikhomirova E.A. - Researcher at the Department of functional diagnostics of SCCH of RAMS.

  6. Graphics Conference Calendar

    Institute of Scientific and Technical Information of China (English)

    2004-01-01

    1. The 13th International Conference in Central Europe on Computer Graphics, Visualization and Computer Vision'2005, University of West Bohemia, Campus-Bory Plzen (very close to Prague, the capital of the Czech Republic)Czech Republic, January 31 - February 4, 2005. http://wscg.zcu.cz, skala@kiv.zcu.cz

  7. International Nuclear Physics Conference

    CERN Document Server

    2016-01-01

    We are pleased to announce that the 26th International Nuclear Physics Conference (INPC2016) will take place in Adelaide (Australia) from September 11-16, 2016. The 25th INPC was held in Firenze in 2013 and the 24th INPC in Vancouver, Canada, in 2010. The Conference is organized by the Centre for the Subatomic Structure of Matter at the University of Adelaide, together with the Australian National University and ANSTO. It is also sponsored by the International Union of Pure and Applied Physics (IUPAP) and by a number of organisations, including AUSHEP, BNL, CoEPP, GSI and JLab. INPC 2016 will be held in the heart of Adelaide at the Convention Centre on the banks of the River Torrens. It will consist of 5 days of conference presentations, with plenary sessions in the mornings, up to ten parallel sessions in the afternoons, poster sessions and a public lecture. The Conference will officially start in the evening of Sunday 11th September with Registration and a Reception and will end late on the afternoon of ...

  8. Creating Better Satellite Conferences.

    Science.gov (United States)

    Horner, Tommy

    1998-01-01

    Presents four ways to improve broadcasts of company satellite conferences, including creative site selection (using facilities at educational institutions rather than hotel rooms); creative programming (using graphics and other interruptions to break up lectures or speeches); creative crew selection; and creative downlink site activities (to…

  9. 2002 NASPSA Conference Abstracts.

    Science.gov (United States)

    Journal of Sport & Exercise Psychology, 2002

    2002-01-01

    Contains abstracts from the 2002 conference of the North American Society for the Psychology of Sport and Physical Activity. The publication is divided into three sections: the preconference workshop, "Effective Teaching Methods in the Classroom;" symposia (motor development, motor learning and control, and sport psychology); and free…

  10. Report on the Conference.

    Science.gov (United States)

    Brown, Ralph S.

    1983-01-01

    The themes of the 1982 annual conference of the American Association of University Professors are outlined. They include the importance of planning, selective versus across-the-board retrenchment strategies, definitions and problems of financial exigency, program reduction, and affirmative action claims. (MSE)

  11. Grammar! A Conference Report.

    Science.gov (United States)

    King, Lid, Ed.; Boaks, Peter, Ed.

    Papers from a conference on the teaching of grammar, particularly in second language instruction, include: "Grammar: Acquisition and Use" (Richard Johnstone); "Grammar and Communication" (Brian Page); "Linguistic Progression and Increasing Independence" (Bernardette Holmes); "La grammaire? C'est du bricolage!" ("Grammar? That's Hardware!") (Barry…

  12. Effects of preferred retinal locus placement on text navigation and development of advantageous trained retinal locus.

    Science.gov (United States)

    Watson, Gale R; Schuchard, Ronald A; De l'Aune, William R; Watkins, Erica

    2006-01-01

    Sixty readers were evaluated for visual function and text-navigation ability. The visual field and preferred retinal locus (PRL) were measured with a scanning laser ophthalmoscope (SLO). We found significant differences in text-navigation ability based on scotoma and PRL placement. Readers with a PRL to the left of or above a scotoma had significantly less text-navigation abilities. Readers with a PRL to the left of a scotoma tended to misread words with similar beginnings and omit the last word on a line. Readers with a PRL above a scotoma tended to skip a line or reread the same line twice. In a follow-up study, seven subjects with a nonadvantageous PRL quickly developed a trained retinal locus (TRL) during instruction with an SLO. Although the readers developed the TRL in about 15 minutes, they read slower with the TRL than the PRL. This TRL research provides promising pilot data.

  13. Escala de Locus de controle ELCO/TELEBRÁS Scale of Locus of control - ELCO

    Directory of Open Access Journals (Sweden)

    Luiz Pasquali

    1998-01-01

    Full Text Available Com base na teoria de Rotter e Escala de Levenson foi elaborada uma escala de Locus de Controle Organizacional (ELCO, composta por 28 itens. A escala foi validada com uma amostra de 350 empregados do Sistema Telebrás. Verificou-se a presença dos 2 fatores previstos na teoria, a saber: internalidade e externalidade, aparecendo a escala de externalidade, com 18 itens, bem estruturada (alfa = 0.81 e a de internalidade, com 10 itens, deixando a desejar no que se refere à consistência interna (alfa = 0.66. Com os dados desta pesquisa foi feita também análise do Locus de Controle desses mesmos empregados. A constatação mais saliente foi a de que o nível de internalidade caiu com o aumento do nível escolar e o aumento da experiência profissional desses mesmos empregados. Estes resultados surpreendentes foram interpretados em termos da situação típica da empresa, que está passando por um período de transição, a saber: a passagem da condição de empresa estatal para empresa privada, o que seria motivo da perda de confiança dos empregados na própria competência, particularmente por parte daqueles com maior competência intelectual e maior experiência profissional. Fez-se igualmente reparos na qualidade psicométrica da escala e da própria teoria do Locus de controle, no sentido de que esta precisa ser melhor axiomatizada para possibilitar a elaboração de escalas mais precisas para a medida dos construtos que propõe.A scale with 28 items, the Organizational Locus of Control (ELCO, was built based on Rotter’s theory and Levenson’s scale. ELCO was validated on a sample of 350 employees of Telebrás, a governmental firm in Brazil. As foreseen from the theory, a principal-axis factoring showed the presence of the expected two factors, namely internal and external locus of control. The external locus of control factor, composed of 18 items, showed good internal consistency (alpha =.81 whereas the internal factor, with 10 items

  14. Genomic organization and sequence dynamics of the AvrPiz-t locus in Magnaporthe oryzae

    Institute of Scientific and Technical Information of China (English)

    Ping LI; Bin BAI; Hong-yan ZHANG; Heng ZHOU; Bo ZHOU

    2012-01-01

    Plants utilize multiple layers of defense mechanisms to fight against the invasion of diverse pathogens.The R gene mediates resistance,in most cases,dependent on the co-existence of its cognate pathogen-derived avirulence (Avr) gene.The rice blast R gene Piz-t corresponds in gene-for-gene fashion to the Magnaporthe oryzae Avrgene AvrPiz-t.In this study,we determined and compared the genomic sequences surrounding the AvrPiz-t gene in both avirulent and virulent isolates,designating as AvrPiz-t-ZB15 and avrPiz-t-70-15 regions,respectively.The sequence of the AvrPiz-t-ZB15 region is 120966 bp whereas avrPiz-t-70-15 is 146292 bp in length.The extreme sequence similarity and good synteny in gene order and content along with the absence of two predicted genes in the avrPiz-t-70-15 region were observed in the predicted protein-coding regions in the AvrPiz-t locus.Nevertheless,frequent presence/absence and highly dynamic organization of transposable elements (TEs) were identified,representing the major variation of the AvrPiz-t locus between different isolates.Moreover,TEs constitute 27.3% and 43.2%of the genomic contents of the AvrPiz-t-ZB15 and avrPiz-t-70-15 regions,respectively,indicating that TEs contribute largely to the organization and evolution of AvrPiz-t locus.The findings of this study suggest that M.oryzae could benefit in an evolutionary sense from the presence of active TEs in genes conferring avirulence and provide an ability to rapidly change and thus to overcome host R genes.

