Using Mendelian randomisation, the researchers analysed genetic variants that predict testosterone levels and their associations with blood clots (thromboembolism), heart failure and heart attack (myocardial infarction) in almost 400,000 men and women from a large genome study and the UK Biobank database. Participants were aged 40 to 75 years and most were of British or European ancestry. Heart conditions were identified from self-reports, hospital and death records, and results were validated using data from another large genome study.
Analysing genetic information in this way avoids some of the problems that afflict traditional observational studies, making the results less prone to unmeasured (confounding) factors, and therefore more likely to be reliable. An association that is observed using Mendelian randomisation therefore strengthens the inference of a causal relationship.
The researchers found in the UK Biobank that in men, endogenous testosterone was associated with a higher risk of blood clots and heart failure, but not heart attack. In another large genetic study from the CARDIoGRAMplusC4D consortium, endogenous testosterone was also found to be associated with a higher risk of heart attack. Associations were less obvious in women.
The researchers point to some study limitations. For example, UK Biobank participants tend to be more highly educated and have healthier lifestyles compared with the general population, which may have affected the results. Nevertheless, they say these findings extend and complement previous findings, and suggest that endogenous testosterone is detrimental for thromboembolism, heart failure, and myocardial infarction, especially in men. Further evidence is needed to clarify whether these findings are relevant to the higher rates of these diseases in men than in women, and suggest it might be worth considering whether existing treatments that lower testosterone could help protect against these conditions.
Evaluation of the causal relation between hematocrit, hemoglobin, HbA1c, testosterone and cardiovascular outcomes in the UK Biobank using Mendelian randomization analysis
The aims of this study are to examine the causal effect of testosterone, HbA1c, hemoglobin and hematocrit on CVD risk factors, prevalent CVD and CVD deaths using Mendelian randomization analysis, with the relevant genetic variants as instruments in the UK Biobank. The proposed research will help investigate how these potential targets of intervention influence population health using Mendelian randomization design which is less susceptible to confounding than observational studies. The results will provide additional insights concerning the drivers of cardiovascular disease, with corresponding implications for public health policies and the development of interventions. We compare cardiovascular events and risk factors according to levels of genetically determined hematocrit, hemoglobin, HbA1c and testosterone. 500,000 participants (full cohort) for the analysis involving hematocrit, hemoglobin, HbA1c and genetic data. We will restrict the analysis involving testosterone and relevant genetic data among men.
|Lead investigator:||Shiu Lun Ryan Au Yeung|
|Lead institution:||University of Hong Kong|