1480-P: TOPMed Metabolomics Association Analysis of Cardiovascular Disease in Participants with Type 2 Diabetes

Type 2 diabetes (T2D) is a prominent risk factor for cardiovascular diseases (CVD). People with T2D are twice as likely to develop heart disease or all-type stroke compared to people without T2D, though the reason behind this excess risk remains unclear. To better understand the molecular mechanisms underlying CVD in T2D, we compared the metabolomics profiles of T2D participants with or without CVD event. Using LC/MS-based metabolite data from the Trans-Omics for Precision Medicine (TOPMed) program, we collected 522 blood metabolite level measurements common to 1356 T2D participants across three TOPMed participating cohorts. We compared metabolite levels in CVD cases that occurred after T2D, versus T2D without CVD at the time of metabolite measurement. We performed cross-sectional pooled association analysis for each metabolite using a mixed effects linear model, with log-transformed and standardized metabolite level as the outcome and CVD event as the predictor, adjusting for age, sex, study population, and self-reported race/ethnicity, accounting for relatedness using a kinship matrix and a correlation-adjusted Bonferroni correction alpha level of 3.0x10^-4 to define significant associations.

We identified 15 significant associations, where CVD is negatively associated with five lipids while positively associated with ten organic acids. We also replicated the effect size direction at a statistically significant level for nine organic acids in a separate TOPMed cohort with 1823 T2D participants. Most of the acids, such as gluconate, ADMA and cystine, have been previously reported as risk factors of CVD. 1-methyladenosine, our novel finding, could be a potential biomarker for CVD in T2D individuals.

Our results established metabolite associations with prevalent CVD in T2D in TOPMed. These associations will pave the way for future mechanistic studies exploring the potential utility of metabolites as therapeutic targets specific for T2D individuals at risk for CVD.