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Other entities represented in this entry:
HGNC Approved Gene Symbol: TCF7L2
Cytogenetic location: 10q25.2-q25.3 Genomic coordinates (GRCh38): 10:112,950,247-113,167,678 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q25.2-q25.3 | {Diabetes mellitus, type 2, susceptibility to} | 125853 | Autosomal dominant | 3 |
The TCL7L2 gene product is a high mobility group (HMG) box-containing transcription factor implicated in blood glucose homeostasis. The study of Yi et al. (2005) suggested that TCL7L2 acts through regulation of proglucagon (138030) through repression of the proglucagon gene in enteroendocrine cells via the Wnt signaling pathway.
The HMG box is a DNA-binding domain. TCF7 (189908), also called TCF1, and LEF1 (153245), also called TCF1-alpha, are human lymphoid transcription factors that contain a virtually identical HMG box. By PCR of human genomic DNA using degenerate oligonucleotides based on the HMG boxes of TCF7 and LEF1, Castrop et al. (1992) identified the TCF7L1 (604652) and TCF7L2 genes, which they called TCF3 and TCF4, respectively. TCF7L1 and TCF7L2 were not expressed in cells of the lymphoid lineage. The deduced amino acid sequences of the HMG boxes of TCF7L1, TCF7L2, and TCF7 show striking homology. The authors suggested the existence of a subfamily of TCF7-like HMG box-containing transcription factors.
Prokunina-Olsson et al. (2009) identified several TCF7L2 splice variants. The full-length protein contains an N-terminal beta-catenin (CTNNB1; 116806)-binding domain, followed by a Groucho (TLE1; 600189)-interacting domain, an evolutionarily conserved C-terminal CRARF (MASP1; 600521)-type domain, and a C-terminal CTBP (602618)-binding site. Using primers based on common exons for PCR analysis, Prokunina-Olsson et al. (2009) detected highest overall TCF7L2 expression in pancreas, followed by colon, brain, small intestine, monocytes, and lung. Lower expression was detected in all other tissues examined, and little to no expression was detected in activated or resting T and B cells. Exon-specific PCR showed tissue-specific expression of several splice variants. Transcripts lacking exons 1 and 2 were predicted to encode proteins lacking the beta-catenin-binding domain. Transcripts containing exon 13b, which encode proteins lacking the CTBP-binding site, were detected only in pancreatic islets, pancreas, and colon. Prokunina-Olsson et al. (2009) concluded that alternative splicing results in TCF7L2 proteins that either repress or activate the WNT signaling pathway.
Inactivation of the APC gene (611731) in colorectal cancers (114500) allows beta-catenin (CTNNB1; 116806) to accumulate and complex with the TCF4 transcription factor, thereby activating the expression of TCF4-regulated genes (Korinek et al., 1997; Morin et al., 1997). That gene activation by the beta-catenin/TCF4 complex is a critical event in cancer development is indicated by the fact that a subset of colorectal cancers that lack somatic mutations in APC show somatic mutations in the beta-catenin gene. These mutations are presumed to render beta-catenin insensitive to regulation by APC and GSK3B (605004). Consequently, beta-catenin accumulates and activates TCF4-regulated genes (Morin et al., 1997).
Rodova et al. (2002) presented evidence for beta-catenin-induced expression of PKD1 (601313). They analyzed the promoter region of PKD1 and identified numerous transactivating factors, including 4 TCF-binding elements (TBEs). Beta-catenin induced a reporter construct containing TBE1 6-fold when cotransfected into HEK293T cells, which express TCF4. Dominant-negative TCF4 or deletion of the TBE1 sequence inhibited the induction. Gel shift assays confirmed that TCF4 and beta-catenin could complex with the TBE1 site, and HeLa cells stably transfected with beta-catenin responded with elevated levels of endogenous PKD1 mRNA. Rodova et al. (2002) concluded that the PKD1 gene is a target of the beta-catenin/TCF pathway.
Van de Wetering et al. (2002) showed that disruption of beta-catenin/TCF4 activity in colorectal cancer cells induced a rapid G1 arrest and blocked a genetic program that was physiologically active in the proliferative compartment of colon crypts. Coincidentally, an intestinal differentiation program was induced. The TCF4 target gene MYC (190080) played a central role in this switch by direct repression of the CDKN1A (116899) promoter. Following disruption of beta-catenin/TCF4 activity, the decreased expression of MYC released CDKN1A transcription, which in turn mediated G1 arrest and differentiation. The authors concluded that the beta-catenin/TCF4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells.
