School of Public Health, University of Hong Kong, Hong Kong SAR, China.
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
BMJ. 2019 Mar 6;364:l476. doi: 10.1136/bmj.l476.
To determine whether endogenous testosterone has a causal role in thromboembolism, heart failure, and myocardial infarction.
Two sample mendelian randomisation study using genetic variants as instrumental variables, randomly allocated at conception, to infer causality as additional randomised evidence.
Reduction by Dutasteride of Prostate Cancer Events (REDUCE) randomised controlled trial, UK Biobank, and CARDIoGRAMplusC4D 1000 Genomes based genome wide association study.
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.
Thromboembolism, heart failure, and myocardial infarction based on self reports, hospital episodes, and death.
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 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 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 gene region had no association with the outcomes.
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.
确定内源性睾酮是否对血栓栓塞、心力衰竭和心肌梗死具有因果作用。
使用遗传变异作为工具变量的两样本孟德尔随机化研究，这些遗传变异在受孕时随机分配，以推断因果关系作为额外的随机证据。
减少前列腺癌事件的度他雄胺（REDUCE）随机对照试验、英国生物库和基于 1000 基因组的心血管疾病加 C4D 全基因组关联研究的 CARDIoGRAMplusC4D。
REDUCE 中 3225 名 50-75 岁的欧洲血统男性；英国生物库中 392038 名 40-69 岁的白种英国男女；以及来自基于 1000 基因组的 CARDIoGRAMplusC4D 研究的约 77%欧洲血统的 171875 名参与者，用于验证。
基于自我报告、住院和死亡的血栓栓塞、心力衰竭和心肌梗死。
在英国生物库的参与者中，有 13691 人患有血栓栓塞症（6208 名男性，7483 名女性），1688 人患有心力衰竭（1186 名男性，502 名女性），12882 人患有心肌梗死（10136 名男性，2746 名女性）。在男性中，基因区域内的变体所预测的内源性睾酮与血栓栓塞（每单位增加经对数转换的睾酮（nmol/L）的优势比 2.09，95%置信区间 1.27 至 3.46）和心力衰竭（7.81，2.56 至 23.8）呈正相关，但与心肌梗死（1.17，0.78 至 1.75）无关。在女性中，相关性不太明显。在验证研究中，基于基因区域变体预测的内源性睾酮与心肌梗死呈正相关（1.37，1.03 至 1.82）。在与结局相关的遗传变异中，没有观察到异质性增加。然而，基因区域内潜在多效性变异预测的内源性睾酮与这些结局无关。
内源性睾酮与男性的血栓栓塞、心力衰竭和心肌梗死呈正相关。这些疾病在男性中的发病率高于女性。内源性睾酮可以通过现有的治疗方法来控制，并且可能是血栓栓塞和心力衰竭的可改变的危险因素。