  15. Indico CONFERENCE: Define the Programme

    CERN Document Server

    CERN. Geneva; Ferreira, Pedro

    2017-01-01

    In this tutorial you are going to learn how to define the programme of a conference in Indico. The program of your conference is divided in different “tracks”. Tracks represent the subject matter of the conference, such as “Online Computing”, “Offline Computing”, and so on.

  16. ALA Conference 2009: Chicago Hope

    Science.gov (United States)

    Berry, John N., III

    2009-01-01

    There is joy among those who have the funds to go to Chicago for the American Library Association (ALA) annual conference, July 9-15. Every librarian knows there is nothing better than a Chicago gathering, with the city's wonderful haunts, museums, restaurants, and fine memories of past conferences. The conference program covers nearly every…

  17. Association of single nucleotide polymorphisms in TCF2 with type 2 diabetes susceptibility in a Han Chinese population.

    Directory of Open Access Journals (Sweden)

    Xuelong Zhang

    Full Text Available Hepatocyte nuclear factor 1β (HNF1β, a transcription factor encoded by the transcription factor 2 gene (TCF2, plays a critical role in pancreatic cell formation and glucose homeostasis. It has been suggested that single nucleotide polymorphisms (SNPs of TCF2 are associated with susceptibility to type 2 diabetes (T2D. However, published results are inconsistent and inclusive. To further investigate the role of these common variants, we examined the association of TCF2 polymorphisms with the risk of T2D in a Han population in northeastern China. We genotyped five SNPs in 624 T2D patients and 630 healthy controls by using a SNaPshot method, and evaluated the T2D risk conferred by individual SNPs and haplotypes. In the single-locus analysis, we found that rs752010, rs4430796 and rs7501939 showed allelic differences between T2D patients and healthy controls, with an OR of 1.26 (95% CI 1.08-1.51, P = 0.003, an OR of 1.23 (95% CI 1.06-1.55, P = 0.001 and an OR of 1.28 (95% CI 1.10-1.61, P = 0.001, respectively. Genotype association analysis of each locus also revealed that the homozygous carriers of the at-risk allele had a significant increased T2D risk compared to homozygous carriers of the other allele (OR 1.78, 95% CI 1.20-2.64 for rs752010; OR 1.82, 95% CI 1.24-2.67 for rs4430796; OR 1.95, 95% CI 1.31-2.90 for rs7501939, even after Bonferroni correction for multiple comparisons. Besides, the haplotype-based analysis demonstrated that AGT in block rs752010-rs4430796-rs7501939 was associated with about 30% increase in T2D risk (OR 1.31, 95% CI 1.09-1.57, P = 0.01. Our findings suggested that TCF2 variants may be involved in T2D risk in a Han population of northeastern China. Larger studies with ethnically diverse populations are warranted to confirm the results reported in this investigation.

  18. Mapping and Genetic Structure Analysis of the Anthracnose Resistance Locus Co-1HY in the Common Bean (Phaseolus vulgaris L.).

    Science.gov (United States)

    Chen, Mingli; Wu, Jing; Wang, Lanfen; Mantri, Nitin; Zhang, Xiaoyan; Zhu, Zhendong; Wang, Shumin

    2017-01-01

    Anthracnose is a destructive disease of the common bean (Phaseolus vulgaris L.). The Andean cultivar Hongyundou has been demonstrated to possess strong resistance to anthracnose race 81. To study the genetics of this resistance, the Hongyundou cultivar was crossed with a susceptible genotype Jingdou. Segregation of resistance for race 81 was assessed in the F2 population and F2:3 lines under controlled conditions. Results indicate that Hongyundou carries a single dominant gene for anthracnose resistance. An allele test by crossing Hongyundou with another resistant cultivar revealed that the resistance gene is in the Co-1 locus (therefore named Co-1HY). The physical distance between this locus and the two flanking markers was 46 kb, and this region included four candidate genes, namely, Phvul.001G243500, Phvul.001G243600, Phvul.001G243700 and Phvul.001G243800. These candidate genes encoded serine/threonine-protein kinases. Expression analysis of the four candidate genes in the resistant and susceptible cultivars under control condition and inoculated treatment revealed that all the four candidate genes are expressed at significantly higher levels in the resistant genotype than in susceptible genotype. Phvul.001G243600 and Phvul.001G243700 are expressed nearly 15-fold and 90-fold higher in the resistant genotype than in the susceptible parent before inoculation, respectively. Four candidate genes will provide useful information for further research into the resistance mechanism of anthracnose in common bean. The closely linked flanking markers identified here may be useful for transferring the resistance allele Co-1HY from Hongyundou to elite anthracnose susceptible common bean lines.

  19. US green building conference - 1994

    Energy Technology Data Exchange (ETDEWEB)

    Fanney, A.H.; Whitter, K.M.; Traugott, A.E.; Simon, L.N. [eds.

    1994-12-31

    This report constitutes the proceedings of the Green Building Conference held in Gaithersburg, Maryland, February 16-17, 1994. The conference was co-sponsored by the National Institute of Standards and Technology (NIST) and the US Green Building Council (USGBC). Over 450 individuals attended the conference representing building product manufacturers, building owners and managers, environmental groups, utilities, contractors, builders, architects, engineers, and the local, state, and the federal governments. The conference provided an opportunity to acquire practical, useful information on green buildings, resources, and guidelines. Eighteen papers were presented at the conference. Separate abstracts and indexing were prepared for each paper for inclusion in the Energy Science and Technology Database.

  20. European Conference on Health Economics.

    Science.gov (United States)

    Malmivaara, Antti

    2010-12-01

    The biennial European Conference on Health Economics was held in Finland this year, at the Finlandia Hall in the centre of Helsinki. The European conferences rotate among European countries and fall between the biennial world congresses organized by the International Health Economics Association (iHEA). A record attendance of approximately 800 delegates from 50 countries around the world were present at the Helsinki conference. The theme of the conference was 'Connecting Health and Economics'. All major topics of health economics were covered in the sessions. For the first time, social care economics was included in the agenda of the European Conference as a session of its own.

