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ABSTRACT: PURPOSE: The osteoprotogerin/receptor activator of NF-kappa β/receptor activator of NF-kappa β ligand (OPG/RANK/RANKL) pathway plays a critical role in bone remodeling. This study investigated associations between serum levels of OPG, soluble RANKL (sRANKL), and the ratio of OPG/sRANKL to risk of incident hip fracture. METHODS: A nested case-control study was conducted among postmenopausal, Caucasian women aged 50-79 at baseline (1993-1998), followed for hip fracture through March 2005 in the Women's Health Initiative Observational Study. 400 incident hip fracture cases were selected and individually matched to 400 controls with no prior fracture or incident hip fracture. Matching factors were baseline age, enrollment date and hormone therapy (HT) exposure. Baseline serum OPG and sRANKL levels were measured using high sensitivity ELISA. Odds ratios were computed for quartiles of each biomarker adjusting for matching factors and hip fracture risk factors. RESULTS: Serum OPG was significantly associated with older age, low physical activity and poorer physical function in control women. sRANKL was inversely associated with total calcium intake in control women, but not associated with age or other fracture risk factors. The odds ratio for hip fracture comparing the highest to lowest quartiles of OPG was 2.28 (95% confidence interval (CI), 1.45-3.61) after adjusting for the matching variables (p-value for linear trend<0.001), and 1.87 (95% CI, 1.15-3.04; p for linear trend=0.02) after adjusting for self-rated health status, physical activity and physical functioning. No significant associations between sRANKL or the ratio of OPG/sRANKL and hip fracture risk were observed. CONCLUSION: Serum OPG levels were independently associated with a nearly two-fold increased risk of hip fracture in postmenopausal women.
Bone 06/2013; · 4.02 Impact Factor
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Marc A Coram,
Qing Duan,
Thomas J Hoffmann,
Timothy Thornton,
Joshua W Knowles,
Nicholas A Johnson,
Heather M Ochs-Balcom,
Timothy A Donlon,
Lisa W Martin,
Charles B Eaton,
Jennifer G Robinson,
Neil J Risch,
Xiaofeng Zhu, Charles Kooperberg,
Yun Li,
Alex P Reiner,
Hua Tang
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ABSTRACT: Blood lipid concentrations are heritable risk factors associated with atherosclerosis and cardiovascular diseases. Lipid traits exhibit considerable variation among populations of distinct ancestral origin as well as between individuals within a population. We performed association analyses to identify genetic loci influencing lipid concentrations in African American and Hispanic American women in the Women's Health Initiative SNP Health Association Resource. We validated one African-specific high-density lipoprotein cholesterol locus at CD36 as well as 14 known lipid loci that have been previously implicated in studies of European populations. Moreover, we demonstrate striking similarities in genetic architecture (loci influencing the trait, direction and magnitude of genetic effects, and proportions of phenotypic variation explained) of lipid traits across populations. In particular, we found that a disproportionate fraction of lipid variation in African Americans and Hispanic Americans can be attributed to genomic loci exhibiting statistical evidence of association in Europeans, even though the precise genes and variants remain unknown. At the same time, we found substantial allelic heterogeneity within shared loci, characterized both by population-specific rare variants and variants shared among multiple populations that occur at disparate frequencies. The allelic heterogeneity emphasizes the importance of including diverse populations in future genetic association studies of complex traits such as lipids; furthermore, the overlap in lipid loci across populations of diverse ancestral origin argues that additional knowledge can be gleaned from multiple populations.
