Transcription Factor 7-like 2 Genotype Research Articles

Associations Between TCF7L2, PPARγ, and KCNJ11 Genotypes and Insulin Response to an Oral Glucose Tolerance Test: A Systematic Review.

Insulin responses to standardized meals differ between individuals. This variability may in part be explained by genotype. This systematic review evaluates associations between genotype and insulin response to an oral glucose tolerance test (OGTT) in terms of insulin area under the curve (AUC). Three electronic databases (Web of Science, Embase, PubMed) were searched for studies investigating associations between insulin AUC after an OGTT and single nucleotide polymorphisms (SNPs) belonging to the transcription factor 7 like 2 (TCF7L2) gene, the peroxisome proliferator-activated receptor gamma (PPARγ) gene, or the potassium inwardly rectifying channel subfamily J member 11 (KCNJ11) gene in persons without diabetes. A total of 5199 articles were identified, of which 38 were included. Among them were family-based studies (9), twin studies (2), and studies with unrelated participants (27). Seventeen articles investigated TCF7L2 (7 SNPs), 14 investigated PPARγ (1 SNP), and 8 investigated KCNJ11 (5 SNPs). For all investigated SNPs, at least half of the reports indicated no statistically significant association with postprandial insulin AUC. No evidence was found for associations between TCF7L2, PPARγ, and KCNJ11 genotypes and insulin AUC after an OGTT. Future studies should investigate the effect of genetic risk scores on postprandial insulin.

Physical Activity, Genetic Susceptibility, and the Risk of Latent Autoimmune Diabetes in Adults and Type 2 Diabetes.

PurposePhysical activity (PA) has been linked to a reduced risk of type 2 diabetes by reducing weight and improving insulin sensitivity. We investigated whether PA is associated with a lower incidence of latent autoimmune diabetes in adults (LADA) and whether the association is modified by genotypes of human leukocyte antigen (HLA), transcription factor 7-like 2 (TCF7L2)-rs7903146, or the fat mass and obesity-associated gene, FTO-rs9939609.MethodsWe combined data from a Swedish case-control study and a Norwegian prospective study including 621 incident cases of LADA and 3596 cases of type 2 diabetes. We estimated adjusted pooled relative risks (RRs) and 95% CI of diabetes in relation to high (≥ 30 minutes of moderate activity 3 times/week) self-reported leisure time PA, compared to sedentariness.ResultsHigh PA was associated with a reduced risk of LADA (RR 0.61; CI, 0.43-0.86), which was attenuated after adjustment for body mass index (BMI) (RR 0.90; CI, 0.63-1.29). The reduced risk applied only to noncarriers of HLA-DQB1 and -DRB1 (RR 0.49; CI, 0.33-0.72), TCF7L2 (RR 0.62; CI, 0.45-0.87), and FTO (RR 0.51; CI, 0.32-0.79) risk genotypes. Adjustment for BMI attenuated but did not eliminate these associations. For type 2 diabetes, there was an inverse association with PA (RR 0.49; CI, 0.42-0.56), irrespective of genotype.Main ConclusionsOur findings indicate that high PA is associated with a reduced risk of LADA in individuals without genetic susceptibility.

Mediterranean Diet Adherence Modulates Anthropometric Measures by TCF7L2 Genotypes among Puerto Rican Adults

