Transcription Factor 7-like 2 Gene Research Articles

Genetic markers predicting sulphonylurea treatment outcomes in type 2 diabetes patients: current evidence and challenges for clinical implementation.

The clinical response to sulphonylurea, an oral antidiabetic agent often used in combination with metformin to control blood glucose in type 2 diabetes (T2DM) patients, has been widely associated with a number of gene polymorphisms, particularly those involved in insulin release. We have reviewed the genetic markers of CYP2C9, ABCC8, KCNJ11, TCF7L2 (transcription factor 7-like 2), IRS-1 (insulin receptor substrate-1), CDKAL1, CDKN2A/2B, KCNQ1 and NOS1AP (nitric oxide synthase 1 adaptor protein) genes that predict treatment outcomes of sulphonylurea therapy. A convincing pattern for poor sulphonylurea response was observed in Caucasian T2DM patients with rs7903146 and rs1801278 polymorphisms of the TCF7L2 and IRS-1 genes, respectively. However, limitations in evaluating the available studies including dissimilarities in study design, definitions of clinical end points, sample sizes and types and doses of sulphonylureas used as well as ethnic variability make the clinical applications challenging. Future studies need to address these limitations to develop personalized sulphonylurea medicine for T2DM management.

TCF7L2 rs7903146 Gene Variation Is Associated with Risk of Type 2 Diabetes in Turkish Population

Type 2 diabetes (T2D) results from combination of environmental factors and genetic determinants. Transcription factor 7-like 2 (TCF7L2) genes have been reported that it plays important role in T2D pathogenesis. In addition, TCF7L2 gene polymorphisms have been linked to T2D through many European populations. In the present study, we investigated TCF7L2 polymorphisms in healthy individuals and T2D patients and aimed to see whether TCF7L2 polymorphisms are associated with T2D in the Turkish population. We genotyped two SNPs of TCF7L2 gene, rs7903146 and rs12255372 in 100 healthy individuals and 100 patients. As a result of the genotype and allele distributions, we found that there were significantly associations between the TCF7L2 rs7903146 and risk of T2D (p=0.0172) in Turkish Population. However, there was no association for TCF7L2 rs12255372 (p=0.395) but GT genotype was higher in patient groups (p=0.0250). Similarly, our data shows that individuals who carry TCF7L2 rs7903146 polymorphism have significant risk of T2D in Turkish population.

The Kruppel-Like Factor 14 (KLF14), Master Gene of Multiple Metabolic Phenotypes: Putative Trans-Regulator Network

Studies of genetics variants in the predisposition to metabolic diseases such as hypertension, dyslipidemias, obesity, diabetes and others related traits show their importance in the understanding of the disease pathophysiology. Many susceptibility genes are identified as associated to these diseases and in the case of type 2 diabetes mellitus (T2DM) and obesity, TCF7L2 (Transcription Factor 7 Like 2) and PPARG (peroxisome proliferator activated receptor gamma) genes are both associated by certain gene polymorphisms. These genes require a network of other genes to present particular phenotypes; in human pancreatic islets for example, ISL1 is a direct target of TCF7L2 and ISL1, in turn, regulates proinsulin production and processing via regulation of PCSK1 (proprotein convertase subtilisin/kexin type 1), PCSK2 (proprotein convertase subtilisin/kexin type 2), SLC30A8 (solute carrier family 30 member 8), MAFA (vmaf avian musculoaponeurotic fibrosarcoma oncogene homolog A), PDX1 (pancreatic and duodenal homeobox 1) and NKX6.1 (NK6 homeobox 1). Furthermore, TCF7L2 might also influence hepatic clearance of insulin via its effect on SLC30A8. As a master trans-regulator related to multiple metabolic phenotypes, KLF14 gene encode for Kruppel-like Factor 14 which is a transcription factor and previously shown by an genome wide association study (GWAS) to be associated with T2DM et high density lipoprotein (HDL) cholesterol levels. This gene constitutes a target for the future understanding of pathophysiological complications and regulation of the metabolic syndrome. This review identifies a network of genes whose expression is associated with KLF14 gene regulation in trans. The protein-protein interactions in the KLF14 protein network may provide a framework for understanding the implication of KLF14 gene in diseases risks.

