Generalization and Fine Mapping of PR Interval Loci in Hispanics: The Population Architecture Using Genomics and Epidemiology (PAGE) Study.

PR interval (PR) prolongation is a predictor of atrial fibrillation, a common cardiac arrhythmia, and is an established risk factor for pacemaker implantation, heart failure, stroke, and all-cause mortality. Previous genome-wide association studies in European (EU) and African (AA) descent populations have identified multiple loci associated with PR. However, it is unclear whether these loci are relevant in other racial groups, including Hispanic/Latinos (HL). Extending studies to include admixed populations such as HL also provides the potential to narrow regions associated with PR and identify population specific variants. Therefore, we evaluated 1,135 SNPs from four previously identified PR loci (SCN5A, SCN10A, CAV1-CAV2, and TBX5-TBX3), fine-mapped on the Illumina Metabochip for association with PR. Associations were examined using linear regression assuming an additive genetic model and adjusting for global ancestry and clinical covariates (age, sex, RR interval, body mass index, height, systolic blood pressure) in 11,800 HL participants from participating studies of the Population Architecture using Genomics and Epidemiology (PAGE) consortia. Three of the four loci (SCN5A, SCN10A, and CAV1-CAV2) generalized to HL populations (P<7.1E-4 based on the number of SNPs correlated at r²>0.2 with EU-identified index SNPs). At each of these loci, we identified SNPs with stronger evidence of association with PR than the EU-identified index SNP when examined in the HL population (SCN5A: rs7374540; SCN10A: rs6801957; CAV-CAV2: rs717957). Conditional analyses also identified two additional independent SNPs at each of the three generalized loci (SCN5A: rs3796387, rs9861242; SCN10A: rs10428132, rs7433723; CAV1-CAV2: rs3801995, rs3807994), representing potential secondary signals. Furthermore, linkage disequilibrium (LD) patterns in Hispanics enabled the narrowing of the regions flanking the EU-identified index SNPs. For example, at the CAV1-CAV2 locus, HL LD patterns indicated that seven SNPs were in LD with rs3807989, the EU-identified index SNP, compared to 17 SNPs that were in LD with rs3807989 when applying EU LD patterns, reducing the size of the region by 71 kilobases. Finally, we examined evidence for population specific signals outside of the specific regions identified in EU populations which were associated with PR in Hispanics by focusing on SNPs uncorrelated with the EU index signals. At all four loci, multiple SNPs had evidence of association independent of the signals examined based on EU results. In conclusion, the same genetic loci that influence PR in European descent populations are also important in Hispanic populations, although we detected evidence for population specific SNPs. These results emphasize the importance of examining genetic associations in diverse populations in order to narrow the genomic interval for future functional interrogation. [ABSTRACT FROM AUTHOR]