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Aim: MicroRNAs play an important role in the maintenance of cellular functions by fine-tuning gene expression levels. The aim of the current study was to identify genetically caused changes in microRNA expression which associate with islet dysfunction in diabetic mice. Methods: To identify novel microRNAs involved in islet dysfunction, transcriptome and miRNome analyses were performed in islets of obese, diabetes-susceptible NZO and diabetes-resistant B6-ob/ob mice and results combined with quantitative trait loci (QTL) and functional in vitro analysis. Results: In islets of NZO and B6-ob/ob mice, 94 differentially expressed microRNAs were detected, of which 11 are located in diabetes QTL. Focusing on conserved microRNAs exhibiting the strongest expression difference and which have not been linked to islet function, miR-205-5p was selected for further analysis. According to transcriptome data and target prediction analyses, miR-205-5p affects genes involved in Wnt and calcium signalling as well as insulin secretion. Over-expression of miR-205-5p in the insulinoma cell line INS-1 increased insulin expression, left-shifted the glucose-dependence of insulin secretion and supressed the expression of the diabetes gene TCF7L2. The interaction between miR-205-5p and TCF7L2 was confirmed by luciferase reporter assay. Conclusion: MiR-205-5p was identified as relevant microRNA involved in islet dysfunction by interacting with TCF7L2. (Less)

SPRY4‐intronic transcript 1 has been found in several kinds of cancers, but the role of SPRY4‐IT1 in breast cancer stem cells has not been studied. We investigated whether SPRY4‐IT1 is involved in the promotion of breast cancer stem cells (BCSCs). We used qRT‐PCR to detect the expression of SPRY4‐IT1 in MCF‐7 cells and MCF‐7 cancer stem cells (MCF‐7 CSCs). The effects of SPRY4‐IT1 on the proliferation and renewal ability of breast cancer cells were investigated by in vitro and in vivo assays (ie in situ hybridization, colony formation assay, sphere formation assay, flow cytometry assay, western blotting, xenograft model and immunohistochemistry). The mechanism of SPPRY4‐IT1 as a ceRNA was studied by a dual‐luciferase reporter assay and bioinformatic analysis. In our study, SPRY4‐IT1 was up‐regulated in MCF‐7 CSCs compared with MCF‐7 cells, and high SPRY4‐IT1 expression was related to reduced breast cancer patient survival. Furthermore, SPRY4‐IT1 overexpression promoted breast cancer cell proliferation and stemness in vitro and in vivo. In addition, SPRY4‐IT1 knockdown suppressed BCSC renewal ability and stemness maintenance in vivo and in vitro. The dual‐luciferase reporter assays indicated that SPRY4‐IT1 as a sponge for miR‐6882‐3p repressed transcription factor 7‐like 2 (TCF7L2) expression. Taken together, these findings demonstrated that SPRY4‐IT1 promotes proliferation and stemness of breast cancer cells as well as renewal ability and stemness maintenance of BCSCs by increasing the expression of TCF7L2 through targeting miR‐6882‐3p.

Summary The pathophysiological influence of gene‐lifestyle interactions on the risk to develop type 2 diabetes (T2D) is currently under intensive research. This systematic review summarizes the evidence for gene‐lifestyle interactions regarding T2D incidence. MEDLINE, EMBASE, and Web of Science were systematically searched until 31 January 2019 to identify publication with (a) prospective study design; (b) T2D incidence; (c) gene‐diet, gene‐physical activity, and gene‐weight loss intervention interaction; and (d) population who are healthy or prediabetic. Of 66 eligible publications, 28 reported significant interactions. A variety of different genetic variants and dietary factors were studied. Variants at TCF7L2 were most frequently investigated and showed interactions with fiber and whole grain on T2D incidence. Further gene‐diet interactions were reported for, eg, a western dietary pattern with a T2D‐GRS, fat and carbohydrate with IRS1 rs2943641, and heme iron with variants of HFE. Physical activity showed interaction with HNF1B, IRS1, PPARγ, ADRA2B, SLC2A2, and ABCC8 variants and weight loss interventions with ENPP1, PPARγ, ADIPOR2, ADRA2B, TNFα, and LIPC variants. However, most findings represent single study findings obtained in European ethnicities. Although some interactions have been reported, their conclusiveness is still low, as most findings were not yet replicated across multiple study populations.