The American Journal of Human Genetics 05/2013; · 10.60 Impact Factor
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Jill M Johnsen,
Paul L Auer,
Alanna C Morrison,
Shuo Jiao,
Peng Wei,
Jeffrey Haessler,
Keolu Fox,
Sean R McGee,
Joshua D Smith,
Christopher S Carlson,
Nicholas Smith,
Eric Boerwinkle, Charles Kooperberg,
Deborah Nickerson,
Stephen S Rich,
David Green,
Ulrike Peters,
Mary Cushman,
Alex P Reiner
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ABSTRACT: Several rare European type 1 and 2N von Willebrand disease missense variants of VWF (including p.Arg2185Gln and p.His817Gln) were recently reported to be common [minor allele frequency (MAF) 10-15%] in apparently healthy African Americans (AA). Using data from the NHLBI Exome Sequencing Project, we assessed the association of these and other common and low frequency VWF coding variants with von Willebrand factor (VWF) and factor VIII (FVIII) levels in a population-based sample of 4,468 AA. Of 30 non-synonymous VWF variants, 6 were significantly and independently associated (P<0.001) with levels of VWF and/or FVIII. Each additional copy of the VWF variants encoding the common p.Thr789Ala or p.Asp1472His amino acid substitutions was associated with 6-8 IU/dL higher VWF levels. The VWF variant encoding p.Arg2185Gln was associated with 7-13 IU/dL lower VWF and FVIII levels. The type 2N-related VWF variant encoding p.His817Gln was associated with 17 IU/dL lower FVIII level but normal VWF level (P=0.57). A novel, rare (MAF=0.8%) missense VWF variant that predicts disruption of an O-glycosylation site (p.Ser1486Leu) and a rare (MAF = 0.7%) variant encoding p.Arg2287Trp were each associated with 30-40 IU/dL lower VWF level (P<0.001). In summary several common and rare VWF missense variants contribute to phenotypic differences in VWF and FVIII among AA.
Blood 05/2013; · 9.90 Impact Factor
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Dajiang J. Liu,
Gina M. Peloso,
Xiaowei Zhan,
Oddgeir Holmen,
Matthew Zawistowski,
Shuang Feng,
Majid Nikpay,
Paul L. Auer,
Anuj Goel,
He Zhang, [......],
Martin Farrall,
Marju Orho-Melander, Charles Kooperberg,
Ruth McPherson,
Hugh Watkins,
Cristen J. Willer,
Kristian Hveem,
Olle Melander,
Sekar Kathiresan,
Gonçalo R. Abecasis
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ABSTRACT: The vast majority of connections between complex disease and common genetic
variants were identified through meta-analysis, a powerful approach that
enables large samples sizes while protecting against common artifacts due to
population structure, repeated small sample analyses, and/or limitations with
sharing individual level data. As the focus of genetic association studies
shifts to rare variants, genes and other functional units are becoming the unit
of analysis. Here, we propose and evaluate new approaches for meta-analysis of
rare variant association. We show that our approach retains useful features of
single variant meta-analytic approaches and demonstrate its utility in a study
of blood lipid levels in ~18,500 individuals genotyped with exome arrays.
05/2013;
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Kira C Taylor,
Cara L Carty,
Logan Dumitrescu,
Petra B Ková,
Shelley A Cole,
Lucia Hindorff,
Fred R Schumacher,
Lynne R Wilkens,
Ralph V Shohet,
P Miguel Quibrera, [......],
Kristin Brown-Gentry,
Garnet Anderson,
Jose Luis Ambite,
Christopher Haiman,
Loïc Le Marchand, Charles Kooperberg,
Dana C Crawford,
Steven Buyske,
Kari E North,
Myriam Fornage
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ABSTRACT: BACKGROUND: High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels are influenced by both genes and the environment. Genome-wide association studies (GWAS) have identified ~100 common genetic variants associated with HDL-C, LDL-C, and/or TG levels, mostly in populations of European descent, but little is known about the modifiers of these associations. Here, we investigated whether GWAS-identified SNPs for lipid traits exhibited heterogeneity by sex in the Population Architecture using Genomics and Epidemiology (PAGE) study. RESULTS: A sex-stratified meta-analysis was performed for 49 GWAS-identified SNPs for fasting HDL-C, LDL-C, and ln(TG) levels among adults self-identified as European American (25,013). Heterogeneity by sex was established when phet < 0.001. There was evidence for heterogeneity by sex for two SNPs for ln(TG) in the APOA1/C3/A4/A5/BUD13 gene cluster: rs28927680 (phet = 7.4x10-7) and rs3135506 (phet = 4.3x10-4), one SNP in PLTP for HDL levels (rs7679; phet = 9.9x10-4), and one in HMGCR for LDL levels (rs12654264; phet = 3.1x10-5). We replicated heterogeneity by sex in five of seventeen loci previously reported by genome-wide studies (binomial p = 0.0009). We also present results for other racial/ethnic groups in the supplementary materials, to provide a resource for future meta-analyses. CONCLUSIONS: We provide further evidence for sex-specific effects of SNPs in the APOA1/C3/A4/A5/BUD13 gene cluster, PLTP, and HMGCR on fasting triglyceride levels in European Americans from the PAGE study. Our findings emphasize the need for considering context-specific effects when interpreting genetic associations emerging from GWAS, and also highlight the difficulties in replicating interaction effects across studies and across racial/ethnic groups.