  1. Restriction fragment length polymorphism mapping of quantitative trait loci for malaria parasite susceptibility in the mosquito Aedes aegypti

    Energy Technology Data Exchange (ETDEWEB)

    Severson, D.W.; Thathy, V.; Mori, A. [Univ. of Wisconsin, Madison, WI (United States)] [and others

    1995-04-01

    Susceptibility of the mosquito Aedes aegypti to the malarial parasite Plasmodium gallinaceum was investigated as a quantitative trait using restriction fragment length polymorphisms (RFLP). Two F{sub 2} populations of mosquitoes were independently prepared from pairwise matings between a highly susceptible and a refractory strain of A. aegypti. RFLP were tested for association with oocyst development on the mosquito midgut. Two putative quantitative trait loci (QTL) were identified that significantly affect susceptibility. One QTL, pgs [2,LF98], is located on chromosome 2 and accounted for 65 and 49% of the observed phenotypic variance in the two populations, respectively. A second QTL, pgs[3,MalI], is located on chromosome 3 and accounted for 14 and 10% of the observed phenotypic variance in the two populations, respectively. Both QTL exhibit a partial dominance effect on susceptibility, wherein the dominance effect is derived from the refractory parent. No indication of epistasis between these QTL was detected. Evidence suggests that either a tightly linked cluster of independent genes or a single locus affecting susceptibility to various mosquito-borne parasites and pathogens has evolved near the LF98 locus; in addition to P. gallinaceum susceptibility, this general genome region has previously been implicated in susceptibility to the filaria nematode Brugia malayi and the yellow fever virus. 35 refs., 2 figs., 3 tabs.

  2. Energy Conferences and Symposia; (USA)

    Energy Technology Data Exchange (ETDEWEB)

    Osborne, J.H.; Simpson, W.F. Jr. (eds.)

    1991-01-01

    Energy Conferences and Symposia, a monthly publication, was instituted to keep scientists, engineers, managers, and related energy professionals abreast of meetings sponsored by the Department of Energy (DOE) and by other technical associations. Announcements cover conference, symposia, workshops, congresses, and other formal meetings pertaining to DOE programmatic interests. Complete meeting information, including title, sponsor, and contact, is presented in the main section, which is arranged alphabetically by subject area. Within a subject, citations are sorted by beginning data of the meeting. New listings are indicated by a bullet after the conference number and DOE-sponsored conferences are indicated by a star. Two indexes are provided for cross referencing conference information. The Chronological Index lists conference titles by dates and gives the subject area where complete information they may be found. The Location Index is alphabetically sorted by the city where the conference will be held.

  3. Computational Intelligence : International Joint Conference

    CERN Document Server

    Rosa, Agostinho; Cadenas, José; Dourado, António; Madani, Kurosh; Filipe, Joaquim

    2016-01-01

    The present book includes a set of selected extended papers from the sixth International Joint Conference on Computational Intelligence (IJCCI 2014), held in Rome, Italy, from 22 to 24 October 2014. The conference was composed by three co-located conferences:  The International Conference on Evolutionary Computation Theory and Applications (ECTA), the International Conference on Fuzzy Computation Theory and Applications (FCTA), and the International Conference on Neural Computation Theory and Applications (NCTA). Recent progresses in scientific developments and applications in these three areas are reported in this book. IJCCI received 210 submissions, from 51 countries, in all continents. After a double blind paper review performed by the Program Committee, 15% were accepted as full papers and thus selected for oral presentation. Additional papers were accepted as short papers and posters. A further selection was made after the Conference, based also on the assessment of presentation quality and audience in...

  4. Multigenic Control and Sex Bias in Host Susceptibility to Spore-Induced Pulmonary Anthrax in Mice▿†

    Science.gov (United States)

    Yadav, Jagjit S.; Pradhan, Suman; Kapoor, Renuka; Bangar, Hansraj; Burzynski, Benjamin B.; Prows, Daniel R.; Levin, Linda

    2011-01-01

    Mechanisms underlying susceptibility to anthrax infection are unknown. Using a phylogenetically diverse panel of inbred mice and spores of Bacillus anthracis Ames, we investigated host susceptibility to pulmonary anthrax. Susceptibility profiles for survival time and organ pathogen load differed across strains, indicating distinct genetic controls. Tissue infection kinetics analysis showed greater systemic dissemination in susceptible DBA/2J (D) mice but a higher terminal bacterial load in resistant BALB/cJ (C) mice. Interestingly, the most resistant strains, C and C57BL/6J (B), demonstrated a sex bias for susceptibility. For example, BALB/cJ females had a significantly higher survival time and required 4-fold more spores for 100% mortality compared to BALB/cJ males. To identify genetic regions associated with differential susceptibility, survival time and extent of organ infection were assessed using mice derived from two susceptibility models: (i) BXD advanced recombinant inbred strains and (ii) F2 offspring generated from polar responding C and D strains. Genome-wide analysis of BXD strain survival identified linkage on chromosomes 5, 6, 9, 11, and 14. Quantitative trait locus (QTL) analysis of the C×DF2 population revealed a significant QTL (designated Rpai1 for resistance to pulmonary anthrax infection, locus 1) for survival time on chromosome 17 and also identified a chromosome 11 locus for lung pathogen burden. The striking difference between genome-wide linkage profiles for these two mouse models of anthrax susceptibility supports our hypothesis that these are multigenic traits. Our data provide the first evidence for a differential sex response to anthrax resistance and further highlight the unlikelihood of a single common genetic contribution for this response across strains. PMID:21628518

  5. Low Cost Upper Atmosphere Sounder (LOCUS)

    Science.gov (United States)

    Gerber, Daniel; Swinyard, Bruce M.; Ellison, Brian N.; Aylward, Alan D.; Aruliah, Anasuya; Plane, John M. C.; Feng, Wuhu; Saunders, Christopher; Friend, Jonathan; Bird, Rachel; Linfield, Edmund H.; Davies, A. Giles; Parkes, Steve

    2014-05-01

    near future. We describe the current instrument configuration of LOCUS, and give a first preview of the expected science return such a mission would yield. The LOCUS instrument concept calls for four spectral bands, a first band at 4.7 THz to target atomic oxygen (O), a second band at 3.5 THz to target hydroxyl (OH), a third band at 1.1 THz to cover several diatomic species (NO, CO, O3, H2O) and finally a fourth band at 0.8 THz to retrieve pointing information from molecular oxygen (O2). LOCUS would be the first satellite instrument to measure atomic oxygen on a global scale with a precision that will allow the retrieval of the global O distribution. It would also be the first time that annual and diurnal changes in O are measured. This will be a significant step forward in understanding the chemistry and dynamics of the MLT. Current indications (derived from CRISTA measurement) lead us to believe that current models only give a poor representation of upper atmospheric O. The secondary target species can help us to address additional scientific questions related to both Climate (distribution of climate relevant gases, highly geared cooling of the MLT in response to Climate change, increased occurrence of Polar Mesospheric Clouds (PMC), etc) and Space Weather (precipitation of electrically charged particles and impact on NOx chemistry, fluctuations of solar Lyman-alpha flux through shown in the the distribution of photochemically active species, etc).