The etiology of adenocarcinoma of the esophagogastric junction (AEG) remains unclear. It is believed that the increasing of AEG may be correlated with the elevated ratio of obesity and overweight. Thus, metabolism‐related genes and variants may play important roles in the occurrence and progress of AEG. The current investigation involved 720 patients with AEG and 1541 healthy controls. We selected transcription factor 7‐like 2 (TCF7L2) rs7903146 and rs290481, INS rs689 and INSR rs1799817 single‐nucleotide polymorphisms (SNPs), and explored the association of these SNPs with lymph node status and risk of AEG. The polymerase chain reaction was harnessed to identify the genotyping of four polymorphisms. We found that TCF7L2 rs290481 (T > C) and INSR rs1799817 (G > A) polymorphisms were associated with the increased susceptibility of AEG (P = .007 and 0.004 for TCF7L2 rs290481 in TC vs TT and TC/CC vs TT models, and P = .040 for INSR rs1799817 in GA/AA vs GG model). We also conducted a subgroup analysis by different cancer stage. We identified that TCF7L2 rs290481, INS rs689, and INSR rs1799817 SNPs increased the susceptibility of AEG in different cancer stage subgroups. In addition, we found that rs290481 SNP in TCF7L2 gene increased the risk of lymph node metastasis in drinking patients with AEG. However, the association of INSR rs1799817 SNP with a decreased risk of lymph node metastasis in smoking patients with AEG was found. Our findings highlight that TCF7L2 rs290481, INS rs689, and INSR rs1799817 polymorphisms may increase the risk of AEG. In addition, TCF7L2 rs290481 and INSR rs1799817 SNPs may influence the lymph node metastasis in patients with AEG.

Objective Type 2 diabetes mellitus (T2DM) has a multifactorial etiology involving a complex interplay between genes and the environment. The prevalence of T2DM among the countries of the Gulf Corporation Council (GCC), including the United Arab Emirates (UAE), ranks among the top 15 in the world. A number of studies have shown an increase in T2DM risk for the "TT" genotype at the rs4506565 and rs12255372 Single Nucleotide Polymorphisms (SNP) of the TCF7L2 gene. However, the association between TCF7L2 and T2DM still needs to be investigated in the UAE population. Therefore, this study analyzed the potential associations with rs4506565 and rs12255372 in UAE subjects. Methods For this case-control study, T2DM patients (n = 890) and healthy subjects (n = 686) were genotyped using a Taqman Real-Time PCR assay. Statistical analysis was performed with the resulting data using the R (version 3.3.1) and STATA (version 13) software packages. Results The rs12255372 SNP was significantly associated with T2DM (OR = 1.16, 95% CI = 1.00-1.34; P = .042). However, no significant association was found for the rs4506565 SNP (P = .120). After gender stratification, a significant association was found for both SNPs in males (Prs4506565 = .009 and Prs12255372 = .021). Interestingly, we found the interaction between the SNP rs4506565 with gender alone (P = .032) and in conjunction with BMI and age (P = .036) confers associations with T2DM. Conclusions These findings suggest that the genetic variants of the TCF7L2 gene are associated with an increased susceptibility to T2DM, especially in Emirati males. Our study also highlights the impact of biological and environmental risk factors including age, BMI, and gender on the genetic susceptibility to T2DM.

Genome-wide association studies (GWAS) have identified multiple single-nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. To evaluate the potential influence of colorectal cancer susceptibility SNPs on disease prognosis, we investigated whether GWAS-identified colorectal cancer risk SNPs and polygenic risk scores (PRSs) might be associated with survival among colorectal cancer patients. A total of 1374 colorectal cancer patients were recruited from the Korean National Cancer Center. For genotyping, 30 colorectal cancer-susceptibility SNPs previously identified by GWAS were selected. The Cox proportional hazard model was used to evaluate associations of these risk SNPs and PRSs with disease-free survival (DFS) and overall survival (OS). The prognostic values were compared between genetic and nongenetic models using Harrell's c index. During the follow-up period (median: 88, 91 months for DFS and OS), 570 DFS (41.5%) and 487 OS (35.4%) events were observed. We found that 5 SNPs were significantly associated with DFS or OS among colorectal cancer patients at P

