Common NOS1AP variants are associated with a prolonged QTc interval in the rotterdam study

• Published in: Circulation (New York, N.Y.) Vol. 116; no. 1; pp. 10 - 16
• Main Authors: AARNOUDSE, Albert-Jan L. H. J, NEWTON-CHEH, Christopher, DE BAKKER, Paul I. W, STRAUS, Sabine M. J. M, KORS, Jan A, HOFMAN, Albert, UITTERLINDEN, André G, WITTEMAN, Jacqueline C. M, STRICKER, Bruno H. C
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 03-07-2007
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Aged; Aged, 80 and over; Alleles; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular Agents - pharmacology; Cardiovascular Agents - therapeutic use; Cardiovascular system; Cohort Studies; Death, Sudden, Cardiac - epidemiology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Electrocardiography - drug effects; Female; Follow-Up Studies; General and cellular metabolism. Vitamins; Genotype; Haplotypes - genetics; Humans; Long QT Syndrome - genetics; Male; Medical sciences; Middle Aged; Netherlands - epidemiology; Pharmacology. Drug treatments; Phenotype; Polymorphism, Single Nucleotide; Proportional Hazards Models; Prospective Studies; Risk Factors; Suburban Population; Vasodilator agents. Cerebral vasodilators; Netherlands; Cardiocirculatory arrest; genetics; Arrhythmia; Heart block; Heart disease; Sudden death; Prolonged QT interval; Electrocardiography; Cardiovascular disease; death, sudden; Conduction disorder; long-QT syndrome
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.106.676783

QT prolongation is an important risk factor for sudden cardiac death. About 35% of QT-interval variation is heritable. In a recent genome-wide association study, a common variant (rs10494366) in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene was found to be associated with QT-interval variation. We tested for association of 2 NOS1AP variants with QT duration and sudden cardiac death.
The Rotterdam Study is a population-based, prospective cohort study of individuals > or = 55 years of age. The NOS1AP variants rs10494366 T>G and rs10918594 C>G were genotyped in 6571 individuals. Heart rate-corrected QT interval (QTc) was determined with ECG analysis software on up to 3 digital ECGs per individual (total, 11,108 ECGs from 5374 individuals). The association with QTc duration was estimated with repeated-measures analyses, and the association with sudden cardiac death was estimated by Cox proportional-hazards analyses. The rs10494366 G allele (36% frequency) was associated with a 3.8-ms (95% confidence interval, 3.0 to 4.6; P=7.8x10(-20)) increase in QTc interval duration for each additional allele copy, and the rs10918594 G allele (31% frequency) was associated with a 3.6-ms (95% confidence interval, 2.7 to 4.4; P=6.9x10(-17)) increase per additional allele copy. None of the inferred NOS1AP haplotypes showed a stronger effect than the individual single-nucleotide polymorphisms. There were 233 sudden cardiac deaths over 11.9 median years of follow-up. No significant association was observed with sudden cardiac death risk.
Common variants in NOS1AP are strongly associated with QT-interval duration in an elderly population. Larger sample sizes are needed to confirm or exclude an effect on sudden cardiac death risk.