BMC Genetics 05/2013; 14(1):33. · 2.47 Impact Factor
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Ellen W Demerath,
Ching-Ti Liu,
Nora Franceschini,
Gary Chen,
Julie R Palmer,
Erin N Smith,
Christina T L Chen,
Christine B Ambrosone,
Alice M Arnold,
Elisa V Bandera, [......],
B Gwen Windham,
Melissa Wellons,
Sarah S Murray,
Michael Nalls,
Aleksandar Rajkovic,
Joel Hirschhorn,
L Adrienne Cupples, Charles Kooperberg,
Joanne M Murabito,
Christopher A Haiman
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ABSTRACT: African American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single nucleotide polymorphisms (SNPs) in a total of 18,089 AA women in 15 cohort studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2,850 women (Stage 2). First, while no SNP passed the pre-specified p< 5 x 10(-8) threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Second, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women.
Human Molecular Genetics 04/2013; · 7.64 Impact Factor
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Ying Wu,
Lindsay L Waite,
Anne U Jackson,
Wayne H-H Sheu,
Steven Buyske,
Devin Absher,
Donna K Arnett,
Eric Boerwinkle,
Lori L Bonnycastle,
Cara L Carty, [......],
Tzung-Dau Wang,
Michael Boehnke,
Christopher A Haiman,
Yii-Der I Chen, Charles Kooperberg,
Themistocles L Assimes,
Dana C Crawford,
Chao A Hsiung,
Kari E North,
Karen L Mohlke
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ABSTRACT: Genome-wide association studies (GWAS) have identified ∼100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1×10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.
PLoS Genetics 03/2013; 9(3):e1003379. · 8.69 Impact Factor
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Heather M Ochs-Balcom,
Leah Preus,
Jean Wactawski-Wende,
Jing Nie,
Nicholas A Johnson,
Fouad Zakharia,
Hua Tang,
Chris Carlson,
Cara Carty,
Zhao Chen, [......],
Li Li,
Song Liu,
Marian L Neuhouser,
Ulrike Peters,
John Robbins,
Michael F Seldin,
Timothy A Thornton,
Cheryl L Thompson, Charles Kooperberg,
Lara E Sucheston
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ABSTRACT: Context:Both genes and environment have been implicated in determining the complex body composition phenotypes in individuals of European ancestry; however, few studies have been conducted in other race/ethnic groups.Objective:We conducted a genome-wide admixture mapping study in an attempt to localize novel genomic regions associated with genetic ancestry.Setting/Participants:We selected a sample of 842 African-American women from the Women's Health Initiative single nucleotide polymorphism (SNP) Health Association Resource for whom several dual-energy X-ray absorptiometry (DXA)-derived bone mineral density (BMD) and fat mass phenotypes were available.Methods:We derived both global and local ancestry estimates for each individual from Affymetrix 6.0 data and analyzed the correlation of DXA phenotypes with global African ancestry. For each phenotype, we examined the association of local genetic ancestry (number of African ancestral alleles at each marker) and each DXA phenotype at 570 282 markers across the genome in additive models with adjustment for important covariates.Results:We identified statistically significant correlations of whole-body fat mass, trunk fat mass, and all 6 measures of BMD with a proportion of African ancestry. Genome-wide (admixture) significance for femoral neck BMD was achieved across 2 regions ∼3.7 MB and 0.3 MB on chromosome 19q13; similarly, total hip and intertrochanter BMD were associated with local ancestry in these regions. Trunk fat was the most significant fat mass phenotype showing strong, but not genomewide significant associations on chromosome Xp22.Conclusions:Our results suggest that genomic regions in postmenopausal African-American women contribute to variance in BMD and fat mass existence and warrant further study.
