Endogenous androgen exposures and ischemic heart disease, a separate sample Mendelian randomization study

Area of Science:

• Reproductive endocrinology
• Cardiovascular disease genetics
• Evolutionary biology

Background:

• Evolutionary theory posits a trade-off between reproduction and longevity.
• Estrogen supplementation has not increased lifespan.
• Testosterone use in older men carries cardiovascular risk warnings, lacking large trial data.

Purpose of the Study:

• To investigate the association between genetic determinants of male reproductive hormone regulation and ischemic heart disease (IHD).
• To explore the roles of follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH), and testicular dysgenesis syndrome (TDS) in IHD risk.

Main Methods:

• Utilized Mendelian randomization, a form of instrumental variable analysis, to estimate unconfounded associations.
• Employed large case-control studies (CARDIoGRAMplusC4D and CARDIoGRAMplusC4D 1000 Genomes) with extensive genotyping data.

Main Results:

• Genetically predicted higher FSH levels showed a positive association with coronary artery disease/myocardial infarction (CAD/MI).
• Genetically predicted lower AMH and higher risk of TDS were inversely associated with CAD/MI.
• Odds ratios indicated significant associations for FSH, AMH, and TDS with CAD/MI risk.

Conclusions:

• Findings align with evolutionary biology, linking genetically predicted higher FSH (higher androgens) to increased IHD risk.
• Genetically predicted lower AMH and higher TDS risk (lower androgens) were associated with decreased IHD risk.
• Androgens may be a modifiable factor in men's vulnerability to IHD, with implications for testosterone therapy and IHD management.