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

Identifier:  imarina:2657402

Handle: https://hdl.handle.net/20.500.11797/imarina2657402

Authors:  Corella, Dolores; Coltell, Oscar; Sorli, Jose V; Estruch, Ramon; Quiles, Laura; Angel Martinez-Gonzalez, Miguel; Salas-Salvado, Jordi; Castaner, Olga; Aros, Fernando; Ortega-Calvo, Manuel; Serra-Majem, Lluis; Gomez-Gracia, Enrique; Portoles, Olga; Fiol, Miquel; Diez Espino, Javier; Basora, Josep; Fito, Montserrat; Ros, Emilio; Ordovas, Jose M

Abstract:
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.