Correlation of the TCF7L2 (rs7903146) polymorphism with an enhanced risk of type 2 diabetes mellitus: a meta-analysis.

Increasing evidence has demonstrated that a transcription factor 7-like 2 (TCF7L2) polymorphism (rs7903146) is significantly associated with type 2 diabetes mellitus (T2DM); however, limited sample size and variance of ethnicity in the studies investigating this association have led to conflicting reports regarding its role. Therefore, a comprehensive meta-analysis was conducted to quantitatively assess the association between the TCF7L2 polymorphism (rs7903146) and T2DM including published case-control studies in global populations. We searched the PubMed, EMbase, CNKI, and Wanfang databases for publications that studied correlation between TCF7L2 polymorphism (rs7903146) and risk of T2DM. Thirty-six studies from 30 eligible papers were identified. After data extraction and reference quality assessment, summary odds ratio and 95% confidence intervals (95%CI) of the TCF7L2 (rs7903146) polymorphism were calculated and combined using the fixed-effect model. Hardy-Weinberg equilibrium was evaluated to determine selection bias of the control subjects. Heterogeneity among studies was examined using the Q-test and the I2 test. Publication bias in studies was assessed using Begg's plots and the Egger test. The results showed that the rs7903146 T allele of the TCF7L2 gene was positively correlated with an enhanced risk of T2DM in the allelic, heterozygote, homozygote, dominant, and recessive models, with odds ratios of 1.35 (T vs C, 95%CI = 1.31-1.39), 1.32 (CT vs CC, 95%CI = 1.27-1.38), 1.74 (TT vs CC, 95%CI = 1.63-1.87), 1.40 (TT+CT vs CC, 95%CI = 1.35-1.46), and 1.59 (TT vs CT+CC, 95%CI = 1.49-1.69), respectively. No obvious publication bias was observed using the Egger linear test.

Association between the rs12255372 variant of the TCF7L2 gene and obesity in a Cameroonian population.

BackgroundThe transcription factor 7-like 2 (TCF7L2) is one of the genes that have been identified as possible determinants of diabetes which is associated with obesity. Data on the genetic causes of obesity in sub-Saharan African populations are very scares. The aim of this study was to assess the association between the transcription factor 7-like 2 (TCF7L2) gene polymorphism (rs12255372 G/T) and obesity and weight-related traits in a Cameroonian population.MethodsA case–control study was conducted on 35 obese and 30 non-obese Cameroonian adults. TCF7L2 rs12255372 genotypes were determined using PCR–RFLP and correlated with BMI and weight-related traits.ResultsNo significant association was observed between the rs12255372 T allele (χ2 = 0.0684, p = 0.79) or the TT genotype (χ2 = 0.372, p = 0.54) of the TCF7L2 gene and obesity in the Cameroonian population. However, amongst the weight-related traits, triglycerides were significantly associated with the T risk allele of the TCF7L2 gene (p = 0.012).ConclusionThis study on Cameroonian subjects replicates the absence of association between the TCF7L2 rs12255372 variant and obesity as observed in European and American populations.

Association of TCF7L2 Genetic Polymorphisms with Type 2 Diabetes Mellitus in the Uygur Population of China.