The SNP rs7903146 at the transcription factor 7-like 2 (TCF7L2) locus is established as the strongest known genetic marker for type 2 diabetes via genome-wide association studies. However, the functional SNPs regulating TCF7L2 expression remain unclear. Here, we show that the SNP rs7074440 is a candidate functional SNP highly linked with rs7903146. A reporter plasmid with rs7074440 normal allele sequence exhibited 15-fold higher luciferase activity compared with risk allele sequence in hepatocytes, demonstrating a strong enhancer activity at rs7074440. Additionally, we identified C-FOS as an activator binding to the rs7074440 enhancer using a TFEL genome-wide screen method. Consistently, knockdown of C-FOS significantly reduced TCF7L2 expression in hepatocytes. Collectively, a novel enhancer regulating TCF7L2 expression was revealed through searching for functional SNPs.

The metabolic syndrome (MetS) is a multicomponent condition with a complex etiology involving genetic and environmental factors. Artichoke leaf extract (ALE) has shown favorable effects on lipid and glucose metabolism. The present study aimed to investigate the effects of ALE supplementation on metabolic parameters in women with MetS, using a nutrigenetics approach. In this double-blind randomized clinical trial, 50 women (aged 20-50 years) with MetS were randomly allocated into the two groups: "ALE group" (received 1,800 mg hydroalcoholic extract of artichoke as four tablets per day) and "placebo group" (received placebo consisted of corn starch, lactose, and avicel as four tablets per day) for 12 weeks. The biochemical and anthropometric parameters were determined before and after the intervention. The FTO-rs9939609 and the TCF7L2-rs7903146 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism. In carriers of A allele of the FTO-rs9939609, ALE supplementation resulted in a statistically significant decrease in serum triglyceride level compared with placebo (-19.11% vs. 10.83%; p .05), with no other significant differences between the two groups. The TCF7L2-rs7903146 polymorphism showed no interaction with response to ALE (p .05). These findings suggest that ALE supplementation may improve serum triglyceride level in A allele genotype of FTO-rs9939609 polymorphism in women with MetS.

Genetic studies have linked the VTI1A-TCF7L2 region with risk of multiple cancers. However, findings from these studies were generally inconclusive. We aimed to provide a synopsis of current understanding of associations between variants in the VTI1A-TCF7L2 region and cancer susceptibility. We conducted a comprehensive research synopsis and meta-analysis to evaluate associations between 17 variants in this region and risk of seven cancers using data from 32 eligible articles totaling 224,656 cancer cases and 324,845 controls. We graded cumulative evidence of significant associations using Venice criteria and false-positive report probability tests. We also conducted analyses to evaluate potential function of these variants using data from the Encyclopedia of DNA Elements (ENCODE) Project. Eight variants showed a nominally significant association with risk of individual cancer (p

Deregulation of the canonical Wnt signaling pathway plays an important role in human tumorigenesis through the accumulation of β‐catenin and subsequent transactivation of TCF7L2. Although some of the consequences associated with the accumulated β‐catenin have been clarified, the comprehensive effect of activated β‐catenin/TCF7L2 transcriptional complex on tumorigenesis remains to be elucidated. To understand the precise molecular mechanisms underlying colorectal cancer, we searched for genes regulated by the complex in colorectal tumors. We performed expression profile analysis of HCT116 and SW480 colon cancer cells treated with β‐catenin siRNAs, and ChIP‐sequencing using anti‐TCF7L2 antibody. Combination of these data with public microarray data of LS174 cells with a dominant‐negative form of TCF7L2 identified a total of 11 candidate genes. In this paper, we focused on FERM domain‐containing protein 5 (FRMD5), and confirmed that it is regulated by both β‐catenin and TCF7L2. An additional reporter assay disclosed that a region in intron1 transcriptionally regulated the expression of FRMD5. ChIP assay also corroborated that TCF7L2 associates with this region. These data suggested that FRMD5 is a novel direct target of the β‐catenin/TCF7L2 complex.

