University of Oulu

Mitchell, R., Ashar, F., Jarvelin, M., Froguel, P., Sotoodehnia, N., Brody, J., Sebert, S., Huikuri, H., Rioux, J., Goyette, P., Newcomb, C., Junttila, M., Arking, D. (2019) Effect of Sex and Underlying Disease on the Genetic Association of QT Interval and Sudden Cardiac Death, 8 (23), e013751. doi:10.1161/JAHA.119.013751

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

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Author: Mitchell, Rebecca N.1; Ashar, Foram N.1; Jarvelin, Marjo‐Riitta2,3,4,5,6;
Organizations: 1Department of Genetic Medicine, McKusick‐Nathans Institute, Johns Hopkins, Baltimore
2Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Finland
3Biocenter Oulu, University of Oulu, Finland
4Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland
5Department of Epidemiology and Biostatistics, MRC‐PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom
6Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, United Kingdom
7Cardiovascular Health Research Unit, Division of Cardiology, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA
8Cardiovascular Health Research Unit, University of Washington, Seattle, WA
9Research Unit of Internal Medicine, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
10Montreal Heart Institute, University of Montreal, Canada
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.2 MB)
Persistent link:
Language: English
Published: John Wiley & Sons, 2019
Publish Date: 2020-03-27


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 NOS1AP 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 (P=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.

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Series: Journal of the American Heart Association
ISSN: 2047-9980
ISSN-E: 2047-9980
ISSN-L: 2047-9980
Volume: 8
Issue: 23
Article number: e013751
DOI: 10.1161/JAHA.119.013751
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
1184 Genetics, developmental biology, physiology
Funding: This work was supported by the National Institutes of Health grant numbers R01HL11267, R01HL116747, and R01HL141989. This work was also supported by an award from the American Heart Association (19SFRN34830063). Fingesture: This work was supported by the Juselius Foundation (Helsinki, Finland); the Council of Health of the Academy of Finland (Helsinki, Finland); the Montreal Heart Institute Foundation; Finnish Foundation for Cardiovascular Research (Helsinki, Finland); and Erkko Foundation (Helsinki, Finland). NFBC1966: The NFBC1966 Study is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the Broad Institute, UCLA, University of Oulu, and the National Institute for Health and Welfare in Finland.
Copyright information: © 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.