Asociación del polimorfismo rs7903146, del gen TCF7L2, con marcadores de adiposidad y metabólicos en población chilena - resultados del estudio GENADIO / Association of the TCF7L2 (RS7903146) genotype with adiposity and metabolic markers in the Chilean adult population

Background: Type 2 diabetes etiology has a strong genetic component. More than 20 genetic variants have been associated with diabetes and other metabolic markers. However, the polymorphism rs7903146 of the TCF7L2 gene has shown the strongest association. Aim: To investigate the association of TCF7L2 (rs7903146) genotype with adiposity and metabolic markers in the Chilean adult population. Material and Methods: The association of TCF7L2 (rs7093146) with adiposity and metabolic markers was studied in 301 participants. The outcomes of the study were adiposity markers (body weight, body mass index (BMI), fat mass and waist circumference) and metabolic markers (blood glucose, insulin, HOMA-IR, lipid profile, high sensitivity C-reactive protein (CRP), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT) and leptin). Results: There was an association between the polymorphism TCF7L2 genotype and fasting blood glucose. The latter increased by 4.86 mg/dl per each copy of the risk allele [(95% confidence intervals (CI): 0.48; 9.24), p = 0.03] in the unadjusted adjusted model. However, this association was slightly attenuated in the fully adjusted model [4.38 mg/dl (95% IC: 0.16; 8.60), p = 0.04)]. There were no associations between the TCF7L2 genotype and any other metabolic or adiposity outcome. Conclusions: These findings confirm the association between the TCF7L2 (rs7903146) and fasting glucose in the Chilean population. However, further studies are needed to confirm the association between the TCF7L2 and diabetes risk in the Chilean population.

Growing pigs developed different types of diabetes induced by streptozotocin depending on their transcription factor 7-like 2 gene polymorphisms / 한국실험동물학회지

The different polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene promote variances in diabetes susceptibility in humans. We investigated whether these genotypes also promote differences in diabetic susceptibility in commercial pigs. Growing pigs (Landrace, both sex, 50–60 kg) with the C/C (n=4) and T/T (n=5) TCF7L2 genotypes were identified and intravenously injected with streptozotocin (STZ, 40 mg/kg) twice in weekly intervals, then a high-energy diet was offered. Oral glucose tolerance tests, blood analyses and the homeostasis model assessment-insulin resistance (HOMA-IR) index calculations were performed. The animals were sacrificed at the end of 12 weeks of treatment to reveal the pancreas histomorphometry. The results showed that all of the treated pigs grew normally despite exhibiting hyperglycemia at two weeks after the induction. The glycemic level of the fasting or postprandial pigs gradually returned to normal. The fasting insulin concentration was significantly decreased for the T/T carriers but not for the C/C carriers, and the resulting HOMA-IR index was significantly increased for the C/C genotype, indicating that the models of insulin dependence and resistance were respectively developed by T/T and C/C carriers. The histopathological results illustrated a significant reduction in the pancreas mass and insulin active sites, which suggested increased damage. The results obtained here could not be compared with previous studies because the TCF7L2 background has not been reported. Growing pigs may be an excellent model for diabetic in children if the animals are genetically pre-selected.

TCF7L2-rs7903146 polymorphism modulates the effect of artichoke leaf extract supplementation on insulin resistance in metabolic syndrome: a randomized, double-blind, placebo-controlled trial / 中西医结合学报

<p><b>BACKGROUND</b>Transcription 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.</p><p><b>OBJECTIVE</b>This study examined the effects of ALE supplementation on metabolic parameters of the TCF7L2-rs7903146 polymorphism in patients with metabolic syndrome (MetS).</p><p><b>DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS</b>This 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.</p><p><b>MAIN OUTCOME MEASURES</b>Anthropometric indices, blood pressure, glucose and lipid profile levels were measured before and after the study. Moreover, patients were genotyped for TCF7L2 polymorphism.</p><p><b>RESULTS</b>ALE 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.</p><p><b>CONCLUSION</b>The responses of insulin and HOMA-IR to ALE supplementation have shown an interaction with single-nucleotide polymorphism rs7903146 in TCF7L2.</p><p><b>TRIAL REGISTRATION</b>Iranian Registry of Clinical Trial IRCT201409033320N9.</p>

Association of rs7903146 polymorphisms in TCF7L2 gene with type 2 diabetes mellitus in Uygur population of Xinjiang / 中国病理生理杂志