Transcription factor 7-like 2 (TCF7L2) genetic variants that predispose individuals to type 2 diabetes (T2D) show inconsistent associations with anthropometric traits. Interaction between TCF7L2 genotypes and dietary factors may help explain these observations. We aimed to examine the potential modulation of TCF7L2-rs7903146 and rs12255372 on anthropometric markers by a Mediterranean diet (MedDiet). Cross-sectional analysis was conducted in 1120 participants (aged 45-75 y) of the Boston Puerto Rican Health Study. Anthropometric variables were measured, and polymorphisms were genotyped using standardized protocols. Diet was assessed using a validated FFQ. The MedDiet was defined based on adherence to 9 food and nutrient components using sex-specific population-based median cut-offs; high adherence was defined as meeting≥4 components. Haplotypes were tested for association with obesity traits, independently and via interaction with the MedDiet. TCF7L2-rs7903146 showed significant interaction with the MedDiet influencing BMI, weight, and waist circumference. The T risk-allele carriers (CT+TT) with a high MedDiet score had lower weight (77.3±1.0 compared with CC 80.9±1.0 kg; P=0.013) and waist circumference (99.2±0.9 compared with CC 102.2±0.9 cm; P=0.021), when compared with CC participants. A low MedDiet score resulted in no significant differences between genotypes. For TCF7L2-rs12255372, we found significant interactions with the MedDiet for weight (P-interaction=0.034) and BMI (P-interaction=0.036). The T allele carriers with a higher MedDiet score showed a trend of lower but no significant differences when compared with CC participants for BMI (P=0.19), weight (P=0.09), and waist circumference (P=0.11). We found significant interactions between the 2 risk-carrying haplotypes and the MedDiet compared with the common haplotype (GC), with lower BMI (β±SE, TT: -1.53±0.68; P-interaction=0.024), weight (TT: -4.16±1.77; P-interaction=0.019), and waist circumference (GT: -5.07±2.50; P-interaction=0.042) at a high MedDiet score. Puerto Ricans with the TCF7L2-rs7903146 and rs12255372 T2D risk genotypes, although still high, had better anthropometric profiles when adhering to a MedDiet, suggesting that this diet may offset unfavorable genetic predisposition.

Contribution of single-nucleotide polymorphism in transcription factor 7-like 2 gene to cardiometabolic risk in adult Nigerians

Background: Single-nucleotide polymorphism in the gene, transcription factor 7-like 2 (TCF7L2), shows the strongest and most consistent association with risk of developing type 2 diabetes (T2D). TCF7L2 has been associated with both impaired beta-cell function and insulin resistance. Gene variants of TCF7L2 may, therefore, contribute to cardiometabolic risk (CMR) and metabolic syndrome (MS). Aims and Objectives: The study aims to examine the relationship between gene variants in TCF7L2 with MS and CMR. Methods: Three hundred and fifty-six adult Nigerians aged between 40 and 100 years participated in a cross-sectional, analytical study. The association between TCF7L2 genotypes and MS and its components was determined. The data were analyzed, and statistical significance was set at P Results: Three hundred and fifty-six individuals participated in the study (35.6% of males and 64.2% of females). About 64.9% of participants had T2D. The prevalence of MS was 26.4%. Among the individuals with the wild-type homozygote genotype CC, heterozygote genotype CT, and homozygote mutant TT, 24.9%, 27.2%, and 30.6% had MS, respectively. The risk T allele was associated with higher mean values of waist circumference and triglyceride than the C allele (P = 0.006 and 0.022, respectively). The T allele had a significant correlation with MS components (P Conclusion: Variants in the TCF7L2 gene are associated with components of MS and correlate with CMR through insulin resistance.

TCF7L2 Genetic Variation Augments Incretin Resistance and Influences Response to a Sulfonylurea and Metformin: The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH).

