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Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian

C M Schooling1,2, J V Zhao1, S L Au Yeung1

  • 1School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Elife
|August 26, 2020
PubMed

Insights

Statins may impact ischemic heart disease (IHD) in men through testosterone. Anakinra showed a reverse association, highlighting sex-specific cardiovascular disease mechanisms and potential new treatments.

Area of Science:

  • Cardiovascular Genetics
  • Endocrinology
  • Pharmacogenomics

Background:

  • Lipid-lowering drugs, including statins, PCSK9 inhibitors, and ezetimibe, are crucial for managing cardiovascular risk.
  • Pleiotropic effects of medications, beyond lipid modification, are increasingly recognized.
  • The role of testosterone in sex-specific cardiovascular disease (CVD) pathogenesis requires further elucidation.

Purpose of the Study:

  • To investigate the potential pleiotropic effects of major lipid modifiers on ischemic heart disease (IHD) mediated by testosterone.
  • To explore sex-specific Mendelian randomization pathways linking lipid modifiers, testosterone, and IHD.
  • To validate findings using a drug (anakinra) with a potential association with increased IHD.

Main Methods:

  • Sex-specific Mendelian randomization analysis utilizing genetic instruments from the UK Biobank.
  • Inclusion of a large cohort: 179,918 men (25,410 IHD cases) and 212,080 women (12,511 IHD cases).
  • Univariable and multivariable analyses were performed to assess causal relationships.

Main Results:

  • Genetically mimicking statin effects in men was associated with altered testosterone levels, which partly mediated IHD risk.
  • Anakinra demonstrated a reverse pattern, with genetically mimicked effects influencing both testosterone and IHD.
  • No significant sex-specific mediation via testosterone was observed for PCSK9 inhibitors or ezetimibe.

Conclusions:

  • Testosterone may partially mediate the effects of statins on ischemic heart disease in men.
  • Findings suggest distinct sex-specific mechanisms for cardiovascular drug actions and disease development.
  • Highlights the importance of sex-specific approaches in cardiovascular disease research, prevention, and treatment.

Keywords:
cardiovascularepidemiologyevolutionary biologyglobal healthnonepleiotropysex-specificstatintestosterone

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