OBJECTIVETo assess the association between a rs7903146(C/T) polymorphism of TCF7L2 gene and metabolic syndrome (MS), plasma lipoprotein, and plasma adiponectin (PA) in Chinese Korean and Han populations from Yanbian region.

METHODSPolymerase chain reaction and DNA sequencing were used to determine the genotype of rs7903146 in 310 Chinese Korean (190 in case group and 120 in control group) and 344 Chinese Han (255 in case group and 89 in control group). ELIAS was used to test serum insulin (INS) and PA.

RESULTSThe frequency of T allele was higher in ethnic Han compared with ethnic Koreans (0.022 vs. 0.008), lower than that of Europeans (0.279) and Africans (0.257), but similar to those of Beijing Chinese and Japanese. For ethnic Korean Chinese, the frequencies of TT and CT genotypes as well as the T allele in patients with EH were significantly higher than those of the control group (P< 0.01), which also showed an increasing trend for both MS and T2DM groups (P=0.09 and P=0.07, respectively). By contrast, for Chinese Han, the frequencies of genotypes and particular allele in patients with MS, T2DM and EH showed no significant difference from those of the control group. For T2DM, EH, and control groups, PA level of individuals with CT or TT genotypes was significantly higher compared with that of the CC genotype (P< 0.05). The TC and LDL-C levels were significantly higher in T2DM, MS and EH groups compared with those of the control group. The PA level was lower in MS group compared with the control group.

CONCLUSIONThe T allele of SNP rs7903146 of TCF7L2 gene may be a risk factor for EH in Chinese Korean population from Yanbian region. The T allele also affects the PA level; lower PA is a risk factor for MS. The rs7903146 polymorphism showed a racial and ethnic difference.

Adiponectin ; blood ; Base Sequence ; China ; ethnology ; Female ; Humans ; Male ; Metabolic Syndrome ; blood ; enzymology ; genetics ; Molecular Sequence Data ; Polymorphism, Single Nucleotide ; Transcription Factor 7-Like 2 Protein ; genetics ; metabolism

BACKGROUNDT cell factor-4 (TCF-4) plays an important role in development and carcinogenesis. Recently, the role of TCF-4 has been described in colon cancer and other cancers. However, whether TCF-4 plays a similar role in lung cancer is unknown. To answer this question, we studied the expression of TCF-4 protein and mRNA in non-small-cell lung cancer (NSCLC) and the relation of TCF-4 expression pattern to histological type and cell differentiation.

METHODSTissue samples from sixty cases of pathologically diagnosed NSCLC and eight normal tissue samples were obtained between September 2001 and March 2003. Immunohistochemistry was used to investigate the distribution of TCF-4 protein. The staining patterns of the tumors were divided into 4 categories: nuclear staining alone or nuclear staining greater than cytoplasmic staining; cytoplasmic staining or cytoplasmic staining greater than nuclear staining; equal nuclear and cytoplasmic staining; no nuclear staining or cytoplasmic staining. The integrated optical density (OD) values of all sections were analyzed by UIC MetaMorph image analysis software. The expression of TCF-4 mRNA was detected by one-step reverse transcription-polymerase chain reaction (RT-PCR). The integrated density values of the PCR products were analyzed semi-quantitatively.

RESULTSImmunohistochemistry showed that there was no expression of TCF-4 in normal tissue. However, TCF-4 was expressed in 86.7% (52/60) of NSCLC samples, mainly in the nuclei of tumor cells. Furthermore, there was a significant difference in TCF-4 localization patterns between squamous cell carcinomas and adenocarcinomas (P < 0.05). The integrated OD values of TCF-4 expression was significantly higher in tumors with moderate-poor cell differentiation than in well differentiated tumors (51.63 +/- 6.67 vs 46.13 +/- 12.31, P < 0.01). There was no TCF-4 mRNA expression in normal tissue. However, 63.9% (23/36) of carcinoma samples expressed TCF-4 mRNA. TCF-4 mRNA expression was significantly higher in tumors with moderate-poor cell differentiation than in well differentiated tumors (P < 0.05). There were no significant differences in mRNA expression in comparison with histological type.