The Journal of clinical endocrinology and metabolism 02/2013; · 6.50 Impact Factor
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Max Leenders,
Samsiddhi Bhattacharjee,
Paolo Vineis,
Victoria Stevens,
H Bas Bueno-de-Mesquita,
Xiao-Ou Shu,
Laufey Amundadottir,
Myron Gross,
Geoffrey S Tobias,
Jean Wactawski-Wende, [......],
Kari G Rabe,
Elio Riboli,
Anne Tjønneland,
Dimitrios Trichopoulos,
Jarmo Virtamo,
Kala Visvanathan,
Joanne W Elena,
Herbert Yu,
Anne Zeleniuch-Jacquotte,
Rachael Z Stolzenberg-Solomon
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ABSTRACT: PURPOSE: The evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed. METHODS: Using biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (<0.02) were followed up in 2,323 cases and 2,340 controls from eight case-control studies (PanC4) that participated in PanScan2. The correlation of SNPs with metabolite levels was assessed for 649 controls from the European Prospective Investigation into Cancer and Nutrition. RESULTS: When both stages were combined, we observed suggestive associations with PanCa for rs10887710 (MAT1A) (OR 1.13, 95 %CI 1.04-1.23), rs1552462 (SYT9) (OR 1.27, 95 %CI 1.02-1.59), and rs7074891 (CUBN) (OR 1.91, 95 %CI 1.12-3.26). After correcting for multiple comparisons, no significant associations were observed in either the first or second stage. The three suggested SNPs showed no correlations with one-carbon biomarkers. CONCLUSIONS: This is the largest genetic study to date to examine the relation between germline variations in OCM-related genes polymorphisms and the risk of PanCa. Suggestive evidence for an association between polymorphisms and PanCa was observed among the cohort-nested studies, but this did not replicate in the case-control studies. Our results do not strongly support the hypothesis that genes related to OCM play a role in pancreatic carcinogenesis.
Cancer Causes and Control 01/2013; · 2.88 Impact Factor
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Ulrike Peters,
Kari E North,
Praveen Sethupathy,
Steve Buyske,
Jeff Haessler,
Shuo Jiao,
Megan D Fesinmeyer,
Rebecca D Jackson,
Lew H Kuller,
Aleksandar Rajkovic, [......],
C Charles Gu,
Denise Houston,
Petra Buzkova,
Marylyn Ritchie,
Tara C Matise,
Loic Le Marchand,
Lucia A Hindorff,
Dana C Crawford,
Christopher A Haiman, Charles Kooperberg
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ABSTRACT: Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3×10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.
PLoS Genetics 01/2013; 9(1):e1003171. · 8.69 Impact Factor
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Sarah A Pendergrass,
Kristin Brown-Gentry,
Scott Dudek,
Alex Frase,
Eric S Torstenson,
Robert Goodloe,
Jose Luis Ambite,
Christy L Avery,
Steve Buyske,
Petra Bůžková, [......],
Yi Lin,
Tara C Matise,
Kristine R Monroe,
Larry Moreland,
Sungshim L Park,
Alex Reiner,
Robert Wallace,
Lynn R Wilkens,
Dana C Crawford,
Marylyn D Ritchie
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ABSTRACT: Using a phenome-wide association study (PheWAS) approach, we comprehensively tested genetic variants for association with phenotypes available for 70,061 study participants in the Population Architecture using Genomics and Epidemiology (PAGE) network. Our aim was to better characterize the genetic architecture of complex traits and identify novel pleiotropic relationships. This PheWAS drew on five population-based studies representing four major racial/ethnic groups (European Americans (EA), African Americans (AA), Hispanics/Mexican-Americans, and Asian/Pacific Islanders) in PAGE, each site with measurements for multiple traits, associated laboratory measures, and intermediate biomarkers. A total of 83 single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) were genotyped across two or more PAGE study sites. Comprehensive tests of association, stratified by race/ethnicity, were performed, encompassing 4,706 phenotypes mapped to 105 phenotype-classes, and association results were compared across study sites. A total of 111 PheWAS results had significant associations for two or more PAGE study sites with consistent direction of effect with a significance threshold of p<0.01 for the same racial/ethnic group, SNP, and phenotype-class. Among results identified for SNPs previously associated with phenotypes such as lipid traits, type 2 diabetes, and body mass index, 52 replicated previously published genotype-phenotype associations, 26 represented phenotypes closely related to previously known genotype-phenotype associations, and 33 represented potentially novel genotype-phenotype associations with pleiotropic effects. The majority of the potentially novel results were for single PheWAS phenotype-classes, for example, for CDKN2A/B rs1333049 (previously associated with type 2 diabetes in EA) a PheWAS association was identified for hemoglobin levels in AA. Of note, however, GALNT2 rs2144300 (previously associated with high-density lipoprotein cholesterol levels in EA) had multiple potentially novel PheWAS associations, with hypertension related phenotypes in AA and with serum calcium levels and coronary artery disease phenotypes in EA. PheWAS identifies associations for hypothesis generation and exploration of the genetic architecture of complex traits.
