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

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.