Background: Genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene have been reported to be strongly associated with type 2 diabetes mellitus (T2DM) in Icelandic, Danish and American populations and further replicated in other European populations, African Americans, Mexican Americans, and Asian populations. The aim of the present study was to investigate the association of TCF7L2 gene polymorphisms with T2DM in a Uygur population of China. Methods: 877 T2DM patients and 871 controls were selected for the present study. Two single nucleotide polymorphisms (SNPs) (rs12255372 and rs7901695) were genotyped by using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. The associations of SNPs and haplotypes with T2DM and linkage disequilibrium (LD) structure of the TCF7L2 gene were analyzed. Results: For total participants and male, the distribution of rs12255372 alleles and the dominant model (Guanine Guanine (GG) genotype vs. Guanine Thymine (GT) genotype + Thymine Thymine (TT) genotype) showed significant difference between T2DM and control subjects (for allele: p = 0.013 and p = 0.002, respectively; for dominant model: p = 0.028 and p = 0.008, respectively). The distribution of rs7901695 alleles and the dominant model (TT genotype vs. Thymine Cytosine (TC) genotype + Cytosine Cytosine (CC) genotype) for total participants and male showed significant difference between T2DM and control subjects (for allele: both p = 0.001; for dominant model: p = 0.006 and p = 0.008, respectively). Conclusions: Our data suggested that the genetic polymorphisms of the TCF7L2 gene were associated with T2DM in the Uygur population of China.

Association of TCF7L2 Polymorphism with Diabetic Nephropathy in the South Indian Population.

The transcription factor 7-like 2 (TCF7L2) gene plays a significant role in the development of type 2 diabetes and diabetic nephropathy. The aim of this study was to investigate the association of TCF7L2 rs12255372 (G/T)polymorphism with type 2 diabetic nephropathy in the South Indian population. A total of 2102 subjects, 927 normal glucose tolerant (NGT) subjects, 598 type 2 diabetic subjects without nephropathy (DM), and 577 type 2 diabetic subjects with nephropathy (DN) were genotyped by MassARRAY. As compared to the NGT group, the odds ratio (adjusted for age, sex, BMI, HbA1c, and systolic BP) computed for the GT/TT genotype taking the GG genotype as reference was found to be 2.02 (95% CI: 1.16-3.51, p = 0.013) for DN and 1.94 (95% CI: 1.36-2.78, p = 0.0002) for DM. The genotype frequency was not significantly different between the DM and DN groups. In conclusion, the rs12255372 polymorphism in the TCF7L2 gene is associated with type 2 diabetes and DN but its association with DN is mediated through diabetes.

Polymorphisms in FTO and TCF7L2 genes of Euro-Brazilian women with gestational diabetes

ObjectiveTo investigate the association between fat mass and obesity-associated (FTO) gene polymorphisms rs8050136C>A and rs9939609T>A, and transcription factor 7-like 2 (TCF7L2) gene polymorphisms rs12255372G>T and rs7903146C>T, in a sample group of pregnant Euro-Brazilian women with or without gestational diabetes mellitus (GDM). MethodsSubjects were classified as either healthy pregnant control (n=200) or GDM (n=200) according to the 2010 criteria of the American Diabetes Association. The polymorphisms were genotyped using fluorescent probes (TaqMan®). ResultsAll groups were in the Hardy–Weinberg equilibrium. The genotype and allele frequencies of the examined polymorphisms did not exhibit significant difference (P>0.05) between the groups. In the healthy and GDM pregnant women groups, the A-allele frequencies (95% CI) of FTO polymorphisms rs8050136 and rs9939609 were 39% (34–44%); 38% (33–43%) and 40% (35–45%); 41% (36–46%), respectively; and the T-allele frequencies of TCF7L2 polymorphisms rs12255372 and rs7903146 were 30% (26–35%), 32% (27–37%) and 29% (25–34%), 36% (31–41%), respectively. ConclusionThe examined polymorphisms were not associated with GDM in the Euro-Brazilian population studied.

Association between the TCF7L2 rs12255372 (G/T) gene polymorphism and type 2 diabetes mellitus in a Cameroonian population: a pilot study.