  6. Low-risk susceptibility alleles in 40 human breast cancer cell lines

    NARCIS (Netherlands)

    M. Riaz (Muhammad); F. Elstrodt (Fons); A. Hollestelle (Antoinette); A. Dehghan (Abbas); J.G.M. Klijn (Jan); M. Schutte (Mieke)

    2009-01-01

    textabstractBackground: Low-risk breast cancer susceptibility alleles or SNPs confer only modest breast cancer risks ranging from just over 1.0 to 1.3 fold. Yet, they are common among most populations and therefore are involved in the development of essentially all breast cancers. The mechanism by w

  7. Low-risk susceptibility alleles in 40 human breast cancer cell lines

    NARCIS (Netherlands)

    M. Riaz (Muhammad); F. Elstrodt (Fons); A. Hollestelle (Antoinette); A. Dehghan (Abbas); J.G.M. Klijn (Jan); M. Schutte (Mieke)

    2009-01-01

    textabstractBackground: Low-risk breast cancer susceptibility alleles or SNPs confer only modest breast cancer risks ranging from just over 1.0 to 1.3 fold. Yet, they are common among most populations and therefore are involved in the development of essentially all breast cancers. The mechanism by w

  8. EL LOCUS DE DISTRIBUCION COMO COROLARIO DEL LOCUS DE CONTROL (THE LOCUS OF DISTRIBUTION AS A COROLLARY TO THE LOCUS OF CONTROL

    Directory of Open Access Journals (Sweden)

    Mayoral Luisa

    2009-08-01

    Full Text Available Resumen: Este es un artículo científico acerca del Locus de Distribución, surgido de un estudio realizado con una población de docentes y alumnos universitarios. Respecto de los primeros, se ha indagado acerca de las atribuciones que se realizaban en torno a las recompensas y sanciones, que ellos distribuían a sus alumnos.Respecto de los segundos, se ha buscado determinar la valoración que estos realizaban de sus profesores, en términos de aquellas atribuciones. Para ello, se utilizaron dos paradigmas clásicamente empleados para verificar la existencia de una norma: el paradigma de la autopresentación (docentes, y el paradigma de los j uicios (alumnos. La cuestión planteada fue determinar si en el caso de los comportamientos distributivos de refuerzos, las causas se atribuían a variables externas -en particular a los receptores de esos refuerzos- y si esas formas de atribución eran conocidas y valoradas o no, por los alumnos. De los resultados, surgió la confirmación de nuestra hipótesis de explicaciones externas en materia de comportamientos distributivos de sanciones en el ámbito de la docencia y la valoración positiva de estas atribuciones por los alumnos.Abstract:This one is a scientific article brings over of the Locus of Distribution, arisen from a study realized with a population of teachers and university pupils. Respect of the first ones, it has been investigated brings over of the attributions that were concerning around the reinforcements which they were distributing to pupils. Respect of the second ones, one has sought to determine the valuation that these realized of the teachers, in terms of those attributions. For it, two paradigms were in use classic used to check the existence of a norm: the paradigm of the auto-presentation (teachers, and the paradigm of the judgments (pupils The raised question was to determine if in case of the distributive behaviours of reinforcements, the reasons were assuming to external

  9. Indico CONFERENCE tutorial

    CERN Document Server

    CERN. Geneva; Manzoni, Alex Marc

    2017-01-01

    This short tutorial explains how to create a CONFERENCE in indico and how to handle abstracts and registration forms, in detail: Timestamps: 1:01 - Programme  2:28 - Call for abstracts  11:50 - Abstract submission  13:41 - Abstract Review 15:41 - The Judge's Role 17:23 - Registration forms' creation 23:34 - Candidate participant's registration/application 25:54 - Customisation of Indico pages - Layout 28:08 - Customisation of Indico pages - Menus 29:47 - Configuring Event reminders and import into calendaring tools   See HERE a recent presentation by Pedro about the above steps in the life of an indico CONFERENCE event.

  10. Metabolic Engineering VII Conference

    Energy Technology Data Exchange (ETDEWEB)

    Kevin Korpics

    2012-12-04

    The aims of this Metabolic Engineering conference are to provide a forum for academic and industrial researchers in the field; to bring together the different scientific disciplines that contribute to the design, analysis and optimization of metabolic pathways; and to explore the role of Metabolic Engineering in the areas of health and sustainability. Presentations, both written and oral, panel discussions, and workshops will focus on both applications and techniques used for pathway engineering. Various applications including bioenergy, industrial chemicals and materials, drug targets, health, agriculture, and nutrition will be discussed. Workshops focused on technology development for mathematical and experimental techniques important for metabolic engineering applications will be held for more in depth discussion. This 2008 meeting will celebrate our conference tradition of high quality and relevance to both industrial and academic participants, with topics ranging from the frontiers of fundamental science to the practical aspects of metabolic engineering.

  11. 7th IAASS Conference

    CERN Document Server

    Rongier, Isabelle

    2015-01-01

    The 7th IAASS Conference, “Space Safety is No Accident” is an invitation to reflect and exchange information on a number of topics in space safety and sustainability of national and international interest. The conference is also a forum to promote mutual understanding, trust and the widest possible international cooperation in such matters. The once exclusive “club” of nations with autonomous sub-orbital and orbital space access capabilities is becoming crowded with fresh and ambitious new entrants. New commercial spaceports are starting operations and others are being built. In the manned spaceflight arena a commercial market is becoming a tangible reality with suborbital spaceflights and government use of commercial services for cargo and crew transportation to orbit. Besides the national ambitions in space, the international cooperation both civil and commercial is also gaining momentum. In the meantime robotic space exploration will accelerate and with it the need to internationally better regulat...

  12. XIX Edoardo Amaldi Conference

    CERN Document Server

    Abousahl, Said; Plastino, Wolfango

    2016-01-01

    This book, comprising contributions presented at the XIX Edoardo Amaldi Conference, examines important aspects of international cooperation aimed at enhancing nuclear safety, security, safeguards (the “3S”), and non-proliferation, thereby assisting in the development and maintenance of the verification regime and progress toward a nuclear weapon-free world. The Conference served as a forum where eminent scientists, diplomats, and policymakers could compare national perspectives and update international collaborations. The book opens by addressing the political, institutional, and legal dimensions of the 3S and non-proliferation; current challenges are discussed and attempts made to identify possible solutions and future improvements. Subsequent sections consider scientific developments that can contribute to increased effectiveness in the implementation of international regimes, particularly in critical areas, technology foresight, and the ongoing evaluation of current capabilities. The closing sections d...

