Abstract WE463: Circulating Metabolites Mediate the Association Between Polygenic Risk Score and Incident Hypertension

Objective: Genetic susceptibility quantified by a polygenic risk score (PRS) is associated with incident hypertension, yet the metabolic pathways linking genetic risk to disease remain unclear. We investigated which circulating metabolites are associated with incident hypertension and whether they mediate the PRS–hypertension association. Methods: We analyzed 8,458 community-dwelling Japanese adults aged ≥20 years (mean [SD] 57.9 [11.8]; 71.0% women) free of hypertension at baseline. Nuclear magnetic resonance spectroscopy quantified 43 plasma metabolites (amino acids, ketone bodies, glycolytic intermediates, etc.). A PRS for systolic blood pressure was derived from a prior genome-wide association study meta-analysis. Incident hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or self-reported antihypertensive treatment. Modified Poisson regression estimated risk ratios (RRs) for PRS–hypertension; multiple linear regression assessed associations between the PRS and each metabolite; mediation analysis quantified metabolite-specific indirect effects. Results: Over a median of 4.3 years of follow-up, 1,333 cases occurred. A higher PRS was associated with incident hypertension (RR 1.44, 95% CI 1.34–1.55). 2-Hydroxybutyric acid, creatinine, glycerol, and caffeine were associated with a higher risk, whereas methionine and acetic acid were associated with a lower risk. Five metabolites, including 2-hydroxybutyric acid, were positively correlated with the PRS, and seven were negatively correlated. 2-Hydroxybutyric acid modestly mediated the PRS–hypertension association (proportion mediated ≈1.0% [95% CI 0.2–3.0%]). Conclusion: 2-Hydroxybutyric acid slightly mediates the association between genetic susceptibility and incident hypertension, suggesting metabolic pathways that could inform prevention or therapeutic strategies.