Identification of Blood Pressure‐Associated Metabolites by Integrating Metabolomic and Genetic Analysis

ABSTRACT This study aimed to identify blood pressure‐associated metabolites and explore their underlying pathways using multiomics data from 1188 Chinese participants. Serum metabolite levels were profiled using untargeted and widely targeted metabolomic technologies. The associations of metabolites as well as ratios with blood pressure were assessed using generalized linear models (GLM). Targeted metabolomics was used to replicate a subset of metabolites. Genome‐wide association studies (GWAS) were performed on all metabolites identified. Potential causality was examined using two‐sample Mendelian randomization (MR) analyses, with partial validation against GWAS results from an independent cohort. This study identified 10 blood pressure‐associated metabolites supported by GLM and MR analyses. Cortisol demonstrated the strongest association with blood pressure, with l ‐glutamic acid and its ratios identified as key drivers. Multiomics integration revealed that a genetic variant near the omega‐3 metabolism genes ( FADS1 / FADS2 ) may influence blood pressure regulation by modulating prostaglandin E3 levels. Mediation analysis indicated that l ‐glutamic acid statistically mediated 12.16–31.53% of the effect of lifestyle factors on blood pressure. These findings enhance our understanding of metabolic mechanisms underlying hypertension and highlight potential biomarkers and therapeutic targets for further investigation.