IJE Advance Access published online on May 29, 2008
International Journal of Epidemiology, doi:10.1093/ije/dyn091
Gender and effects of a common genetic variant in the NOS1 regulator NOS1AP on cardiac repolarization in 3761 individuals from two independent populations
1Department of Health Sciences, University of Leicester, UK, LE1 7RH.
2Department of Genetics, University of Leicester, UK, LE1 7RH.
3Department of Clinical Physiology, Tampere University Hospital and Medical School, University of Tampere, Finland.
4Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, UK, LE3 9QP.
5Department of Pharmacological Sciences, Medical School, University of Tampere.
6Ragnar Granit Institute, Tampere University of Technology, Finland.
7Tampere Polytechnic, University of Applied Sciences, Finland.
8Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK, G31 2ER.
9Department of Clinical Chemistry, Tampere University Hospital, Centre for Laboratory Medicine, Tampere, Finland.
10University of Tampere Medical School, Tampere, Finland.
*Corresponding author. Department of Health Sciences and Department of Genetics, MRC Clinician Scientist Fellow, Genetic Epidemiology Group, 2nd Floor, Adrian Building, University of Leicester, Leicester LE1 7RH. E-mail: mt47{at}leicester.ac.uk
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Abstract |
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Background A longer heart-rate corrected QT interval (QTc) is associated with increased risk of ventricular arrhythmias. Women have longer resting QTc and are more likely than men to develop drug-induced QT prolongation. Recent studies have shown association between resting QTc and a common variant (rs10494366) of the NOS1 regulator, NOS1AP. We investigated the association between rs10494366 in NOS1AP and QTc, and assessed gender-specific NOS1AP associations with QTc during rest and after exercise.
Methods We investigated the SNP associations with resting QTc in 919 women and 918 men from 504 representative families in the UK GRAPHIC study, and with QTc at rest and at 3 min recovery after exercise in 699 women and 1225 men referred for exercise testing in the Finnish FINCAVAS study.
Results In the GRAPHIC study the minor allele (G) of the NOS1AP SNP rs10494366 prolonged QTc by 4.59 ms (95% CI 2.77–6.40; P = 7.63/107) in women, but only by 1.62 ms (95% CI –0.15 to 3.38; P = 0.073) in men (gender-SNP interaction term P = 0.025). In the FINCAVAS study the G allele significantly prolonged QTc in both women (P = 0.0063) and men (P = 0.0043) at 3 min recovery after exercise, but at rest an association was only seen in women (P = 0.020 excluding outliers).
Conclusions A common NOS1AP variant prolongs QTc with a difference between genders. Further studies should aim to confirm this finding and to assess whether NOS1AP genotype influences the risk of drug-induced QT prolongation and risk of consequent arrhythmias.
Keywords Cardiac repolarization, QTc, NOS1AP, gender, genetic association
Accepted 29 April 2008