| Full gene name: | transcription factor 7-like 2 (T-cell specific, HMG-box) |
|---|---|
| Entrez Gene ID: | 6934 |
| Location: | 10q25.3 |
| Synonyms: | TCF4, TCF-4 |
| Type: | protein-coding |
SNPs given by the user that are near or inside this gene:
| SNP | Distance (bp) | Direction |
|---|---|---|
| rs7903146 | 0 | within |
This gene encodes a high mobility group (HMG) box-containing transcription factor that plays a key role in the Wnt signaling pathway. The protein has been implicated in blood glucose homeostasis. Genetic variants of this gene are associated with increased risk of type 2 diabetes. Several transcript variants encoding multiple different isoforms have been found for this gene.[provided by RefSeq, Oct 2010]
| OMIM ID: | `OMIM ID 602228 `_ |
|---|
Allelic Variants (Selected Examples)
.0001 DIABETES MELLITUS, NONINSULIN-DEPENDENT, SUSCEPTIBILITY TO
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 (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 Reserch (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.
.0002 DIABETES MELLITUS, NONINSULIN-DEPENDENT, SUSCEPTIBILITY TO
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 (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)).
.0003 DIABETES MELLITUS, NONINSULIN-DEPENDENT, SUSCEPTIBILITY TO
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 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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