Aims/Introduction Studies have been carried out to evaluate the correlation between TCF7L2 genetic polymorphisms and gestational diabetes mellitus (GDM) risk. However, the conclusions from these studies are incomplete, because partial single nucleotide polymorphisms (SNPs) were analyzed. We carried out a meta-analysis aimed to systematically evaluate TCF7L2 gene polymorphisms and GDM susceptibility in all population and racial/ethnic subgroups to afford a foundation for future research. Materials and Methods Published studies censoring TCF7L2 variants and GDM risk were captured from the EMBASE, PubMed, CNKI and Wanfang databases. The meta-analysis was processed using software of RevMan 5.2 and Stata13. The relationship between TCF7L2 polymorphism and GDM occurrence was evaluated by pooled odds ratios. Stratified analysis based on race/ethnicity was also carried out. The allele-specific odds ratios and 95% confidence intervals were counted, and based on homogeneity evaluated using the I2-test, fixed- or random-effects pooled measures were selected. Results A total of 22 studies were covered, capturing eight TCF7L2 SNPs and involving 5,573 cases and 13,266 controls. Six of eight SNPs showed significant relationships with GDM occurrence, of which the SNPs rs7903146, rs12255372 and rs7901695 were the most powerful. Stratified analysis by race/ethnicity showed discrepant results in these three SNPs. In Caucasians and other races, all these SNPs were found to have a significant association with GDM risk, but in Asians, only SNP rs7903146 showed a significant association. Conclusions Six of eight SNPs were found to have significant associations between TCF7L2 variants and GDM risk in the overall population, with the most powerful in SNPs being rs7903146, rs12255372 and rs7901695, but the contribution of these SNPs to GDM risk were variable among different racial/ethnic groups.

Background Genome-wide association studies (GWAS) of type 2 diabetes (T2D) have discovered a number of loci that contribute to susceptibility to the disease. Future challenges include elucidation of functional mechanisms through which these GWAS-identified loci modulate T2D disease risk. The aim of the present study was to comprehensively characterize T2D associated single nucleotide polymorphisms (SNPs) and genes through computational approaches. Methods Computational biology approaches used in the present study included comparative genomic analyses and functional annotation using GWAS3D and RegulomeDB, investigation of the effects of T2D-associated SNPs on miRNA binding and protein phosphorylation, and gene ontology, pathway enrichment, protein-protein interaction (PPI) networks and functional module analysis of T2D-associated genes from previously published GWAS. Results Computational analysis identified a number of T2D GWAS-associated SNPs that were located at protein binding sites, including CCCTC-binding factor (CTCF), E1A binding protein p300 (EP300), hepatocyte nuclear factor 4alpha (HNF4A), transcription factor 7 like 2 (TCF7L2), forkhead box A1 (FOXA1) and A2 (FOXA2), and potentially affected the binding of miRNAs and protein phosphorylation. Pathway enrichment analysis confirmed two well-known maturity onset diabetes of the young and T2D pathways, whereas PPI network analysis identified highly interconnected "hub" genes, such as TCF7L2, melatonin receptor 1B (MTNR1B), and solute carrier family 30 (zinc transporter), member 8 (SLC30A8), that created two tight subnetworks. Conclusions The results provide objectives and clues for future experimental studies and further insights into the molecular pathogenesis of T2D.

Aims/Introduction Previous studies have suggested a possible relationship between type 2 diabetes mellitus susceptibility loci and diabetic complications. The present study aimed to investigate the associations between type 2 diabetes mellitus loci with peripheral nerve function in a Chinese population with type 2 diabetes mellitus. Materials and Methods A total of 1,900 type 2 diabetes mellitus patients were recruited in the study. We selected ten single nucleotide polymorphisms (SNPs) from ten type 2 diabetes mellitus susceptibility genes previously confirmed in Chinese patients. Genotyping was carried out by using a MassARRAY Compact Analyzer. Peripheral nerve function was evaluated by nerve conduction studies in all participants. The composite Z-scores for nerve conduction parameters including conduction velocity (CV), amplitude and latency were calculated, respectively. Results Rs5219 of KCNJ11 (E23K, G→A) was identified to be associated with all the parameters obtained from nerve conduction studies (Z-score of CV: β = 0.113, P = 0.01; Z-score of amplitude: β = 0.133, P = 0.01; Z-score of latency: β = −0.116, P = 0.01) after adjustment for covariates including age, duration and glycated hemoglobin. Specifically, each copy of the A allele was related to better outcomes. CDKAL1 rs7756992 and TCF7L2 rs7903146 correlated with the composite Z-score of amplitude (P = 0.028 and P = 0.016, respectively), but not CV (P = 0.393 and P = 0.281, respectively) or latency (P = 0.286 and P = 0.273, respectively). There were no significant associations between the other seven SNPs and peripheral nerve function. Conclusions Rs5219 at KCNJ11 (E23K) was associated with peripheral nerve function in a Chinese population with type 2 diabetes mellitus, suggesting shared genetic factors for type 2 diabetes mellitus and diabetic polyneuropathy in this population.

