Sex differences in the risk of coronary heart disease associated with type 2 diabetes: a Mendelian Randomization analysis

Tricia Peters, Michael V Holmes, Brent Richards, Tom M 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 Peters

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

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.

RESEARCH DESIGN AND 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 (251,420 women and 212,049 men). Weighted median, MR-Egger, MR-pleiotropy residual sum and outlier, 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 1.13 [95% CI 1.08–1.18] per 1-log unit increase in odds of type 2 diabetes) and men (1.21 [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.
Original languageEnglish
Article numberdc201137
Pages (from-to)556-562
Number of pages7
JournalDiabetes Care
Volume44
Issue number2
Early online date4 Dec 2020
DOIs
Publication statusPublished - Feb 2021

Bibliographical note

Funding Information:
(University of Oxford), did not accept any personal payment. J.B.R. has served as an advisor to GlaxoSmithKline. M.I.M. has served on advisory panels for Pfizer, Novo Nordisk, and Zoe Global; has received honoraria from Merck, Pfizer, Novo Nordisk, and Eli Lilly; and has received research funding from AbbVie, AstraZeneca, Boehringer Ingelheim,EliLilly,Janssen,Merck,NovoNordisk, Pfizer, Roche, Sanofi Aventis, SERVIER, and Takeda. As of June 2019, M.I.M. is an employee of Genentech and a holder of Roche stock. As of January 2020, A.M. is an employee of Genentech and a holder of Roche stock. No other potential conflicts of interest relevant to this article were reported. Author Contributions. T.M.P. analyzed the data, wrote the manuscript, and contributed to the study design and conception. M.V.H., J.B.R., M.W.,andL.M.O.contributedtothestudydesign and reviewed/edited the manuscript. T.P. con-tributedtothestudydesignanddataanalysisand reviewed the manuscript. V.F. contributed to the data analysis and reviewed the manuscript. C.M.L., F.W.A., C.P.N., N.J.S., and G.D.S reviewed/edited the manuscript. M.I.M. and A.M. contributed data and reviewed/edited the manuscript. S.A.E.P. contributed to the study design and data analysis and wrote the manuscript. T.M.P. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding Information:
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 (NIHR) Oxford Biomedical Research Centre (M.V.H.). J.B.R. is supported by 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, the Fonds de Recherche Qu?ebec Sant?e (FRQS), and an FRQS Clinical Research Scholarship. C.M.L. is supported by the Li Ka Shing Foundation, the NIHR Oxford Biomedical Research Centre, National Institutes of Health grants CRR00070 CR00.01 and 5P50-HD-028138-27, WT-SSI/John Fell funds, and Widenlife. F.W.A. is supported by University College London Hospitals NIHR Biomedical Research Centre. C.P.N. and N.J.S. are supported by the British Heart Foundation. M.I.M. is supported by Wellcome Trust grants 090532, 098381, 203141, and 212259 and National Institute of Diabetes and Digestive and Kidney Diseases grant U01-DK-105535 and was a Wellcome investigator and an NIHR senior investigator. L.M.O. is supported by a UK Medical Research Council Population Health Scientist fellowship (MR/M014509/1). S.A.E.P. is supported by a UK Medical Research Council Skills Development Fellowship (MR/P014550/1).

Funding Information:
European DIAMANTE investigators for making data available. This research has been conducted using the UK Biobank resource under application number 24281. 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 (NIHR) Oxford Biomedical Research Centre (M.V.H.). J.B.R. is supported by 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, the Fonds de Recherche Québec Santé (FRQS), and an FRQS Clinical Research Scholarship. C.M.L. is supported by the Li Ka Shing Foundation, the NIHR Oxford Biomedical Research Centre, National Institutes of Health grants CRR00070 CR00.01 and 5P50-HD-028138-27,WT-SSI/JohnFellfunds,andWidenlife.F.W.A. is supported by University College London Hospitals NIHR Biomedical Research Centre. C.P.N. and N.J.S. are supported by the British Heart Foundation. M.I.M. is supported by Wellcome Trust grants 090532, 098381, 203141, and 212259 and National Institute of Diabetes and Digestive and Kidney Diseases grant U01-DK-105535 and was a Wellcome investigator and an NIHR senior investigator. L.M.O. is supported by a UK Medical Research Council Population Health Scientist fellowship (MR/M014509/1). S.A.E.P. is supported by a UK Medical Research Council Skills Development Fellowship (MR/P014550/1).

Publisher Copyright:
© 2020 by the American Diabetes Association.

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