ObjectivesA risk haplotype in SLC16A11 characterized by alterations in fatty acid metabolism emerged as a genetic risk factor associated with increased susceptibility to type 2 diabetes (T2D) in Mexican population. Its role on treatment responses is not well understood. We aim to determine the impact of the risk haplotype on the metabolomic profile during a lifestyle intervention (LSI). MethodsWe recruited Mexican-mestizo individuals with at least one prediabetes criteria according to the American Diabetes Association with a BMI between 25 and 45 kg/m2. We conducted a 24-week quasi-experimental LSI study for diabetes prevention. Here, we compared longitudinal plasma Liquid Chromatography /Mass Spectrometry metabolomic changes between carriers and non-carriers. We analyzed the association of risk haplotype with metabolites leveraging repeated assessments using multivariable adjusted linear mixed models. ResultsBefore the intervention, carriers (N=21) showed higher levels of hippurate, C16.carnitine, glycine, and cinnamoylglycine. After 24 weeks of lifestyle intervention (LSI), carriers exhibited a deleterious metabolomic profile. This profile was characterized by increased levels of hippurate, cinnamoglycine, xanthosine, N-acetylputrescine, L-Acetylcarnitine, Ceramide(d18:1/24:1), and decreased levels of citrulline and Phosphatidylethanolamine (P-36:4)/PE(O-36:5). These metabolites were associated with higher levels of total cholesterol, triglycerides and LDL-C. The effect of LSI on the risk haplotype was notably more pronounced in its impact on two metabolites: methylmalonylcarnitine (Interaction beta= -0.56, P interaction= 0.014) and betaine (Interaction beta= -0.64, P interaction=0.017). Interestingly, lower consumption across visits of polyunsaturated (β= -0.038, P= 0.017) fatty acids were associated with higher levels of methylmalonylcarnitine. Covariates for adjustment across models included age, sex, genetic ancestry principal components and BMI. ConclusionsOur study highlights the persistence of deleterious metabolomic patterns associated with the risk haplotype before and during a 24-week LSI. We also emphasize the potential regulatory role of polyunsaturated fatty acids on methylmalonylcarnitine levels suggesting a route for improving interventions for individuals with high genetic risk.