Genetic validation of neurokinin 3 receptor antagonists for ischemic heart disease prevention in men – A one-sample Mendelian randomization study

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 (r(2) < 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.