Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: mendelian randomisation study in UK Biobank [基因预测睾酮与血栓栓塞、心力衰竭和心肌梗死的关联：基于英国生物银行的孟德尔随机研究]

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BMJ 2019; 364 doi: https://doi.org/10.1136/bmj.l476 (Published 06 March 2019)
Cite this as: BMJ 2019;364:l476

Authors
Shan Luo, Shiu Lun Au Yeung, Jie V Zhao, Stephen Burgess, C Mary Schooling

Abstract
Objective To determine whether endogenous testosterone has a causal role in thromboembolism, heart failure, and myocardial infarction.

Design Two sample mendelian randomisation study using genetic variants as instrumental variables, randomly allocated at conception, to infer causality as additional randomised evidence.

Setting Reduction by Dutasteride of Prostate Cancer Events (REDUCE) randomised controlled trial, UK Biobank, and CARDIoGRAMplusC4D 1000 Genomes based genome wide association study.

Participants 3225 men of European ancestry aged 50-75 in REDUCE; 392 038 white British men and women aged 40-69 from the UK Biobank; and 171 875 participants of about 77% European descent, from CARDIoGRAMplusC4D 1000 Genomes based study for validation.

Main outcome measures Thromboembolism, heart failure, and myocardial infarction based on self reports, hospital episodes, and death.

Results Of the UK Biobank participants, 13 691 had thromboembolism (6208 men, 7483 women), 1688 had heart failure (1186, 502), and 12 882 had myocardial infarction (10 136, 2746). In men, endogenous testosterone genetically predicted by variants in the JMJD1C gene region was positively associated with thromboembolism (odds ratio per unit increase in log transformed testosterone (nmol/L) 2.09, 95% confidence interval 1.27 to 3.46) and heart failure (7.81, 2.56 to 23.8), but not myocardial infarction (1.17, 0.78 to 1.75). Associations were less obvious in women. In the validation study, genetically predicted testosterone (based on JMJD1C gene region variants) was positively associated with myocardial infarction (1.37, 1.03 to 1.82). No excess heterogeneity was observed among genetic variants in their associations with the outcomes. However, testosterone genetically predicted by potentially pleiotropic variants in the SHBG gene region had no association with the outcomes.

Conclusions Endogenous testosterone was positively associated with thromboembolism, heart failure, and myocardial infarction in men. Rates of these conditions are higher in men than women. Endogenous testosterone can be controlled with existing treatments and could be a modifiable risk factor for thromboembolism and heart failure.