TY - JOUR T1 - Impact of ancestry and common genetic variants on QT interval in African Americans. JF - Circ Cardiovasc Genet Y1 - 2012 A1 - Smith, J Gustav A1 - Avery, Christy L A1 - Evans, Daniel S A1 - Nalls, Michael A A1 - Meng, Yan A A1 - Smith, Erin N A1 - Palmer, Cameron A1 - Tanaka, Toshiko A1 - Mehra, Reena A1 - Butler, Anne M A1 - Young, Taylor A1 - Buxbaum, Sarah G A1 - Kerr, Kathleen F A1 - Berenson, Gerald S A1 - Schnabel, Renate B A1 - Li, Guo A1 - Ellinor, Patrick T A1 - Magnani, Jared W A1 - Chen, Wei A1 - Bis, Joshua C A1 - Curb, J David A1 - Hsueh, Wen-Chi A1 - Rotter, Jerome I A1 - Liu, Yongmei A1 - Newman, Anne B A1 - Limacher, Marian C A1 - North, Kari E A1 - Reiner, Alexander P A1 - Quibrera, P Miguel A1 - Schork, Nicholas J A1 - Singleton, Andrew B A1 - Psaty, Bruce M A1 - Soliman, Elsayed Z A1 - Solomon, Allen J A1 - Srinivasan, Sathanur R A1 - Alonso, Alvaro A1 - Wallace, Robert A1 - Redline, Susan A1 - Zhang, Zhu-Ming A1 - Post, Wendy S A1 - Zonderman, Alan B A1 - Taylor, Herman A A1 - Murray, Sarah S A1 - Ferrucci, Luigi A1 - Arking, Dan E A1 - Evans, Michele K A1 - Fox, Ervin R A1 - Sotoodehnia, Nona A1 - Heckbert, Susan R A1 - Whitsel, Eric A A1 - Newton-Cheh, Christopher KW - Adult KW - African Americans KW - Aged KW - Electrocardiography KW - European Continental Ancestry Group KW - Female KW - Genealogy and Heraldry KW - Genetic Variation KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.

METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN.

CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.

VL - 5 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23166209?dopt=Abstract ER - TY - JOUR T1 - Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts. JF - Circ Cardiovasc Genet Y1 - 2012 A1 - Butler, Anne M A1 - Yin, Xiaoyan A1 - Evans, Daniel S A1 - Nalls, Michael A A1 - Smith, Erin N A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Buxbaum, Sarah G A1 - Whitsel, Eric A A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Benjamin, Emelia J A1 - Berenson, Gerald S A1 - Bis, Josh C A1 - Chen, Wei A1 - Deo, Rajat A1 - Ellinor, Patrick T A1 - Heckbert, Susan R A1 - Heiss, Gerardo A1 - Hsueh, Wen-Chi A1 - Keating, Brendan J A1 - Kerr, Kathleen F A1 - Li, Yun A1 - Limacher, Marian C A1 - Liu, Yongmei A1 - Lubitz, Steven A A1 - Marciante, Kristin D A1 - Mehra, Reena A1 - Meng, Yan A A1 - Newman, Anne B A1 - Newton-Cheh, Christopher A1 - North, Kari E A1 - Palmer, Cameron D A1 - Psaty, Bruce M A1 - Quibrera, P Miguel A1 - Redline, Susan A1 - Reiner, Alex P A1 - Rotter, Jerome I A1 - Schnabel, Renate B A1 - Schork, Nicholas J A1 - Singleton, Andrew B A1 - Smith, J Gustav A1 - Soliman, Elsayed Z A1 - Srinivasan, Sathanur R A1 - Zhang, Zhu-Ming A1 - Zonderman, Alan B A1 - Ferrucci, Luigi A1 - Murray, Sarah S A1 - Evans, Michele K A1 - Sotoodehnia, Nona A1 - Magnani, Jared W A1 - Avery, Christy L KW - Adult KW - African Americans KW - Cohort Studies KW - Electrocardiography KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.

METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)).

CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.

VL - 5 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23139255?dopt=Abstract ER - TY - JOUR T1 - Genetic risk factors for BMI and obesity in an ethnically diverse population: results from the population architecture using genomics and epidemiology (PAGE) study. JF - Obesity (Silver Spring) Y1 - 2013 A1 - Fesinmeyer, Megan D A1 - North, Kari E A1 - Ritchie, Marylyn D A1 - Lim, Unhee A1 - Franceschini, Nora A1 - Wilkens, Lynne R A1 - Gross, Myron D A1 - Bůzková, Petra A1 - Glenn, Kimberly A1 - Quibrera, P Miguel A1 - Fernandez-Rhodes, Lindsay A1 - Li, Qiong A1 - Fowke, Jay H A1 - Li, Rongling A1 - Carlson, Christopher S A1 - Prentice, Ross L A1 - Kuller, Lewis H A1 - Manson, JoAnn E A1 - Matise, Tara C A1 - Cole, Shelley A A1 - Chen, Christina T L A1 - Howard, Barbara V A1 - Kolonel, Laurence N A1 - Henderson, Brian E A1 - Monroe, Kristine R A1 - Crawford, Dana C A1 - Hindorff, Lucia A A1 - Buyske, Steven A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Peters, Ulrike KW - Alleles KW - Body Mass Index KW - Ethnic Groups KW - Gene Frequency KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Metagenomics KW - Obesity KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

OBJECTIVE: Several genome-wide association studies (GWAS) have demonstrated that common genetic variants contribute to obesity. However, studies of this complex trait have focused on ancestrally European populations, despite the high prevalence of obesity in some minority groups.

