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...

Authors: CORELLA, DOLORES - University Of Valencia; COLTELL, OSCAR - University Jaume I Of Castellon; SORLI, JOSE - University Of Valencia; ESTRUCH, RAMÓN - Instituto De Salud Carlos Iii; QUILES, LAURA - University Of Valencia; MARTÍNEZ-GONZÁLEZ, MIGUEL - University Of Navarra; SALAS-SALVADO, JORDI - University Rovira I Virgili; CASTANER, OLGA - Hospital Del Mar Medical Research Institute; ARÓS, FERNANDO - Hospital Txagorritxu; ORTEGA-CALVO, MANUEL - Hospital Del Mar Medical Research Institute; SERRA-MAJEM, LLUÍS - University Of Las Palmas De Gran Canaria; GOMEZ-GRACIA, ENRIQUE - University Of Malaga; PORTOLES, OLGA - University Of Valencia; FIOL, MIQUEL - Son Espases Hospital; ESPINO, JAVIER DIEZ - University Of Navarra; BASORA, JOSEP - University Rovira I Virgili; FITO, MONTSERRAT - Hospital Del Mar Medical Research Institute; ROS, EMILIO - Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS); ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Nutrients
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/17/2016
Publication Date: 12/6/2016
Citation: Corella, D., Coltell, O., Sorli, J.V., Estruch, R., Quiles, L., Martínez-González, M.Á., Salas-Salvado, J., Castaner, O., Arós, F., Ortega-Calvo, M., Serra-Majem, L., Gomez-Gracia, E., Portoles, O., Fiol, M., Espino, J., Basora, J., Fito, M., Ros, E., Ordovas, J.M. 2016. 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. Nutrients. 8(12):793. https://doi.org/10.3390/nu8120793.

Interpretive Summary: Obesity and diabetes are two related and common diseases in Westernized societies. Both are determined by a complex mix of genetic and environmental factors. One the best known genetic factors affecting both of these diseases is the TCF7L2 gene. Previous studies looking at 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. Therefore, it is important to know the relative contribution of these multiple players (T2D, obesity, TCF7L2 and diet). We investigated gene-obesity interactions between the TCF7L2-rs7903146 C>T polymorphism on T2D. We studied 7,018 PREDIMED participants at baseline and longitudinally over ~9 years. Obesity significantly interacted with the TCF7L2-rs7903146 on T2D prevalence, with a greater association in non-obese subjects. Accordingly, we prospectively observed in non-T2D subjects that its association with T2D incidence was stronger in non-obese than in obese subjects. Accordingly, TCF7L2-predictive value was higher in non-obese subjects. In conclusion, we provide strong evidence supporting the need for considering obesity when analyzing TCF7L2 effects and propose the use of obesity-specific genetic risk scores for T2D.

Technical 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.