Associations between Genetic Variants in the NOS1AP (CAPON) Gene and Cardiac Repolarization in the Old Order Amish

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Abstract
Background: Through a genome-wide association study, we discovered an association of the electrocardiographic QT interval with polymorphisms in the NOS1AP (CAPON) gene. The purpose of the current study was to replicate this association in the Old Order Amish. Methods: Four NOS1AP SNPs were selected that captured all major haplotypes in the region of interest (∼120 kb segment). Genotyping was completed in 763 subjects from the Heredity and Phenotype Intervention (HAPI) Heart Study. Association analyses were performed using a variance components methodology, accounting for relatedness of individuals. Results: Heritability of the QT interval was 0.50 ± 0.09 (p = 1.9 × 10–9). All four SNPs were common with a high degree of correlation between SNPs. Two of the four SNPs (pairwise r2 = 0.86) were significantly associated with variation in adjusted QT interval (rs1415262, p = 0.02 and rs10494366, p = 0.006, additive models for both). SNP rs10494366 explained 0.9% of QT interval variability, with an average genetic effect of 6.1 ms. Haplotypes that contained the minor allele for rs10494366 were associated with longer QT interval. Conclusions: This study provides further evidence that NOS1AP variants influence QT interval and further validates the utility of genome-wide association studies, a relatively new approach to gene discovery.