ADRB3, LEPR, FTO and PPARG variants contribute to obesity-related metabolic syndrome in Brazilian adults: a polygenic risk score approach

Abstract Objective Polymorphisms in genes involved in obesity-related metabolic pathways are associated with metabolic syndrome (MetS). We hypothesized that variants in FTO, LEP, LEPR, ADRB3, ADIPOQ , TCF7L2 , ENPP1 , APOA5, PPARG , and CYP11B2 are associated with MetS and obesity-related traits. Methods A group of 420 subjects (179 with MetS and 241 without MetS) was selected from a Brazilian adult cohort. Clinical, anthropometric, metabolic and inflammatory data were assessed. Genetic variants were analyzed by qPCR and their association with non-genetic variables were explored using multivariate logistic and linear regression analyses. Using logistic regression results weighted by clinically relevant variants, we evaluated the prognostic capability of a polygenic risk score (PRS) model for MetS risk. Results ADRB3 rs4994A>G (OR:3.71, 95%CI:1.71-8.03, p = 0.001) and LEPR rs1137100A>G (OR: 2.52, 95%CI: 1.33-4.79, p = 0.005) were associated with high risk of MetS. ADRB3 rs4994A>G, LEPR rs1137100A>G, FTO rs17817449T>G and PPARG rs1801282C>G predicted anthropometric, metabolic and inflammatory alterations related to MetS ( p < 0.05). Normalized values of PRS (nPRS) were higher in subjects with MetS, although ROC analysis demonstrated to discriminate MetS with limited sensitivity (AUC-ROC = 0.616, p < 0.001), increasing values of nPRS were associated with higher number of MetS components ( p < 0.001). Conclusion Variants in ADRB3, LEPR , FTO and PPARG play an important role in adiposity related to MetS, contributing to metabolic disturbances and pro-inflammatory state that increase cardiovascular risk in adult subjects. The integration of these variants into a polygenic risk score highlights a cumulative genetic susceptibility, as reflected by higher scores in MetS and a clear gradient across the number of MetS components.