PLoS Genetics 01/2013; 9(1):e1003087. · 8.69 Impact Factor
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Ulrike Peters,
Shuo Jiao,
Fredrick R Schumacher,
Carolyn M Hutter,
Aaron K Aragaki,
John A Baron,
Sonja I Berndt,
Stéphane Bézieau,
Hermann Brenner,
Katja Butterbach, [......],
Darin Taverna,
Stephen N Thibodeau,
Cornelia M Ulrich,
Emily White,
Yongbing Xiang,
Brent W Zanke,
Yi-Xin Zeng,
Ben Zhang,
Wei Zheng,
Li Hsu
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ABSTRACT: BACKGROUND & AIMS: Heritable factors contribute to development of colorectal cancer (CRC). Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. METHODS: We conducted a genome-wide association study (GWAS) that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. RESULTS: Based on the combined analysis we identified a locus that reached the conventional genome-wide significance level at <5.0 x 10-8: an intergenic region on chromosome 2q32.3, close toNABP1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR]=1.15 per risk allele;P =3.7 x 10-8). We also found evidence for 3 additional loci with P values <5.0 x 10-7: a locus within theLAMC1gene on chromosome 1q25.3 (rs10911251; OR=1.10 per risk allele;P =9.5 x 10-8), a locus within theCCND2gene on chromosome 12p13.32 (rs3217810 per risk allele; OR=0.84;P =5.9 x 10-8), and a locus in theTBX3gene on chromosome 12q24.21 (rs59336, OR=0.91 per risk allele;P =3.7 x 10-7). CONCLUSIONS: In a large GWAS, we associated polymorphisms close toNABP (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms inLAMC1 (this is the second gene in the laminin family to be associated with CRCs),CCND2 (which encodes for cyclin D2), andTBX3 (which encodes a T-box transcription factor and is a target of Wnt signaling to -catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
Gastroenterology 12/2012; · 11.68 Impact Factor
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Chen Wu,
Peter Kraft,
Rachael Stolzenberg-Solomon,
Emily Steplowski,
Michelle Brotzman,
Mousheng Xu,
Poorva Mudgal,
Laufey Amundadottir,
Alan A Arslan,
H Bas Bueno-de-Mesquita, [......],
Jean Wactawski-Wende,
Chengfeng Wang,
Kai Yu,
Anne Zeleniuch-Jacquotte,
Stephen Chanock,
Robert Hoover,
Patricia Hartge,
Charles S Fuchs,
Dongxin Lin,
Brian M Wolpin
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ABSTRACT: BACKGROUND AND OBJECTIVE: Survival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma. METHODS: We analysed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (p≤10(-5)) were advanced to a joint analysis with 363 additional patients from China (ChinaPC). RESULTS: In the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21 and 1p36.13, tagged by rs12362504 (p=1.63×10(-7)), rs981621 (p=1.65×10(-7)) and rs16861827 (p=3.75×10(-7)), respectively. 131 SNPs with p≤10(-5) were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; p=1.72×10(-7)) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The HR (95% CI) for death was 0.74 (0.66 to 0.84) in PanScan I, 0.79 (0.65 to 0.97) in ChinaPC and 0.76 (0.68 to 0.84) in the joint analysis. CONCLUSIONS: Germline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.
