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

Author:

Peters Tricia M.12ORCID,Holmes Michael V.3456ORCID,Richards J. Brent12ORCID,Palmer Tom67,Forgetta Vincenzo1,Lindgren Cecilia M.8910,Asselbergs Folkert W.111213,Nelson Christopher P.1415,Samani Nilesh J.1415,McCarthy Mark I.91617,Mahajan Anubha916,Davey Smith George618,Woodward Mark192021ORCID,O’Keeffe Linda M.622,Peters Sanne A.E.192023ORCID

Affiliation:

1. Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Montreal, Quebec, Canada

2. Division of Endocrinology, Department of Medicine, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

3. Medical Research Council Population Health Research Unit, University of Oxford, Oxford, U.K.

4. Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, U.K.

5. National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, U.K.

6. Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K.

7. Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K.

8. Big Data Institute, Li Ka Shing Center for Health Information and Discovery, Oxford University, Oxford, U.K.

9. Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.

10. Program in Medical and Population Genetics, Broad Institute, Boston, MA

11. Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands

12. Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, U.K.

13. Health Data Research UK and Institute of Health Informatics, University College London, London, U.K.

14. Department of Cardiovascular Sciences, University of Leicester, Leicester, U.K.

15. National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, U.K.

16. Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, University of Oxford, Oxford, U.K.

17. Oxford National Institute for Health Research Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, U.K.

18. School of Social and Community Medicine, University of Bristol, Bristol, U.K.

19. George Institute for Global Health, University of Oxford, Oxford, U.K.

20. George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia

21. Department of Epidemiology, Johns Hopkins University, Baltimore, MD

22. School of Public Health, University College Cork, Cork, Ireland

23. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands

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.

Funder

Lady Davis Institute for Medical Research and the Department of Medicine, Jewish General Hospital

Medical Research Council

British Heart Foundation

National Institute for Health Research

Canadian Institutes of Health Research

Canadian Foundation for Innovation

NIH Foundation

Cancer Research UK

Fonds de Recherche Québec Santé

Li Ka Shing Foundation

National Institutes of Health

WT-SSI/John Fell funds

Wellcome Trust

National Institute of Diabetes and Digestive and Kidney Diseases

Publisher

American Diabetes Association

Subject

Advanced and Specialized Nursing,Endocrinology, Diabetes and Metabolism,Internal Medicine

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