Received: 14 December 2015 Revised: 24 May 2016 Accepted: 5 June 2016 Published on: 5 July 2016 DOI: 10.1002/gepi.21991 RESEARCH ARTICLE Obesity and associated lifestyles modify the effect of glucose metabolism-related genetic variants on impaired glucose homeostasis among postmenopausal women Su Yon Jung 1 Eric M. Sobel 2 Jeanette C. Papp 2 Carolyn J. Crandall 3 Alan N. Fu 4 Zuo-Feng Zhang 4 1 Translational Sciences Section, Jonsson Com- prehensive Cancer Center, School of Nursing, University of California, Los Angeles, Los Angeles, California, United States of America 2 Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America 3 Division of General Internal Medicine, Depart- ment of Internal Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America 4 Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, California, United States of America Correspondence Dr. Su Yon Jung, Translational Sciences Section, Jonsson Comprehensive Cancer Center, School of Nursing, University of California Los Angeles, 700 Tiverton Ave, 3-264 Factor Building, Los Angeles, California 90095, United States of America. Email: sjung@sonnet.ucla.edu ABSTRACT Purpose: Impaired glucose metabolism-related genetic variants likely interact with obesity-modifiable factors in response to glucose intolerance, yet their interconnected pathways have not been fully charac- terized. Methods: With data from 1,027 postmenopausal participants of the Genomics and Randomized Trials Network study and 15 single-nucleotide polymorphisms (SNPs) associated with glucose homeostasis, we assessed whether obesity, physical activity, and high dietary fat intake interact with the SNP–glucose vari- ations. We used regression analysis plus stratification and graphic approaches. Results: Across carriers of the 15 SNPs, fasting levels of glucose, insulin, and homeostatic model assessment-insulin resistance (HOMA-IR) were higher in obese, inactive, and high fat-diet women than in their respective counterparts. Carriers within subgroups differently demonstrated the direction and/or magnitude of the variants’ effect on glucose-relevant traits. Variants in GCKR, GCK, DGKB/TMEM195 (P for interactions = 0.02, 0.02, and 0.01), especially, showed interactions with obesity: obese, inactive, and high fat-diet women had greater increases in fasting glucose, insulin, and HOMA-IR levels. Obese carriers at TCF7L2 variant had greater increases in fasting glucose levels than nonobese carriers (P for interaction = 0.04), whereas active women had greater decreases in insulin and HOMA-IR levels than inactive women (P for interaction = 0.02 in both levels). Conclusions: Our data support the important role of obesity in modifying glucose homeostasis in response to glucose metabolism–relevant variants. These findings may inform research on the role of glucose home- ostasis in the etiology of chronic disease and the development of intervention strategies to reduce risk in postmenopausal women. KEYWORDS glucose metabolism–related genetic variant, high-fat diet, obesity, physical activity, postmenopausal women INTRODUCT I O N Glucose intolerance is thought to be central in the develop- ment of chronic diseases such as type 2 diabetes mellitus (T2DM), metabolic syndrome, and cardiovascular disease (CVD) (Ainsworth, Haskell, & Whitt, 2000; Arcidiacono, Iiritano, & Nocera, 2012; Belkina & Denis, 2010; McCarthy, 2010). In particular, hyperinsulinemia and insulin resis- tance (IR) are key determinants of many obesity-relevant cancers, including reproductive (e.g. breast, endometrial, Genet. Epidemiol. 2016;40: 520–530 prostatic, ovarian) and nonreproductive (e.g. colorectal, kidney, esophageal, gastric, pancreatic, liver) cancers (Boesgaard et al., 2010; Bookman, Din-Lovinescu, & Worrall, 2013; Clayton et al., 2011). Besides its importance in glucose homeostasis, insulin is an essential hormone in anabolic processes in early cell growth and development, directly through the insulin receptor and indirectly through the insulin-like growth factor receptor (IGFR), and via their main downstream signaling pathways (Boesgaard et al., 2010; Clayton et al., 2011). Insulin receptors that are mainly found www.geneticepi.org © 2016 WILEY PERIODICALS, INC.