Batlle et al. (2002) showed that beta-catenin and TCF inversely control the expression of the EphB2 (600997)/EphB3 (601839) receptors and their ligand, ephrin B1 (EFNB1; 300035), in colorectal cancer and along the crypt-villus axis. Disruption of EphB2 and EphB3 genes revealed that their gene products restrict cell intermingling and allocate cell populations within the intestinal epithelium. In EphB2/EphB3-null mice, the proliferative and differentiated populations intermingled. In adult EphB3 -/- mice, Paneth cells did not follow their downward migratory path, but scattered along crypt and villus. The authors concluded that, in the intestinal epithelium, beta-catenin and TCF couple proliferation and differentiation to the sorting of cell populations through the EphB/ephrin B system.
Nateri et al. (2005) showed that phosphorylated c-JUN (165160) interacts with the HMG-box transcription factor TCF4 to form a ternary complex containing c-JUN, TCF4, and beta-catenin. Chromatin immunoprecipitation assays revealed JNK (see 601158)-dependent c-JUN-TCF4 interaction on the c-JUN promoter, and c-JUN and TCF4 cooperatively activated the c-JUN promoter in reporter assays in a beta-catenin-dependent manner. In the Apc(Min) mouse model of intestinal cancer (see 611731), genetic abrogation of c-JUN N-terminal phosphorylation or gut-specific conditional c-JUN inactivation reduced tumor number and size and prolonged life span. Therefore, Nateri et al. (2005) concluded that the phosphorylation-dependent interaction between c-JUN and TCF4 regulates intestinal tumorigenesis by integrating JNK and APC/beta-catenin, 2 distinct pathways activating WNT (see 164820) signaling.
Glucuronic acid epimerase (GLCE; 612134) is responsible for epimerization of D-glucuronic acid (GlcA) to L-iduronic acid (IdoA) of the cell surface polysaccharide heparan sulfate (HS), endowing the nascent HS polysaccharide chain with the ability to bind growth factors and cytokines. Using stepwise deletion and site-directed mutagenesis, Ghiselli and Agrawal (2005) identified 2 cis-acting binding elements for the beta-catenin-TCF4 complex in the enhancer region of the GLCE promoter. Electrophoretic mobility shift and supershift analyses confirmed binding of beta-catenin-TCF4 to these sequences of GLCE. GLCE expression in human colon carcinoma cell lines correlated with the degree of activation of the beta-catenin-TCF4 transactivation complex. Furthermore, ectopic expression of beta-catenin-TCF4 increased the GLCE transcript level and enhanced the rate of GlcA epimerization in HS. Ghiselli and Agrawal (2005) concluded that the beta-catenin-TCF4 transactivation pathway plays a major role in modulating GLCE expression, thus contributing to regulation of HS biosynthesis and its structural organization.
TCF/LEF proteins form transcriptional units with CTNNB1 in the Wnt signaling pathway during embryogenesis and tumor formation. Yamada et al. (2006) had previously reported that NLK (609476) negatively regulates Wnt signaling via phosphorylation of TCF/LEF proteins. By yeast 2-hybrid and coimmunoprecipitation analyses, they found that Xenopus and human NARF (RNF138; 616319) interacted with NLK. NARF ubiquitinated TCF4 and LEF1, but not NLK, in a dose-dependent manner. Inclusion of wildtype NLK, but not kinase-dead NLK, enhanced the interaction between NARF and TCF4 or LEF1. NLK facilitated NARF-dependent ubiquitination of TCF4 and LEF1 and enhanced proteasome-mediated degradation of TCF4 and LEF1. Reporter gene assays confirmed that NARF inhibited TCF/LEF-dependent activation of a Wnt-responsive element. Expression of Narf in Xenopus embryos inhibited Ctnnb1-dependent secondary axis formation, and knockdown of NARF in HeLa cells enhanced WNT3A (606359)-dependent gene expression. Yamada et al. (2006) concluded that NARF is an NLK-associated negative regulator of Wnt signaling that ubiquitinates phosphorylated TCF/LEF proteins, targeting them for degradation.
