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Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: mendelian randomisation study in UK Biobank.
BMJ 2019; 364:l476BMJ

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.

Authors+Show Affiliations

School of Public Health, University of Hong Kong, Hong Kong SAR, China.School of Public Health, University of Hong Kong, Hong Kong SAR, China.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. MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.School of Public Health, University of Hong Kong, Hong Kong SAR, China. School of Public Health and Health Policy, City University of New York, 55 West 125th Street, New York, NY 10027, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30842065

Citation

Luo, Shan, et al. "Association of Genetically Predicted Testosterone With Thromboembolism, Heart Failure, and Myocardial Infarction: Mendelian Randomisation Study in UK Biobank." BMJ (Clinical Research Ed.), vol. 364, 2019, p. l476.
Luo S, Au Yeung SL, Zhao JV, et al. Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: mendelian randomisation study in UK Biobank. BMJ. 2019;364:l476.
Luo, S., Au Yeung, S. L., Zhao, J. V., Burgess, S., & Schooling, C. M. (2019). Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: mendelian randomisation study in UK Biobank. BMJ (Clinical Research Ed.), 364, p. l476. doi:10.1136/bmj.l476.
Luo S, et al. Association of Genetically Predicted Testosterone With Thromboembolism, Heart Failure, and Myocardial Infarction: Mendelian Randomisation Study in UK Biobank. BMJ. 2019 03 6;364:l476. PubMed PMID: 30842065.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: mendelian randomisation study in UK Biobank. AU - Luo,Shan, AU - Au Yeung,Shiu Lun, AU - Zhao,Jie V, AU - Burgess,Stephen, AU - Schooling,C Mary, Y1 - 2019/03/06/ PY - 2019/3/8/entrez PY - 2019/3/8/pubmed PY - 2019/4/11/medline SP - l476 EP - l476 JF - BMJ (Clinical research ed.) JO - BMJ VL - 364 N2 - 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. SN - 1756-1833 UR - https://www.unboundmedicine.com/medline/citation/30842065/Association_of_genetically_predicted_testosterone_with_thromboembolism_heart_failure_and_myocardial_infarction:_mendelian_randomisation_study_in_UK_Biobank_ L2 - http://www.bmj.com/cgi/pmidlookup?view=long&pmid=30842065 DB - PRIME DP - Unbound Medicine ER -