CONCLUSIONSThe sub-cellular distribution of TCF-4 may correlate with NSCLC histological type. High expression of TCF-4 mRNA and protein may be associated with the degree of cell differentiation in NSCLC.

Carcinoma, Non-Small-Cell Lung ; chemistry ; Cytoskeletal Proteins ; metabolism ; Female ; Humans ; Immunohistochemistry ; Lung Neoplasms ; chemistry ; Male ; Middle Aged ; RNA, Messenger ; analysis ; TCF Transcription Factors ; Trans-Activators ; metabolism ; Transcription Factor 7-Like 2 Protein ; Transcription Factors ; analysis ; genetics ; beta Catenin

Carcinoma, Non-Small-Cell Lung ; metabolism ; pathology ; Cell Membrane ; metabolism ; Cell Nucleus ; metabolism ; Cytoplasm ; metabolism ; Humans ; Lung Neoplasms ; metabolism ; pathology ; Signal Transduction ; TCF Transcription Factors ; metabolism ; Transcription Factor 7-Like 2 Protein ; Wnt Proteins ; physiology ; beta Catenin ; metabolism

This cohort study was designed to evaluate the association of transcription factor 7-like 2 (TCF7L2) and proglucagon gene (GCG) variants with disordered glucose metabolism and the incidence of type 2 diabetes mellitus (T2DM) in a rural adult Chinese population. A total of 7,751 non-T2DM participants ⋝18 years old genotyped at baseline were recruited. The same questionnaire interview and physical and blood biochemical examinations were performed at both baseline and follow-up. During a median 6 years of follow-up, T2DM developed in 227 participants. After adjustment for potential contributory factors, nominally significant associations were seen between TT genotype and the recessive model of TCF7L2 rs7903146 and increased risk of T2DM [hazard ratio (HR)=4.068, 95% confidence interval (CI): 1.270-13.026; HR=4.051, 95% CI: 1.268-12.946, respectively]. The TT genotype of rs7903146 was also significantly associated with higher fasting plasma insulin level and the homeostasis model assessment of insulin resistance in case of new-onset diabetes. In addition, the TCF7L2 rs290487 TT genotype was associated with abdominal obesity and the GCG rs12104705 CC genotype was associated with both general obesity and abdominal obesity in case of new-onset diabetes.
Adult ; Cohort Studies ; Diabetes Mellitus, Type 2 ; complications ; genetics ; Female ; Humans ; Insulin ; secretion ; Insulin Resistance ; genetics ; Male ; Middle Aged ; Obesity ; complications ; genetics ; Polymorphism, Single Nucleotide ; Proglucagon ; genetics ; Transcription Factor 7-Like 2 Protein ; genetics