AIM: To investigate whether rs7903146 polymorphisms in transcription factor 7-like 2 (TCF7L2) gene are associated with susceptibility to type 2 diabetes mellitus (T2DM) in Chinese Uygur population.METHODS: In this case-control study, 935 cases of T2DM patients were recruited in T2DM group, and 971 healthy examination individuals were selected as normal control.The TCF7L2 gene polymorphism was detected by matrix-assisted laser desorption/ionization time-of-flight mass spectrum.RESULTS: Significant differences in the frequencies of CC, CT and TT genotypes and the frequencies of C and T alleles on TCF7L2 rs7903146 were found between T2DM group and control group(P<0.05).As compared with C allele, the patients with T allele had a significantly higher risk of T2DM with OR of 1.190 (95% CI: 1.034~1.371).As compared with CC genotype, the patients with CT genotype had a significantly higher risk of T2DM with OR of 1.374 (95% CI: 1.122~1.683), and the patients with CT+TT genotype had a significantly higher risk of T2DM with OR of 1.307 (95% CI: 1.090~1.567).The levels of fasting plasma glucose, serum creatinine and blood urea nitrogen were higher in all participants with CT+TT genotype of rs7903146 than those with CC genotype, which showed a significant difference (P<0.05).CONCLUSION: The polymorphisms of rs7903146 in TCF7L2 gene may be associated with T2DM in Uygur population from Xinjiang region.The T allele and CT genotype of rs7903146 are the risk factors for T2DM.

Study on correlation between TCF7L2 gene rs3814570 polymorphisms with T2DM in Uygur Population of Xinjiang / 重庆医学

Objective To investigate the correlation between TCF7L2 gene rs3814570 polymorphisms with type 2 diabetes mellitus(T2DM) in Uygur population of Xinjiang area.Methods By adopting the case-control study design,949 cases of T2DM were recruited as the observation group and 963 individuals Undergoing healthy physical examination were selected as the control group.The TCF7L2 gene polymorphism was detected by matrix-assisted laser desorption/ionization-time of flight(MALDI-TOF).Results The statistical differences in frequencies of CC,CT and TT genotypes and the C and T allele frequencies on TCF7L2 rs3814570 were found between the T2DM group and control group(P＜0.05).The risk of suffering from T2DM in the carriers of CT genotype was 0.331 times of that in the carriers of CC genotype(OR =0.331,95 ％ CI:0.166-0.661,P =0.002),the risk of suffering from T2DM in the carriers of TT genotype was 0.539 times of that in the carriers of CC genotype(OR=0.539,95％CI:0.348-0.834,P=0.005),and the risk of suffering from T2DM in the carriers of T allele was 0.501 times of that in the carriers of C allele(OR=0.501,95 ％ CI:0.377-0.664,P＜ 0.01).Among all subjects,the FPG level of the CT + TT genotype group on TCF7L2 gene rs3814570 locus was significantly lower than that of the CC genotype group(P＜0.05).Conclusion The rs3814570 locus in TCF7L2 gene may be associated with T2DM occurrence in Uygur population of Xinjiang area,the T allele and TT genotype might be protective factors of T2DM.

The association between the rs11196218A/G polymorphism of the TCF7L2 gene and type 2 diabetes in the Chinese Han population: a meta-analysis

Transcription factor 7-like 2 has been shown to be associated with type 2 diabetes mellitus in multiple ethnic groups in recent years. In the Chinese Han population in particular, numerous studies have evaluated the association between the rs11196218A/G polymorphism of the transcription factor 7-like 2 gene and type 2 diabetes mellitus. However, the results have been inconsistent, so we performed a meta-analysis to assess the association. Odds ratio and 95% confidence interval values were calculated using a random-effects model or a fixed-effects model based on heterogeneity analysis. The quality of the included studies was evaluated using the Newcastle-Ottawa Scale. Subgroup analyses were conducted based on conformity with Hardy-Weinberg equilibrium in the control group as well as on other variables, such as age, sex and body mass index. Sensitivity analysis was also performed to detect heterogeneity and to assess the stability of the results. In total, 10 case-control studies comprising 7,491 cases and 12,968 controls were included in this meta-analysis. The combined analysis indicated that the rs11196218A/G polymorphism was not associated with type 2 diabetes mellitus (G vs. A, OR=1.04, 95% CI=0.97–1.13, p=0.28). The subgroup analyses also did not show any association between the rs11196218A/G polymorphism and the risk of type 2 diabetes mellitus. Furthermore, the results of the subgroup analyses indicated that the absence of an association was not influenced by age, sex or body mass index. The results of the sensitivity analysis verified the reliability and stability of this meta-analysis. In conclusion, this study indicated that there is no significant association between the rs11196218A/G polymorphism and the risk of type 2 diabetes mellitus in the Chinese Han population.