Gut 11/2012; · 10.11 Impact Factor
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ABSTRACT: OBJECTIVES: To examine associations between angiotensin-converting enzyme (ACE) inhibitor and statin medications and baseline and mean annual change in physical performance measures and muscle strength in older women. DESIGN: Prospective cohort study. PARTICIPANTS: Participants from the Women's Health Initiative Clinical Trials aged 65 to 79 at baseline who had physical performance measures, self-report of health insurance, and no prior history of stroke or congestive heart failure were included (N = 5,777). Women were recruited between 1993 and 1998. MEASUREMENTS: Medication use was ascertained through a baseline inventory. Physical performance measures (timed 6-m walk, repeated chair stands in 15 seconds) and grip strength were assessed at baseline and follow-up Years 1, 3, and 6. Multivariable-adjusted linear repeated-measures models were adjusted for demographic and health characteristics. RESULTS: ACE inhibitor use was associated with lower mean grip strength at baseline (22.40 kg, 95% confidence interval (CI) = 21.89-22.91 vs 23.18 kg, 95% CI 23.02-23.34; P = .005) and greater mean annual change in number of chair stands (-0.182, 95% CI -0.217 to -0.147 vs -0.145, 95% CI -0.156 to -0.133; P = .05) than nonuse. Statin use was not significantly associated with baseline measures or mean annual change for any outcome. A subgroup analysis suggested that statin use was associated with less mean annual change in chair stands (P = .006) in the oldest women. CONCLUSION: These results do not support an association between statin or ACE inhibitor use and slower decline in physical performance or muscle strength and thus do not support the use of these medications for preserving functional status in older adults.
Journal of the American Geriatrics Society 11/2012; · 3.74 Impact Factor
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Joanne W Elena,
Emily Steplowski,
Kai Yu,
Patricia Hartge,
Geoffrey S Tobias,
Michelle J Brotzman,
Stephen J Chanock,
Rachael Z Stolzenberg-Solomon,
Alan A Arslan,
H Bas Bueno-de-Mesquita, [......],
Michael S Simon,
Nadia Slimani,
Dimitrios Trichopoulos,
Kala Visvanathan,
Jarmo Virtamo,
Brian M Wolpin,
Anne Zeleniuch-Jacquotte,
Charles S Fuchs,
Robert N Hoover,
Myron Gross
[show abstract]
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ABSTRACT: PURPOSE: Diabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan). METHODS: The pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case-control study design. Subjects who were diagnosed with diabetes near the time (<2 years) of pancreatic cancer diagnosis were excluded from all analyses. All analyses were adjusted for age, race, gender, study, alcohol use, smoking, BMI, and family history of pancreatic cancer. RESULTS: Self-reported diabetes was associated with a forty percent increased risk of pancreatic cancer (OR = 1.40, 95 % CI: 1.07, 1.84). The association differed by duration of diabetes; risk was highest for those with a duration of 2-8 years (OR = 1.79, 95 % CI: 1.25, 2.55); there was no association for those with 9+ years of diabetes (OR = 1.02, 95 % CI: 0.68, 1.52). CONCLUSIONS: These findings provide support for a relationship between diabetes and pancreatic cancer risk. The absence of association in those with the longest duration of diabetes may reflect hypoinsulinemia and warrants further investigation.
