Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes

Grant, Struan F A; Þorleifsson, Guðmar; Reynisdóttir, Inga; Benediktsson, Rafn; Manolescu, Andrei; Sainz, Jesús; Helgason, Agnar; Stefánsson, Hreinn; Emilsson, Valur; Helgadóttir, Anna; Styrkársdóttir, Unnur; Magnússon, Kristinn P.; Walters, G. Bragi; Pálsdóttir, Ebba; Jónsdóttir, Þorbjörg; Gudmundsdottir, Thorunn; Gylfason, Arnaldur; Saemundsdottir, Jona; Wilensky, Robert L.; Reilly, Muredach P.; Rader, Daniel J.; Bagger, Yu Z.; Christiansen, Claus; Gudnason, Vilmundur; Sigurðsson, Gunnar; Þorsteinsdóttir, Unnur; Gulcher, Jeffrey R.; Kong, Augustine; Stefánsson, Kári

doi:10.1038/ng1732

Cited by 2,018 publications

(1,721 citation statements)

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“…Data are expressed as mean+SEM. *p< 0.05 si5-LO1 and/or si5-LO2 vs scramble siRNA genes controlling beta cell function also play an important role in adult-onset type 2 diabetes, suggesting that insulin secretion-related mechanisms may make more significant genetic contributions to common forms of type 2 diabetes than previously recognised [22][23][24][25][26]. Thus, identification of novel pathways regulating beta cell function and/or insulin secretion may lead to a better understanding of type 2 diabetes and its underlying aetiology.…”

Section: Discussionmentioning

confidence: 99%

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

et al. 2008

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Aims/hypothesis We previously used an integrative genetics approach to demonstrate that 5-lipoxygenase (5-LO) deficiency in mice (Alox5 −/− ) protects against atherosclerosis despite increasing lipid levels and fat mass. In the present study, we sought to further examine the role of 5-LO in adiposity and pancreatic function. Methods Alox5 −/− and wild-type (WT) mice were characterised with respect to adiposity and glucose/insulin metabolism using in vivo and in vitro approaches. The role of ALOX5 in pancreatic function in human islets was assessed through short interfering RNA (siRNA) knockdown experiments. Results Beginning at 12 weeks of age, Alox5 −/− mice had significantly increased fat mass, plasma leptin levels and fasting glucose levels, but lower fasting insulin levels (p< 0.05). Although Alox5 −/− mice did not exhibit insulin resistance, they had impaired insulin secretion in response to a bolus glucose injection. Histological analyses revealed Diabetologia (2008) that Alox5 −/− mice had increased islet area, beta cell nuclear size, and numbers of beta cells/mm 2 islet (p < 0.05), indicative of both hyperplasia and hypertrophy. Basal and stimulated insulin secretion in isolated Alox5 −/− islets were significantly lower than in WT islets (p <0.05) and accompanied by a three-to fivefold decrease in the expression of the genes encoding insulin and pancreatic duodenal homeobox 1 (Pdx1). Direct perturbation of ALOX5 in isolated human islets with siRNA decreased insulin and PDX1 gene expression by 50% and insulin secretion by threefold (p<0.05). Conclusions/interpretation These results provide strong evidence for pleiotropic metabolic effects of 5-LO on adiposity and pancreatic function and may have important implications for therapeutic strategies targeting this pathway for the treatment of cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

et al. 2008

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“…Grant et al (2006) identified DG10S478 located in intron 3-exon 4 of the TCF7L2 gene on chromosome 10q25.2 (in a well-defined LD block of 92.1 kb based on CEU HapMap v16; GenBank NM 030756) that had an r 2 of 0.95 with the rs12255372 SNP [6]. The authors suggest that the TCF7L2 variants increase T2D risk by altering proglucagon gene expression [6] in enteroendrocrine cells [24] via the Wnt signaling pathway [26]. Florez et al (2006) reported that individuals with the TT genotype have decreased insulin secretion [7].…”

Section: Discussionmentioning

confidence: 99%

“…Polymorphisms in TCF7L2 have been associated with disease susceptibility. Specifically, Grant et al (2006) demonstrated that a polymorphism in TCF7L2 is associated with increased risk of type II diabetes (T2D) [6][7][8][9][10][11][12] by impaired beta-cell function [7,9]. Epidemiologic studies have suggested that hyperinsulinemia may be related to the risk of colon adenoma and cancer [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk

Hazra

Fuchs

Chan

et al. 2008

Cancer Causes Control

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Interaction of TCF7l2 with translocated β-catenin in the nucleus transiently converts TCF7L2 to transcription factor activators, which induce the expression of target genes, including cyclin D1 and c-myc, in colorectal carcinogenesis. We evaluated the association of a polymorphism in TCF7L2 (RS12255372) which previously has been strongly associated with risk of Type II Diabetes, with colorectal cancer (CRC) and adenoma in the prospective Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) cohorts. In the NHS and HPFS control populations, the TCF7L2 T-allele frequency ranged from 28 to 30% and the genotype distribution was in agreement with Hardy-Weinberg equilibrium. Overall, there was suggestive evidence for an inverse association associated with homozygosity for the minor allele of RS12255372 (TCF7L2 TT) and CRC (conditional and covariate adjusted OR=0.63, 95%CI: 0.37-1.08; P for heterogeneity 0.52 for the association in women and men), which was more evident among women (OR=0.39, 95%CI: 0.16 -0.91). The polymorphism was not associated with risk of colorectal adenoma. Furthermore, we observed no evidence of effect modification between the TCF7L2 SNP and covariates such as family history or with genetic variants in the APC Asp1822Val SNP (NHS cancer p-interaction=0.40, NHS adenoma p-interaction 0.10). In summary, the marginal association of TCF7L2 SNP with CRC may be due to chance, but warrants further laboratory and epidemiological investigation.

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“…However, still lacking is knowledge on whether patients with LADA have the same frequency of the few type 2 diabetes susceptibility genes that have reproducibly been associated with type 2 diabetes, e.g. the Pro12Ala single-nucleotide polymorphism in PPARG, the E23K SNP in KCNJ11, or the recently described polymorphisms in TCF7L2 [13][14][15].…”

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confidence: 99%