Gender and effects of a common genetic variant in the NOS1 regulator NOS1AP on cardiac repolarization in 3761 individuals from two independent populations

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 = 7.63/10(7)) 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.