Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transcription factor 7-like 2 (TCF7L2) is part of the Wnt signaling pathway. Genetic variants within TCF7L2 on chromosome 10q were recently reported to be associated with type 2 diabetes in Icelandic, Danish, and American (U.S.) samples. We previously observed a modest logarithm of odds score of 0.61 on chromosome 10q, approximately 1 Mb from TCF7L2, in the Finland-United States Investigation of NIDDM Genetics study. We tested the five associated TCF7L2 single nucleotide polymorphism (SNP) variants in a Finnish sample of 1,151 type 2 diabetic patients and 953 control subjects. We confirmed the association with the same risk allele (P value <0.05) for all five SNPs. Our strongest results were for rs12255372 (odds ratio [OR] 1.36 [95% CI 1.15-1.61], P = 0.00026) and rs7903146 (1.33 [1.14-1.56], P = 0.00042). Based on the CEU HapMap data, we selected and tested 12 additional SNPs to tag SNPs in linkage disequilibrium with rs12255372. None of these SNPs showed stronger evidence of association than rs12255372 or rs7903146 (OR < or =1.26, P > or = 0.0054). Our results strengthen the evidence that one or more variants in TCF7L2 are associated with increased risk of type 2 diabetes.
Diabetes 2006 Sep
PMID:Association of transcription factor 7-like 2 (TCF7L2) variants with type 2 diabetes in a Finnish sample. 1693 17

Transcription factor 7-like 2 (TCF7L2) regulates genes involved in cell proliferation and differentiation. The TCF7L2 gene is located on chromosome 10q25 in a region of replicated linkage to type 2 diabetes. Recently, a microsatellite marker in intron 3 (DG10S478) and five correlated single nucleotide polymorphisms (SNPs) were identified in Icelandic individuals that showed strong association with type 2 diabetes, which was replicated in Danish and European-American cohorts. We genotyped four of the SNPs (rs7901695, rs7903146, rs11196205, and rs12255372) in Amish subjects with type 2 diabetes (n = 137), impaired glucose tolerance (IGT; n = 139), and normal glucose tolerance (NGT; n = 342). We compared genotype frequencies in subjects with type 2 diabetes with those with NGT and found marginal association for rs7901695 (P = 0.05; odds ratio [OR] 1.51); comparison between NGT control subjects and the combined type 2 diabetes/IGT case group showed strong association with rs7901695 and rs7903146 (P = 0.008-0.01; OR 1.53-1.57) and marginal association with rs11196205 and rs12255372 (P = 0.07 and P = 0.04, respectively). In an expanded set of 698 Amish subjects without diabetes, we found no association with insulin and glucose levels during a 3-h oral glucose tolerance test. We also genotyped these SNPs in nondiabetic, non-Amish subjects (n = 48), in whom intravenous glucose tolerance tests were performed, and found an association between rs7901695 and rs7903146 and insulin sensitivity (P = 0.003 and P = 0.005, respectively) and disposition index (P = 0.04 and P = 0.007, respectively). These data provide replicating evidence that variants in TCF7L2 increase the risk for type 2 diabetes and novel evidence that the variants likely influence both insulin secretion and insulin sensitivity.
Diabetes 2006 Sep
PMID:Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in the Amish: replication and evidence for a role in both insulin secretion and insulin resistance. 1693 18