Abnormal activation of Wnt signaling pathway is closely related to the occurrence of tumor, and T cell factor 4 (Tcf4 ) and beta-catenin are important signal transmission factors of this pathway. The aim of the present study is to explore the significance and correlation between expression of Tcf4, beta-catenin and secreted frizzled related protein 1(SFRP1), suppressor gene of Wnt signaling pathway, in colorectal carcinoma and their correlations to the clinicopathological factors. The expressions of Tcf4, beta-catenin and SFRP1 were performed with immunohistochemistry staining in 97 cases of primary colorectal carcinoma and 40 cases of normal colorectal mucosa tissues. The results showed that the abnormal expression rates of Tcf4 and beta-catenin in colorectal carcinoma were significantly higher than those in the control groups (P<0.01). The positive rate of SFRP1 was significantly lower than those in the control groups (P<0.01). The abnormal expression rates of Tcf4 and beta-catenin were also related to the lymph node metastasis and Dukes stage (P<0.05). A significant correlation was found between the expressions of SFRP1 and Tcf4, beta-catenin (P<0.05). Overexpression of Tcf4 and beta-catenin was related to poor prognosis (P<0.05). But the survival rates of the group with SFRP1 expressions were higher than those in group without SFRP1 expressions (P<0.05). Cox multifactor regression analysis indicated that Dukes stage, expression of beta-catenin and SFRP1 were independent risk factors of colorectal carcinoma (P<0.05). The results suggested that the abnormal expression of Tcf4 and beta-catenin in colorectal cancer may be related to the reduced or absent expression of SFRP1. beta-catenin accumulation in the nuclei formed complexes with Tcf4 is one of the important molecular switch maintaining colorectal malignant phenotype. The combined detection of these indexes may perform an important role in predicting the progression and prognosis of colorectal cancer, and could provide new molecular targets for gene treatment of colorectal cancer.
Carcinoma ; metabolism ; Colorectal Neoplasms ; metabolism ; Disease Progression ; Humans ; Intercellular Signaling Peptides and Proteins ; metabolism ; Lymphatic Metastasis ; Membrane Proteins ; metabolism ; Phenotype ; Prognosis ; Risk Factors ; Transcription Factor 7-Like 2 Protein ; metabolism ; Wnt Signaling Pathway ; beta Catenin ; metabolism

OBJECTIVEThe goal of this study is to investigate the inappropriate activation of Wnt pathway in the hepatocarcinogenesis.

METHODSWe analyzed the alterations of three key components of Wnt pathway, beta-catenin, glycogen synthase kinase 3beta (GSK-3beta) and T cell factor 4 (Tcf-4), in 34 samples of hepatocellular carcinoma (HCC) and paracancerous normal liver by immunohistochemistry, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), direct sequencing, semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization.

RESULTSWe found 61.8% (21/34) of all the HCCs examined showed an abnormal beta-catenin protein accumulation in the cytoplasm or nuclei. RT-PCR-SSCP and direct sequencing showed that beta-catenin exon 3 mutations existed in 44.1% (15/34) of the HCCs. No mutations of GSK-3beta or Tcf-4 were detected in HCCs. Moreover, mRNA of beta-catenin and Tcf-4 but not GSK-3beta was found to be over expressed in HCCs. On analyzing the relationship between alterations of beta-catenin or Tcf-4 and C-myc or Cyclin D1 expression, we found that the mutations of beta-catenin as well as over expression of beta-catenin or Tcf-4 gene were independently correlated with C-myc gene over expression in HCCs.

CONCLUSIONSOur present findings strongly suggest mutations of beta-catenin as well as over expression of beta-catenin and Tcf-4 gene activate the Wnt pathway in HCC independently with the target gene most likely to be C-myc.

Carcinoma, Hepatocellular ; metabolism ; Cytoskeletal Proteins ; genetics ; physiology ; Glycogen Synthase Kinase 3 ; genetics ; physiology ; Glycogen Synthase Kinase 3 beta ; Humans ; Immunohistochemistry ; Liver Neoplasms ; metabolism ; Polymerase Chain Reaction ; Polymorphism, Single-Stranded Conformational ; Proto-Oncogene Proteins ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; TCF Transcription Factors ; Trans-Activators ; genetics ; physiology ; Transcription Factor 7-Like 2 Protein ; Transcription Factors ; genetics ; physiology ; Wnt Proteins ; Zebrafish Proteins ; beta Catenin

OBJECTIVETo study the associations of single nucleotide polymorphisms (SNPs) of TCF7L2, CDKAL1, SLC30A8, HHEX with diabetic retinopathy (DR) and nephropathy (DN) in type 2 diabetes mellitus.

