1. Genetic predictors of testosterone and their associations with cardiovascular disease and risk factors: A Mendelian randomization investigation
- Author
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Schooling, C Mary, Luo, Shan, Au Yeung, Shiu Lun, Thompson, Deborah J, Karthikeyan, Savita, Bolton, Thomas R, Mason, Amy M, Ingelsson, Erik, Burgess, Stephen, Thompson, Deborah [0000-0003-1465-5799], Karthikeyan, Savita [0000-0002-4798-5746], Mason, Amy [0000-0002-8019-0777], Burgess, Stephen [0000-0001-5365-8760], and Apollo - University of Cambridge Repository
- Subjects
Male ,Jumonji Domain-Containing Histone Demethylases ,BMI, body mass index ,CAD, coronary artery disease ,HDL, high-density lipoprotein ,Blood Pressure ,Receptors, Cell Surface ,Coronary Artery Disease ,Article ,Risk Factors ,LDL, low-density lipoprotein ,Mendelian randomization ,Humans ,Genetic epidemiology ,Sex hormones ,Testosterone ,Genetic Predisposition to Disease ,RCT, randomized controlled trial ,Disease aetiology ,Aged ,Anthropometry ,SHBG, sex hormone-binding globulin ,Genetic Variation ,Oxidoreductases, N-Demethylating ,Mendelian Randomization Analysis ,Middle Aged ,Lipids ,United Kingdom ,United States ,Stroke ,Adiponectin ,Causal inference ,Genome-Wide Association Study - Abstract
Background Testosterone supplementation has been linked to increased cardiovascular disease risk in some observational studies. The causal role of testosterone can be investigated using a Mendelian randomization approach. Methods and results We assessed genetic associations of variants in two gene regions (SHBG and JMJD1C) with several cardiovascular risk factors (lipids, adiponectin, blood pressure, anthropometric traits) plus male pattern baldness, including control outcomes and potential mediators. We assessed genetic associations with coronary artery disease (CAD) risk in the CARDIoGRAMplusC4D consortium (171,191 individuals including 60,801 cases), and associations with CAD and ischaemic stroke risk in the UK Biobank (367,643 individuals including 25,352 CAD cases and 3650 ischaemic stroke cases). Genetic predictors of increased serum testosterone were associated with lipids, blood pressure, and height. There was some evidence of an association with risk of CAD (SHBG gene region: odds ratio (OR) 0.95 per 1 unit increase in log-transformed testosterone [95% confidence interval: 0.81–1.12, p = 0.55]; JMJD1C gene region: OR 1.24 [1.01–1.51, p = 0.04]) and ischaemic stroke both overall (SHBG: OR 1.05 [0.64, 1.73, p = 0.83]; JMJD1C: OR 2.52 [1.33, 4.77, p = 0.005]) and in men. However, associations with some control outcomes were in the opposite direction to that expected. Conclusions Sex hormone-related mechanisms appear to be relevant to cardiovascular risk factors and for stroke (particularly for men). However, the extent that these findings are specifically informative about endogenous testosterone or testosterone supplementation is unclear. These findings underline a fundamental limitation for the use of Mendelian randomization where biological knowledge about the function of genetic variants is uncertain., Highlights • Genetic predictors of testosterone were associated with cardiovascular risk factors, such as lipids and blood pressure. • However, associations were not consistent between the two gene regions considered in this analysis. • Some genetic predictors of increased testosterone associated with higher coronary artery disease and ischaemic stroke risk. • This suggests that some sex hormone-related mechanisms are implicated in cardiovascular disease. • However, the extent to which these analyses are predictive of the effects of testosterone supplementation is unclear.
- Published
- 2018