Moore et al. (2008) showed that epitope-tagged mammalian Mtgr1 (CBFA2T2; 603672), Mtg8 (RUNX1T1; 133435), and Mtg16 (CBFA2T3; 603870) interacted with human TCF4 in cotransfected COS-7 cells. Beta-catenin disrupted interaction of Mtg proteins with TCF4. Additional studies demonstrated that MTG proteins act downstream of beta-catenin in the Wnt signaling pathway.
Shu et al. (2009) found decreased TCF7L2 protein levels in pancreatic sections from 7 patients with type 2 diabetes mellitus (T2D; 125853) compared with 7 healthy controls. Expression of the receptors for glucagon-like peptide-1 (GLP1R; 138032) and glucose-dependent insulinotropic polypeptide (GIPR; 137241) was decreased in human T2D islets as well as in isolated human islets treated with siRNA to TCF7L2 (siTCF7L2). Insulin secretion stimulated by glucose, GLP1, and GIP (137240), but not KCl or cyclic adenosine monophosphate (cAMP), was impaired in siTCF7L2-treated isolated human islets. Loss of TCF7L2 resulted in decreased GLP1 and GIP-stimulated AKT (AKT1; 164730) phosphorylation, and AKT-mediated Foxo-1 (FOXO1A; 136533) phosphorylation and nuclear exclusion. Shu et al. (2009) suggested that beta-cell function and survival may be regulated through an interplay between TCF7L2 and GLP1R/GIPR expression and signaling in T2D.
Nakano et al. (2010) identified a conserved region within intron 1 of the mouse and human TMEPAI genes (606564). Using mouse and human constructs and cell lines, they found that a reporter construct driven by the conserved region of mouse intron 1 could be activated via TGF-beta (190180) or Wnt (see 606359) signaling individually or by these pathways synergizing to elevate activity. Wnt signaling included an interaction between beta-catenin (116806) and Tcf7l2, with Tcf7l2 bound to a specific Tcf7l2-binding site. The TGF-beta signaling components included Smad3 (603109), Smad4 (600993), and Tcf7l2, with the 2 Smad proteins bound directly to 3 Smad-binding elements adjacent to the Tcf7l2-binding site.
Sotelo et al. (2010) identified a highly conserved enhancer element, designated enhancer E, over 340 kb telomeric to the MYC gene. Reporter gene assays and chromatin immunoprecipitation analysis revealed that beta-catenin/TCF4 interacted with enhancer E and activated expression of a MYC reporter. Chromosome conformation capture assays suggested formation of long-range DNA looping between the enhancer and the MYC promoter.
Duncan et al. (2019) showed that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula region of the rodent brain, where it regulates the function of nicotinic acetylcholine receptors. Inhibition of Tcf7l2 signaling in the medial habenula increased nicotine intake in mice and rats. Nicotine increased levels of blood glucose by Tcf7l2-dependent stimulation of the medial habenula. Virus-tracing experiments identified a polysynaptic connection from the medial habenula to the pancreas, and wildtype rats with a history of nicotine consumption showed increased circulating levels of glucagon (138030) and insulin (176730), and diabetes-like dysregulation of blood glucose homeostasis. By contrast, mutant Tcf7l2 rats were resistant to these actions of nicotine. Duncan et al. (2019) concluded that their findings suggested that TCF7L2 regulates the stimulatory actions of nicotine on a habenula-pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions.
Duval et al. (2000) determined the genomic structure of TCF4. They identified 17 exons, of which 5 were alternative. Either experimentally or in silico by a BLAST approach in EST databases, they observed 4 alternative splice sites. The alternative use of 3 consecutive exons located in the 3-prime part of the TCF4 gene changed the reading frames used in the last exon, leading to the synthesis of a number of TCF4 isoforms with short, medium, or long C-terminal ends.
Prokunina-Olsson et al. (2009) identified 18 exons in the TCF7L2 gene, including 6 alternative exons (3a, 4a, 12, 13, 13a, and 13b). They also identified several short in-frame insertions in exons 4a, 6, and 8. Six possible transcription start sites are located upstream of exon 2, and translational start codons are present in exons 1 and 3.
VTI1A/TCF7L2 Fusion Gene
Bass et al. (2011) reported whole-genome sequencing from 9 individuals with colorectal cancer (114500), including primary colorectal tumors and matched adjacent nontumor tissues, at an average of 30.7x and 31.9x coverage, respectively. They identified an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A (614316) and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with beta-catenin in colorectal carcinogenesis, the fusion lacks the TCF4 beta-catenin-binding domain. Bass et al. (2011) found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference-mediated knockdown.