OBJECTIVEThe rs7903146 T allele in transcription factor 7 like 2 (TCF7L2) is strongly associated with type 2 diabetes (T2D), but the mechanisms for increased risk remain unclear. We evaluated the physiologic and hormonal effects of TCF7L2 genotype before and after interventions that influence glucose physiology.RESEARCH DESIGN AND METHODSWe genotyped rs7903146 in 608 individuals without diabetes and recorded biochemical data before and after 1) one dose of glipizide (5 mg) on visit 1 and 2) a 75-g oral glucose tolerance test (OGTT) performed after administration of metformin 500 mg twice daily over 2 days. Incretin levels were measured in 150 of the 608 participants.RESULTSTT risk-allele homozygotes had 1.6 mg/dL higher baseline fasting glucose levels and 2.5 pg/mL lower glucagon levels per T allele than carriers of other genotypes at baseline. In a subset of participants, the T allele was associated with higher basal glucagon-like peptide 1 (GLP-1) levels at visit 1 (β = 1.52, P = 0.02 and β = 0.96, P = 0.002 for total and active GLP-1, respectively), and across all points of the OGTT after metformin administration. Regarding drug response, the T allele was associated with a shorter time (β = −7.00, P = 0.03) and a steeper slope (β = 0.23, P = 0.04) to trough glucose levels after glipizide administration, and lower visit 2 fasting glucose level adjusted for visit 1 fasting glucose level (β = −1.02, P = 0.04) and a greater decline in glucose level between visits (β = −1.61, P = 0.047) after metformin administration.CONCLUSIONSOur findings demonstrate that common variation at TCF7L2 influences acute responses to both glipizide and metformin in people without diabetes and highlight altered incretin signaling as a potential mechanism by which TCF7L2 variation increases T2D risk.

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

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.

Evaluation of Transcription Factor 7 like 2 polymorphisms and haplotypes in risk of Type 2 Diabetes

Abstract Type 2 diabetes (T2D) is a chronic disorder with different genetics and environmental factors. It is one of growing diseases in the world. Previous studies show association between Transcription Factor 7 Like2 (TCF7L2) and T2D. The current study set to evaluate the relation between TCF7L2 polymorphisms and T2D in Southeast Iran. The present case-control study was done on 250 T2D and 250 healthy controls (HCs). For genotyping polymorphisms TCF7L2 (rs11196205) and (rs4132670) Amplification-Refractory Mutation System-Polymers Chain Reaction (ARMS-PCR) was used. The results showed frequency rates of GC and CC genotypes increased in patients compared to controls (31% vs. 6% and 55% vs. 8%, respectively), showing a statistically significant difference (OR=2.67(1.37-5.21), P<0.05 and OR=3.31(1.92-5.71), P< 0.05, respectively). The C allele was associated with an increased risk of T2D, with the frequency of 28% and 11% in patients and controls, respectively (OR=3.11 (2.22-4.37), P< 0.05). Another Polymorphism of this gene TCF7L2 (rs4132670) was not associated with T2D. Furthermore, the haplotype analysis revealed that rs11196205C/rs4132670C and rs11196205C/rs4132670T are risk factors against T2D (OR=2.08 (1.49-2.86, P<0.05 and OR=1.72 (1.06-2.78) P<0.05, respectively). The findings demonstrated that TCF7L2 (rs11196205) genotypes GC, CC, and allele (C) confer risk for susceptibility to T2D.

Impact of the TCF7L2 genotype on risk of hypoglycaemia and glucagon secretion during hypoglycaemia.

IntroductionIn healthy carriers of the T allele of the transcription factor 7-like 2 (TCF7L2), fasting plasma glucagon concentrations are lower compared with those with the C allele. We hypothesised that presence of the T allele is associated with a diminished glucagon response during hypoglycaemia and a higher frequency of severe hypoglycaemia (SH) in type 1 diabetes (T1DM).Material and methodsThis is a post hoc study of an earlier prospective observational study of SH and four mechanistic studies of physiological responses to hypoglycaemia. 269 patients with T1DM were followed in a one-year observational study. A log-linear negative binomial model was applied with events of SH as dependent variable and TCF7L2 alleles as explanatory variable. In four experimental studies including 65 people, TCF7L2 genotyping was done and plasma glucagon concentration during experimental hypoglycaemia was determined.ResultsIncidences of SH were TT 0.54, TC 0.98 and CC 1.01 episodes per patient-year with no significant difference between groups. During experimental hypoglycaemia, the TCF7L2 polymorphism did not influence glucagon secretion.DiscussionPatients with T1DM carrying the T allele of the TCF7L2 polymorphism do not exhibit diminished glucagon response during hypoglycaemia and are not at increased risk of severe hypoglycaemia compared with carriers of the C allele.