AIMS To test the hypothesis that non-obese individuals with childhood-onset Type 1 diabetes and the rs7903146 TT genotype would be less likely to have high-risk human leukocyte antigen (HLA) genotypes and alleles. METHODS We studied a cohort of 105 non-obese participants in the T1D Exchange Biobank Residual Insulin Study who had childhood-onset Type 1 diabetes [mean (sd) age at onset and recruitment, respectively, 9.9 (4.15) and 14.4 (4.13) years; 84.8% non-Hispanic white]. We analysed islet autoantibodies (glutamic acid decarboxylase 65, islet cell autoantigen 512/islet antigen-2 and zinc transporter 8), non-fasting random C-peptide levels, HLA type and TCF7L2 single nucleotide polymorphism rs7903146 in this cohort. RESULTS None of the 13 individuals with the rs7903146 TT genotype carried the highest Type 1 diabetes risk HLA genotype, i.e. DRB1*03:01/DR4 (DRB1*0401, *04:05 or *04:02), compared with 29.4% (27/92) of those without it (P=0.023). The DRB1*03:01 allele was present in 15.4% (2/13) of individuals with the single nucleotide polymorphism, compared with 59.8% (55/92) of those without it (P=0.003). Analyses restricted to autoantibody-positive individuals (n=80) yielded similar results. The HLA DRB1*15:01 allele, which affords dominant protection against Type 1 diabetes, was found in one participant, who had multiple islet autoantibodies and carried the rs7903146 TT genotype. CONCLUSIONS These findings further support the hypothesis that TCF7L2 gene variation contributes to diabetogenesis in a subset of young people with Type 1 diabetes, opening possible new pathways for therapy and prevention.

AIM The burden of Type 2 diabetes is alarmingly high in South Asia, a region that has many genetically diverse ethnic populations. Genome-wide association studies (GWAS) conducted largely in European populations have identified a number of loci predisposing to Type 2 diabetes risk, however, the relevance of such genetic loci in many South Asian sub-ethnicities remains elusive. The aim of this study was to replicate 49 single nucleotide polymorphisms (SNPs) previously identified through GWAS in Punjabis living in Pakistan. METHODS We examined the association of 49 SNPs in 853 Type 2 diabetes cases and 1945 controls using additive logistic regression models after adjusting for age and gender. RESULTS Of the 49 SNPs investigated, eight showed a nominal association (P < 0.05) that also remained significant after controlling for the false discovery rate. The most significant association was found for rs7903146 at the TCF7L2 locus. For a per unit increase in the risk score comprising of all the 49 SNPs, the odds ratio in association with Type 2 diabetes risk was 1.16 (95% CI 1.13-1.19, P < 2.0E-16). CONCLUSION These results suggest that some Type 2 diabetes susceptibility loci are shared between Europeans and Punjabis living in Pakistan.

We previously investigated the association between single nucleotide polymorphisms (SNPs) in genes related to obesity and inflammation and colorectal cancer in the CLUE II cohort. However, the relationships between these SNPs and colorectal adenomas have not been well evaluated. In a nested case-control study of 135 incident adenoma cases and 269 matched controls in the CLUE II cohort (1989–2000), we genotyped 17 candidate SNPs in 12 genes (PPARG, TCF7L2, ADIPOQ, LEP, IL10, CRP, TLR4, IL6, IL1B, IL8, TNF, RNASEL) and 19 tagSNPs in three genes (IL10, CRP, and TLR4). Conditional logistic regression was used to calculate odds ratios (OR) for adenomas (overall and by size, histology, location, number). Polymorphisms in the inflammatory-related genes CRP, ADIPOQ, IL6, and TLR4 were observed to be associated with adenoma risk. At rs1205 in CRP, T (minor allele) carriers had a higher risk (OR 1.67, 95%CI 1.07–2.60; reference: CC) of adenomas overall and adenomas with aggressive characteristics. At rs1201299 in ADIPOQ, the AC genotype had a higher risk (OR 1.58, 95%CI 1.00–2.49) of adenomas, while the minor AA genotype had a borderline inverse association (OR 0.44, 95%CI 0.18–1.08; reference: CC). At rs1800797 in IL6, the AA genotype had a borderline inverse association (OR 0.53, 95%CI 0.27–1.05; reference: GG). Three TLR4 tagSNPs (rs10116253, rs1927911, rs7873784) were associated with adenomas among obese participants. None of these SNPs were associated with colorectal cancer in our prior study in CLUE II, possibly suggesting a different genetic etiology for early colorectal neoplasia.