BackgroundTo study the relationship between the rs12255372 (G/T) polymorphism of the transcription factor 7-like 2 (TCF7L2) and type 2 diabetes mellitus (T2DM) in a Cameroonian population.MethodsThis case–control study included 60 T2DM patients and 60 healthy normoglycemic controls, all unrelated and of Cameroonian origin, aged above 40 years (range 40–87). The Restriction Fragment Length Polymorphism - Polymerase Chain Reaction (RFLP-PCR) was used for genotyping.ResultsThe T allele frequency was significantly higher in the diabetic group (0.44) than in the control group (0.17). This allele was significantly associated to a greater risk of developing T2DM as compared to the G allele (OR = 3.92, 95% CI 2.04 – 7.67, p < 0.0001). The codominant (additive) model explained best the risk of developing the disease, as the TT genotype was significantly associated to T2DM when compared to the GG genotype (OR = 4.45, 95% CI 1.64 – 12.83, p = 0.0014). By logistic regression adjusted for age, this OR was 4.33 (95% CI: 1.57 – 11.92, p = 0.005).ConclusionOur findings suggest that the rs12255372 (G/T) polymorphism of the TCF7L2 gene is an important risk factor for T2DM in the Cameroonian population.

A case-control association study of K121Q (rs 1044498) and G/T (rs 1225572) variants in ENPP1 and TCF7L2 genes with type 2 diabetes mellitus in north Indian Punjabi population

Recently, the transcription factor-7-like 2 (TCF7L2) and ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) genes have been identified to have a significant functional role in determining susceptibility to type 2 diabetes. The purpose of this study was to confirm the reported association between K121Q and G/T polymorphisms of the ENPP1 and TCF7L2 genes, respectively with increased risk of type 2 diabetes mellitus in north Indian Punjabi population. A total of 450 participants consisting of 239 type 2 diabetes mellitus (T2DM) and 211 healthy subjects were recruited for this study. Genotyping was performed by PCR-RFLP method. Anthropometric and physiometric variables such as height, weight, body mass index (BMI), waist to hip ratio (WHR), waist circumference (WC), hip circumference (HC), biceps skinfold, triceps skinfold, SBP, DBP, MBP, pulse rate and pulse pressure were measured using standard protocol. The chi-square analyses were used to test the significant difference in genotype, allele frequencies and Hardy-Weinberg equilibrium deviation. Associations of genotypes with T2DM and its corresponding p values were calculated using logistic regression. The results revealed that anthropometric and clinical characteristics such as WHR, fasting and random glucose levels, SBP, DBP, pulse rate and pulse pressure have significant (p < 0.001) differences between T2DM and control subjects. However, none of the anthropometric and clinical characteristics have found a significant difference with respect to their genotypic distributions for both of genes except DBP for ENPP1 K121Q polymorphism. The distributions of frequencies of Q allele of rs 1044498 (K121Q) and T allele of rs 1225572 (G/T) polymorphism of ENPP1 and TCF7L2 genes were higher in T2DM patient patients but differences were not statistically significant. The association analysis of the present results showed K121Q variant of ENPP1 gene and G/T variant of TCF7L2 gene have a significant association with type 2 diabetes with dominant and recessive model of action, respectively, in north Indian Punjabi populations.

Liver-specific expression of dominant-negative transcription factor 7-like 2 causes progressive impairment in glucose homeostasis.