Duval et al. (2000) mapped the TCF7L2 gene to chromosome 10q25.3 by FISH.
Type 2 Diabetes Mellitus, Susceptibility to
Reynisdottir et al. (2003) found suggestive linkage of type 2 diabetes mellitus (T2D; 125853) to chromosome 10q in an Icelandic population. The 10q linkage region had also been observed in Mexican Americans (Duggirala et al., 1999). Grant et al. (2006) genotyped 228 microsatellite markers in Icelandic individuals with type 2 diabetes and controls throughout a 10.5-Mb interval on 10q. A microsatellite, DG10S478, within intron 3 of the TCF7L2 gene was associated with type 2 diabetes; p = 2.1 x 10(-9). This was replicated in a Danish cohort, p = 4.8 x 10(-3), and also in a U.S. cohort, p = 3.3 x 10(-9). Two SNPs, rs12255372 (602228.0002) and rs7903146 (602228.0001), were in strong linkage disequilibrium with DG10S478 and showed similarly robust associations with type 2 diabetes (p less than 10(-15)). Compared with noncarriers, heterozygous and homozygous carriers of the at-risk alleles (38% and 7% of the population, respectively) have relative risks of 1.45 and 2.41. This corresponds to a population-attributable risk of 21%.
Florez et al. (2006) tested whether the 2 SNPS identified by Grant et al. (2006) predicted the progression to diabetes in persons with impaired glucose tolerance in a diabetes prevention program in which lifestyle intervention or treatment with metformin was compared with placebo. The 2 SNPs appeared to be associated with an increased risk of diabetes among persons with impaired glucose tolerance. The risk-conferring genotypes in TCF7L2 were associated with impaired beta-cell function but not with insulin resistance.
To find genetic variants influencing susceptibility to type 2 diabetes, Sladek et al. (2007) tested 392,935 SNPs in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified 4 loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci included a nonsynonymous polymorphism in the zinc transporter SLC30A8 (611145), which is expressed exclusively in insulin-producing beta cells, and 2 linkage disequilibrium blocks that contain genes potentially involved in beta cell development or function: IDE (146680)-KIF11 (148760)-HHEX (604420) and EXT2 (608210)-ALX4 (605420). Sladek et al. (2007) concluded that these associations explained a substantial portion of disease risk and constituted proof of principle for the genomewide approach to the elucidation of complex genetic traits.
Using a logistic regression model incorporating individual ancestry, sex, age, body mass index, and education in 286 Mexican patients with type 2 diabetes mellitus and 275 controls, Parra et al. (2007) analyzed the DG10S478 microsatellite in intron 3 and 2 SNPs, rs12255372 and rs7903146, in introns 4 and 3, respectively, of the TCF7L2 gene. All 3 markers were in tight disequilibrium in this Mexican sample. Parra et al. (2007) observed a significant association between rs12255372 and DG10S478 with type 2 diabetes mellitus (OR = 1.78, p = 0.017, and OR = 1.62, p = 0.041, respectively). The results for rs7903146 were not significant.
Zeggini et al. (2007) performed a genomewide association study of type 2 diabetes using data for 1,924 diabetic cases and 2,938 population controls generated by the Wellcome Trust Case Control Consortium (2007) and analysis of 3,757 additional cases and 5,346 controls, as well as equivalent data from other international consortia. The strongest association signals genomewide were observed for SNPs in the TCF7L2 gene. At SNP rs7901695 an odds ratio of 1.37, CI = 1.25-1.49, p = 6.7 x 10(-13) was achieved. This SNP was in strong linkage disequilibrium with rs7903146. In a similar study by Scott et al. (2007), the rs7903146 SNP reached genomewide significance in the all-data metaanalysis with an OR of 1.37, p = 1.0 x 10(-48). In the study of the Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research (2007), TCF7L2 was the third ranked association (P less than 10(-6)), and the authors noted that this association was among the top results in the whole-genome scans of the Wellcome Trust Case Control Consortium (2007), Scott et al. (2007), and Sladek et al. (2007). The consistency of these findings suggested that TCF7L2 is the single largest effect of a common SNP on type 2 diabetes risk in European populations.
