Unraveling the potential effects of non-synonymous single nucleotide polymorphisms (nsSNPs) on the Protein structure and function of the human SLC30A8 gene on type 2 diabetes and colorectal cancer: An In silico approach
M. M. UddinMd. Tanvir HossaınMd. Arju HossainAsif AhsanKamrul Hasan ShamimMd. Arif HossenMd. Shahinur RahmanMd Habibur RahmanKawsar AhmedFrancis M. BuiKawsar Ahmed
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TCF7L2
Objective: Single nucleotide polymorphisms (SNPs) within the transcription factor 7-like 2 (TCF7L2) gene are well known risk variants for type 2 diabetes (T2DM). The rs7903146 SNP is involved in glucose- and incretin-induced insulin secretion and in proinsulin conversion. The aim of this international multicentric retrospective analysis was to assess and compare the effect of the TCF7L2 rs7903146 T risk variant on the development and clinical course of gestational diabetes mellitus (GDM).
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Economic affluence has altered Indian lifestyles, which is seen to be the primary contributing factor to the country's current diabetes epidemic. There is, however, insufficient evidence that Indian populations are aware of the loci related to type 2 diabetes. To determine the degree of genetic variability, it is important to assess the previously linked gene candidates as well as find additional genetic variations in Indian communities. Type 2 diabetes mellitus (T2DM), a complicated disease, is caused by a genetic predisposition as well as several environmental factors that interact significantly. The transcription factor 7-like-2 gene (TCF7L2) single nucleotide polymorphisms rs7903146 (C/T) and rs12255372 (G/T) have been proven to be the most sensitive genes to T2DM, influencing pancreatic islet formation via the Wnt/-catenin signaling pathway. The TCF7L2 gene polymorphism and its usage in the early diagnosis and prognosis of diabetes mellitus will be summarized in this chapter along with the present state of knowledge and clinical relevance.
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Objective: Single nucleotide polymorphisms (SNPs) within the transcription factor 7-like 2 (TCF7L2) gene are recognized risk variants for type 2 diabetes (T2D). The aim of this international multicentric analysis was to evaluate the effect of the T risk variant rs7903146 on the development and clinical course of GDM.
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Objectives: The aim of this study was to investigate the possible role of TCF7L2 rs 7903146 (C/T) variant on susceptibility of T2DM among Egyptian children and adolescents. Patients and methods: 30 T2DM pediatric patients, 20 obese children and 20 control subjects were enrolled in the study and subjected to: anthropometric measurements, routine laboratory studies including lipid profile, fasting serum insulin level and homeostatic model assessment of insulin secretion and β cell function. The rs7903146 (C/T) polymorphism was genotyped using the PCR-RFLP method. Results: T allele of TCF7L2 rs7 903146 (C/T) was associated with T2DM in the study (P<0.001; OR=5.96, 95% CI: (2.58-16.22). Haplotype analyses showed a higher distribution of haplotype TT in the T2DM patients than the control group [56.7% vs. 15.0%, P<0.002; χ2=11.66]. Association of TCF7L2 rs7903146 and clinical and metabolic measures in T2D patients revealed significantly lower levels of fasting insulin and Homa β among carriers of T allele. Also, no significant interaction was found between T2D risk and BMI (SDS) regarding rs7903146 SNP. Conclusion: Our data prove that rs7903146 (C/T) variant of the TCF7L2 gene is associated with T2DM in our study.
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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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Background Type 2 diabetes mellitus (T2DM) is a very common polygenic metabolic disorder. Single-nucleotide polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene have been reported to affect T2DM susceptibility by affecting insulin secretion and via its involvement in the Wnt signaling pathway. Patients and methods The present study investigated the association of rs7903146(C/T) polymorphism of the TCF7L2 gene with T2DM. The study involved 42 Egyptian adults who were diagnosed with T2DM and 42 healthy adults taken as controls. Allele-specific PCR was performed to detect TCF7L2 gene polymorphism. Results No association was found between the rs7903146 polymorphisms of TCF7L2 gene and susceptibility to T2DM, using both dominant and recessive models. Conclusion In our study, we could not prove the suggested association between rs7903146(C/T) polymorphism of the TCF7L2 gene and T2DM in Egyptians. Further Egyptian studies are needed to confirm the results of this study.
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Single nucleotide polymorphisms of the TCF7L2 gene demonstrate the strongest association with the risk of developing type 2 diabetes, linking its effects to changes in insulin secretion. The mechanism of action of hypoglycaemic drugs used in treatment of type 2 diabetes is, to a certain extent, related to their influence on the function of β-cells, which implies that variants of the TCF7L2 gene will affect the therapeutic effect of certain anti-hyperglycaemic drugs, including the variability in the effects of incretin-based therapy, and sulphonylurea derivatives. Along with the direct influence of the TCF7L2 gene on the function of β-cells, there is evidence of the effects of TCF7L2 gene polymorphism on the susceptibility to external risk factors associated with the development of type 2 diabetes, including the alimentary factors. Pharmacogenetic studies in diabetology have at present the greatest potential in terms of selection of the optimal comprehensive anti-hyperglycaemic therapy based on preliminary genetic testing, which might improve the outcomes of treatment and the prognosis for the course of type 2 diabetes, reducing the number of life-threatening complications. Key words: GPP-1 agonists, TCF7L2 gene, metformin, nutrition, type 2 diabetes, sulphonylureas
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