  13. 2013 APPLEPIES Conference

    CERN Document Server

    2014-01-01

    This book provides a thorough overview of cutting-edge research on electronics applications relevant to industry, the environment, and society at large. A wide spectrum of application domains are covered, from automotive to space and from health to security, and special attention is devoted to the use of embedded devices and sensors for imaging, communication, and control. The book is based on the 2013 APPLEPIES Conference, held in Rome, which brought together researchers and stakeholders to consider the most significant current trends in the field of applied electronics and to debate visions for the future. Areas covered by the conference included information communication technology; biotechnology and biomedical imaging; space; secure, clean, and efficient energy; the environment; and smart, green, and integrated transport. As electronics technology continues to develop apace, constantly meeting previously unthinkable targets, further attention needs to be directed toward the electronics applications and th...

  14. Mississippi Climate & Hydrology Conference

    Energy Technology Data Exchange (ETDEWEB)

    Lawford, R.; Huang, J.

    2002-05-01

    The GEWEX Continental International Project (GCIP), which started in 1995 and completed in 2001, held its grand finale conference in New Orleans, LA in May 2002. Participants at this conference along with the scientists funded through the GCIP program are invited to contribute a paper to a special issue of Journal of Geophysical Research (JGR). This special JGR issue (called GCIP3) will serve as the final report on scientific research conducted by GCIP investigators. Papers are solicited on the following topical areas, but are not limited to, (1) water energy budget studies; (2) warm season precipitation; (3) predictability and prediction system; (4) coupled land-atmosphere models; (5) climate and water resources applications. The research areas cover observations, modeling, process studies and water resources applications.

  15. The OzT8 locus in rice protects leaf carbon assimilation rate and photosynthetic capacity under ozone stress.

    Science.gov (United States)

    Chen, Charles P; Frei, Michael; Wissuwa, Matthias

    2011-07-01

    Tropospheric ozone (O₃) is a phytotoxic air pollutant whose current background concentrations in parts of East Asia have caused estimated rice yield losses of up to 20%; currently, however, little is known about the mechanisms of O₃ tolerance in rice. We previously identified a quantitative trait locus (QTL) in rice called OzT8, which was associated with relative dry weight under ozone stress. The photosynthetic response in SL46, a Nipponbare (NB)-Kasalath chromosome segment substitution line (SL) containing the OzT8 locus, was compared to the parent NB in multiple ozone fumigation experiments (100 ppb, 8 h d⁻¹, 23 d). By day 23, SL46 showed significantly less reduction of photosynthetic capacity compared to NB; the maximum carboxylation rate of ribulose 1·5-bisphosphate carboxylase/oxygenase (Rubisco) decreased by 24% in SL46 compared to 49% in NB, and the maximum electron transport rate decreased by 16 and 39%, respectively. The midday carbon assimilation rates also showed a similar trend, but there was no genotypic difference in stomatal conductance. These results indicate that the OzT8 locus confers ozone tolerance via biochemical acclimation, not avoidance, making it a potentially valuable target for breeding of ozone tolerance into future rice lines. The sequence of photosynthetic response of rice to ozone stress and related tolerance factors are also discussed.

  16. Effect of Variants of Penicillin-Binding Protein 2 on Cephalosporin and Carbapenem Susceptibilities in Neisseria gonorrhoeae.

    Science.gov (United States)

    Bharat, Amrita; Demczuk, Walter; Martin, Irene; Mulvey, Michael R

    2015-08-01

    To characterize the relationship between penicillin-binding protein 2 (PBP2/penA) and susceptibility to extended-spectrum cephalosporins (ESCs) and carbapenem antibiotics, we compared 17 PBP2 variants in Neisseria gonorrhoeae. Nonmosaic and mosaic variants of PBP2 caused decreased susceptibility to ESCs and, to a lesser extent, to carbapenems. An A501P substitution in mosaic XXXIV_A501P conferred decreased susceptibility to ESCs but restored carbapenem susceptibility to wild-type levels. These results could aid the molecular surveillance of antimicrobial resistance to these agents.

  17. Genomic study in Mexicans identifies a new locus for triglycerides and refines European lipid loci

    Science.gov (United States)

    Weissglas-Volkov, Daphna; Aguilar-Salinas, Carlos A.; Nikkola, Elina; Deere, Kerry A.; Cruz-Bautista, Ivette; Arellano-Campos, Olimpia; Muñoz-Hernandez, Linda Liliana; Gomez-Munguia, Lizeth; Ordoñez-Sánchez, Maria Luisa; Reddy, Prasad MV Linga; Lusis, Aldons J.; Matikainen, Niina; Taskinen, Marja-Riitta; Riba, Laura; Cantor, Rita M.; Sinsheimer, Janet S.; Tusie-Luna, Teresa; Pajukanta, Päivi

    2013-01-01

    Background The Mexican population and others with Amerindian heritage exhibit a substantial predisposition to dyslipidemias and coronary heart disease. Yet, these populations remain underinvestigated by genomic studies, and to date, no genome-wide association (GWA) studies have been reported for lipids in these rapidly expanding populations. Methods and Findings We performed a two-stage GWA study for hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) in Mexicans (n=4,361) and identified a novel Mexican-specific genome-wide significant locus for serum triglycerides (TGs) near the Niemann-Pick type C1 protein (NPC1) gene (P=2.43×10−08). Furthermore, three European loci for TGs (APOA5, GCKR, and LPL) and four loci for HDL-C (ABCA1, CETP, LIPC and LOC55908) reached genome-wide significance in Mexicans. We utilized cross-ethnic mapping to narrow three European TG GWA loci, APOA5, MLXIPL, and CILP2 that were wide and contained multiple candidate variants in the European scan. At the APOA5 locus, this reduced the most likely susceptibility variants to one, rs964184. Importantly, our functional analysis demonstrated a direct link between rs964184 and postprandial serum apoAV protein levels, supporting rs964184 as the causative variant underlying the European and Mexican GWA signal. Overall, 52 of the 100 reported associations from European lipid GWA meta-analysis generalized to Mexicans. However, in 82 of the 100 European GWA loci, a different variant other than the European lead/best-proxy variant had the strongest regional evidence of association in Mexicans. Conclusions This first Mexican GWA study of lipids identified a novel GWA locus for high TG levels; utilized the inter-population heterogeneity to significantly restrict three previously known European GWA signals; and surveyed whether the European lipid GWA SNPs extend to the Mexican population. PMID:23505323

  18. Moldova. Historic regional conference.

    Science.gov (United States)

    Moshin, V

    1995-05-01

    The Directorate of Maternal and Child Health and the Family Planning Association of Moldova organized a regional conference, which was held October 18-19, 1994, in Kishinev, Moldova, with the support of the United Nations Population Fund (UNFPA), the World Health Organization (WHO), and the International Planned Parenthood Federation (IPPF). The conference,"Problems of Family Planning in Eastern Europe," was attended by approximately 400 Moldovan delegates of governmental and nongovernmental organizations (NGOs), and by 25 delegates from Romania, Russia, Belarus, the Ukraine, and Georgia. The President of Moldova and the Ministry of Public Health of Moldova gave their approval. The main objectives of the conference were to inform the public about the recommendations of the ICPD, to analyze the status of women's reproductive health and family planning in Eastern Europe, and to find ways of implementing the ICPD Plan of Action. Major problems identified during the conference were: 1) the social and economic problems facing most families; 2) the high rate of morbidity and mortality; 3) the decrease in birth rate; 4) the increase in abortions; 5) the rising incidence of venereal disease; and 6) the absence of an effective family planning system. It was agreed that cooperation between governments and NGOs is essential in designing population programs for each country. The following goals were set: 1) to provide populations with sufficient contraceptives; 2) to actively promote family planning concepts through the mass media; 3) to train specialists and to open family planning offices and centers; 4) to introduce sex education in the curricula of Pedagogical Institutes; and 5) to create national and regional statistical and sociological databases on population issues.