In 2 cohorts of Scandinavian subjects followed for 22 years, Lyssenko et al. (2007) found that the CT/TT genotypes of rs7903146 strongly predicted future type 2 diabetes. Extensive metabolic studies in a subset of Swedish and Finnish individuals from the cohort indicated that increased risk of type 2 diabetes conferred by TCF7L2 variants involves the enteroinsular axis, enhanced expression of the gene in islets, and impaired insulin secretion.
Ng et al. (2007) examined 22 SNPs spanning the TCF7L2 gene for association with type 2 diabetes in Hong Kong Chinese. In a case-control study, they replicated an association with rs11196205 (602228.0003) (OR, 2.11; 95% CI, 1.04-4.26), previously identified in Japanese. They did not find an association with rs7903146 (OR, 1.27; 95% CI, 0.71-2.29), previously identified in Caucasians, but did identify another SNP, rs11196218 G allele, located in an adjacent linkage disequilibrium block, that conferred independent risk for type 2 diabetes (OR, 1.43; 95% CI, 1.14-1.79) and contributed high-population attributable risk of 42%. They replicated the association with rs11196218 and its haplotype for type 2 diabetes in a family sample (p less than 0.05).
Miyake et al. (2008) analyzed 5 SNPs in the TCF7L2 gene in 2,214 Japanese individuals with type 2 diabetes and 1,873 controls and replicated significant association with the minor alleles of rs7903146, rs12255372, and rs11196205, confirming that TCF7S2 is an important susceptibility gene for type 2 diabetes in the Japanese population. They did not, however, replicate previously reported associations with rs11196218 or rs290487.
Somatic Mutations
Duval et al. (2000) performed a mutation screen of a series of 24 colorectal cancer cell lines using denaturing gradient gel electrophoresis (DGGE) and/or direct sequencing. They found a total of 12 variants, of which 8 were in coding regions. The variants included 4 examples of the deletion of an A in an (A)9 coding repeat previously identified in a colorectal cancer cell line by Duval et al. (1999).
Associations Pending Confirmation
Dias et al. (2021) reported 11 unrelated, primarily pediatric individuals with variable neurodevelopmental disorders who had de novo heterozygous variants in the TCF7L2 gene. The patients were ascertained through the GeneMatcher program after exome sequencing was performed. There were 2 splice site, 2 nonsense, 2 frameshift, and 5 missense variants identified. The missense variants, which occurred at conserved residues and were not present in the gnomAD database, clustered in or near the HMG domain. The splice site variants were predicted to alter splicing, and the nonsense and frameshift mutations were predicted to result in nonsense-mediated mRNA decay. All patients had speech and language delay, and 8 had delayed gross motor skills with mildly delayed walking (by 24 months). Only 5 were noted to have impaired intellectual development; 1 patient was nonverbal at age 7 years. Many patients had behavioral abnormalities, including autism, attention deficit-hyperactivity disorder, communication problems, and sleep disturbances. About half of the patients had myopia. Additional variable features included nonspecific facial dysmorphism, skin abnormalities, and distal skeletal defects. Functional studies of the variants and studies of patient cells were not performed, although the authors postulated haploinsufficiency as a pathogenic molecular mechanism.
To study the physiologic role of Tcf4 (which is encoded by the Tcf7l2 gene), Korinek et al. (1998) disrupted Tcf7l2 by homologous recombination. The homozygous-null mice died shortly after birth. A single histopathologic abnormality was observed. An apparently normal transition of intestinal endoderm into epithelium occurred at approximately embryonic day (E) 14.5. However, no proliferative compartments were maintained in the prospective crypt regions between the villi. As a consequence, the neonatal epithelium was composed entirely of differentiated, nondividing villus cells. Korinek et al. (1998) concluded that the genetic program controlled by Tcf7l2 maintains the crypt stem cells of the small intestine. The constitutive activity of Tcf4 in APC-deficient epithelial cells may contribute to their malignant transformation by maintaining stem cell characteristics.
Nguyen et al. (2009) found that knockout of Tcf3 or Tcf4 individually had no overt effect on hair phenotype in mice, but Tcf3/Tcf4 double knockout resulted in a severe skin and hair defects. Newborn Tcf3/Tcf4-null skin was thinner than normal and often lacked whiskers. Tcf3/Tcf4-null skin showed signs of apoptosis and, when grafted onto nude mice, became shrunken, was unable to repair wounds, and was progressively lost, showing an inability to maintain long-term self-renewing populations of skin epithelia. Tcf3/Tcf4-null skin cells grew poorly in culture and did not survive passaging. Microarray analysis of mRNAs expressed by normal and Tcf3/Tcf4-null skin suggested that Tcf3 and Tcf4 maintain skin epithelial stem cells through Wnt-dependent and Wnt-independent signaling.
