The effect of sex and underlying disease on the genetic association of QT interval and sudden cardiac death

Background Sudden cardiac death (SCD) accounts for ~300,000 deaths annually in the US. Men have a higher risk of SCD and are more likely to have underlying coronary artery disease (CAD) than women. In contrast, women are more likely to have arrhythmic events in the setting of inherited or acquired QT prolongation. Moreover, there is evidence of sex differences in the underlying genetics of QT interval duration. Using sex- and CAD-stratified analyses, we assess differences in genetic association between prolonged QT interval and SCD risk. Methods We examined 2,282 SCD subjects with autopsy-confirmed underlying disease from the Fingesture cohort and 3,561 Finnish controls. The SCD subjects were stratified by underlying disease (ischemic vs. non-ischemic) and by sex. We used logistic regression to test for association between the top QT interval associated SNP, rs12143842 (in the NOS1AP locus), and SCD risk. We also performed Mendelian randomization to test for causal association of QT interval in the various subgroups. Results Female SCD victims with underlying non-ischemic disease had the strongest association between rs12143842 and SCD risk (OR=1.37; 95% CI, 1.07-1.75) and the strongest causal association, established using Mendelian randomization, between prolonged QT interval and SCD (OR in SCD risk per SD increase in QT, 3.60; 95% CI, 1.22-10.49). Ischemic SCD victims, irrespective of sex, did not show an association between rs12143842 and SCD risk or a causal association for QT interval. Conclusions This study provides evidence that the causal effect of QT prolongation on SCD risk differs by sex and underlying disease.