  19. Genome sequencing conference II

    Energy Technology Data Exchange (ETDEWEB)

    1990-01-01

    Genome Sequencing Conference 2 was held September 30 to October 30, 1990. 26 speaker abstracts and 33 poster presentations were included in the program report. New and improved methods for DNA sequencing and genetic mapping were presented. Many of the papers were concerned with accuracy and speed of acquisition of data with computers and automation playing an increasing role. Individual papers have been processed separately for inclusion on the database.

  20. Durable broad-spectrum powdery mildew resistance in pea er1 plants is conferred by natural loss-of-function mutations in PsMLO1

    NARCIS (Netherlands)

    Humphry, M.; Reinstädler, A.; Ivanov, S.; Bisseling, T.; Panstruga, R.

    2011-01-01

    Loss-of-function alleles of plant-specific MLO (Mildew Resistance Locus O) genes confer broad-spectrum powdery mildew resistance in monocot (barley) and dicot (Arabidopsis thaliana, tomato) plants. Recessively inherited powdery mildew resistance in pea (Pisum sativum) er1 plants is, in many aspects,

  1. Conference on Logical Methods

    CERN Document Server

    Remmel, Jeffrey; Shore, Richard; Sweedler, Moss; Progress in Computer Science and Applied Logic

    1993-01-01

    The twenty-six papers in this volume reflect the wide and still expanding range of Anil Nerode's work. A conference on Logical Methods was held in honor of Nerode's sixtieth birthday (4 June 1992) at the Mathematical Sciences Institute, Cornell University, 1-3 June 1992. Some of the conference papers are here, but others are from students, co-workers and other colleagues. The intention of the conference was to look forward, and to see the directions currently being pursued, in the development of work by, or with, Nerode. Here is a brief summary of the contents of this book. We give a retrospective view of Nerode's work. A number of specific areas are readily discerned: recursive equivalence types, recursive algebra and model theory, the theory of Turing degrees and r.e. sets, polynomial-time computability and computer science. Nerode began with automata theory and has also taken a keen interest in the history of mathematics. All these areas are represented. The one area missing is Nerode's applied mathematica...

  2. 2004 Mutagenesis Gordon Conference

    Energy Technology Data Exchange (ETDEWEB)

    Dr. Sue Jinks-Robertson

    2005-09-16

    Mutations are genetic alterations that drive biological evolution and cause many, if not all, human diseases. Mutation originates via two distinct mechanisms: ''vertical'' variation is de novo change of one or few bases, whereas ''horizontal'' variation occurs by genetic recombination, which creates new mosaics of pre-existing sequences. The Mutagenesis Conference has traditionally focused on the generation of mutagenic intermediates during normal DNA synthesis or in response to environmental insults, as well as the diverse repair mechanisms that prevent the fixation of such intermediates as permanent mutations. While the 2004 Conference will continue to focus on the molecular mechanisms of mutagenesis, there will be increased emphasis on the biological consequences of mutations, both in terms of evolutionary processes and in terms of human disease. The meeting will open with two historical accounts of mutation research that recapitulate the intellectual framework of this field and thereby place the current research paradigms into perspective. The two introductory keynote lectures will be followed by sessions on: (1) mutagenic systems, (2) hypermutable sequences, (3) mechanisms of mutation, (4) mutation avoidance systems, (5) mutation in human hereditary and infectious diseases, (6) mutation rates in evolution and genotype-phenotype relationships, (7) ecology, mutagenesis and the modeling of evolution and (8) genetic diversity of the human population and models for human mutagenesis. The Conference will end with a synthesis of the meeting as the keynote closing lecture.

  3. Molecular mapping of the putative gonadoblastoma locus on the Y chromosome.

    Science.gov (United States)

    Salo, P; Kääriäinen, H; Petrovic, V; Peltomäki, P; Page, D C; de la Chapelle, A

    1995-11-01

    Based on the high incidence of gonadoblastoma in females with XY gonadal dysgenesis or 45,X/46,XY mosaicism, the existence of a susceptibility locus on the Y chromosome (GBY) has been postulated. We attempted to map GBY by making use of a recently developed dense map of Y-chromosomal sequence-tagged sites (STSs). In two female patients with gonadoblastoma, small marker chromosomes contained portions of the Y chromosome, and a single region of overlap could be defined extending from probe pDP97 in interval 4B, which contains the centromere, to marker sY182 in interval 5E of the proximal long arm. This interval is contained in a YAC contig that comprises approximately 4 Mb of DNA. Our findings confirm the previous localization of GBY and greatly refine it. The localization of GBY overlaps with the region to which a putative growth determinant, GCY, was recently assigned.

  4. Multi-locus sequence type analysis of Shigellas pp. isolates from Tehran, Iran

    Science.gov (United States)

    Shahsavan, Shadi; Nobakht, Maliheh; Rastegar-Lari, Abdolaziz; Owlia, Parviz; Bakhshi, Bita

    2016-01-01

    Background and Objectives: Strains of Shigella spp. can cause shigellosis, or bacillary dysentery. that is a public health problem worldwide. The aim of this study was to describe the population structure and genetic relatedness of multidrug resistant S. sonnei and S. flexneri isolated during a one year period from children with diarrhea in Tehran, Iran. Materials and Methods: A total of 70 Shigella spp. were detected during the study period. Twenty MDR isolates of Shigella spp. were randomly selected and used in this study. Bacterial identification was performed by conventional biochemical and serological and confirmed by molecular method. After antimicrobial susceptibility testing, we used Multilocus sequence typing (MLST) for subtyping isolates. Results: We found 14 Shigella sonnei and 6 Shigella flexneri isolates. Results of MLST showed five sequence types (ST) (145, 152, 241, 245, 1502) and BURST analysis revealed the largest number of single locus variant (SLV) and highest frequency (FREQ) for ST152. ST 152 with nine members was predicted as the founder by BURST. Frequency for ST 1502 and ST 245 was four isolates and the least frequency was seen for ST 241 and 145 with one and two members, respectively. ST 145 and ST 245 were described as singletons in BURST. All isolates with ST145 and ST245 were identified as Shigella flexneri. Conclusion: Annual Multi locus sequence typing of MDR Shigella would help us in better understanding of dominant species and comparing our results with the same studies in other countries especially our neighbor countries in source tracking purposes.