Investigations on the metabolic role of the Wnt signaling pathway and hepatic transcription factor 7-like 2 (TCF7L2) have generated opposing views. While some studies demonstrated a repressive effect of TCF7L2 on hepatic gluconeogenesis, a recent study using liver-specific Tcf7l2(-/-) mice suggested the opposite. As a consequence of redundant and bidirectional actions of transcription factor (TCF) molecules and other complexities of the Wnt pathway, knockout of a single Wnt pathway component may not effectively reveal a complete metabolic picture of this pathway. To address this, we generated the liver-specific dominant-negative (DN) TCF7L2 (TCF7L2DN) transgenic mouse model LTCFDN. These mice exhibited progressive impairment in response to pyruvate challenge. Importantly, LTCFDN hepatocytes displayed elevated gluconeogenic gene expression, gluconeogenesis, and loss of Wnt-3a-mediated repression of gluconeogenesis. In C57BL/6 hepatocytes, adenovirus-mediated expression of TCF7L2DN, but not wild-type TCF7L2, increased gluconeogenesis and gluconeogenic gene expression. Our further mechanistic exploration suggests that TCF7L2DN-mediated inhibition of Wnt signaling causes preferential interaction of β-catenin (β-cat) with FoxO1 and increased binding of β-cat/FoxO1 to the Pck1 FoxO binding site, resulting in the stimulation of Pck1 expression and increased gluconeogenesis. Together, our results using TCF7L2DN as a unique tool revealed that the Wnt signaling pathway and its effector β-cat/TCF serve a beneficial role in suppressing hepatic gluconeogenesis.

Association of TCF7L2 gene polymorphisms with susceptibility to type 2 diabetes mellitus in a Chinese Hui population.

Diabetes is one of costly chronic diseases. Previous studies across several ethnicities have shown that polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene were strongly associated with susceptibility to type 2 diabetes (T2DM). In the present study, the association between the TCF7L2 gene and the susceptibility to T2DM in a Chinese Hui population was interrogated. Polymerase chain reaction (PCR)- restriction fragment length polymorphism analysis and allelic specific PCR were employed for examining the TCF7L2 gene rs12255372 (G>T) and rs290487 (C>T), and rs7901695 (T>C) polymorphisms, respectively, in 109 healthy individuals and 111 subjects with T2DM who were of Chinese Hui descent and lived in the Ningxia Hui Autonomous Region of China. The results showed that the genotypic frequency of rs290487 and the allelic frequency distributions of the rs7901695 and rs290487 loci were not significantly different between patients and controls in this population. However, both the genotypic and the allelic frequencies at rs12255372 exhibited statistical differences between the patients with T2DM and the unaffected cohort (P < 0.01). In addition, the frequency of the G allele at the rs12255372 locus in the patients was higher than that in healthy individuals (OR = 1.198, 95%CI = 1.097-1.307). These findings suggest that the TCF7L2 rs12255372 (G>T) polymorphism might be one of the most important genetic factors associated with T2DM susceptibility, and that individuals in the Chinese Hui population who carry a G allele at this locus might be at risk to develop T2DM.

Association of TCF7L2 Gene Polymorphisms with T2DM in the Population of Juana Koslay, San Luis Province, Argentina

Polymorphisms in the gene coding for transcription factor 7 like 2 (TCF7L2) are recognized as the strongest common genetic risk factors for Type 2 Diabetes Mellitus (T2DM) across multiple ethnicities. This study was conducted to evaluate an association between TCF7L2 variants and diabetes susceptibility in the population of Juana Koslay, San Luis, Argentina. We genotyped 2 single nucleotide polymorphisms (SNP) rs7903146 and rs12255372 in controls and diabetic subjects. Association with T2DM was found for both SNPs rs7903146 and rs12255372 in the whole sample (under a dominant genetic model, the odds ratios (OR) were 3.43, 95% CI [1.879 - 6.255], p < 0.0001 and OR = 4.40, 95% CI [2.318 - 8.351], p < 0.0001, respectively). The risk conferred by homozygotes is much higher than the heterozygote carriers and it is marked in case of rs7903146. The haplotype that consisted of two minor alleles (TT) or the haplotypes carrying at least one of the minor alleles at SNP rs7903146 or rs12255372 (i.e. CT or TG) were more frequent in the group of T2DM. The impact of TCF7L2 variation on T2DM risk in Juana Koslay population is compatible with that demonstrated by a range of studies conducted in various ethnic groups.

Non-Association between rs7903146 and rs12255372 Polymorphisms in Transcription Factor 7-Like 2 Gene and Type 2 Diabetes Mellitus in Jahrom City, Iran.