Sulfonylurea drugs including chlorpropamide, gliclazide, tolbutamide, glipizide, glibenclamide (glyburide) and glimepiride are the most widely used oral hypoglycaemic agents in people with type 2 diabetes. This review investigates the impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of sulfonylurea drugs. CYP2C9 is the major enzyme involved in sulfonylurea drug metabolism. CYP2C9 variant allele carriers have significant lower apparent clearance of these medicines. CYP2C19 genotype is more influential for gliclazide pharmacokinetics when compared to CYP2C9. Sulfonylurea pharmacodynamics is affected by several genes. Sulfonylurea receptor 1 (SUR1, ABCC8 gene) and K+ inward rectifier Kir6.2 (KCNJ11) have been correlated to significant variation in sulfonylurea response. Diabetics with the SUR1 exon 33 G allele are more sensitive to gliclazide and the rs5210 variant of the KCNJ11 gene was associated with improved clinical efficacy of gliclazide. Carriers of Transcription factor 7-like 2 (TCF7L2) variants are more likely to fail sulfonylurea therapy. On the other hand, patients with HNF-1alpha mutations had a significant greater response to gliclazide when compared to those with type 2 diabetes. The Arg972 polymorphism of insulin receptor substrate 1 (IRS1) may lead to secondary failure of sulfonylurea therapy. Calpain 10 gene (CAPN10) polymorphism has also been linked to sulfonylurea drug response. Despite the available evidence, larger population studies that investigate the pharmacokinetics and pharmacodynamics of sulfonylurea drugs are needed to investigate the influence of key SNPs amidst all potential contributing factors to variability in response to these which inturn will provide information to optimise sulfonylurea use in people with diabetes.
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PMID:Influence of genetic polymorphisms on the pharmacokinetics and pharmaco-dynamics of sulfonylurea drugs. 1979 32

Transcription factor 7-like 2 gene (TCF7L2) has been associated with type 2 diabetes. We investigated the association of the rs7903146 SNP in this gene with clinical profile of type 2 diabetes (T2DM) patients. The study involved 980 patients with diabetic nephropathy (44%), diabetic retinopathy (42%), CVD (65%) and early onset of diabetes (45%) and 924 healthy controls. Subjects were genotyped for rs7903146 by PCR-RFLP. Genotype frequencies significantly differed between T2DM patients and controls (p<0.01, odds ratio (OR) for TT genotype 2.49 (95% confidence interval (CI) 1.84-3.39). An association was observed between rs7903146 and nephropathy (p<0.001), with 22% of TT homozygotes in this subgroup vs. 11% in patients without nephropathy (p=0.006, OR for TT 2.83, 95% CI 1.94-4.13). Association was stronger in patients with early onset of diabetes (34% of TT vs. 12% in the late onset, p<0.001). In DN group 71% of TT homozygotes had an early onset (OR 7.64, 95% CI 4.98-11.73 vs. controls). Our results confirm association of rs7903146 in the TCF7L2 gene with increased risk of type 2 diabetes. The T allele is strongly associated with nephropathy, especially in early onset of diabetes.
Diabetes Res Clin Pract 2011 Sep
PMID:Transcription factor 7-like 2 (TCF7L2) gene polymorphism and complication/comorbidity profile in type 2 diabetes patients. 2164 71

In various populations worldwide, common variants of the TCF7L2 (Transcription factor 7-like 2) gene are associated with the risk of type 2 diabetes mellitus (T2DM). The aim was to investigate the association between rs12255372 (G/T) polymorphism in the TCF7L2 gene and T2DM in an Iranian population. 236 unrelated patients with T2DM, and 255 normoglycemic controls without diabetes were studied. The PCR-RFLP method was used for genotyping rs12255372 (G/T) polymorphism, and the SPSS version 18.0 for Windows for statistical analysis. The minor T allele of TCF7L2 rs12255372 was found to significantly increase the risk of T2DM, with an allelic odds ratio (OR) of 1.458 (95% CI 1.108-1.918, p = 0.007). A significant difference in TT genotype was observed between T2DM patients and normoglycemic controls (OR 2.038, 95% CI 1.147-3.623; p = 0.014). On assuming dominant and recessive models, ORs of 1.52 [95% CI (1.05-2.21) p = 0.026)] and 1.74 [95% CI (1.01-3.00) p = 0.043] were obtained, respectively, thereby implying that the co-dominant model would best fit the susceptible gene effect. This study further confirms the TCF7L2 gene as enhancing susceptibility to the development of T2DM.
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PMID:Association of the TCF7L2 rs12255372 (G/T) variant with type 2 diabetes mellitus in an Iranian population. 2288 88