Genetic prediction of the metabolic syndrome

SummaryBackgroundThe metabolic syndrome (MetS) is a constellation of factors associated with increased risk of cardiovascular disease (CVD) and type 2 diabetes (T2D). It has been difficult to identify an underlying unifying pathogenic mechanism for the different components. As the syndrome shows high heritability one way to search for such common mechanisms could to be to try to identify genetic variants contributing to MetS.MethodsIn total 1937 of 2293 non-diabetic individuals participating in the Botnia prospective study were free of MetS at baseline (M/F: 873/1064; age 44 ± 14 years; BMI 25 ± 4 kg/m2; 25% had IFG or IGT or both). Variants in the peroxisome proliferator-activated receptor gamma (PPARG P12A), β1-, β2- and β3-adrenergic receptor (ADRB1 G389R; ADRB2 Q27E; ADRB3 W64R), adiponectin (APM1 SNP −11,377 C > G, 276 G > T, I2019D), and PPARG co-activator-1 alpha (PPARGC1A G482S) genes were studied for their ability to predict MetS defined using the NCEP ATPIII criteria. We also repeated the analyses using the WHO and IDF criteria for defining MetS.ResultsDuring a median 6-year follow-up, 267 (13.8%) persons developed MetS. The PPARG (PP) (HR 1.49 [1.10–3.01], P = 0.011) and the ADRB1 G389R (GG/GR) (1.43 [1.14–1.80], P = 0.0022) predicted future MetS. ADRB1 G389R and ADRB3 W64R variants showed an interaction effect, implying that the MetS risk was further increased if an individual carried both GG/GR and RR/WR genotypes (2.02 [1.34–3.05], P < 0.001). Among the individual MetS components, the PP (PPARG) and GG/GR (ADRB1) genotypes were associated with increase in triglycerides (coefficient 0.016 and 0.0162, P < 0.05; respectively). In addition, the GG/GR genotypes (coefficient 0.013, P = 0.036) were also associated with increase in fasting glucose concentrations over time. Variants in the ADRB2, APM1 and PPARGC1A genes did not influence risk of future MetS.ConclusionWe demonstrate in a prospective study that variants in the PPARG and ADRB1 genes predict development of MetS and that the risk conferred by the ADRB1 variant is further increased by variants in the ADRB3 gene.