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

Mo2048 Regulation of Intestinal Permeability by MicroRNA-29a/B Cluster

Brain-gut interaction plays a key role in pathophysiology of irritable bowel syndrome (IBS). We reported a genetic association between β3-aderenoceptor and cholinergic receptor muscarinic 3 polymorphisms in IBS (Hepato-Gastroenterol 2011;58:1474-1478). We examined the association of brain-gut peptides, such as calcitonin gene-related peptide (CGRP α, encoded by CALCA), transient receptor potential vanilloid-1 (TRPV-1) and transcription factor 7-like2 (TCF7L2) polymorphisms with IBS. Methods: DNA was obtained from 108 IBS patients; (53 diarrhea type IBS-D, 31 constipation type IBS-C, 8 mixed type IBS-M, 16 unsubtyped IBS-U) and 61 controls. For the analyses IBS-(M + U) was combined into one group (NonDNonC). CALCA, TRPV-1 and TCF7L2 polymorphisms were determined by the polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) method. Results: The frequencies of the three genotypes; CALCA, TRPV-1 and TCF7L2 were not significantly different between IBS patients and controls. The distribution of the three genotypes was not significantly different between IBS-D, IBS-C and NonDNonC. The three genotypes frequencies were not significantly different between males and females in IBS. The frequencies of the three genotypes were not significantly different between under and over 3 years of disease duration in IBS. The frequencies of the TRPV-1 genotypes in IBS were significantly different between over 65 years old and under 65 years old. The frequencies of the CALCA and TCF7L2 genotypes in IBS were not significantly different between patients over 65 years old and under 65 years old. Conclusions: TRPV-1 polymorphisms are likely associated with age in IBS. TRPV-1 polymorphisms could be associated with IBS. S-727 AGA Abstracts Mo2050 Colorectal Transit During Acute Episodes of Diverticulitis Antonella Toma, Luca Bertini, Emanuele Casciani, Gianfranco Gualdi, Enrico Corazziari Background. Acute diverticulitis of the sigmoid colon presents with pain and bowel alterations: being constipation or diarrhea reported by 50% and 25%-35% of the patients respectively (Kelley MT, 2008). The colorectal mechanism leading to these opposite bowel behaviors is likely associated with a different distribution of colorectal contents as consequence of the motor activity of the large bowel. Aim. To assess distribution of colorectal contents during an episode of acute diverticulitis. Methods. Patients having the first episode of diverticulitis and no diverticulitis complications (Hinchey 1a) were recruited. CT scans of the abdomen and pelvis were performed within 4 hours from the onset of the acute diverticulitis episode in 22 patients (F=9; mean age 55.4±16.8 yrs; range 23-85) admitted to the emergency department. CT-scan datasets were scanned with a 16 MDCT scanner and image analysis was conducted on the reconstructed thin-slice portal-venous phase. Controls were 32 patients (F=12; mean age 68.5±9.4 yrs; range 50-85) with asymptomatic diverticula of the sigmoid and submitted to CT scan evaluation for not acute extra-gastrointestinal disease conditions. The large bowel was subdivided into 7 segments: ascending colon, right transverse colon, left transverse colon, proximal descending colon, distal descending colon, sigmoid and rectum. The absence/presence of contents, liquid, gas or semiquantitative (+,++,+++) amount of solid feces, were assessed and reported independently by three observers. Interobserver agreement was substantial (Cohen's Kappa=0.73). Results. In comparison to controls, patients with acute diverticulitis showed more frequently (a) gas or absence of contents in the sigmoid colon (p≤0.05), (b) less solid feces (27% vs. 56%, p ≤0.05) and more gas (45% vs. 16%, p≤0.05) in the distal descending colon, (c) equal amount of solid feces and more liquid feces in the right part of the colon, from the ascending (36% vs. 9%, p ≤0.05) to midtransverse colon (23% vs. 0%, p≤0.01) and (d) more liquid feces in the rectum (27% vs. 3%, p ≤0.01). Summary. During episode of diverticulitis the distribution of large bowel contents indicates that (a) sigmoid colon often contains gas or no content, (b) feces, solid and liquid, as well as gas are retained proximal to the sigmoid, being the solid and liquid feces mainly retained in the right part of the colon ,and the gas mainly retained in the descending colon, and (c) liquid feces are mainly present in the rectum. Conclusive hypothesis. The inflamed sigmoid may cause (a) constipation by inhibiting right to left colon transit of solid feces and being of obstacle to transit of gas and liquid contents through the sigmoid and, (b) by inhibiting the absorption of water, there is an increased amount of liquid feces in the colorectal that leads to diarrhea.

