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

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.

The Diabetes Gene and Wnt Pathway Effector TCF7L2 Regulates Adipocyte Development and Function

“…In humans, the effect of the TCF7L2 risk allele on T2DM is modulated by obesity, and T2DM prevalence is higher in nonobese carriers (11,12). Moreover, TCF7L2 SNPs have been associated with obesity (58), but this association remains controversial and may be the result of ascertainment bias (59).…”

“…Consistent with an inhibitory effect of Wnt activation on adipogenesis, overexpression of TCF7L2 lacking its b-catenin binding domain promotes adipogenesis in preadipocytes and in L6 myotubes (4,10). In humans, obesity interacts with the TCF7L2 risk allele to enhance T2DM prevalence in nonobese subjects (11,12), and the TCF7L2 gene is differentially methylated in adipose tissue of patients with T2DM (13). Moreover, weight loss after gastric bypass surgery led to differential expression of TCF7L2 mRNA isoforms in subcutaneous fat biopsy samples.…”

Impact of Genetic Variants on the Individual Potential for Body Fat Loss

“…Recent studies have uncovered the association among obesity, genetic factors, and dietary habit or physical activity. They include genetic loci contributing to dietary habit on obesity, the effects of gene-environment interactions on obesity, and modifying effects of dietary habit on the association between genetic factors and obesity [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. As rising life expectancy, the biological insights about obesity from previous studies led to present the need for the personalized diet.…”

Science and Healthy Meals in the World: Nutritional Epigenomics and Nutrigenetics of the Mediterranean Diet

“…It is widely known that obesity, already a social/medical problem per se, is related with T2D [118], but only few nutrigenetic studies have described a very close link between specific polymorphism(s), obesity, and T2D risk. Nutrigenetic studies within a cohort of MD consumers showed a close relation between the allelic variants rs7903146 C>T in the Transcription Factor 7-Like 2 (TCF7L2) gene, obesity, and T2D [119]. By analyzing several parameters in multiple complex correlations, including adherence to MD, and by extending the study to other polymorphic T2D-related genes, the authors have obtained a specific "genetic risk score" for each obesity-related allele, and in doing so they have provided a semi-quantitative tool for all owners of risky genotypes to counteract their susceptibility, at least to T2D, by the consumption of specific MD foods.…”