Regulation effect of TCF7L2 gene silence on the expression of insulin degrading enzyme in insulin resistant HepG2 cells / 解放军医学杂志

Objective To evaluate the effects of transcription factor 7-like 2 (TCF7L2) silence on the expression of insulin degrading enzyme (IDE) in insulin resistance (IR) model HepG2 cells and its possible mechanism. Methods The HepG2 cells were divided into blank group, TCF7L2 interference group, empty vector group, IR group, IR+TCF7L2 interference group, IR+empty vector group. IR-HepG2 cell model was induced by in vitro cultivation o the cells in high concentration of insulin (5 X 10-6 mol/L) for 24 hours; GOD-POD and 2-NBDG method was used to verify successful reproduction of IR-cell model. TCF7L2 specific siRNA lentivirus vector (LV-TCF7L2-siRNA) was constructed with TCF7L2 mRNA coding sequence as the interference target, and it was used to transfect the cells in blank group and IR group. Empty vector virus was used to transfect the cells in empty vector group and IR+empty vector group. The expressions of TCF7L2 and IDE mRNA were detected by qRT-PCR, and the changes in the expression of TCF7L2, IDE, insulin stimulated protein kinase B(AKT) and phosphorylated protein kinase B(p-AKT) were detected by Western blotting. The uptake rate of 2-deoxy-D-glucose (2-NBDG) was analyzed by flow cytometry. Results Compared with that in control group, the glucose consumption and the uptake rate of 2-NBDG significantly decreased in IR group (P<0.01), proving that the IR cell model had been reproduced successfully. Western bloting and qRT-PCR revealed that the expression levels of TCF7L2 and IDE mRNA and protein were obviously decreased in IR group compared with that in blank group (P<0.05), in TCF7L2 interference group than in blank group and empty vector group, and in IR+TCF7L2 interference group than in blank group and IR+empty vector group (P<0.05). Afer physiological insulin stimulation, the expression levels of p-AKT protein decreased more signifcantly in IR group and IR+TCF7L2 interference group than in blank group (P<0.01), while no statistically signifcant difference in the total AKT protein level was found among all the groups. 2-NBDG uptake rate was significantly decreased in TCF7L2 interference group as compared with that in blank group and empty vector group, and also in IR+TCF7L2 interference group than in IR group and IR+empty vector group, respectively P<0.01. ConclusionTe mechanism of IR induced by the interaction of TCF7L2 and IDE might be related to the decreased expression of the insulin signaling pathway key enzyme p-AKT protein.

Correlation between TCF7L2 gene polymorphism and genetic susceptibility in women with gestational diabetes mellitus / 中华妇产科杂志

