Abstract P311: Metabolomic Associations With Blood Pressure and Hypertension in Multi-Ethnic Populations

Abstract

Introduction: Hypertension (HTN) is a leading cause of cardiovascular disease and premature death. A few circulating metabolites have been associated with blood pressure or HTN; however, findings from multi-ethnic populations are limited. Methods: Discovery analysis included eight population-based cohorts from the Trans-Omics for Precision Medicine (TOPMed) consortium, including adults of White, Black and Hispanic/Latino ancestries. Replication analyses were performed in six independent studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and TOPMed. Fixed-effect inverse variance weighted meta-analysis was applied, on study- and ethnic-specific linear and logistic regression results, to estimate circulating metabolites association with systolic (SBP), diastolic blood pressure (DBP), and HTN cross-sectionally, adjusting for age, sex, body mass index, smoking status, lipids, kidney function, and diabetes prevalence. Global metabolomic analysis and pathway enrichment were performed to identify potentially altered metabolic pathways, and two-sample Mendelian randomization (MR) was performed to test for causal relationships between replicated metabolites and SBP, DBP, and HTN. Results: Out of 1,055 meta-analyzed metabolites, 336 were significantly associated (FDR&lt0.05) with all three BP traits among 17,767 participants (7,097 White, 5,406 Black, and 5,264 Hispanic/Latino). Xanthopterin had the strongest positive association (SBP: β=3.16, DBP: β=1.78, HTN: OR=1.34), and NH4_C18:2 CE had the strongest inverse association (SBP: β=-2.31, DBP: β=-1.49, HTN: OR=0.75), per SD increase of the metabolite level. The directions of associations were generally consistent across sex and racial/ethnic groups. Pathway enrichment analysis identified two enriched pathways (FDR&lt0.05): alanine, aspartate and glutamate metabolism and citrate cycle. Of 222 metabolites available for replication, 114 metabolites associated with all three traits (FDR&lt0.05) among 20,567 participants. MR analysis identified 18 potentially causal associations between metabolites and BP traits, including palmitoylcarnitine - a carnitine derivative that showed consistent positive causal associations across SBP, DBP and HTN (FDR&lt0.05).