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利用人类遗传学了解睾酮对男性和女性疾病的影响。

Using human genetics to understand the disease impacts of testosterone in men and women.

机构信息

University of Exeter Medical School, University of Exeter, Exeter, UK.

Medical Research Council (MRC) Epidemiology Unit, University of Cambridge, Cambridge, UK.

出版信息

Nat Med. 2020 Feb;26(2):252-258. doi: 10.1038/s41591-020-0751-5. Epub 2020 Feb 10.

DOI:10.1038/s41591-020-0751-5
PMID:32042192
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7025895/
Abstract

Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.

摘要

睾酮补充治疗因其对性功能、骨骼健康和身体成分的影响而被广泛应用，但其对疾病结局的影响尚不清楚。为了更好地理解这一点，我们在 425097 名英国生物银行研究参与者中确定了睾酮水平和相关性激素特征的遗传决定因素。利用 2571 个全基因组显著关联，我们证明了睾酮水平的遗传决定因素在性别之间存在显著差异，并且遗传上较高的睾酮对女性的代谢性疾病有害，但对男性有益。例如，遗传决定的 1 个标准差更高的睾酮水平会增加女性 2 型糖尿病（比值比（OR）=1.37（95%置信区间（95%CI）：1.22-1.53））和多囊卵巢综合征（OR=1.51（95%CI：1.33-1.72））的风险，但会降低男性 2 型糖尿病的风险（OR=0.86（95%CI：0.76-0.98））。我们还发现，较高的睾酮水平对女性的乳腺癌和子宫内膜癌以及男性的前列腺癌有不良影响。我们的研究结果提供了睾酮对疾病影响的见解，并强调了性别特异性遗传分析的重要性。

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