TCF7L2 is associated with type 2 diabetes in nonobese individuals from Tunisia

Bouhaha, R.; Choquet, Hélène; Meyre, David; Kamoun, Hassen; Ennafaa, Hajer; Baroudi, Thouraya; Sassi, R.; Vaxillaire, Martine; Elgaaïed, Amel Benammar; Froguel, Philippe; Cauchi, Stéphane

doi:10.1016/j.patbio.2009.01.003

Cited by 15 publications

(16 citation statements)

References 15 publications

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“…While this is the case in other population groups, some studies reported a weak 33,34 or no association [35][36][37][38] . Other studies highlighted the effect of the TCF7L2 polymorphisms on the progression of T2DM 35,39 , in some ethnic population groups these variants were associated with responses to medication 40,41 , and in others their effect on the disease was modulated by the type of diet [42][43][44] .Our results [1.43 (1.00 to 2.04), p= 0.053] are comparable to those reported for other African ethnic population groups 17,18,20 . It is possible that TCF7L2 polymorphisms have different effects in various ethnic population groups depending on the diet.…”

Section: Discussionsupporting

confidence: 81%

“…Although few number of T2DM susceptibility genes discovered through candidate gene, linkage analyses, and GWA studies elsewhere have been replicated in African studies [16][17][18][19][20][21] , it must also be emphasized that many other association studies failed to show significant and replicable findings [22][23][24] . Therefore in this study we investigated three genes, namely, TCF7L2, FTO, and ENPP1 as risk factors for T2DM in a South African ethnic population group of Mixed-ancestry (Coloureds) with a unique genetic architecture.…”

Section: Introductionmentioning

confidence: 99%

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Contribution of ENPP1, TCF7L2, and FTO polymorphisms to type 2 diabetes in mixed ancestry ethnic population of South Africa

et al. 2016

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Background: Transcription factor 7-like 2 gene (TCF7L2), fat mass and obesity-associated gene (FTO), and ectonucleotide pyrophosphatase/phosphodiesterase gene (ENPP1) are known risk loci for type 2 diabetes (T2DM) mostly in European populations. Objectives: To assess the association of these genes with T2DM risk in a South African mixed-ancestry population. Methods: Five hundred and sixty six participants were genotyped for ENPP1-rs997509 and -rs1044498, FTO-9941349 and -rs3751812, TCF7L2-rs12255372 and -rs7903146 polymorphisms using Taqman genotyping assays and validated by automated sequencing to assess the association of the polymorphisms with cardiometabolic traits. Results: In logistic regression models adjusted for age, sex, body mass index (BMI) and insulin resistance, minor allele of rs997509 was associated with a higher risk of prevalent T2DM under a recessive model [odd ratio 4.60 (95% confidence interval: 1.07 to 19.86); p = 0.040].Under additive model, the rs7903146 [1.43 (1.00 to 2.04); p= 0.053] and rs9941349 [1.43 (1.00 to 2.04); p = 0.052] minor alleles showed marginally significant associations with a high risk of T2DM. However, only the rs7903146 alleles (p=0.011) and genotypes (p=0.025) distributions were statistically significantly different between diabetic and non-diabetic individuals. Conclusion: Our findings demonstrate that ENPP1, TCF7L2, and FTO may predispose to T2DM in the mixed-ancestry population.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Contribution of ENPP1, TCF7L2, and FTO polymorphisms to type 2 diabetes in mixed ancestry ethnic population of South Africa

et al. 2016

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“…These findings were observed in other populations [12,13,14,15]. Nevertheless, this potential heterogeneity by obesity has not been widely reflected in the analytical approaches of subsequent investigations, and most of them have not formally tested the interaction between the TCF7L2-rs7903146 polymorphism and obesity status in determining T2D risk.…”