Shu et al. (2009) showed robust differences in TCF7L2 expression in pancreatic beta cells of rodent models of type 2 diabetes mellitus. While mRNA levels were approximately 2-fold increased in isolated islets from the diabetic db/db mouse, the Vancouver Diabetic Fatty (VDF) Zucker rat, and the high fat/high sucrose diet-treated mouse compared with the nondiabetic rodent controls, protein levels were decreased.
Savic et al. (2011) found that Tcf7l2 -/- mice were born at the expected mendelian ratio, but they were hypoglycemic at birth and died within 24 hours. Tcf7l2 +/- mice were leaner than wildtype littermates and displayed enhanced glucose tolerance when fed a high-fat diet. Mice engineered to carry up to 3 extra copies of Tcf7l2 driven by a 92-kb human TCF7L2 promoter region developed dose-dependent glucose intolerance, with elevated fasting insulin levels compared with wildtype littermates.
In an Icelandic population, Grant et al. (2006) found strong linkage disequilibrium between a SNP in the TCF7L2 gene, rs7903146, and a microsatellite marker in intron 3, DG10S478, associated with type 2 diabetes (T2D; 125853) (p = 2.1 x 10(-9)).
Helgason et al. (2007) refined the definition of the TCF7L2 type 2 diabetes risk variant, HapB(T2D), to the ancestral T allele of the SNP rs7903146 through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. They also identified another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European, and West African populations. Notably, HapA shows a suggestive association with body mass index (BMI) and altered concentrations of the hunger-satiety hormones ghrelin (GHRL; 605353) and leptin (LEP; 164160) in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism.
Type 2 diabetes genes may influence birthweight through maternal genotype, by increasing maternal glycemia in pregnancy, or through fetal genotype, by altering fetal insulin secretion. Freathy et al. (2007) assessed the role of the TCF7L2 gene in birthweight. They genotyped the polymorphism rs7903146 in 15,709 individuals whose birthweight was available from 6 studies and in 8,344 mothers from 3 studies. Each fetal copy of the predisposing allele was associated with an 18-gram increase in birthweight (p = 0.001) and each maternal copy with a 30-gram increase in offspring birthweight (p = 2.8 x 10(-5)).. Stratification by fetal genotype suggested that the association was driven by maternal genotype. Analysis of diabetes-related traits in 10,314 nondiabetic individuals suggested that the most likely mechanism is that the risk allele reduces maternal insulin secretion, which results in increased maternal glycemia in pregnancy and hence increased offspring birthweight. Freathy et al. (2007) combined information from the other common variant known to alter fetal growth, the -30G-A polymorphism of glucokinase (138079). The 4% of offspring born to mothers carrying 3 or 4 risk alleles were 119 grams heavier than were the 32% born to mothers with none, comparable to the impact of maternal smoking during pregnancy. Freathy et al. (2007) concluded that this was the first type 2 diabetes susceptibility allele to be reproducibly associated with birthweight. Thus, common gene variants can substantially influence normal birthweight variation.
In a study of 286 Mexican patients with type 2 diabetes mellitus and 275 controls, Parra et al. (2007) did not find a significant association between rs7903146 and the disease.
In genomewide association studies of type 2 diabetes, The Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research (2007), Zeggini et al. (2007), and Scott et al. (2007) confirmed association of the SNP rs7903146 with diabetes susceptibility. Scott et al. (2007) obtained an OR of 1.37, p = 1.0 x 10(-48) for rs7903146 in a metaanalysis of data from international consortia.
In a genomewide association study for type 2 diabetes in 1,399 Icelandic cases and 5,275 controls, Steinthorsdottir et al. (2007) found that rs7903146 conferred the most significant risk, with an OR of 1.38 and p = 1.82 x 10(-10) in all individuals with type 2 diabetes.
Mayans et al. (2007) genotyped 4 SNPs in the TCF7L2 gene in 872 Swedish patients with type 2 diabetes and 857 age-, sex-, and geographically-matched controls and replicated the previously identified association between rs7093146 and disease (p = 0.00002).
