Corella, DoloresColtell, OscarSorlí, Jose VEstruch, RamónQuiles, LauraMartínez-González, Miguel ÁngelSalas-Salvadó, JordiCastañer, OlgaArós, FernandoOrtega-Calvo, ManuelSerra-Majem, LluísGómez-Gracia, EnriquePortolés, OlgaFiol, MiquelDíez Espino, JavierBasora, JosepFitó, MontserratRos, EmilioOrdovás, José M2025-01-072025-01-072016-12-06https://hdl.handle.net/10668/25674Nutrigenetic 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/PREDIMED studyT2D-genetic risk scoresTCF7L2TCF7L2-predictive valueobesitytype-2 diabetesAdultAgedAged, 80 and overDiabetes Mellitus, Type 2FemaleGenetic HeterogeneityGenetic MarkersGenetic Predisposition to DiseaseGenetic VariationHumansIncidenceLongitudinal StudiesMaleMiddle AgedNutrigenomicsObesityPolymorphism, GeneticPredictive Value of TestsPrevalenceProspective StudiesRisk FactorsTranscription Factor 7-Like 2 Proteinresearch article27929407open access10.3390/nu81207932072-6643PMC5188448https://www.mdpi.com/2072-6643/8/12/793/pdf?version=1480994002https://pmc.ncbi.nlm.nih.gov/articles/PMC5188448/pdf