Common NOS1AP variants are associated with a prolonged QTc interval in the Rotterdam Study.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Aarnoudse
Albert-Jan L H J
AJ
Department of Epidemiology and Biostatistics, Erasmus Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
Newton-Cheh
Christopher
C
de Bakker
Paul I W
PI
Straus
Sabine M J M
SM
Kors
Jan A
JA
Hofman
Albert
A
Uitterlinden
André G
AG
Witteman
Jacqueline C M
JC
Stricker
Bruno H C
BH
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002317:Cardiovascular Agents / Q000494:pharmacology / Q000627:therapeutic use; D015331:Cohort Studies; D016757:Death, Sudden, Cardiac / Q000453:epidemiology; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D013383:Suburban Population
D048868:Adaptor Proteins, Signal Transducing; D002317:Cardiovascular Agents; C488081:NOS1AP protein, human