Cancer Causes and Control 10/2012; · 2.88 Impact Factor
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Folkert W Asselbergs,
Yiran Guo,
Erik P A van Iperen,
Suthesh Sivapalaratnam,
Vinicius Tragante,
Matthew B Lanktree,
Leslie A Lange,
Berta Almoguera,
Yolande E Appelman,
John Barnard, [......],
Nilesh J Samani,
Alex P Reiner,
Robert A Hegele,
John J P Kastelein,
Aroon D Hingorani,
Philippa J Talmud,
Hakon Hakonarson,
Clara C Elbers,
Brendan J Keating,
Fotios Drenos
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ABSTRACT: Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
The American Journal of Human Genetics 10/2012; · 10.60 Impact Factor
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ABSTRACT: C-reactive protein (CRP) is a systemic inflammation marker that predicts future cardiovascular risk. CRP levels are higher in African Americans and Hispanic Americans than in European Americans, but the genetic determinants of CRP in these admixed United States minority populations are largely unknown. We performed genome-wide association studies (GWASs) of 8,280 African American (AA) and 3,548 Hispanic American (HA) postmenopausal women from the Women's Health Initiative SNP Health Association Resource. We discovered and validated a CRP-associated variant of triggering receptors expressed by myeloid cells 2 (TREM2) in chromosomal region 6p21 (p = 10(-10)). The TREM2 variant associated with higher CRP is common in Africa but rare in other ancestral populations. In AA women, the CRP region in 1q23 contained a strong admixture association signal (p = 10(-17)), which appears to be related to several independent CRP-associated alleles; the strongest of these is present only in African ancestral populations and is associated with higher CRP. Of the other genomic loci previously associated with CRP through GWASs of European populations, most loci (LEPR, IL1RN, IL6R, GCKR, NLRP3, HNF1A, HNF4A, and APOC1) showed consistent patterns of association with CRP in AA and HA women. In summary, we have identified a common TREM2 variant associated with CRP in United States minority populations. The genetic architecture underlying the CRP phenotype in AA women is complex and involves genetic variants shared across populations, as well as variants specific to populations of African descent.
The American Journal of Human Genetics 08/2012; 91(3):502-12. · 10.60 Impact Factor
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Christy L Avery,
Praveen Sethupathy,
Steven Buyske,
Qianchuan He,
Dan-Yu Lin,
Dan E Arking,
Cara L Carty,
David Duggan,
Megan D Fesinmeyer,
Lucia A Hindorff, [......],
Kristen K Patton,
Ulrike Peters,
Ralph V Shohet,
Nona Sotoodehnia,
Alicia M Young, Charles Kooperberg,
Christopher A Haiman,
Karen L Mohlke,
Eric A Whitsel,
Kari E North
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ABSTRACT: The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.
PLoS Genetics 08/2012; 8(8):e1002870. · 8.69 Impact Factor
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ABSTRACT: Unraveling the nature of genetic interactions is crucial to obtaining a more complete picture of complex diseases. It is thought that gene-gene interactions play an important role in the etiology of cancer, cardiovascular, and immune-mediated disease. Interactions among genes are defined as phenotypic effects that differ from those observed for independent contributions of each gene, usually detected by univariate logistic regression methods. Using a multivariate extension of linkage disequilibrium (LD), we have developed a new method, based on distances between sample covariance matrices for groups of single nucleotide polymorphisms (SNPs), to test for interaction effects of two groups of genes associated with a disease phenotype. Since a disease-associated interacting locus will often be in LD with more than one marker in the region, a method that examines a set of markers in a region collectively can offer greater power than traditional methods. Our method effectively identifies interaction effects in simulated data, as well as in data on the genetic contributions to the risk for graft-versus-host disease following hematopoietic stem cell transplantation.
Genetic Epidemiology 07/2012; 36(6):622-30. · 3.44 Impact Factor
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ABSTRACT: In this article, the authors propose to simultaneously test for marginal genetic association and gene-environment interaction to discover single nucleotide polymorphisms that may be involved in gene-environment or gene-treatment interaction. The asymptotic independence of the marginal association estimator and various interaction estimators leads to a simple and flexible way of combining the 2 tests, allowing for exploitation of gene-environment independence in estimating gene-environment interaction. The proposed test differs from the 2-df test proposed by Kraft et al. (Hum Hered. 2007;63(2):111-119) in two respects. First, for the genetic association component, it tests for marginal association, which is often the primary objective in inference, rather than the main effect in a model with gene-environment interaction. Second, the gene-environment testing component can easily exploit putative gene-environment independence using either the case-only estimator or the empirical Bayes estimator, depending on whether the goal is gene-treatment interaction in a randomized trial or gene-environment interaction in an observational study. The use of the proposed joint test is illustrated through simulations and a genetic study (1993-2005) from the Women's Health Initiative.
American journal of epidemiology 07/2012; 176(2):164-73. · 5.59 Impact Factor
