A common NOS1AP genetic polymorphism is associated with increased cardiovascular mortality in users of dihydropyridine calcium channel blockers.
OBJECTIVE
Recently, a polymorphism in the NOS1AP gene (rs10494366), a regulator of neuronal nitric oxide synthase (nNOS), was associated with QTc prolongation. Both nNOS and calcium channel blockers (CCBs) regulate intracellular calcium levels and have an important role in cardiovascular homeostasis. The aim was to investigate whether this polymorphism is associated with cardiovascular mortality in users of CCBs.


METHODS
The data from the Rotterdam study, a population-based closed cohort study of Caucasian individuals of > or =55 years of age, were used. We identified 1113 participants in the Rotterdam Study who were prescribed CCBs for the first time between 1991 and 2005. All-cause and cardiovascular mortality was assessed in participants who were prescribed CCBs with different NOS1AP rs10494366 genotypes using Cox proportional hazard models.


RESULTS
In participants starting on dihydropyridine CCBs (amlodipine, nifedipine and others) all-cause mortality (n = 79) risks were higher in participants with the TG [hazard ratio (HR) 2.57, 95% confidence interval (CI) 1.24, 5.34] or the GG genotype (HR 3.18, 95% CI 1.18, 8.58) than in participants with the referent TT genotype. Cardiovascular mortality (n = 54) risks were 3.51 (95% CI 1.41, 8.78) for the TG genotype and 6.00 (95% CI 1.80, 20.0) for the GG genotype. No differences in all-cause mortality or cardiovascular mortality were seen in participants starting with the nondihydropyridine CCBs verapamil or diltiazem.


CONCLUSIONS
The minor G allele of rs10494366 in the NOS1AP gene is associated with increased all-cause and cardiovascular mortality in Caucasian users of dihydropyridine CCBs. The mechanism underlying the observed association is unknown.
Becker
Matthijs L
ML
Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, The Netherlands.
Visser
Loes E
LE
Newton-Cheh
Christopher
C
Hofman
Albert
A
Uitterlinden
André G
AG
Witteman
Jacqueline C M
JC
Stricker
Bruno H Ch
BH
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D015331:Cohort Studies; D004095:Dihydropyridines / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models
D048868:Adaptor Proteins, Signal Transducing; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C488081:NOS1AP protein, human