Objective A prior genome-wide association study (GWAS) in Pima Indians identified variation within FOXO1A that modestly associated with early-onset (onset age

Background The aim of this study was to investigate the role of common variants in the genes SLC30A8, KCNQ1, and TCF7L2 in the association between birth weight and increased risk of type 2 diabetes in Han Chinese. Methods Seven variants (SLC30A8-rs13266634 and rs2466293; KCNQ1-rs2237895 and rs2074196; and TCF7L2-rs11196218, rs7903146, and rs290487) were genotyped in 1181 individuals born in Peking Union Medical College Hospital from 1921 to 1954 by Taqman allelic discrimination assay. All the subjects were stratified by birth weight into groups of ≥3000 g and

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.

Background Variation in TCF7L2 gene is associated with type 2 diabetes and with gestational diabetes mellitus in several populations, but there are no data in Mexican women with gestational diabetes mellitus. In this study, we examined metabolic and hormonal measurements as well as TCF7L2 genetic variants. Methods We selected 108 pregnant women with normal glucose tolerance and 90 with gestational diabetes mellitus according to 2010 American Diabetes Association criteria matched for gestational week. We collected data on blood pressure, body mass index (BMI) and concentrations of blood glucose, HbA1c, lipids profile, insulin and glucagon-like peptide-1 (GLP-1). The genotyping of rs7903146 and rs12255372 polymorphisms were made with polymerase chain reaction–restriction fragment length polymorphism. Results Actual and pre-gestational BMI, fasting glucose and HbA1c were higher (p

Variation in transcription factor 7-like 2 (TCF7L2), the strongest genetic risk factor for type 2 diabetes (T2D), may play a role in prostate cancer (PCa) depending on lifestyle factors. The aims of this study were to determine if TCF7L2 rs7903146 is associated with risk of PCa and if the association is modified by lifestyle factors independently of T2D status.

Aims/Introduction Type 1 diabetes mellitus is a serious disorder characterized by destruction of pancreatic β-cells, culminating in absolute insulin deficiency. Genetic factors contribute to the susceptibility of type 1 diabetes mellitus. The aim of the present study was to identify more susceptibility genes of type 1 diabetes mellitus. Materials and Methods We carried out an initial gene-based genome-wide association study in a total of 4,075 type 1 diabetes mellitus cases and 2,604 controls by using the Gene-based Association Test using Extended Simes procedure. Furthermore, we carried out replication studies, differential expression analysis and functional annotation clustering analysis to support the significance of the identified susceptibility genes. Results We identified 452 genes associated with type 1 diabetes mellitus, even after adapting the genome-wide threshold for significance (P

We characterised 62 non-diabetic, middle-aged, Caucasians with and without the T risk allele of rs7903146 in transcription factor 7-like 2 (TCF7L2) with regard to secretion of insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) as well as insulin sensitivity and endogenous glucose production. All participants had a 3-h oral glucose tolerance test (OGTT), an intravenous glucose tolerance test and a euglycaemic, hyperinsulinaemic clamp. After adjustment for age and sex, risk T allele carriers had higher haemoglobin A1c levels (p?=?0.030), reduced first-phase insulin response (p?=?0.048), higher peripheral insulin sensitivity (p?=?0.050) and lower fasting GIP concentrations (p?=?0.003) than CC allele carriers. The latter was also reflected by lower total GIP secretion during the OGTT (p?=?0.018). We found no significant differences in endogenous glucose production, hepatic insulin sensitivity or fasting concentrations of glucose, insulin, glucagon and GLP-1 between the groups. The findings suggest that the effect of TCF7L2 on diabetes risk may include reduced secretion of GIP.