  5. Locus of control and cerebral asymmetry.

    Science.gov (United States)

    De Brabander, B; Boone, C; Gerits, P

    1992-08-01

    Data about the lack of synchronism of flexor carpi ulnaris peak EMG values of bimanual reactions during a semantic and during a visuospatial discrimination reaction time task are reported. The effects of type of task as well as the presence or absence of an unexpected stimulus preceding the reaction stimulus on lack of synchronism clearly depend upon the locus of control of the subjects, as measured on Rotter's I-E scale. On the basis of several arguments it is proposed that the measure of lack of synchronism reflects in an opposite sense the amount of dopaminergic activation or motor readiness in the sense in which Pribram and McGuinness in 1975 and Tucker and Williamson in 1984 have defined these concepts. The results for 15 women and 18 men show that more internally oriented subjects are more activated by a semantic task and by an unexpected preparatory stimulus in this type of task than more externally oriented subjects. The opposite appears to hold on the visuospatial task and unexpected preparatory stimuli therein. Together with earlier findings about reaction times and a number of relevant findings in the literature, the results are interpreted as indicative of basic differences in asymmetric tonic activation of the cerebral hemispheres between more internally and more externally oriented subjects. A model is proposed to explain phasic activating effects which ensue when tonically more left- or right-activated subjects perform left- or right-hemisphere tasks and when supplementary irrelevant stimuli are received.

  6. THE LOCUS COERULEUS AND CENTRAL CHEMOSENSITIVITY

    Science.gov (United States)

    Gargaglioni, Luciane H.; Hartzler, Lynn K.; Putnam, Robert W.

    2010-01-01

    The locus coeruleus (LC) lies in the dorsal pons and supplies noradrenergic (NA) input to many regions of the brain, including respiratory control areas. The LC may provide tonic input for basal respiratory drive and is involved in central chemosensitivity since focal acidosis of the region stimulates ventilation and ablation reduces CO2-induced increased ventilation. The output of LC is modulated by both serotonergic and glutamatergic inputs. A large percentage of LC neurons are intrinsically activated by hypercapnia. This percentage and the magnitude of their response are highest in young neonates and decrease dramatically after postnatal day P10. The cellular bases for intrinsic chemosensitivity of LC neurons are comprised of multiple factors, primary among them being reduced extracellular and intracellular pH, which inhibit inwardly rectifying and voltage-gated K+ channels, and activate L-type Ca2+ channels. Activation of KCa channels in LC neurons may limit their ultimate response to hypercapnia. Finally, the LC mediates central chemosensitivity and contains pH-sensitive neurons in amphibians, suggesting that the LC has a long-standing phylogenetic role in respiratory control. PMID:20435170

  7. Network susceptibilities: Theory and applications

    Science.gov (United States)

    Manik, Debsankha; Rohden, Martin; Ronellenfitsch, Henrik; Zhang, Xiaozhu; Hallerberg, Sarah; Witthaut, Dirk; Timme, Marc

    2017-01-01

    We introduce the concept of network susceptibilities quantifying the response of the collective dynamics of a network to small parameter changes. We distinguish two types of susceptibilities: vertex susceptibilities and edge susceptibilities, measuring the responses due to changes in the properties of units and their interactions, respectively. We derive explicit forms of network susceptibilities for oscillator networks close to steady states and offer example applications for Kuramoto-type phase-oscillator models, power grid models, and generic flow models. Focusing on the role of the network topology implies that these ideas can be easily generalized to other types of networks, in particular those characterizing flow, transport, or spreading phenomena. The concept of network susceptibilities is broadly applicable and may straightforwardly be transferred to all settings where networks responses of the collective dynamics to topological changes are essential.

  8. Variants in linkage disequilibrium with the late cornified envelope gene cluster deletion are associated with susceptibility to psoriatic arthritis.

    LENUS (Irish Health Repository)

    Bowes, John

    2010-12-01

    A common deletion mapping to the psoriasis susceptibility locus 4 on chromosome 1q21, encompassing two genes of the late cornified envelope (LCE) gene cluster, has been associated with an increased risk of psoriasis vulgaris (PsV). One previous report found no association of the deletion with psoriatic arthritis (PsA), suggesting it may be a specific risk factor for PsV. Given the genetic overlap between PsA and PsV, a study was undertaken to investigate whether single nucleotide polymorphisms (SNPs) mapping to this locus are risk factors for PsA in a UK and Irish population.

  9. Topological Susceptibility from Slabs

    CERN Document Server

    Bietenholz, Wolfgang; Gerber, Urs

    2015-01-01

    In quantum field theories with topological sectors, a non-perturbative quantity of interest is the topological susceptibility chi_t. In principle it seems straightforward to measure chi_t by means of Monte Carlo simulations. However, for local update algorithms and fine lattice spacings, this tends to be difficult, since the Monte Carlo history rarely changes the topological sector. Here we test a method to measure chi_t even if data from only one sector are available. It is based on the topological charges in sub-volumes, which we denote as slabs. Assuming a Gaussian distribution of these charges, this method enables the evaluation of chi_t, as we demonstrate with numerical results for non-linear sigma-models.

  10. Susceptibility to anchoring effects

    Directory of Open Access Journals (Sweden)

    Todd McElroy

    2007-02-01

    Full Text Available Previous research on anchoring has shown this heuristic to be a very robust psychological phenomenon ubiquitous across many domains of human judgment and decision-making. Despite the prevalence of anchoring effects, researchers have only recently begun to investigate the underlying factors responsible for how and in what ways a person is susceptible to them. This paper examines how one such factor, the Big-Five personality trait of openness-to-experience, influences the effect of previously presented anchors on participants' judgments. Our findings indicate that participants high in openness-to-experience were significantly more influenced by anchoring cues relative to participants low in this trait. These findings were consistent across two different types of anchoring tasks providing convergent evidence for our hypothesis.

  11. Can Pierce’s disease PdR1 resistance introgressed into Vitis vinifera be translocated from a resistant rootstock to a susceptible scion?

    Science.gov (United States)

    The goal of this research is to evaluate the potential of a non-transgenic, PD resistant Vitis vinifera selection used as an experimental rootstock to confer systemic resistance to PD susceptible V. vinifera scions. Source of PD susceptible plant material was the wine grape variety ‘Chardonnay’, kno...