In 2 cohorts of Scandinavian subjects followed for 22 years, Lyssenko et al. (2007) found that the CT/TT genotypes of rs7903146 strongly predicted future type 2 diabetes. Extensive metabolic studies in a subset of Swedish and Finnish individuals from the cohort showed that the risk T allele was associated with impaired insulin secretion, incretin effects, and an enhanced rate of hepatic glucose production. TCF7L2 expression in human islets was increased 5-fold in type 2 diabetes, particularly in carriers of the TT genotype; overexpression of TCF7L2 in human islets reduced glucose-stimulated insulin secretion.
Ng et al. (2007) examined 22 SNPs spanning the TCF7L2 gene in 433 Hong Kong Chinese hospitalized with early-onset type 2 diabetes and 419 controls and did not find a significant association with rs7903146.
Miyake et al. (2008) analyzed 5 SNPs in the TCF7L2 gene in 2,214 Japanese individuals with type 2 diabetes and 1,873 controls and confirmed significant association with the minor allele of rs7903146 (OR, 1.48; p = 2.7 x 10(-4)). The association remained significant after adjustment for age, sex, and BMI (adjusted p = 0.0011).
To identify regulatory DNA active in human pancreatic islets, Gaulton et al. (2010) profiled chromatin by formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIRE-seq). By mapping sequence variants to open chromatin sites, they found that rs7903146 is located in islet-selective open chromatin. In addition, human islet samples heterozygous for rs7903146 showed allelic imbalance in islet FAIRE signals, with the chromatin state more open in chromosomes carrying the risk 'T' allele. Using allele-specific luciferase reporter constructs in islet beta-cell lines, Gaulton et al. (2010) demonstrated that the rs7903146 variant alters enhancer activity, indicating that genetic variation at this locus acts in cis with local chromatin and regulatory changes.
Prokunina-Olsson et al. (2009) stated that rs7903146 in intron 3 and rs12255372 (602228.0002) in intron 4 are 50 kb apart and within a 92-kb block of linkage disequilibrium. Savic et al. (2011) found that the 92-kb region containing rs7903146 had strong enhancer activity when expressed in transgenic mice.
In an Icelandic population, Grant et al. (2006) found strong linkage disequilibrium between a SNP in intron 4 of the TCF7L2 gene, rs12255372, and a microsatellite marker in intron 3, DG10S478, associated with type 2 diabetes (T2D; 125853) (p = 2.1 x 10(-9)).
Using a logistic regression model incorporating individual ancestry, sex, age, body mass index, and education in 286 Mexican patients with type 2 diabetes mellitus and 275 controls, Parra et al. (2007) analyzed the DG10S478 microsatellite in intron 3 and rs12255372 in intron 4 of the TCF7L2 gene. All 3 markers were in tight disequilibrium in the Mexican sample. Parra et al. (2007) observed a significant association between rs12255372 and DG10S478 and type 2 diabetes mellitus (OR = 1.78, p = 0.017, and OR = 1.62, p = 0.041, respectively).
Mayans et al. (2007) genotyped 4 SNPs in the TCF7L2 gene in 872 Swedish patients with type 2 diabetes and 857 age-, sex-, and geographically-matched controls and replicated the previously identified association between rs12255372 and disease (p = 0.000004).
Miyake et al. (2008) analyzed 5 SNPs in the TCF7L2 gene in 2,214 Japanese individuals with type 2 diabetes and 1,873 controls and confirmed significant association with the minor allele of rs12255372 (OR, 1.70; p = 9.8 x 10(-5)). The association remained significant after adjustment for age, sex, and BMI (adjusted p = 7.0 x 10(-4)).
Ng et al. (2007) examined 22 SNPs spanning the TCF7L2 gene for association with type 2 diabetes (125853) in Hong Kong Chinese. In a case-control study, they replicated an association with the at-risk C allele of rs11196205 (OR, 2.11; 95% CI, 1.04-4.26), previously identified in a Japanese population (see Hayashi et al., 2007).
Miyake et al. (2008) analyzed 5 SNPs in the TCF7L2 gene in 2,214 Japanese individuals with type 2 diabetes and 1,873 controls and confirmed significant association with the minor allele of rs11196205 (OR, 1.39; p = 4.6 x 10(-4)). The association remained significant after adjustment for age, sex, and BMI (adjusted p = 0.0053).
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