Metabolomic Profile of Genetic Liability to Type 2 Diabetes Among 125,000 Mexican Adults: A Mendelian Randomization Study

Abstract

OBJECTIVE The Mexican population experiences a notably high prevalence of type 2 diabetes (T2D) and high T2D-associated disease risks. We used targeted plasma nuclear magnetic resonance metabolomics data within a Mendelian randomization framework to characterize the metabolomic profile of genetically predicted liability to T2D in this population. RESEARCH DESIGN AND METHODS Between 1998 and 2004, 50,000 men and 100,000 women aged ≥35 years were recruited from Mexico City. Mendelian randomization analyses used a genetic risk score (GRS) comprising 1,055 established T2D-associated risk variants and eight pathway-specific T2D GRSs constructed from nonoverlapping subsets of these variants to estimate associations with 143 metabolic biomarkers (including lipids, lipoproteins, fatty acids, amino acids, ketone bodies, and other low-molecular-weight biomarkers). RESULTS Among 125,587 included participants, the T2D GRS explained 6.0% of T2D liability and was not associated with major potential confounders of the relationships of T2D with the circulating metabolome. Genetically predicted liability to T2D was strongly positively associated with concentrations of VLDL particles and lipids within these, with triglycerides, branch-chain amino acids, and glycoprotein acetyls, and more modestly positively associated with intermediate-density lipoprotein and LDL, particularly small LDL, particles. Inverse associations were found with relative concentrations of several fatty acids. Pathway-specific T2D GRSs all associated with higher T2D risk but showed differential relationships with circulating metabolic biomarkers. CONCLUSIONS T2D is associated with widespread changes in the circulating metabolome among adults in Mexico, reflecting diverse biological mechanisms and highlighting the importance of effective T2D management, including control of T2D-associated dyslipidemia, in this population.