Corella, DoloresColtell, OscarSorli, Jose V.Estruch, RamonQuiles, LauraAngel Martinez-Gonzalez, MiguelSalas-Salvado, JordiCastaner, OlgaAros, FernandoOrtega-Calvo, ManuelSerra-Majem, LluisGomez-Gracia, EnriquePortoles, OlgaFiol, MiquelDiez Espino, JavierBasora, JosepFito, MontserratRos, EmilioOrdovas, Jose M.2023-02-122023-02-122016-12-012072-6643http://hdl.handle.net/10668/19310Nutrigenetic 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/TCF7L2type-2 diabetesobesityT2D-genetic risk scoresTCF7L2-predictive valuePREDIMED studySusceptibility lociCommon variantsAssociationPreventionPopulationDiseaseTraitsWeightresearch articleopen access10.3390/nu8120793https://www.mdpi.com/2072-6643/8/12/793/pdf389144100041