DESIGN AND METHODS: As part of the "Population Architecture using Genomics and Epidemiology (PAGE)" Consortium, we investigated the association between 13 GWAS-identified single-nucleotide polymorphisms (SNPs) and BMI and obesity in 69,775 subjects, including 6,149 American Indians, 15,415 African-Americans, 2,438 East Asians, 7,346 Hispanics, 604 Pacific Islanders, and 37,823 European Americans. For the BMI-increasing allele of each SNP, we calculated β coefficients using linear regression (for BMI) and risk estimates using logistic regression (for obesity defined as BMI ≥ 30) followed by fixed-effects meta-analysis to combine results across PAGE sites. Analyses stratified by racial/ethnic group assumed an additive genetic model and were adjusted for age, sex, and current smoking. We defined "replicating SNPs" (in European Americans) and "generalizing SNPs" (in other racial/ethnic groups) as those associated with an allele frequency-specific increase in BMI.

RESULTS: By this definition, we replicated 9/13 SNP associations (5 out of 8 loci) in European Americans. We also generalized 8/13 SNP associations (5/8 loci) in East Asians, 7/13 (5/8 loci) in African Americans, 6/13 (4/8 loci) in Hispanics, 5/8 in Pacific Islanders (5/8 loci), and 5/9 (4/8 loci) in American Indians.

CONCLUSION: Linkage disequilibrium patterns suggest that tagSNPs selected for European Americans may not adequately tag causal variants in other ancestry groups. Accordingly, fine-mapping in large samples is needed to comprehensively explore these loci in diverse populations.

VL - 21 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23712987?dopt=Abstract ER - TY - JOUR T1 - Investigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study. JF - BMC Genet Y1 - 2013 A1 - Taylor, Kira C A1 - Carty, Cara L A1 - Dumitrescu, Logan A1 - Bůzková, Petra A1 - Cole, Shelley A A1 - Hindorff, Lucia A1 - Schumacher, Fred R A1 - Wilkens, Lynne R A1 - Shohet, Ralph V A1 - Quibrera, P Miguel A1 - Johnson, Karen C A1 - Henderson, Brian E A1 - Haessler, Jeff A1 - Franceschini, Nora A1 - Eaton, Charles B A1 - Duggan, David J A1 - Cochran, Barbara A1 - Cheng, Iona A1 - Carlson, Chris S A1 - Brown-Gentry, Kristin A1 - Anderson, Garnet A1 - Ambite, Jose Luis A1 - Haiman, Christopher A1 - Le Marchand, Loïc A1 - Kooperberg, Charles A1 - Crawford, Dana C A1 - Buyske, Steven A1 - North, Kari E A1 - Fornage, Myriam KW - Female KW - Genetic Heterogeneity KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Lipids KW - Male KW - Polymorphism, Single Nucleotide KW - Population Groups AB -

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 (p(het) = 7.4 x 10(-7)) and rs3135506 (p(het) = 4.3 x 10(-4)one SNP in PLTP for HDL levels (rs7679; p(het) = 9.9 x 10(-4)), and one in HMGCR for LDL levels (rs12654264; p(het) = 3.1 x 10(-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.

VL - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23634756?dopt=Abstract ER - TY - JOUR T1 - Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. JF - PLoS One Y1 - 2015 A1 - Bis, Joshua C A1 - Sitlani, Colleen A1 - Irvin, Ryan A1 - Avery, Christy L A1 - Smith, Albert Vernon A1 - Sun, Fangui A1 - Evans, Daniel S A1 - Musani, Solomon K A1 - Li, Xiaohui A1 - Trompet, Stella A1 - Krijthe, Bouwe P A1 - Harris, Tamara B A1 - Quibrera, P Miguel A1 - Brody, Jennifer A A1 - Demissie, Serkalem A1 - Davis, Barry R A1 - Wiggins, Kerri L A1 - Tranah, Gregory J A1 - Lange, Leslie A A1 - Sotoodehnia, Nona A1 - Stott, David J A1 - Franco, Oscar H A1 - Launer, Lenore J A1 - Stürmer, Til A1 - Taylor, Kent D A1 - Cupples, L Adrienne A1 - Eckfeldt, John H A1 - Smith, Nicholas L A1 - Liu, Yongmei A1 - Wilson, James G A1 - Heckbert, Susan R A1 - Buckley, Brendan M A1 - Ikram, M Arfan A1 - Boerwinkle, Eric A1 - Chen, Yii-Der Ida A1 - de Craen, Anton J M A1 - Uitterlinden, André G A1 - Rotter, Jerome I A1 - Ford, Ian A1 - Hofman, Albert A1 - Sattar, Naveed A1 - Slagboom, P Eline A1 - Westendorp, Rudi G J A1 - Gudnason, Vilmundur A1 - Vasan, Ramachandran S A1 - Lumley, Thomas A1 - Cummings, Steven R A1 - Taylor, Herman A A1 - Post, Wendy A1 - Jukema, J Wouter A1 - Stricker, Bruno H A1 - Whitsel, Eric A A1 - Psaty, Bruce M A1 - Arnett, Donna KW - African Americans KW - Aged KW - Antihypertensive Agents KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Incidence KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Treatment Outcome AB -

BACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.

METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).

RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

VL - 10 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26516778?dopt=Abstract ER -