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Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study

¹ Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
² Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
³ Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts
⁴ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
⁵ Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
⁶ Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Address correspondence and reprint requests to Donald W. Bowden, PhD, Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail: dbowden{at}wfubmc.edu

Abbreviations: ECG, electrocardiogram; NOS1AP, nitric oxide synthase 1 adaptor protein; QTc, corrected QT interval; SCD, sudden cardiac death; SNP, single nucleotide polymorphism

OBJECTIVES—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 and 127 African Americans 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 (European Americans, n = 514; African Americans, n = 115), excluding from the analyses individuals taking QT-altering medications.

RESULTS—In European Americans, rs10494366 minor homozygotes had a 9.3-ms-longer QT interval compared with major homozygotes (P = 5.7 x 10^–5); rs10918594 minor homozygotes had a 12.5-ms-longer QT interval compared with major homozygotes (P = 1.5 x 10^–6). Restricting analyses to the diabetic European Americans strengthened the effect despite the reduction in sample size (11.3-ms difference, P = 5.1 x 10^–5; 13.9-ms difference, P = 1.6 x 10^–6, respectively). No association between the NOS1AP SNPs and QT interval duration was observed in the limited number of African Americans.

CONCLUSIONS—Two NOS1AP SNPs are strongly associated with QT interval duration in a predominately diabetic European-American 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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