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Effect of Sex and Underlying Disease on the Genetic Association of QT Interval and Sudden Cardiac Death.

TitleEffect of Sex and Underlying Disease on the Genetic Association of QT Interval and Sudden Cardiac Death.
Publication TypeJournal Article
Year of Publication2019
AuthorsMitchell RN, Ashar FN, Jarvelin M-R, Froguel P, Sotoodehnia N, Brody JA, Sebert S, Huikuri H, Rioux J, Goyette P, Newcomb CE, M Junttila J
Secondary AuthorsArking DE
JournalJ Am Heart Assoc
Volume8
Issue23
Paginatione013751
Date Published2019 12 03
ISSN2047-9980
Abstract

Background Sudden cardiac death (SCD) accounts for ≈300 000 deaths annually in the United States. Men have a higher risk of SCD and are more likely to have underlying coronary artery disease, while 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 genetics of QT interval duration. Using sex- and coronary artery disease-stratified analyses, we assess differences in genetic association between longer QT interval and SCD risk. Methods and Results We examined 2282 SCD subjects and 3561 Finnish controls. The SCD subjects were stratified by underlying disease (ischemic versus nonischemic) and by sex. We used logistic regression to test for association between the top QT interval-associated single-nucleotide polymorphism, rs12143842 (in the locus), and SCD risk. We also performed Mendelian randomization to test for causal association of QT interval in the various subgroups. No statistically significant differences were observed between the sexes for associations with rs12143842, despite the odds ratio being higher in females across all subgroup analyses. Consistent with our hypothesis, female non-ischemics had the highest odds ratio point estimate for association between rs12143842 and SCD risk and male ischemics the lowest odds ratio point estimate (=0.036 for difference). Similar trends were observed for the Mendelian randomization analysis. Conclusions While individual subgroup comparisons did not achieve traditional criteria for statistical significance, this study is consistent with the hypothesis that the causal association of longer QT interval on SCD risk is stronger in women and nonischemic individuals.

DOI10.1161/JAHA.119.013751
Alternate JournalJ Am Heart Assoc
PubMed ID31747862
PubMed Central IDPMC6912973
Grant ListT32 GM007814 / GM / NIGMS NIH HHS / United States
R01 HL116747 / HL / NHLBI NIH HHS / United States
R01 HL141989 / HL / NHLBI NIH HHS / United States
R01 HL112671 / HL / NHLBI NIH HHS / United States