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Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis

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posted on 04.12.2020, 17:16 by Tricia M. Peters, Michael V. Holmes, J. Brent Richards, Tom Palmer, Vincenzo Forgetta, Cecilia M. Lindgren, Folkert W. Asselbergs, Christopher P. Nelson, Nilesh J. Samani, Mark I. McCarthy, Anubha Mahajan, George Davey Smith, Mark Woodward, Linda M. O’Keeffe, Sanne A.E. Peters
Objective: Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding.

Methods: Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (N=251,420 women and 212,049 men). Weighted-median, MR Egger, MR-PRESSO and radial MR from summary-level analyses were used for pleiotropy assessment.

Results: MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.08-1.18 per 1-log unit increase in odds of type 2 diabetes) and men (OR 1.21, 95% CI 1.17-1.26 per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy, however, results were similar after correction for outlier SNPs.

Conclusions: This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes.

Funding

This research is supported by the Lady Davis Institute for Medical Research and the Department of Medicine, Jewish General Hospital (T.M.P.); the UK Medical Research Council, British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512), and the National Institute for Health Research Oxford Biomedical Research Centre (M.V.H.); the Canadian Institutes of Health Research (CIHR), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation, the NIH Foundation, Cancer Research UK and the Fonds de Recherche Québec Santé (FRQS), and a FRQS Clinical Research Scholarship (J.B.R.); The Li Ka Shing Foundation, The National Institute for Health Research Biomedical Research Centre, Oxford, National Institutes of Health (CRR00070 CR00.01) and WT-SSI/John Fell funds, Widenlife and NIH (5P50HD028138-27) (C.M.L.); University College London Hospitals National Institute for Health Research Biomedical Research Centre (F.W.A.); the British Heart Foundation (C.P.N. and N.J.S.); Wellcome Trust 090532, 098381, 203141 and 212259, and NIDDK U01-DK105535, was a Wellcome Investigator and an NIHR Senior Investigator (M.I.M.); a UK Medical Research Council Population Health Scientist fellowship (MR/M014509/1) (L.M.O.K.); a UK Medical Research Council Skills Development Fellowship (MR/P014550/1) (S.A.E.P.).

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