BackgroundTranscription factor 7-like 2 (TCF7L2) is a transcription factor in the Wnt signaling pathway. High levels of TCF7L2 have been reported in most human tissues, including the heart, lung, brain, liver, kidney, placenta, adipose tissues, and pancreatic β-cells. The purpose of this study was to assess the association between TCF7L2 polymorphisms (rs12255372 and rs7903146) and type 2 diabetes mellitus in the city of Jahrom, Iran.MethodsThis case-control study was conducted with 200 patients referred to Diabetes Clinics and 200 healthy subjects in Jahrom City. Biochemical characteristics were first determined. TCF7L2 rs1255372 and rs7903146 polymorphisms were then genotyped using the polymerase chain reaction-restriction fragment length polymorphism method.ResultsT-allele frequencies of both single nucleotide polymorphisms (SNPs) were significantly higher in diabetic patients than in normal glucose-tolerant subjects (rs12255372: 20.3% vs. 14.5%; rs7903146: 28.5% vs. 22.25%). The rs12255372 (G/T) polymorphism analysis showed an odds ratio of 0.473 (95% confidence interval [CI], 0.170 to 1.314; P=0.151) for the TT genotype and 0.646 (95% CI, 0.410 to 1.019; P=0.060) for the TG genotype, compared with the GG genotype. The rs7903146 (C/T) polymorphism odds ratios for TT and TC genotypes were 0.564 (95% CI, 0.280 to 1.135; P=0.109) and 0.751 (95% CI, 0.487 to 1.157; P=0.194) compared with the CC genotype, respectively.ConclusionThe rs12255372 and rs7903146 SNPs of the TCF7L2 gene were not associated with insulin resistance in the evaluated population.

The gene polymorphisms of UCP1 but not PPAR γ and TCF7L2 are associated with diabetic retinopathy in Chinese type 2 diabetes mellitus cases.

This study was designed to investigate the association between the polymorphisms in three insulin resistance-related genes, uncoupling protein-1 (UCP1), peroxisome proliferator-activated receptor γ (PPARγ) and transcription factor 7-like 2 (TCF7L2) and the susceptibility to diabetic retinopathy (DR) in a Chinese type 2 diabetes mellitus (T2DM) cohort. A total of 792 patients with T2DM were enrolled and categorized into two groups: (1) the DR group consisted of 448 patients, which was further subclassified into a proliferative DR (PDR) group with 220 patients and a non-proliferative DR (NPDR) group with 228 patients; (2) the diabetes without retinopathy (DNR) group, comprised 344 patients who had no signs of DR. Single-nucleotide polymorphisms (SNPs), rs1800592 in the UCP1 gene, rs1801282, rs3856806 and rs1249719 in the PPARγ gene and rs11196205 in the TCF7L2 gene were genotyped in this study. For SNP rs1800592 of the UCP1 gene, the frequency of allele G and genotype GG was significantly higher in the PDR group than in the DNR group (allele OR: 1.32, 95% CI: 1.03-1.68, p = 0.03; genotype OR: 1.72, 95%CI: 1.06-2.79, p = 0.03). No evident association was found between the allele frequencies and genotype distributions of any individual SNP in the PPARγ or TCF7L2 genes and DR, PDR or NPDR. Haplotype analyses of the PPARγ gene did not provide any evidence for an association with DR, PDR or NPDR in this Chinese T2DM cohort. This study suggests that the SNP rs1800592 in the UCP1 gene is associated with increased risk of PDR in the Chinese T2DM population.

Correlation between TCF7L2 gene polymorphism and genetic susceptibility in women with gestational diabetes mellitus

To investigate the relationship between single nucleotide polymorphism (SNP) of transcription factor 7-like 2 (TCF7L2) at locus rs7903146, rs290487, rsl1196205, rs12255372 and genetic susceptibility in women with gestational diabetes mellitus (GDM). 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. (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 rs11196205 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 rs11196205 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 rs11196205 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). 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.

