Sex differences in the risk of coronary heart disease associated with type 2 diabetes: A mendelian randomization analysis

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

doi:10.2337/dc20-1137

Sex differences in the risk of coronary heart disease associated with type 2 diabetes: A mendelian randomization analysis

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

School of Public Health

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	556-562
Number of pages	7
Journal	Diabetes Care
Volume	44
Issue number	2
DOIs	https://doi.org/10.2337/dc20-1137
Publication status	Published - Feb 2021

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10.2337/dc20-1137

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Peters, T. M., Holmes, M. V., Brent Richards, J., Palmer, T., Forgetta, V., Lindgren, C. M., Asselbergs, F. W., Nelson, C. P., Samani, N. J., McCarthy, M. I., Mahajan, A., Smith, G. D., Woodward, M., O’keeffe, L. M., & Peters, S. A. E. (2021). Sex differences in the risk of coronary heart disease associated with type 2 diabetes: A mendelian randomization analysis. Diabetes Care, 44(2), 556-562. https://doi.org/10.2337/dc20-1137

@article{5e565981fb2f440eacd714a882c6044c,

title = "Sex differences in the risk of coronary heart disease associated with type 2 diabetes: A mendelian randomization analysis",

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.",

author = "Peters, \{Tricia M.\} and Holmes, \{Michael V.\} and \{Brent Richards\}, J. and Tom Palmer and Vincenzo Forgetta and Lindgren, \{Cecilia M.\} and Asselbergs, \{Folkert W.\} and Nelson, \{Christopher P.\} and Samani, \{Nilesh J.\} and McCarthy, \{Mark I.\} and Anubha Mahajan and Smith, \{George Davey\} and Mark Woodward and O{\textquoteright}keeffe, \{Linda M.\} and Peters, \{Sanne A.E.\}",

note = "Publisher Copyright: {\textcopyright} 2020 by the American Diabetes Association.",

year = "2021",

month = feb,

doi = "10.2337/dc20-1137",

language = "English",

volume = "44",

pages = "556--562",

journal = "Diabetes Care",

issn = "0149-5992",

publisher = "American Diabetes Association Inc.",

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Peters, TM, Holmes, MV, Brent Richards, J, Palmer, T, Forgetta, V, Lindgren, CM, Asselbergs, FW, Nelson, CP, Samani, NJ, McCarthy, MI, Mahajan, A, Smith, GD, Woodward, M, O’keeffe, LM & Peters, SAE 2021, 'Sex differences in the risk of coronary heart disease associated with type 2 diabetes: A mendelian randomization analysis', Diabetes Care, vol. 44, no. 2, pp. 556-562. https://doi.org/10.2337/dc20-1137

TY - JOUR

T1 - Sex differences in the risk of coronary heart disease associated with type 2 diabetes

T2 - A mendelian randomization analysis

AU - Peters, Tricia M.

AU - Holmes, Michael V.

AU - Brent Richards, J.

AU - Palmer, Tom

AU - Forgetta, Vincenzo

AU - Lindgren, Cecilia M.

AU - Asselbergs, Folkert W.

AU - Nelson, Christopher P.

AU - Samani, Nilesh J.

AU - McCarthy, Mark I.

AU - Mahajan, Anubha

AU - Smith, George Davey

AU - Woodward, Mark

AU - O’keeffe, Linda M.

AU - Peters, Sanne A.E.

PY - 2021/2

Y1 - 2021/2

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85099956448

U2 - 10.2337/dc20-1137

DO - 10.2337/dc20-1137

M3 - Article

C2 - 33277303

AN - SCOPUS:85099956448

SN - 0149-5992

VL - 44

SP - 556

EP - 562

JO - Diabetes Care

JF - Diabetes Care

IS - 2

ER -

Sex differences in the risk of coronary heart disease associated with type 2 diabetes: A mendelian randomization analysis

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