Section: Introductionmentioning

confidence: 92%

“…Currently, the rs7903146 C > T Single nucleotide polymorphism (SNP) in the Transcription Factor 7-Like 2 (TCF7L2) gene is the locus most strongly associated with T2D risk at the population level [9,10,11]. However, despite the strong overall association of this SNP with higher T2D risk, various studies have suggested a modulation of this association by obesity [6,12,13,14,15]. …”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, this potential heterogeneity by obesity has not been widely reflected in the analytical approaches of subsequent investigations, and most of them have not formally tested the interaction between the TCF7L2-rs7903146 polymorphism and obesity status in determining T2D risk. A contributory factor is that previous findings were mainly based on cross-sectional or case-control studies [5,6,9,12,13,14] with a strong likelihood of being affected by potential biases, more prospective studies being required to assess this interaction on T2D incidence. Moreover, in addition to the TCF7L-2-rs7903146 SNP, other SNPs have been associated with T2D risk [10,16,17,18].…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2016

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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.

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Wild-type genotypes of BRCA1 gene SNPs combined with micro-RNA over-expression in mammary tissue leading to familial breast cancer with an increased risk of distant metastases’ occurrence

et al. 2014

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Germ line deleterious mutations of BRCA1 gene are not the unique factor that could inactivate BRCA1 protein which leads to familial breast cancer onset with distant metastases' occurrence. The present research explores the role that could be assigned to BRCA1 SNPs to inactivate BRCA1 protein and therefore to the occurrence of familial breast cancer with an increased risk of distant metastases' occurrence. The presence or the absence of BRCA1 protein was first analyzed by applying the immunohistochemistry technique to the tumors with sporadic and familial breast cancer. Then, a case-control study was conducted including 40 patients with familial breast cancer, 46 ones with sporadic breast cancer and 34 healthy controls based on the genotyping of nine BRCA1 SNPs (c.442.58delT, c.2082C>T, c.2311T>C, c.2612C>T, c.3113A>G, c.3119G>A, c.3548A>G, c.4308T>C and 4837A>G) via direct sequencing. Finally, the functional role that could be assigned to these SNPs was focused upon. miRbase site was used as a bioinformatics tool to predict potential micro-RNAs (miRs) targeting SNPs that are associated with familial breast cancer according to the results of this research. These predicted miRs were confirmed by Q-PCR analysis and correlated with BRCA1 protein expression among patients along with potential distant metastases. Clinical outcome showed that distant metastasis concerned 45 % of familial breast cancer patients and 19.5 % with sporadic breast cancer. Analysis of BRCA1 protein expression revealed a negative staining among 46.6 % of familial breast cancer patients and only 16.6 % within sporadic breast cancer ones. The association of four variants was identified within BRCA1 gene (c.442.58 delT, c.2311T>C, c.2612C>T and c.4308T>C) to familial breast cancer across their wild genotypes. miR-1179 was selected as potential miR that targets the region of BRCA1 mRNA containing the c.2311T>C variant within the TT genotype. The expression of miR-1179 was significantly associated with familial breast cancer patients without BRCA1 deleterious mutations compared to those with sporadic breast cancer according to TT genotype along with BRCA1 negative staining and according to the occurrence of distant metastases. Combination between TT genotype of c.2311T>C and miR-1179 over-expression could generate a lack of BRCA1 protein leading to a high risk of familial breast cancer with distant metastases.

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TCF7L2 is associated with type 2 diabetes in nonobese individuals from Tunisia

Cited by 15 publications

References 15 publications

Contribution of ENPP1, TCF7L2, and FTO polymorphisms to type 2 diabetes in mixed ancestry ethnic population of South Africa

Contribution of ENPP1, TCF7L2, and FTO polymorphisms to type 2 diabetes in mixed ancestry ethnic population of South Africa

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

Wild-type genotypes of BRCA1 gene SNPs combined with micro-RNA over-expression in mammary tissue leading to familial breast cancer with an increased risk of distant metastases’ occurrence

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