TCF7L2 rs7903146 impairs islet function and morphology in non-diabetic individuals

Transcription factor 7-like 2 (TCF7L2) is a Wnt-signalling-associated transcription factor. Genetic studies have clearly demonstrated that DNA polymorphisms within TCF7L2 confer the strongest known association with increased risk of type 2 diabetes. However, the impact of the TCF7L2 type-2-diabetes-associated rs7903146 T allele on biological function and morphology of human pancreatic islets is unknown. Paraffin sections of pancreases from 187 brain-deceased donors (HbA(1c) <6.5% [48 mmol/mol]) were used to genotype the TCF7L2 variant rs7903146 and evaluate its impact on islet morphology and alpha and beta cell subpopulations following immunostaining for glucagon and C-peptide. Following islet isolation, we investigated the correlation between TCF7L2 genotype and in vitro islet functional variables from our in-house pancreatic database. TCF7L2 rs7903146 (T/T) was associated with reduced basal and glucose-stimulated insulin secretion in isolated human islets, and reduced islet density in whole pancreas. Morphological analysis demonstrated islet size was increased in T/T carriers. Furthermore, rs7903146 was associated with an increased glucagon/C-peptide ratio, especially in bigger islets. The TCF7L2 variant rs7903146 risk allele is associated with impaired insulin secretion, reduction of total islet number and quantitative as well as qualitative morphological changes in human islets. Understanding how the TCF7L2 genotype modulates its activity and how TCF7L2 impacts the islet morphology may aid the design of new therapeutic approaches for the treatment of type 2 diabetes.

Consistente asociación del polimorfismo rs7903146 en el gen TCF7L2 con mayor riesgo de diabetes en población mediterránea española

Introduction Type 2 diabetes (T2D) can induce the expression of cell adhesion molecules (ICAM, VCAM) and cytokines (IL-6 and CRP). Possibly related to these mechanisms, the transcription factor 7-like 2 (TCF7L2) gene has been associated with T2D in distinct populations, but there are few data for the Mediterranean population. Our objective was to study the association of this gene with T2D and inflammation markers in a population at high cardiovascular risk. Methods We included 1,001 high cardiovascular risk participants in the PREDIMED-Valencia study. Fasting blood glucose and plasma lipid concentrations were determined. Plasma concentrations of IL-6, CRP, VCAM and ICAM were also determined in a random subsample. The rs7903146 (C > T) polymorphism in the TCF7L2 gene was analyzed. Results The prevalence of T2D was 47.4%. The frequency of genotypes was 38.1% for CC, 47.7% for CT and 14.3% for TT (the allelic frequency of the T allele was 0.381). We found statistically significant differences in fasting plasma glucose concentrations depending on the TCF7L2 genotype (CC: 117.3 ± 37.8; CT: 124.1 ± 41.1; TT: 128.7 ± 45.2 mg/dl; p = 0.011). T allele carriers had an increased risk of T2D (OR = 1.37; 95% CI: 1.05-1.80; p = 0.022) compared with CC individuals. The T allele was also associated with higher concentrations of VCAM (CC: 914.3 ± 355.4; CT: 1147.0 ± 422.6; TT: 1258.1 ± 447.3 ng/ml; p = 0.001). No statistically significant differences were found for the other markers of inflammation. Conclusion Consistent with the results obtained in other European populations, this study found that the T allele of the rs7903146 polymorphism in the TCF7L2 gene is associated with an increased risk of T2D in a Mediterranean Spanish population.