  12. PREFACE: Wake Conference 2015

    Science.gov (United States)

    Barney, Andrew; Nørkær Sørensen, Jens; Ivanell, Stefan

    2015-06-01

    The 44 papers in this volume constitute the proceedings of the 2015 Wake Conference, held in Visby on the island of Gotland in Sweden. It is the fourth time this conference has been held. The Wake Conference series started in Visby, where it was held in 2009 and 2011. In 2013 it took place in Copenhagen where it was combined with the International Conference on Offshore Wind Energy and Ocean Energy. In 2015 it is back where it started in Visby, where it takes place at Uppsala University Campus Gotland, June 9th-11th. The global yearly production of electrical energy by wind turbines has grown tremendously in the past decade and it now comprises more than 3% of the global electrical power consumption. Today the wind power industry has a global annual turnover of more than 50 billion USD and an annual average growth rate of more than 20%. State-of-the-art wind turbines have rotor diameters of up to 150 m and 8 MW installed capacity. These turbines are often placed in large wind farms that have a total production capacity corresponding to that of a nuclear power plant. In order to make a substantial impact on one of the most significant challenges of our time, global warming, the industry's growth has to continue for a decade or two yet. This in turn requires research into the physics of wind turbine wakes and wind farms. Modern wind turbines are today clustered in wind farms in which the turbines are fully or partially influenced by the wake of upstream turbines. As a consequence, the wake behind the wind turbines has a lower mean wind speed and an increased turbulence level, as compared to the undisturbed flow outside the farm. Hence, wake interaction results in decreased total production of power, caused by lower kinetic energy in the wind, and an increase in the turbulence intensity. Therefore, understanding the physical nature of the vortices and their dynamics in the wake of a turbine is important for the optimal design of a wind farm. This conference is aimed

  13. Conference Report: The First ATLAS.ti User Conference

    OpenAIRE

    Evers, Jeanine C.; Silver, Christina

    2014-01-01

    This report on the First ATLAS.ti User Conference shares our impressions and experiences as longstanding ATLAS.ti users and trainers about the First ATLAS.ti User Conference in Berlin 2013. The origins, conceptual principles and development of the program are outlined, the conference themes discussed and experiences shared. Finally, the future of the program is discussed.URN: http://nbn-resolving.de/urn:nbn:de:0114-fqs1401197

  14. automatic generation of root locus plots for linear time invariant ...

    African Journals Online (AJOL)

    user

    root locus as a time domain technique for system design and analysis. The Tool Box can also ... theory, it has equally been applied to classical formulation and the ... major constraint, therefore the use of complex graphical ..... The computation.

  15. Y-Chromosome short tandem repeat, typing technology, locus ...

    African Journals Online (AJOL)

    Aghomotsegin

    technology, locus information and allele frequency in different ... DNA can be used to study human evolution. Besides ... STR markers are important for human identification ..... discovery resource for research on human genetic variation.

  16. LOCUS OF CONTROL AND JOB SATISFACTION: PSU EMPLOYEES

    Directory of Open Access Journals (Sweden)

    Lakshman Vijayashree

    2011-11-01

    Full Text Available Previous research studies have demonstrated that internal/external locus of control impacts jobsatisfaction. The present study thus aims to analyze type of locus of control and its relation with jobsatisfaction. The study will be of great help for organization to understand and know what type oflocus of control their employees has and how it has an impact on job satisfaction.The objectives of this study were: 1- To identify the type of Locus of Control (i.e. Internal orExternal present in Public Sector Units (PSU in Bangalore and 2- To analyze the impact of differenttype of Locus of Control on job satisfaction of PSU Employees. Further hypothesis was also set tocheck the relationship between locus of control and job satisfaction. In addition, the relationshipbetween different demographic factors was also examined. The tool used for this study was LocoInventory. The concept of locus of control by Levenson (1972 was used to develop Loco Inventory(Locus of Control in Organization Inventory. The survey used a questionnaire, which had thirty fivestatements which highlights the factors that determine the locus of control and job satisfaction levelof the employees. The Ratio, ANOVA, and Correlation analysis were used as statistical techniquesfor analysis.The results indicate that there is a positive correlation between internal locus of control and jobsatisfaction as well as between External (other locus of control and job satisfaction. And in case ofExternal (Chance locus of control and job satisfaction there exists partial positive correlation. As perthis study Job satisfaction level among the employees is also good as the mean is 17, which is closerto maximum scale value of 25. As per ANOVA table there is a significant variance betweeninternality and age as well as between externality (chance and age. There is no significantrelationship between internality and demographic factors like gender and education. There is nosignificant relationship between

  17. Computational Intelligence : International Joint Conference

    CERN Document Server

    Dourado, António; Rosa, Agostinho; Filipe, Joaquim; Kacprzyk, Janusz

    2016-01-01

    The present book includes a set of selected extended papers from the fifth International Joint Conference on Computational Intelligence (IJCCI 2013), held in Vilamoura, Algarve, Portugal, from 20 to 22 September 2013. The conference was composed by three co-located conferences:  The International Conference on Evolutionary Computation Theory and Applications (ECTA), the International Conference on Fuzzy Computation Theory and Applications (FCTA), and the International Conference on Neural Computation Theory and Applications (NCTA). Recent progresses in scientific developments and applications in these three areas are reported in this book. IJCCI received 111 submissions, from 30 countries, in all continents. After a double blind paper review performed by the Program Committee, only 24 submissions were accepted as full papers and thus selected for oral presentation, leading to a full paper acceptance ratio of 22%. Additional papers were accepted as short papers and posters. A further selection was made after ...

  18. Joint US/German Conference

    CERN Document Server

    Gulledge, Thomas; Jones, Albert

    1993-01-01

    This proceedings volume contains selected and refereed contributions that were presented at the conference on "Recent Developments and New Perspectives of Operations Research in the Area of Production Planning and Control" in Hagen/Germany, 25. - 26. June 1992. This conference was organized with the cooperation of the FernuniversiHit Hagen and was jointly hosted by the "Deutsche Gesellschaft fur Operations Research (DGOR)" and the "Manufacturing Special Interest Group of the Operations Research Society of America (ORSA-SIGMA)". For the organization of the conference we received generous financial support from the sponsors listed at the end of this volume. We wish to express our appreciation to all supporters for their contributions. This conference was the successor of the JOInt ORSA/DGOR-conference in Gaithersburg/Maryland, USA, on the 30. and 31. July 1991. Both OR-societies committed themselves in 1989 to host joint conferences on special topics of interest from the field of operations research. This goal ...

  19. 14th International Cryocooler Conference

    CERN Document Server

    Ross, Ronald G

    2007-01-01

    This is the 14th volume in the conference series. Over the years the International Cryocoolers Conference has become the preeminent worldwide conference for the presentation of the latest developments and test experiences with cryocoolers. The typical applications of this technology include cooling space and terrestrial infrared focal plane arrays, space x-ray detectors, medical applications, and a growing number of high-temperature superconductor applications.

  20. 15th International Cryocooler Conference

    CERN Document Server

    Ross, Ronald G

    2009-01-01

    This is the 15th volume in the conference series. Over the years the International Cryocooler Conference has become the preeminent worldwide conference for the presentation of the latest developments and test experiences with cryocoolers. The typical applications of this technology include cooling space and terrestrial infrared focal plane arrays, space x-ray detectors, medical applications, and a growing number of high-temperature superconductor applications.

  1. International conference on string theory

    CERN Document Server

    2017-01-01

    The Strings 2017 conference is part of the "Strings" series of annual conferences, that bring the entire string theory community together. It will include reviews of major developments in the field, and specialized talks on specific topics. There will also be several public lectures given b