Sa1358 Comparison of Gastric Motor Functions and Satiation in Overweight and Obese Adults With Allelic Variants At the TCF7l2 Locus to Adults With Common Alleles

Background: Candidate genes have been associated with development of obesity and diabetes. In three Caucasian population studies, the transcription factor 7-like 2 (TCF7L2) gene polymorphism rs7903146 (TT genotype) was predictive of the development of type 2 diabetes mellitus (T2DM). It is unclear whether TCF7L2 gene polymorphisms are associated with alterations of gastric motor functions or satiation. Aim: To determine whether genetic variations of TCF7L2 gene rs7903146 are associated with gastric emptying (GE), gastric accommodation (GA), satiation, satiety or postprandial plasma glucagon-like peptide 1 (GLP1) levels in overweight and obese people. Methods: 271 overweight or obese participants, predominantly Caucasian, underwent, on separate days, validated measurements of intermediate phenotypes: GE of solids and liquids by scintigraphy, gastric volume (GV) by SPECT during fasting and after 200mL Ensure® (accommodation GV), satiation (maximal tolerated volume, MTV) by Ensure® (1 kcal/mL) ingested at 30mL/min, satiety by kcal intake during a buffet meal ingested 4h after intake of the Ensure® meal for the GV test, and fasting and postprandial plasma GLP-1measured by radioimmunoassay. Genotyping of TCF7L2 gene rs7903146 was by TaqMan® SNP Assay. From the 271 participants, we identified 22 individuals with TCF7L2 rs7903146 TT homozygotes and 44 ageand gender-matched CC homozygotes. We tested associations of TCF7L2 genotype with each intermediate phenotype using ANCOVA based on the general genetic model. Results: Data are shown in table. Early phase of GE solids was faster with TCF7L2 TT compared to CC: T1/2 (p=0.031), GE lag time (or time for 10% emptied, p=0.031), percentage GE at 60min (p=0.029). However, percentage emptied at 2-4h was not different in the TT and CC groups. Mean postprandial GLP-1 levels (a measure of AUC) were higher in TT homozygotes compared to CC homozygotes (p=0.026). There were no associations of the TCF7L2 gene with age, BMI, GE of liquids, accommodation GV, satiation (MTV and aggregate symptoms score 30min postMTV), and satiety (kcal ingested 4h later). Although not statistically significant, the mean MTV was 140kcal greater with TT than CC genotype. Conclusion: TCF7L2 homozygous T genotype (rs7903146) is associated with faster gastric emptying of solids in overweight and obese adults; these findings may explain the propensity to develop postprandial hyperglycemia or T2DM, and the non-significant increase in kcal intake may contribute to obesity. The higher postprandial GLP-1 levels in TT homozygotes reflect the faster emptying of the first 50% of the meal; the data are consistent with elevated GLP-1 slowing the emptying of the second half of the meal. Overall, these data suggest important contribution of gastric function to the metabolic effects of TCF7L2 mechanisms. Funding: NIH DK67071

PW374 The Country Access to Cardiac Health (CATCH) Program: Addressing the confounders of referral, attendance and access for rural patients post myocardial infarction

It is assumed that genetic factors play crucial role in nephrolithiasis. The present study was conducted to explore the role of Human Transcription Factor-7 like-2 (TCF7L2) β-defensin (DEFB1) and CD14 gene polymorphism in development and progression of nephrolithiasis.The genotypes of TCF7L2, DEFB1 and CD14 polymorphism were determined in 240 nephrolithiasis patients and 240 healthy controls by restriction digestion method of PCR. The levels of serum TCF7L2, DEFB1, CD14, uric acid and other biochemical parameters were measured both in nephrolithiasis patients and healthy control.The patients and control groups showed 30% and 50% 1654 AA DEFB1 genotype respectively. The Allele frequency in case of patient's group was 63.67% while in control group it was 36.33%. The mean serum DEFB1 levels of the patients and control groups attained were 115.66 and 239.43 pg/mL respectively. The allele frequency of TCF7L2 in patients and controls were 44.17% and 70.0% for C-allele, 55.83% and 30.00% for T-allele respectively. The mean of serum TCF7L2 levels were significantly decreased in patients compared to control group.The present findings are first of its class that validates a considerable connection of DEFB1 and TCF7L2 gene polymorphisms with nephrolithiasis and could probably act as indicators to estimate the risk associated to nephrolithiasis.