METHODSA total of 479 subjects with DR,248 with DN and 650 without DR or DN were recruited to assess the associations between SNPs of TCF7L2 (rs7903146, rs6585205, rs11196218), CDKAL1 (rs10946398,rs4712527), SLC30A8 (rs13266634, rs3802177, rs11558471) and HHEX (rs1111875, rs7923837) and the development of DR and DN.

RESULTSThere were significant differences in genotypic and allele frequencies of rs11558471 (SLC30A8) between DR and control groups (P< 0.05), the odds ratio (OR) values of A and AA were 1.27 and 1.68. The distributions of genotype and allele frequency for rs11196218 (TCF7L2) were significantly different between DN and control group (P=0.0051,OR=1.37). However, the P value after Bonferroni correction showed no significant difference. No significant differences were found in the distributions of rs13266634 and rs3802177 (SLC30A8), rs10946398 (CDKAL1), rs6585205, rs7903146 and rs11196218 (TCF7L2) and rs7923837 (HHEX) between DR and control groups, and nor significant differences were found in distributions of rs6585205 (TCF7L2), rs4712527 (CDKAL1), rs13266634, rs3802177 and rs11558471 (SLC30A8), and 7923837 (HHEX) between DN and control groups, though for all comparison the OR values were greater than 1.

CONCLUSIONPolymorphisms of SLC30A8 and TCF7L2 genes may be associated with the development of DR and DN, respectively. Association between the polymorphisms of CKDAL1, TCF7L2 and HHEX genes and DR, and between the polymorphisms of SLC30A8, HHEX and CDKAL1 genes and DN, cannot be excluded.

Cation Transport Proteins ; genetics ; Cyclin-Dependent Kinase 5 ; genetics ; Diabetes Mellitus, Type 2 ; complications ; genetics ; Diabetic Angiopathies ; genetics ; Female ; Homeodomain Proteins ; genetics ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Transcription Factor 7-Like 2 Protein ; genetics ; Transcription Factors ; genetics ; Zinc Transporter 8 ; tRNA Methyltransferases

BACKGROUNDTranscription factor 7-like 2 (TCF7L2)-rs7903146 polymorphism is associated with increased risk of type 2 diabetes. The response of insulin and insulin resistance to artichoke leaf extract (ALE) may be affected by TCF7L2-rs7903146 polymorphism.

OBJECTIVEThis study examined the effects of ALE supplementation on metabolic parameters of the TCF7L2-rs7903146 polymorphism in patients with metabolic syndrome (MetS).

DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONSThis double-blind clinical trial was conducted on 80 patients with MetS in Sina Clinic, Khoy, Iran. The patients were randomized into ALE or placebo groups to receive either ALE (1800 mg/d as four tablets) or matching placebo for 12 weeks.

MAIN OUTCOME MEASURESAnthropometric indices, blood pressure, glucose and lipid profile levels were measured before and after the study. Moreover, patients were genotyped for TCF7L2 polymorphism.

RESULTSALE supplementation decreased insulin level and the homeostasis model assessment of insulin resistance (HOMA-IR) in patients with the TT genotype of TCF7L2-rs7903146 polymorphism (P < 0.05). There was no significant interaction between blood pressure, glucose and lipid profile response to ALE supplementation.

CONCLUSIONThe responses of insulin and HOMA-IR to ALE supplementation have shown an interaction with single-nucleotide polymorphism rs7903146 in TCF7L2.

TRIAL REGISTRATIONIranian Registry of Clinical Trial IRCT201409033320N9.

Adult ; Blood Glucose ; metabolism ; Cynara scolymus ; Dietary Supplements ; Double-Blind Method ; Female ; Genotype ; Humans ; Insulin ; blood ; Insulin Resistance ; genetics ; Male ; Metabolic Syndrome ; blood ; drug therapy ; genetics ; Middle Aged ; Phytotherapy ; Plant Extracts ; pharmacology ; Polymorphism, Single Nucleotide ; Transcription Factor 7-Like 2 Protein ; genetics