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Association of NOS1AP genetic variants with QT interval duration in families from the Diabetes Heart Study

Allison B. Lehtinen, Ph.D.^,,, Christopher Newton-Cheh, M.D., M.P.H.^,,||, Julie T. Ziegler, M.A.^#, Carl D. Langefeld, Ph.D.^#, Barry I. Freedman, M.D.^**, Kurt R. Daniel, D.O.^**, David M. Herrington, M.D., M.H.S.^**, and Donald W. Bowden, Ph.D.^,,,,**

Department of Biochemistry
Center for Human Genomics
Public Health Sciences^#
Internal Medicine**, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts
and Program in Medical and Population Genetics^||, Broad Institute of Harvard and MIT, Cambridge Massachusetts

Objective: Prolongation of the electrocardiographic QT interval is a risk factor for sudden cardiac death (SCD). Diabetic individuals are at increased risk for prolonged QT interval and SCD. We sought to replicate the finding that genetic variants in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene are associated with QT interval duration in a type 2 diabetes enriched sample of European ancestry.

Research Design and Methods: Two single nucleotide polymorphisms (SNPs) in NOS1AP were genotyped in 624 European Americans (EAs) and 127 African Americans (AAs) from 400 pedigrees enriched for type 2 diabetes. An additive genetic model was tested for each SNP in ancestry-specific analyses in the total sample and the diabetic subset (EA n=514, AA n=115), excluding from the analyses individuals taking QT-altering medications.

Results: In EAs, rs10494366 minor homozygotes had a 9.3 msec longer QT interval compared to major homozygotes (p=5.7x10^–5); rs10918594 minor homozygotes had a 12.5 msec longer QT interval compared to major homozygotes (p=1.5x10^–6). Restricting analyses to the diabetic EAs strengthened the effect despite the reduction in sample size (11.3 msec difference, p=5.1x10^–5; 13.9 msec difference, p=1.6x10^–6, respectively). No association between the NOS1AP SNPs and QT interval duration was observed in the limited number of AAs.

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 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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