TCF7L2 polymorphisms and inflammatory markers before and after treatment with fenofibrate

BackgroundInflammation is implicated in causing diabetes. We tested whether transcription factor 7 like-2 (TCF7L2) gene polymorphisms (rs12255372 and rs7903146), consistently associated with type 2 diabetes, are associated with plasma concentrations of inflammatory markers before and after three weeks of daily treatment with fenofibrate.MethodsMen and women in the Genetics of Lipid-Lowering Drugs and Diet Network study (n = 1025, age 49 ± 16 y) were included. All participants suspended use of lipid-lowering drugs for three weeks and were then given 160 mg/day of fenofibrate for three weeks. Inflammatory markers and lipids were measured before and after fenofibrate. ANOVA was used to test for differences across TCF7L2 genotypes.ResultsUnder the additive or dominant model, there were no significant differences (P > 0.05) in the concentrations of inflammatory markers (hsCRP, IL-2, IL-6, TNF-α and MCP-1) across TCF7L2 genotypes in the period before or after treatment. For both rs12255372 and rs7903146, homozygote T-allele carriers had significantly higher (P < 0.05) post-fenofibrate concentrations of MCP-1 in the recessive model. No other significant associations were detected.ConclusionOverall these data show no association between TCF7L2 polymorphisms and the inflammatory markers suggesting that the effects of TCF7L2 on diabetes may not be via inflammation.

Investigation of effects of three candidate genes on leg action and fat deposition traits in pigs (Short communication)

Data from 188 sows were used in the current study to examine the effects of high mobility group AThook1 (HMGA1), transcription factor 7-like-2 (TCF7L2) and insulin-like growth factor binding protein 3 (IGFBP3) genes on leg action and fat deposition traits, and further to explore the possible relationships between these genes on both traits. The candidate genes used in the study are known for their roles in fat deposition and growth. Overall leg action was scored on a scale of 1 (good movement) to 9 (leg weakness). Fatness traits included 10 th rib backfat (BF10), adjusted 10 th rib backfat to 125 kg (adjBF10) and last rib backfat (last BF), measured by ultrasonic imaging approach. The association analyses between single nucleotide polymorphisms (SNPs) and traits were performed using PROC MIXED procedures of SAS. The results showed that the associations between HMGA1, TCF7L2 and IGFBP3 genotypes with fat deposition traits were mostly suggestive in this limited data set. Leg action was also suggestively associated with IGFBP3 gene effects but was not associated with HMGA1 and TCF7L2 genes. Thus, IGFBP3 AA homozygote individuals tended to have had better movements (5.40), and were fatter when compared to GG homozygotes (5.84). The results from this study suggest a possible association between the IGFBP3 gene effects on both leg action and fatness. Therefore, further studies must be carried out in several populations, and using larger data to demonstrate these results conclusively.

Interactions between TCF7L2 genotype and growth hormone-induced changes in glucose homeostasis in small for gestational age children

