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Impact of ancestry and common genetic variants on QT interval in African Americans.

ABSTRACT: 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.

SUBMITTER: Smith JG

PROVIDER: S-EPMC3568265 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Impact of ancestry and common genetic variants on QT interval in African Americans.

Smith J Gustav JG Avery Christy L CL Evans Daniel S DS Nalls Michael A MA Meng Yan A YA Smith Erin N EN Palmer Cameron C Tanaka Toshiko T Mehra Reena R Butler Anne M AM Young Taylor T Buxbaum Sarah G SG Kerr Kathleen F KF Berenson Gerald S GS Schnabel Renate B RB Li Guo G Ellinor Patrick T PT Magnani Jared W JW Chen Wei W Bis Joshua C JC Curb J David JD Hsueh Wen-Chi WC Rotter Jerome I JI Liu Yongmei Y Newman Anne B AB Limacher Marian C MC North Kari E KE Reiner Alexander P AP Quibrera P Miguel PM Schork Nicholas J NJ Singleton Andrew B AB Psaty Bruce M BM Soliman Elsayed Z EZ Solomon Allen J AJ Srinivasan Sathanur R SR Alonso Alvaro A Wallace Robert R Redline Susan S Zhang Zhu-Ming ZM Post Wendy S WS Zonderman Alan B AB Taylor Herman A HA Murray Sarah S SS Ferrucci Luigi L Arking Dan E DE Evans Michele K MK Fox Ervin R ER Sotoodehnia Nona N Heckbert Susan R SR Whitsel Eric A EA Newton-Cheh Christopher C

Circulation. Cardiovascular genetics 20121119 6

<h4>Background</h4>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.<h4>Methods and results</ ...[more]

PMID: 23166209

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Project description: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.

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Impact of ancestry and common genetic variants on QT interval in African Americans.

Publications

Impact of ancestry and common genetic variants on QT interval in African Americans.

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