Association of rs7903146, rs12255372, and rs290487 polymorphisms in TCF7L2 gene with type 2 diabetes in an Iranian Kurdish ethnic group.

Single nucleotide polymorphisms (SNPs) within the transcription factor 7-like 2 (TCF7L2) gene are well known risk variants for type 2 diabetes mellitus (T2DM). The association between TCF7L2 SNPs and T2DM has been investigated in several studies, but the results are controversial. In this study, we investigated whether the rs7903146, rs12255372, and rs290487 polymorphisms of TCF7L2 are associated with T2DM per se or metabolic traits related to this disease in a Kurdish ethnic group of Iran. In all, 173 patients with T2DM and 173 normoglycemic subjects were included in this study. All subjects were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Genotypic and allelic frequencies were then analyzed in each group. Serum lipids, fasting glucose, fasting serum insulin, HOMA-IR, and HbA1c levels were determined by conventional methods. T-allele and genotype frequencies of rs7903146, rs12255372, and rs290487 were significantly different between T2DM and control subjects. The CT genotype (OR = 1.98, p = 0.008), TT genotype (OR = 3.54, p = 0.024), and the dominant model (OR = 2.16, p = 0.002) of rs7903146 were associated with T2DM. The GT genotype (OR = 2.23, p = 0.005), TT genotype (OR = 4.25, p = 0.046), and the dominant model (OR = 2.2, p = 0.001) of rs12255372 gave a higher risk for T2DM. The carriers of CT genotype of rs290487 showed a significantly increased risk for T2DM (OR = 2.24, p = 0.003). Similarly, the dominant model of this SNP was found to be significantly associated with T2DM (OR = 2.25, p = 0.002). The control subjects carrying the T-allele of rs7903146 had higher levels of total cholesterol (CC; 4.52 +/- 1.03 vs. CT + TT; 5.00 +/- 1.2 mmol/L, p = 0.009) than those with CC genotype. Normoglycemic subjects carrying GT + TT genotypes of rs12255372 had a significantly higher WHR (GG; 0.90 +/- 0.059 vs. GT + TT; 0.93 +/- 0.07, p = 0.038) as compared with those with the GG genotype. The T-allele of rs12255372, rs7903146, and rs290487 polymorphisms of TCF7L2 confer susceptibility to T2DM in the Kurdish population of Iran.

Meta-analysis of variant rs 7903146 of TCF7L2 gene with secondary complications of Type 2 Diabetes Mellitus

Persistent hyperglycemia in patients with Type 2 diabetes mellitus is driving force for developing secondary complications like neuropathy, retinopathy, nephropathy, cardiomyopathy and wound healing impairment in them. Other genetic risk factor includes variants of transcription factor 7-like 2 (TCF7L2) gene, which have been shown to be associated with these several secondary complications individually. The present study represents a systematic review and Meta analysis using electronic databases like PubMed, OMIM, ISI web of science and Embase to see the role of rs7903146 C>T variant of the TCF7L2 gene with secondary complications of T2DM. Data was collected using literature-based searching to perform a Meta analysis to pool the odds ratio (OR). This Meta analysis comprised of a total of 2060 cases with secondary complication of T2DM and 3049 age matched controls. Publication bias and study-between heterogeneity were also evaluated. The present Meta analysis of included studies showed a highly significant association of risk genotype TT with development of secondary complications in T2DM.