Abstract 4401: Two Independent Genetic Variants in NOS1AP are Associated with QT interval in a Multi-Ethnic Population: the Dallas Heart Study
Extremes of QT interval are associated with increased risk for sudden cardiac death (SCD), and thus identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous work revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We thus sought to characterize the effects of NOS1AP genetic variants in the multi-ethnic population-based Dallas Heart Study (DHS). Among 3,557 participants in DHS with available DNA, those without QT interval, heart rate, age, and/or sex information, and those with QRS >120 or undetermined ethnicity were excluded, resulting in 2,949 samples available for analysis (501 Hispanic, 1,506 Black, 942 White). Sex- and ethnicity-stratified linear regression was used to correct QT interval for heart rate and age. Eight SNPs spanning the region previously associated with QT interval were genotyped, and ethnic-specific analyses were performed under an additive genetic model. The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in the White participants (+2.6 ms, P<0.005) as well as in Blacks (+3.2 ms, P<3.6 × 10 –5), with the same direction of effect in Hispanics (+1.5 ms, P<0.17). A second SNP, rs16856785, which was uncorrelated with rs16847548 (r2 < 0.01 in Blacks) was also associated with QT interval in Blacks (+1.6 ms, P<0.01), with qualitatively similar results in Whites (+0.9 ms, P<0.33) and Hispanics (+0.6 ms, P<0.66). Adjusting for local and global ancestry using Ancestry Informative Markers did not significantly alter the results. Comparing Blacks homozygous at both SNPs for the QT lengthening allele to Blacks homozygous for the complementary alleles revealed a 13.9 ms difference in QT interval. These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends in Hispanics. Further, a second, independent site within NOS1AP has been implicated in modulating QT interval, highlighting the importance of NOS1AP genetic variants in regulating QT interval.