Abstract 4411: Associations Between Genetic Variations in NOS1AP and QT Interval Duration in Four Racial/Ethnic Groups in the Multi-Ethnic Study of Atherosclerosis (MESA)
QT interval is an independent risk factor for sudden cardiac death (SCD). A genome wide association study identified NOS1AP variants associated with QT, which has been replicated in predominantly Caucasian populations. MESA provides an unprecedented opportunity to study single nucleotide polymorphisms (SNP)-trait associations in an ethnically diverse cohort. Twenty-eight tagging SNPs, starting in the first intron and spanning the entire gene, were genotyped using the Illumina GoldenGate assay in 2880 men and women, age 45–84 years, without known CVD in MESA, including equal numbers of Caucasians (CAU), African-Americans (AFA), Hispanics (HIS) and Chinese (CHN) US subjects. Those with QRS> 120msec or on QT altering medications were excluded (n=174). QT was determined using Marquette 12SL. Associations between QT interval and genotypes were evaluated using multiple linear regression, adjusted for heart rate, age, gender, and study center, stratified by racial/ethnic group, using an additive model of inheritance. The distribution of 2 SNPs in HIS deviated from Hardy-Weinberg equlibrium (HWE; p<0.002), likely due to population admixture. These 2 SNPs were not associated with QT variation. Of SNPs in HWE, associations between genotype and QT interval were more significant in CAU (10 SNPs, p values= 1.1× 10E-6 - 0.03) than in HIS (4 SNPs, p= 0.003 – 0.04) or CHN (5 SNPs, p= 0.007 – 0.04). No statistically significant associations were seen in AFA. In CAU, each additional copy of the minor allele in rs1572495 was associated with a 1.5% increase in QT (p= 0.03). The minor alleles of 3 SNPs were associated with longer QT in both CAU (p= 7.4E-5- 0.02) and HIS (p= 0.003– 0.02). The preponderance of significant CAU and HIS SNPs were at the 5′ end of NOS1AP (some within similar LD blocks), while significant associations in CHN were only at the 3′ end. NOS1AP variants are associated with QT interval in CAU, HIS, and CHN. Location of significant SNPs varies across racial/ethnic groups. We have identified possible novel variants at the 3′ end of NOS1AP associated with QT in CHN only. Further genotyping within these regions should be pursued to determine functional genetic variants affecting QT interval and the potential risk for SCD.