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      Associations of TCF7L2 gene polymorphisms with the risk of diabetic nephropathy : A case–control study

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          Abstract

          The aim of the study was to explore the correlation between rs7903146 and rs290487 polymorphisms in transcription factor 7-like 2 ( TCF7L2) gene and diabetic nephropathy (DN) in Chinese Han population.

          Polymerase chain reaction–restriction fragment length polymorphism was used to determine genotypes of TCF7L2 polymorphisms in 90 patients with DN and 96 diabetes patients without DN. The linkage disequilibrium (LD) and haplotype analysis were performed with haploview software. Hardy–Weinberg equilibrium was assessed in the control group based on the genotype distributions of TCF7L2 polymorphisms. The genotype, allele, and haplotype distribution differences between the case and control groups were analyzed by chi-squared test, and odds ratio (OR) and 95% confidence interval (CI) were used to indicate the relative risk of DN.

          People carrying TT genotype of rs7903146 were more easily to be attacked by DN than CC genotype carriers ( P = .02, OR = 4.26, 95% CI = 1.12–16.24). Meanwhile, T allele also showed 1.85 times risk to suffer from DN compared with C allele (OR = 1.85, 95% CI = 1.02–3.10). However, there was no significant difference in genotypes and alleles frequencies of rs290487 between 2 groups. The strong LD existed between the 2 single nucleotide polymorphisms and haplotype T–T (rs7903146–rs290487) increased the susceptibility to DN (OR = 2.63, 95% CI = 1.31–5.25).

          TCF7L2 rs7903146 polymorphism may be associated with the susceptibility to DN in Chinese Han population, but rs290487 is not. Additionally, haplotype is also a risk factor for DN.

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          Most cited references30

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          TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta.

          The proglucagon gene (glu) encodes glucagon, expressed in pancreatic islets, and the insulinotropic hormone GLP-1, expressed in the intestines. These two hormones exert critical and opposite effects on blood glucose homeostasis. An intriguing question that remains to be answered is whether and how glu gene expression is regulated in a cell type-specific manner. We reported previously that the glu gene promoter in gut endocrine cell lines was stimulated by beta-catenin, the major effector of the Wnt signaling pathway, whereas glu mRNA expression and GLP-1 synthesis were activated via inhibition of glycogen synthase kinase-3beta, the major negative modulator of the Wnt pathway (Ni, Z., Anini, Y., Fang, X., Mills, G. B., Brubaker, P. L., & Jin, T. (2003) J. Biol. Chem. 278, 1380-1387). We now show that beta-catenin and the glycogen synthase kinase-3beta inhibitor lithium do not activate glu mRNA or glu promoter expression in pancreatic cell lines. In the intestinal GLUTag cell line, but not in the pancreatic InR1-G9 cell line, the glu promoter G2 enhancer-element was activated by lithium treatment via a TCF-binding motif. TCF-4 is abundantly expressed in the gut but not in pancreatic islets. Furthermore, both TCF-4 and beta-catenin bind to the glu gene promoter, as detected by chromatin immunoprecipitation. Finally, stable introduction of dominant-negative TCF-4 into the GLUTag cell line repressed basal glu mRNA expression and abolished the effect of lithium on glu mRNA expression and GLP-1 synthesis. We have therefore identified a unique mechanism that regulates glu expression in gut endocrine cells only. Tissue-specific expression of TCF factors thus may play a role in the diversity of the Wnt pathway.
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            US Renal Data System 2010 Annual Data Report.

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              A role for the beta-catenin/T-cell factor signaling cascade in vascular remodeling.

              Beta-catenin and T cell factor (Tcf) are distal components of the highly conserved Wnt pathway that govern cell fate and proliferation in lower organisms. Thus, we hypothesized that the regulation of beta-catenin and Tcf played a critical role in vascular remodeling. The first objective was to define beta-catenin expression in vascular smooth muscle cells (VSMCs) after balloon injury. Indeed, beta-catenin mRNA and protein were significantly elevated 7 days after balloon injury in the rat carotid artery. We hypothesized that beta-catenin accumulation in response to vascular injury inhibited VSMC apoptosis. In line with our hypothesis, transfection of a degradation-resistant beta-catenin transgene into rat VSMCs significantly inhibited apoptosis. Accumulation of beta-catenin also resulted in a 10-fold increase in the activation of Tcf. To test if Tcf was necessary to confer beta-catenin-induced survival, loss of function studies were carried out with a dominant negative Tcf-4 transgene lacking the beta-catenin binding domain, Tcf4(N31). Indeed, loss of Tcf-4 activity abolished beta-catenin-induced survival. We further postulated that beta-catenin and Tcf promoted cell cycle progression by activating cyclin D1, a target gene of Tcf-4. Beta-catenin activated cyclin D1, and this activation was partially blocked with loss of Tcf-4. In parallel, blockade of Tcf-4 resulted in inhibition of [3H]thymidine incorporation and partial blockade of the G1-S phase transition. In conclusion, beta-catenin and Tcf-4 play a dual role in vascular remodeling by inhibiting VSMC apoptosis and promoting proliferation.
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                Author and article information

                Journal
                Medicine (Baltimore)
                Medicine (Baltimore)
                MEDI
                Medicine
                Wolters Kluwer Health
                0025-7974
                1536-5964
                October 2018
                05 October 2018
                : 97
                : 40
                : e8388
                Affiliations
                [a ]Department of Nephrology
                [b ]Department of Infectious Diseases, Linyi Central Hospital, Linyi, Shandong, China.
                Author notes
                []Correspondence: Shuxia Guo, Department of Nephrology, Linyi Central Hospital, No. 17, Health Road, Yishui County, Linyi, Shandong 276400, China (e-mail: de34hyf@ 123456126.com ).
                Article
                MD-D-17-01008 08388
                10.1097/MD.0000000000008388
                6200515
                30290587
                0b9c9c66-9372-4275-a3e4-089dcc31dbe3
                Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0

                History
                : 17 February 2017
                : 26 September 2017
                Categories
                5300
                Research Article
                Observational Study
                Custom metadata
                TRUE

                diabetic nephropathy,haplotype,polymorphism,tcf7l2 gene
                diabetic nephropathy, haplotype, polymorphism, tcf7l2 gene

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