@article{Luo2019,
title = {The association of genetically-predicted testosterone with thromboembolism, heart failure and myocardial infarction: a Mendelian randomization study using UK Biobank},
author = {Shan Luo and Shiu Lun and Au Yeung and Jie V Zhao and Stephen Burgess and C Mary Schooling},
url = {https://www.bmj.com/content/364/bmj.l476},
year = {2019},
date = {2019-03-06},
journal = {BMJ},
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.},
keywords = {14864, genetics, heart failure, testosterone},
pubstate = {published},
tppubtype = {article}
}

@article{Yeung2018b,
title = {The Impact of Glycated Hemoglobin (HbA1c) on Cardiovascular Disease Risk: A Mendelian Randomization Study Using UK Biobank},
author = {Shiu Lun Au Yeung and Shan Luo and Mary C Schooling},
url = {http://care.diabetesjournals.org/content/early/2018/06/21/dc18-0289.long},
year = {2018},
date = {2018-06-28},
journal = {Diabetes Care},
abstract = {OBJECTIVE Glycated hemoglobin (HbA1c) is positively associated with cardiovascular disease (CVD), although evidence is primarily observational. Mendelian randomization studies have only examined its relation with subtypes of CVD. We examined the relation of HbA1c with CVD and its subtypes in the UK Biobank using Mendelian randomization.
RESEARCH DESIGN AND METHODS We used 38 genetic variants strongly and independently related to HbA1c (n = 123,665) applied to the UK Biobank (n = 392,038). We used inverse variance weighting (IVW) to obtain the associations of HbA1c with CVD, coronary artery disease (CAD), stroke, and its subtypes. Sensitivity analyses included Mendelian randomization (MR)-Egger, a weighted median and exclusion of potentially invalid single nucleotide polymorphisms (SNPs). We also applied the same genetic instruments to CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) plus The Coronary Artery Disease (C4D) Genetics) 1000 Genomes–based genome-wide association study (n = 184,305) as a validation for CAD.

RESULTS In the UK Biobank, HbA1c was not associated with CVD using IVW (odds ratio (OR) 1.11 per %, 95% CI 0.83–1.48). However, HbA1c was associated with increased CAD risk (OR 1.50 per %, 95% CI 1.08–2.11) with directionally consistent results from MR-Egger and weighted median. The positive association with CAD was more pronounced when we excluded potentially invalid SNPs (OR 2.24 per %, 95% CI 1.55–3.25). The positive association was replicated in CARDIoGRAM (OR 1.52 per %, 95% CI 1.03–2.26). The association of HbA1c with stroke and its subtypes was less clear given the low number of cases.

CONCLUSIONS HbA1c likely causes CAD. The underlying mechanisms remain to be elucidated.},
keywords = {14864, cardiovascular risk, diabestes, genetics},
pubstate = {published},
tppubtype = {article}
}

@article{Schooling2018,
title = {Genetic predictors of testosterone and their associations with cardiovascular disease and risk factors: A Mendelian randomization investigation},
author = {Mary C Schooling and Shan Luo and Shiu Lun Au Yeung and Deborah J Thompson and Savita Karthikeyan and Thomas R Bolton and Amy M Mason and Erik Ingelsson and Stephen Burgess and Stephen Burgess},
url = {https://www.ncbi.nlm.nih.gov/pubmed/29804699},
year = {2018},
date = {2018-05-18},
journal = {International Journal of Cardiology},
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.},
keywords = {13721, 14864, cardiovascular disease, genetics},
pubstate = {published},
tppubtype = {article}
}