Calcium channel blockers, NOS1AP, and heart-rate-corrected QT prolongation.
OBJECTIVE
To study whether NOS1AP single nucleotide polymorphisms (SNPs), rs10494366 T>G and rs10918594 C>G, modify the heart-rate-corrected QT (QTc) prolonging effect of calcium channel blockers.


BACKGROUND
Common variation in the NOS1AP gene has been associated with QT interval variation in several large population samples. NOS1 is presumed to influence intracellular calcium.


METHODS
The prospective population-based Rotterdam Study includes 16 603 ECGs from 7565 participants (>or=55 years), after exclusion of patients with left ventricular hypertrophy, left and right bundle branch block, as well as carriers of pacemakers. The endpoint was the length of the QTc interval in calcium channel blocker users and non-users with the minor alleles compared with the major alleles (wild type). We used a repeated-measurement analysis, adjusted for all known confounders.


RESULTS
Use of verapamil was associated with a significant QTc interval prolongation [6.0 ms 95% confidence interval (CI) 1.7; 10.2] compared with non-users. Furthermore, users of verapamil with the rs10494366 GG genotype showed significantly more QTc prolongation than users with the TT genotype [25.4 ms (95% CI: 5.9-44.9)] (P value for multiplicative interaction 0.0038). Users of isradipine with the GG genotype showed more QTc prolongation than users with the TT genotype [19.8 ms (95% CI: 1.9-37.7)]; however, SNP rs10494366 did not modify the effect on QTc interval on a multiplicative scale (P=0.3563). SNP rs10918594 showed similar results.


CONCLUSIONS
In conclusion, we showed that the minor alleles of both NOS1AP SNPs significantly potentiate the QTc prolonging effect of verapamil.
van Noord
Charlotte
C
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Aarnoudse
Albert-Jan L H J
AJ
Eijgelsheim
Mark
M
Sturkenboom
Miriam C J M
MC
Straus
Sabine M J M
SM
Hofman
Albert
A
Kors
Jan A
JA
Newton-Cheh
Christopher
C
Witteman
Jacqueline C M
JC
Stricker
Bruno H Ch
BH
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000483:Alleles; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015331:Cohort Studies; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D013383:Suburban Population; D014700:Verapamil / Q000494:pharmacology*
D048868:Adaptor Proteins, Signal Transducing; D002121:Calcium Channel Blockers; C488081:NOS1AP protein, human; D014700:Verapamil