Genetic validation of neurokinin 3 receptor antagonists for ischemic heart disease prevention in men - A one-sample
1Li Ka Shing Faculty of Medicine, School of Public Health, The University of Hong Kong, 1/F, Patrick Manson Building (North Wing), 7 Sassoon Road, Pokfulam, Hong Kong, China; Graduate School of Public Health and Health Policy, City University of New York, New York, NY, USA.
Insights
Neurokinin 3 receptor (NK3R) antagonists may prevent ischemic heart disease (IHD) in men by modulating testosterone levels. Genetic validation supports their potential as a novel therapeutic strategy for male IHD prevention.
Area of Science:
- Cardiovascular Disease
- Endocrinology
- Genetics
Background:
- Ischemic heart disease (IHD) is a major cause of mortality in men, with limited targeted interventions.
- Testosterone's role in IHD is emerging, prompting investigation into testosterone-modulating therapies.
- Neurokinin 3 receptor (NK3R) antagonists influence testosterone and are being explored for various conditions.
Purpose of the Study:
- To genetically validate the use of NK3R antagonists for preventing IHD in men.
- To investigate the association between genetic variants affecting testosterone and IHD risk.
- To assess the impact of genetically mimicked NK3R antagonism on related health outcomes.
Main Methods:
- A one-sample Mendelian randomization (MR) study utilized UK Biobank data.
- Independent genetic variants predicting testosterone in men, specifically targeting the TACR3 gene, were identified.
- Associations with IHD and control outcomes (puberty timing, fatherhood, hypertension, prostate cancer) were analyzed using summary statistics.
Main Results:
- Two TACR3 variants (rs116646027 and rs1351623) were identified in men.
- Genetically mimicked NK3R antagonism showed an inverse association with IHD risk (OR 0.54).
- Expected associations were observed with control outcomes, including reduced hypertension and prostate cancer risk.
Conclusions:
- Genetic evidence supports NK3R antagonists as a potential new strategy for IHD prevention in men.
- Further research is warranted to explore their protective effects against prostate cancer.
- This study provides a genetic basis for considering NK3R antagonists in male cardiovascular health.
Background:
Ischemic heart disease (IHD) is a leading cause of mortality, particularly for men. Few interventions have focused on protecting specifically men. Emerging evidence may implicate testosterone. Neurokinin 3 receptor (NK3R) antagonists, an existing class of drugs being considered as treatments for reproductive conditions in women, affect testosterone; this study addresses genetic validation of their use to prevent IHD in men.
Methods:
A one-sample Mendelian randomization (MR) study using the UK Biobank cohort study, based on independent (r2 < 0.005) genetic variants predicting testosterone in men (n = 157738) at genome wide significance in the target gene for NK3R antagonists (TACR3), was used to assess associations with IHD (cases=15056, non-cases=151964) and positive control outcomes (relative age voice broke, children fathered, hypertension) in men and a negative control outcome (IHD) in women using summary statistics. A two-sample MR study using the PRACTICAL consortium was used for the positive control outcome of prostate cancer.
Findings:
Two relevant TACR3 genetic variants (rs116646027 and rs1351623) were identified in men. Genetically mimicked NK3R antagonists were inversely associated with IHD (odds ratio 0.54 per standard deviation lower testosterone, 95% confidence interval 0.31, 0.94) and with control outcomes (older relative age voice broke, fewer children and lower risk of hypertension and prostate cancer) as expected in men and in women (unrelated to IHD).
Interpretation:
Genetic validation of a role of NK3R antagonists in IHD suggests their consideration as a new means of preventing IHD in men. Whether they protect against prostate cancer might bear further consideration.
Funding:
This study had no funding.
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