The Transcription factor 7-like 2 (TCF7L2) rs7903146 gene polymorphism has been associated with risk of developing type 2 diabetes mellitus (DM), possibly by decreasing insulin secretion. Small for gestational age (SGA) birth has been associated with type 2 DM in later life. Growth hormone (GH) treatment reduces insulin sensitivity and increases insulin secretion. Therefore, GH-treated SGA children are an ideal group to investigate whether the TCF7L2 rs7903146 genotype is associated with changes in glucose homeostasis. To determine the impact of the TCF7L2 rs7903146 polymorphism on changes in insulin secretion and insulin sensitivity during 4 years of GH treatment in children born SGA. A total of 246 Caucasian short children born SGA, with a median age of 7.8 years. Insulin sensitivity and insulin secretion were measured by the frequently sampled intravenous glucose tolerance test (FSIGT) (n = 68) and homeostasis model assessment (HOMA) calculations (all). There was no association between rs7903146 genotype and insulin sensitivity or insulin secretion at baseline but after adjustment for possible confounders, insulin secretion was higher in the CT/TT group than in the CC group. During GH treatment, carriers of the rs7903146 T allele had an increase in insulin secretion similar to that of carriers of the CC genotype. The decrease in insulin sensitivity was only significant in the CT/TT group, but the difference in decrease between genotype groups did not reach significance (P = 0.06). The disposition index (insulin secretion x insulin sensitivity), which is an estimate of beta cell function, was not associated with genotype and did not change during GH treatment. The TCF7L2 rs7903146 polymorphism is not associated with the change in insulin secretion during GH treatment in short SGA children.

Transcription factor 7–like 2 polymorphism modulates glucose and lipid homeostasis, adipokine profile, and hepatocyte apoptosis in NASH #

Genetic factors underlying the association of NAFLD with diabetes and atherosclerosis are unknown. Recent human studies suggest transcription factor 7-like 2 (TCF7L2) polymorphism predisposes to diabetes through modulation of beta-cell function and modulates lipid levels in familial dyslipidemia. Emerging experimental evidence connects TCF7L2 to adipocyte metabolism and lipid homeostasis, as well. We tested if TCF7L2 polymorphism is a risk factor for nonalcoholic fatty liver disease (NAFLD) and if it modulates liver injury, glucose homeostasis, lipoprotein, and adipokine profiles in NASH. TCF7L2 genotype and dietary habits of 78 nondiabetic normolipidemic NAFLD subjects and 156 age-, body mass index-, sex-matched healthy controls were assessed. In 39 biopsy-proven nonalcoholic steatohepatitis (NASH) and matched controls TCF7L2 polymorphism was correlated to liver histology and oral glucose tolerance test-derived parameters of glucose homeostasis. Patients with NASH and controls consumed a high-fat meal and TCF7L2 genotype was correlated to postprandial circulating lipoproteins, adipokines, and cytokeratin-18 fragments. The TCF7L2 CT/TT genotype was more frequent in NAFLD and predicted the presence and severity of liver disease, of beta-cell dysfunction, of reduced incretin effect and hepatic insulin resistance in NASH; it also modulated postprandial hepatocyte apoptosis, lipoproteins, and adipokine profiles in both groups. TCF7L2 polymorphism predisposes to NAFLD and significantly impacts liver injury, glucose homeostasis, and postprandial lipoprotein and adipokine responses to fat ingestion. This polymorphism also modulates a fat-induced increase in circulating markers of hepatocyte apoptosis in NASH. Targeting postprandial lipemia, at least in at-risk TCF7L2 genotypes, may improve liver disease and glucose dysmetabolism in these patients.

Variation in TCF7L2 Influences Therapeutic Response to Sulfonylureas

There is considerable interindividual variation in sulfonylurea response in type 2 diabetes. Transcription factor 7-like 2 (TCF7L2) variants have been identified to be strongly associated with type 2 diabetes risk, probably due to decreased beta-cell function. We hypothesized that variation in TCF7L2 would influence response to sulfonylureas but not metformin. We studied the effect of TCF7L2 rs12255372 and rs7903146 genotypes on glycemic response. The DARTS/MEMO (Diabetes Audit and Research Tayside/Medicines Monitoring Unit) collaboration database includes prescribing, biochemistry, and clinical phenotype of all patients with diabetes within Tayside, Scotland, from 1992. Of these, the TCF7L2 genotype was determined in 4,469 patients with type 2 diabetes recruited to GoDARTS (Genetics of Diabetes Audit and Research Tayside) between 1997 and July 2006. A total of 901 incident sulfonylurea users and 945 metformin users were identified. A logistic regression was used with treatment failure defined as an A1C >7% within 3-12 months after treatment initiation. Covariates included the TCF7L2 genotype, BMI, sex, age diagnosed, drug adherence, and drug dose. A1C pretreatment was available in a subset of patients (sulfonylurea n = 579; metformin n = 755). Carriers of the risk allele were less likely to respond to sulfonylureas with an odds ratio (OR) for failure of 1.95 (95% CI 1.23-3.06; P = 0.005), comparing rs12255372 T/T vs. G/G. Including the baseline A1C strengthened this association (OR 2.16 [95% CI 1.21-3.86], P = 0.009). A similar, although slightly weaker, association was seen with rs7903146. No association was seen between metformin response and either single nucleotide polymorphism, after adjustment for baseline A1C. TCF7L2 variants influence therapeutic response to sulfonylureas but not metformin. This study establishes that genetic variation can alter response to therapy in type 2 diabetes.

