NOS1AP Polymorphisms Modify QTc Interval Duration But Not Cardiac Arrest Risk in Hypertrophic Cardiomyopathy.
BACKGROUND
The accurate prediction of the risk of sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) remains elusive. Corrected QT interval (QTc) duration is a known risk factor in various cardiac conditions. Single nucleotide polymorphisms (SNPs) have been linked to QTc length, and to SCD. Here we investigated the role of 21 candidate SNPs in QTc duration and SCD events in patients with HCM.


RESULTS
This HCM registry-based study included patients with an ECG, medical history, first SCD event data, and DNA available. Each individual SNP was assessed using logistic regression for associations with 2 outcomes: a prolonged QTc ( ≥440 milliseconds), and first SCD event (SCD, resuscitated cardiac arrest, and appropriate implantable cardioverter defibrillator (ICD) shock for ventricular fibrillation/ventricular tachycardia (VF/VT). In 272 HCM patients, there were 31 SCD events (8 SCD, 9 resuscitated cardiac arrest, 14 ICD shocks for VF/VT; 11%). A QTc ≥ 500 milliseconds was associated with SCD events on multivariate analysis (odds ratio [OR] = 4.0, 95% confidence interval [CI], 1.19-12.02, P = 0.016). In 228 Caucasian patients, 2 SNPs in the NOS1AP gene (rs10494366 and rs12143842) were associated with a prolonged QTc after correction for multiple testing. This remained significant after adjustment for current age, sex, and ≥1 SCD risk factor (OR 1.59 per copy of the minor allele, 95% CI 1.08-2.39, P = 0.022, and OR 1.63, 95% CI 1.09-2.49, P = 0.020, respectively). No SNPs were directly associated with SCD events.


CONCLUSIONS
SNPs in the NOS1AP gene influence QTc interval duration but we have not demonstrated a direct association with the risk of SCD.
Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Nikki
N
Earle
Sydney Medical School, University of Sydney, Sydney.|Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Camperdown, Australia.|Department of Cardiology, Royal Prince Alfred Hospital, Sydney.
Jodie
J
Ingles
Sydney Medical School, University of Sydney, Sydney.|Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Camperdown, Australia.
Richard D
RD
Bagnall
Sydney Medical School, University of Sydney, Sydney.|Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Camperdown, Australia.|Department of Cardiology, Royal Prince Alfred Hospital, Sydney.
Belinda
B
Gray
Greenlane Paediatric and Congenital Cardiac Services, Starship Childrens Hospital, Auckland, New Zealand.
Jackie
J
Crawford
Greenlane Cardiovascular Services, Auckland City Hospital, Auckland, New Zealand.
Warren
W
Smith
Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Andrew N
AN
Shelling
Diagnostic Genetics, LabPlus, Auckland City Hospital, Auckland, New Zealand.
Donald R
DR
Love
Sydney Medical School, University of Sydney, Sydney.|Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Camperdown, Australia.|Department of Cardiology, Royal Prince Alfred Hospital, Sydney.
Chris
C
Semsarian
Greenlane Paediatric and Congenital Cardiac Services, Starship Childrens Hospital, Auckland, New Zealand.
Jonathan R
JR
Skinner
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D002312:Cardiomyopathy, Hypertrophic / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology*; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D016757:Death, Sudden, Cardiac; D017147:Defibrillators, Implantable; D004562:Electrocardiography; D005260:Female; D006323:Heart Arrest / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D006801:Humans; D008133:Long QT Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009520:New Zealand / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D016896:Treatment Outcome
D048868:Adaptor Proteins, Signal Transducing; C488081:NOS1AP protein, human; D004247:DNA
QTc interval; hypertrophic cardiomyopathy; single nucleotide polymorphisms; sudden death