title: Endogenous androgen exposures and ischemic heart disease, a separate sample Mendelian randomization study.
abstract: BACKGROUND
  Evolutionary biology suggests growth and reproduction trade-off against longevity. Correspondingly estrogen supplementation failed to increase lifespan. Testosterone supplementation is widely used by older men, although regulators have warned of its cardiovascular risk. No large trial of testosterone exists. We examined how genetic determinants of up-regulation (follicle-stimulating hormone (FSH)) and down-regulation (anti-Müllerian hormone (AMH) and testicular dysgenesis syndrome (TDS)) of mainly the male reproductive system are associated with ischemic heart disease (IHD).
  
  
  METHODS
  Separate sample instrumental variable analysis with genetic instruments, i.e., Mendelian randomization, was used to obtain unconfounded estimates using large case-control studies of coronary artery disease/myocardial infarction (CAD/MI) with extensive genotyping, i.e., CARDIoGRAMplusC4D (64,374 CAD/MI cases, 130,681controls), or CARDIoGRAMplusC4D 1000 Genomes (60,801 cases, 123,504 controls).
  
  
  RESULTS
  Genetically predicted FSH was positively associated with CAD/MI (odds ratio (OR) 1.08, 95% confidence interval (CI) 1.03 to 1.13 per mIU/mL FSH). Genetically predicted AMH and TDS were inversely associated with CAD/MI (OR 0.93, 95% CI 0.87 to 0.998 per ng/mL log AMH and OR 0.89, 95% CI 0.81 to 0.98 per log OR higher risk of TDS).
  
  
  CONCLUSIONS
  As expected from evolutionary biology, genetically predicted FSH, related to higher androgens in men and women, was positively associated with IHD, while genetically predicted AMH and TDS, related to lower androgens in men, were inversely associated with IHD. Androgens might be a modifiable causal factor underlying men's greater vulnerability to IHD, with corresponding implications for use of testosterone supplementation as well as for prevention and treatment of IHD.
authors.affiliation: School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. Electronic address: janezhao@hku.hk.
authors.forename: Jie V
authors.initials: JV
authors.lastname: Zhao
authors.affiliation: School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; City University of New York, School of Public Health and Health Policy, New York, NY, USA. Electronic address: cms1@hku.hk.
authors.forename: C Mary
authors.initials: CM
authors.lastname: Schooling
mesh_terms: D000728:Androgens / Q000378:metabolism*; D002681:China / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D015994:Incidence; D057182:Mendelian Randomization Analysis / Q000379:methods*; D017202:Myocardial Ischemia / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D000728:Androgens
keywords: Androgens; Ischemic heart disease; Mendelian randomization