Objective To investigate the relationship between single nucleotide polymorphism (SNP) of transcription factor 7-like 2 (TCF7L2) at locus rs7903146,rs290487,rsl1196205,rs 12255372 and genetic susceptibility in women with gestational diabetes mellitus (GDM).Methods As a case-control study,100 pregnant women with GDM and 100 healthy pregnant women in the Maternal and Children Health Hospital of Jiangxi Province were recruited from January 2010 to July 2013.Clinical parameters,including body mass index (BMI),fasting insulin (FINS),fasting plasma glucose (FPG) and homeostatic model assessment-insulin resistance index (HOMA-IR) were measured after admission to hospital.Allelespecific PCR was used to analyze the SNP of TCF7L2 at locus rs7903146,rs290487,rs11196205,rs12255372.Results (1)The BMI,FPG,FINS and HOMA-IR in GDM group were(27.4±3.0) kg/m2,(5.6±1.0) mmol/L,(6.2±3.4) mU/L and 1.8± 1.0,and were (24.2±2.9) kg/m2,(5.3±0.8) mmol/L,(4.5±2.8) mU/L,1.2± 0.8 in the control group,respectively.The differences had statistically significance (P＜0.05).(2)The SNP of TCF7L2 gene,locus rs7903146 were CC,CT and TT genotype; the SNP of locus rs290487 were CC,CT and TT genotype; and the SNP of locus rs1 1196205 were GG and CC genotype; while the SNP of locus rs12255372 was GG genotype.(3)The distribution frequencies of genotype CC,CT and TT at locus rs7903146 in the GDM group were 40％ (40/100),36％ (36/100) and 24％ (24/100),respectively.While in the control group,they were 55％ (55/100),38％ (38/100) and 7％ (7/100),respectively.The frequencies of C and T allele of rs7903146 were 58％and 42％ in the GDM group,and in the control group they were 74％ (148/200) and 26％ (52/200).The differences of genotype distribution and C/T allele frequency of rs7903146 between the two groups were statistically significant (P＜0.05).(4)The distribution frequencies of genotype CC,CT and TT at locus rs290487 in the GDM group were 12 ％ (12/100),36 ％ (36/100) and 52％ (52/100),and were 16％ (16/100),34％ (34/100) and 50％ (50/100) in the control group.The frequencies of C and T allele of rs290487 were 30％ (60/200) and 70％ (140/200) in the GDM group,and were 33％ (66/200) and 67％ (134/200) in the control group.There was no difference of genotype distribution and C/T allele frequency of rs290487 between the two groups (P＞0.05).(5)The distribution frequencies of genotype GG and CC at locus rs1 1196205 in the GDM group were 99％ (99/100) and 1％ (1/ 100),while those in the control group were 100％(100/100) and 0％.The frequency of G and C allele of rs1 1196205 were 99％(198/200) and 1％(2/200) in the GDM group,while in the control group were 100％ (200/200) and 0.There was no difference of genotype distribution and G/C allele frequency of rs11196205 between the two groups (P＞0.05).(6)The distribution frequencies of genotype GG at locus rs12255372 were 100％(100/100) in both the GDM group and the control group.The frequencies of G allele of rs12255372 were 100％ (200/200) in both the GDM group and the control group.There was no difference of genotype distribution and G allele frequency of rs12255372 between the two groups (P＞0.05).(7)After adjusting for age,gestational age,BMI,FPG and FINS,pregnant women with TT genotype at locus rs7903146 were more likely to have hyperglycemia compared with the C allele carriers (OR=2.77,95％ CI:1.03-7.57,P＜0.05).Conclusions The polymorphism of locus rs7903146 in TCF7L2 gene may be associated with genetic susceptibility in women with GDM.TT genotype is likely to be risk factor in the pathogenesis of GDM.

Association of single nucleotide polymorphism of transcription factor 7-like 2 gene with gestational diabetes mellitus / 中华内分泌代谢杂志

Objective To investigate the relationship between gene polymorphism of transcripion factor 7-like 2 (TCF7L2) at positions rs290487, rs11196205, rs11196218 and gestational diabetes mellitus (GDM) in Chinese women.Methods In 1140 unrelated pregnant Northern Chinese women (335 women with GDM, 158 gestational cases with impaired glucose tolerance and 647 pregnant non-diabetic controls) ,three single nucleotide polymorphisms (rs290487, rs11196205, and rs11196218) in the TCF7L2 gene were genotyped using ligase detection reaction (LDR).In the present study, cases with GDM and impaired glucose tolerance (IGT) were indistinguishable clinically and biochemically, and were combined into case group.Results The frequency of C allele of rs290487 was 41.6% in case group, being significantly higher than that in control group (36.3%, P=0.012).There was significant difference in the frequency of CC genotype between case group and control group (18.7% vs 14.0%, P=0.033).Compared with T allele carriers, CC genotype carriers had a 1.418-fold increased risk of GDM (95% CI 1.028-1.955).After adjusting for age, body mass index, family history of diabetes,systolic blood pressure,and diastolic blood pressure, pregnant women with CC genotype carriers of rs290487 were more prone to hyperglycemia compared with the T allele carriers (OR 1.518, 95% CI 1.064-2.166).Conclusions The TCF7L2 rs290487 variant may contribute to the genetic predisposition to GDM.CC genotype is likely to be associated with an increased risk of GDM in the pregnant Chinese women.

Association of TCF7L2 gene rs290487 polymorphism and polycystic ovarian syndrome in Hans in Anhui Province / 中华内分泌代谢杂志

One-hundred and sixty-nine women with polycystic ovarian syndrome (PCOS)and 95 healthy women were enrolled. All subjects were genotyped for rs290487 ( transcription factor 7-like 2 gene) by TaqManMGB probe hybridization assay. The results showed that polymorphism rs290487 had association with PCOS in Han people in Anhui area. The allele C was associated with the risk of PCOS. Genotype CC seems to be the risk factor of insulin resistance in PCOS patients.