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  3. Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: mendelian randomisation study in UK Biobank
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Research

Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: mendelian randomisation study in UK Biobank

BMJ 2019; 364 doi: https://doi.org/10.1136/bmj.l476 (Published 06 March 2019) Cite this as: BMJ 2019;364:l476
  1. Shan Luo, PhD candidate1,
  2. Shiu Lun Au Yeung, assistant professor1,
  3. Jie V Zhao, research assistant professor1,
  4. Stephen Burgess, statistician2 3,
  5. C Mary Schooling, professor1 4
  1. 1School of Public Health, University of Hong Kong, Hong Kong SAR, China
  2. 2Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  3. 3MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
  4. 4School of Public Health and Health Policy, City University of New York, 55 West 125th Street, New York, NY 10027, USA
  1. Correspondence to: C M Schooling cms1{at}hku.hk (or @cmschooling1 on Twitter)
  • Accepted 24 January 2019

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.

Footnotes

  • Contributors: SL, SLAY, and CMS designed the study, wrote the research plan, and interpreted the results. SL undertook analyses with feedback from SLAY and CMS. SL wrote the first draft of the manuscript with critical comments and revision from SLAY, JVZ, SB, and CMS. CMS is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This research was funded by Small Project Funding, University of Hong Kong (201409176231). Stephen Burgess is supported by a Sir Henry Dale fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number 204623/Z/16/Z). The funders had no role in the design, analyses, interpretation of results, writing of the paper, or decision for publication.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work other than detailed above; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: The UK Biobank received ethical approval from the research ethics committee (REC reference for UK Biobank 11/NW/0382) and participants provided written informed consent. No ethics approval was acquired for the analysis using publicly available data (CARDIoGRAMplusC4D 1000 Genomes based genome wide association study).

  • Data sharing: The data reported in this paper are available by application directly to the UK Biobank. The genetic associations with the outcomes in the UK Biobank and CARDIoGRAMplusC4D consortium are provided in the supplementary data. Software code in R for implementing the mendelian randomisation analysis, including the principal components analysis, is provided in the supplementary note.

  • The lead author (the manuscript’s guarantor) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as originally planned (and, if relevant, registered) have been explained.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.

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