Metabolomic Signatures of Prediabetes in Mexican Americans: The Role of Genetics and Macronutrients

Prediabetes is one of the main health concerns in public health, and various etiological factors contribute to its onset. This study aimed to evaluate genetic associations and gene-macronutrient interaction with prediabetes-related metabolites to understand how genetic variation and dietary intake contribute to dysglycemia. We analyzed a total of 482 self-identified Mexican American participants recruited from Starr County, Texas in 2018-2019. Untargeted metabolomic profiling was performed using LC-MS. Nutrient densities of six macronutrients were derived from a 106-item food frequency questionnaire. Genetic associations for each metabolite were tested using Generalized linear Mixed Model Association Tests (GMMAT). Gene-macronutrient interactions on prediabetes-associated metabolites were assessed with the Mixed Model Association Test for GEne-Environment Interaction (MAGEE). Age, gender, and BMI were included as covariates in all association tests. Among 308 named and 2,471 unnamed metabolites, 17 novel variant-metabolite pairs were discovered, including rs10947898 in LRFN2 associated with diacylglycerol DG32:1(p-value: 8.95E-09). Among 145 named and 687 unnamed metabolites after filtering, gene-macronutrient interaction analyses identified seven named metabolites, including a variant(rs111251222) in MXD3 that interacted with monounsaturated fat to influence eicosadienoic acid levels (Interaction p-value: 9.88E-09). Prediabetes and nutrient-related metabolites in Mexican Americans showed significant genetic associations and gene-nutrient interactions.