Abstract
Background: Prolongation of the electrocardiographic QT interval is a risk factor for sudden cardiac death (SCD) in unselected samples as well as in post-myocardial infarction patients or those with diabetes. Common genetic variants in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene have been reported to be associated with QT interval duration in individuals of European ancestry. We sought to replicate the association of NOS1AP variants with QT interval duration in pedigrees enriched for type 2 diabetes mellitus (T2DM). Methods and Results: Two single nucleotide polymorphisms (SNPs) in the NOS1AP gene, rs10494366 and rs10918594, were genotyped in a collection of 937 European Americans (EAs) and 177 African Americans (AAs) in 450 pedigrees containing at least two siblings with T2DM. An additive genetic model was tested for each SNP in ancestry-specific analyses using SOLAR in the total sample and in the diabetic subset (EA n=778, AA n=159), with and without exclusion of QT-altering medications. In the EA individuals, rs10494366 minor allele homozygotes had an 8.9 msec longer mean QT interval compared to major homozygotes (additive model p=4.4x10 -3 ); rs10918594 minor homozygotes had a 12.9 msec longer mean QT interval compared to major homozygotes (p=9.9x10 -5 ). Excluding users of QT-altering medications in the diabetic-only EA sample (n=514) strengthened the association despite the reduction in sample size (20.6 msec difference, p=2.0x10 -5 ; 23.4 msec difference, p=8.9x10 -7 , respectively). No association between the NOS1AP SNPs and QT interval duration was observed in the limited number of AA individuals examined. Conclusions: Two NOS1AP SNPs are strongly associated with QT interval duration in a predominately diabetic EA sample. Stronger effects of NOS1AP variants in diabetic individuals compared to previously reported unselected samples suggest that this patient subset may be particularly susceptible to genetic variants that influence myocardial depolarization and repolarization as manifest in the QT interval.
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