Polymorphism in the Transcription Factor 7-Like 2 (TCF7L2) Gene Is Associated With Reduced Insulin Secretion in Nondiabetic Women

Recently, the transcription factor 7-like 2 (TCF7L2) gene on chromosome 10q25.2 has been linked with type 2 diabetes among Caucasians, with disease associations noted for single nucleotide polymorphisms (SNPs) rs12255372 and rs7903146. To investigate mechanisms by which TCF7L2 could contribute to type 2 diabetes, we examined the effects of these SNPs on clinical and metabolic traits affecting glucose homeostasis in 256 nondiabetic female subjects (138 European Americans and 118 African Americans) aged 7-57 years. Outcomes included BMI, percent body fat, insulin sensitivity (S(i)), acute insulin response to glucose (AIR(g)), and the disposition index (DI). Homozygosity for the minor allele (TT) of SNP rs12255372 occurred in 9% of individuals and was associated with a 31% reduction in DI values in a recessive model. The at-risk allele TT was also associated with lower AIR(g) adjusted for S(i) in both ethnic groups, whereas rs12255372 genotype was not associated with measures of adiposity or with S(i). The T allele of rs12255372 was also associated with increased prevalence of impaired fasting glucose. Genotypes at rs7903146 were not associated with any metabolic trait. Lower S(i) and higher AIR(g) observed in the African-American compared with the European-American subgroup could not be explained by the TCF7L2 genotype. Our data suggest that the TCF7L2 gene is an important factor regulating insulin secretion, which could explain its association with type 2 diabetes.

Association Analysis of 6,736 U.K. Subjects Provides Replication and Confirms TCF7L2 as a Type 2 Diabetes Susceptibility Gene With a Substantial Effect on Individual Risk

Recent data suggest that common variation in the transcription factor 7-like 2 (TCF7L2) gene is associated with type 2 diabetes. Evaluation of such associations in independent samples provides necessary replication and a robust assessment of effect size. Using four TCF7L2 single nucleotide polymorphisms (SNPs; including the two most associated in the previous study), we conducted a case-control study in 2,158 type 2 diabetic subjects and 2,574 control subjects and a family-based association analysis in 388 parent-offspring trios all from the U.K. All SNPs showed powerful associations with diabetes in the case-control analysis, with strongest effects at rs7903146 (allele-wise relative risk 1.36 [95% CI 1.24-1.48], P = 1.3 x 10(-11)). Data were consistent with a multiplicative model. The family-based analyses provided independent evidence for association at all loci (e.g., rs4506565, 62% transmission, P = 7 x 10(-5)) with no parent-of-origin effects. The frequency of diabetes-associated TCF7L2 genotypes was greater in cases ascertained for positive family history and early onset (rs4606565, P = 0.02); the population-attributable risk, estimated from the least-selected cases, is approximately 16%. The overall evidence for association for these variants (P = 4.4 x 10(-14) combining case-control and family-based analyses for rs4506565) exceeds genome-wide significance criteria and clearly establishes TCF7L2 as a type 2 diabetes susceptibility gene of substantial importance.