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00925njm 22002777a 4500 dc Corella, Dolores author Coltell, Oscar author Sorli, Jose V. author Estruch, Ramon author Quiles, Laura author Angel Martinez-Gonzalez, Miguel author Salas-Salvado, Jordi author Castaner, Olga author Aros, Fernando author Ortega-Calvo, Manuel author Serra-Majem, Lluis author Gomez-Gracia, Enrique author Portoles, Olga author Fiol, Miquel author Diez Espino, Javier author Basora, Josep author Fito, Montserrat author Ros, Emilio author Ordovas, Jose M author 2016 Nutrigenetic studies analyzing gene-diet interactions of the TCF7L2-rs7903146 C > T polymorphism on type-2 diabetes (T2D) have shown controversial results. A reason contributing to this may be the additional modulation by obesity. Moreover, TCF7L2-rs7903146 is one of the most influential variants in T2D-genetic risk scores (GRS). Therefore, to increase the predictive value (PV) of GRS it is necessary to first see whether the included polymorphisms have heterogeneous effects. We comprehensively investigated gene-obesity interactions between the TCF7L2-rs7903146 C > T polymorphism on T2D (prevalence and incidence) and analyzed other T2D-polymorphisms in a sub-sample. We studied 7018 PREDIMED participants at baseline and longitudinally (8.7 years maximum follow-up). Obesity significantly interacted with the TCF7L2-rs7903146 on T2D prevalence, associations being greater in non-obese subjects. Accordingly, we prospectively observed in non-T2D subjects (n = 3607) that its association with T2D incidence was stronger in non-obese (HR: 1.81; 95\% CI: 1.13-2.92, p = 0.013 for TT versus CC) than in obese subjects (HR: 1.01; 95\% CI: 0.61-1.66; p = 0.979; p-interaction = 0.048). Accordingly, TCF7L2-PV was higher in non-obese subjects. Additionally, we created obesity-specific GRS with ten T2D-polymorphisms and demonstrated for the first time their higher strata-specific PV. In conclusion, we provide strong evidence supporting the need for considering obesity when analyzing the TCF7L2 effects and propose the use of obesity-specific GRS for T2D. Nutrients. 2016; 8(12):793 10.3390/nu8120793 2072-6643 Nutrients http://hdl.handle.net/20.500.13003/10080 27929407 L613545861 2-s2.0-85003946080 http://hdl.handle.net/20.500.12105/5172 389144100041 TCF7L2 Type-2 diabetes Obesity T2D-genetic risk scores TCF7L2-predictive value PREDIMED study SUSCEPTIBILITY LOCI MEDITERRANEAN DIET INSULIN-RESISTANCE COMMON VARIANTS BODY-FAT ASSOCIATION POPULATION PREVENTION TRIAL MASS Polymorphism of the Transcription Factor 7-Like 2 Gene (TCF7L2) Interacts with Obesity on Type-2 Diabetes in the PREDIMED Study Emphasizing the Heterogeneity of Genetic Variants in Type-2 Diabetes Risk Prediction: Time for Obesity-Specific Genetic Risk Scores