Abstract P357: Genome-Wide Association Study of the PR Interval in Hispanic Populations

Abstract

BACKGROUND: The PR interval (PR) is an electrocardiographic measure of atrial and atrioventricular nodal conduction. PR prolongation has been associated with atrial fibrillation, pacemaker implantation, heart failure, and all-cause mortality. Although Hispanic/Latino (HL) populations have high burdens of cardiovascular morbidity and mortality, they remain a chronically understudied population, with previous genome-wide association studies of PR limited to European (EU), African (AA), and Asian (AS) descent populations. METHODS: We included 13,507 participants of HL ancestry from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and Women’s Health Initiative clinical trials (WHI). PR was automatically measured from digital electrocardiogram tracings recorded using standardized methods in all participants. Genotype data were imputed to the 1000 Genomes Phase 1 reference panel, and associations were examined using linear regression assuming an additive genetic model and adjusting for global ancestry, study center or region, clinical covariates (age, sex, heart rate, height, body mass index, systolic blood pressure, beta blocker use), and study weights (HCHS/SOL only). Study-specific results were combined using a fixed-effects, inverse variance weighted meta-analysis. Linkage disequilibrium (LD) patterns were examined using LocusZoom, and r2 values were calculated using 1000 Genomes reference populations. RESULTS: We identified six loci associated with PR in HL populations at genome-wide significant levels: SLC8A1, SCN5A, SCN10A, ARHGAP24, CAV1/CAV2, and SOX5. At these loci, index SNPs had important effects (β range: 2-4 ms) and common minor allele frequencies (MAF range: 13-40%). Of note, five of the six identified loci were previously associated with PR in EU populations, and four in AA populations; however, the association with SLC8A1 has been found only in AS populations. Whereas the SLC8A1 index SNP, rs17026148, is common in AS (MAF = 50%), AA (MAF = 15%), and HL populations (MAF = 17%), it is rare in EU populations (MAF < 5%). Interestingly, SLC8A1 LD patterns are similar across AS, EU, and HL populations in this region. CONCLUSIONS: Our results suggest that genetic determinants of PR are consistent across race/ethnicity but that previous studies in EU populations were either underpowered to detect the SLC8A1 locus or that it resides on an Asian/American Indian haplotype, thus underscoring the importance of conducting genetic studies in diverse populations.