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.
Highlights
The QT interval (QT), as measured by the resting 12-lead electrocardiogram (ECG), reflects the duration of ventricular depolarization and repolarization, providing a non-invasive assessment of an average ventricular action potential
For loci associated with QT in African Americans, we investigated whether patterns of linkage disequilibrium (LD) within African Americans could narrow the regions likely to harbor the biologically relevant variant
60% of participants are directly genotyped on the Metabochip; the remaining 40% have genotypes imputed from the Affymetrix 6.0 panel (Methods)
Summary
The QT interval (QT), as measured by the resting 12-lead electrocardiogram (ECG), reflects the duration of ventricular depolarization and repolarization, providing a non-invasive assessment of an average ventricular action potential. Numerous factors influencing QT have been identified, including heart rate [4], structural heart disease [5,6], gender [7,8], age [9], and medication use [10,11,12], a large portion of the variance in QT remains unexplained. Initial evidence was provided by studies of inherited cardiac arrhythmias including long- and short-QT syndromes, which identified rare and highly penetrant mutations in ion channel and ion channel associated genes associated with QT [13]. Studies have reported that ventricular repolarization (as measured by QT) is heritable [14,15,16,17]. Recent genome-wide association (GWA) studies performed in populations of predominantly European descent have identified common SNPs in twelve loci, including NOS1AP, KCNH2, and PLN [18,19,20,21,22,23], that influence the distribution of QT
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