Background: Recent genome-wide association studies (GWAS) have identified more than 40 common sequence variants associated with type 2 diabetes (T2D). However, the results are not always the same in populations with differing genetic backgrounds. In the present study, we evaluated a hypothesis that a North Asian population living in a geographic area with unusually harsh environmental conditions would develop unique genetic risks. Methods: A population-based association study was performed with 21 single-nucleotide polymorphisms (SNPs) in nine genes selected according to the results of GWAS conducted in other populations. The study participants included 393 full-heritage Mongolian individuals (177 diagnosed with T2D and 216 matched controls). Genotyping was performed by TaqMan methodology. Results: The strongest association was detected with SNPs located within the potassium channel-coding genes KCNQ1 (highest odds ratio [OR] = 1.92; P = 3.4 × 10−5) and ABCC8 (OR = 1.79; P = 5 × 10−4). Genetic variants identified as strongly influencing the risk of T2D in other populations (e.g. KCNJ11 or TCF7L2) did not show significant association in Mongolia. Conclusions: The strongest T2D risk-associated SNPs in Mongolians are located within two of three tested potassium channel-coding genes. Accumulated variations in these genes may be related to the exposure to harsh environmental conditions.

SummaryObjective Insulin resistance is a core feature of polycystic ovary syndrome (PCOS). Recently, genome-wide association studies have reported a number of single-nucleotide polymorphisms (SNPs) with reproducible associations and susceptibilities to type 2 diabetes. We examined the potential association between the diabetogenic genes uncovered in the genome-wide association studies and PCOS in Korean women. Design Case–control study. Patients Women with or without PCOS. Measurements DNA samples from 377 patients with PCOS and 386 age-matched controls were genotyped. Results None of the 12 SNPs in the six genes (KCNJ11, TCF7L2, SLC30A8, HHEX, FTO and CDKAL1) uncovered in the genome-wide association studies were associated with PCOS. For further analysis, the patients with PCOS were divided into two or three subgroups according to genotype, and the associations between the genotypes and insulin resistance or insulin secretory capacity were assessed. No SNPs were significantly associated with HOMA-IR, HOMA βcell (%), or 2-h 75-g oral glucose tolerance test insulin levels in the patients with PCOS; there were no significant associations with other serum hormonal and metabolic markers, such as androgen or glucose levels. Conclusions Our results suggest that the six type 2 diabetes–associated genes identified in genome-wide association studies are not associated with PCOS.

The importance of lifestyle intervention for the prevention and treatment of type 2 diabetes (T2D) has been underscored by the limited benefit of pharmacologic therapies. We sought to determine whether genetic variants that contribute to T2D risk modify the response of weight and waist circumference to an intensive lifestyle intervention (ILI) in patients with obesity and T2D. Look AHEAD (Action for Health in Diabetes) is a randomized clinical trial comparing an ILI with a control condition on the risk of cardiovascular disease in overweight adults with T2D. We analyzed 28 single-nucleotide polymorphisms (SNPs) at/near 17 T2D-susceptibility genes in 3,903 consented participants. We genetically characterized the cohort by assessing whether T2D-susceptibility loci were overrepresented compared with a nondiabetic community-based cohort (N = 1,016). We evaluated the association of individual variants and a composite genetic risk score (GRS) with anthropometric traits at baseline and after 1-year of intervention. Look AHEAD subjects carried more T2D-susceptibility alleles than the control population. At baseline, TCF7L2 risk alleles and the highest GRS were associated with lower BMI and waist circumference. Nominally significant genotype-by-intervention interactions were detected for 1-year change in waist circumference with JAZF1, MTNR1B, and IRS1, and BMI with JAZF1. Highest GRS was associated with a greater reduction in waist circumference at year 1, although the variance in change attributable to the GRS was small. This study shows that the genetic burden associated with T2D risk does not undermine the effect of lifestyle intervention and suggests the existence of additional genomic regions, distinct from the T2D-susceptibility loci, which may enhance or mitigate weight loss.

Polycystic ovary syndrome (PCOS) is a complex genetic disease characterized by heritable reproductive and metabolic abnormalities. Genetic variants associated with the reproductive phenotype have been mapped to the fibrillin-3 (FBN3) gene and to a novel transcription factor-7-like 2 (TCF7L2) locus (rs11196236 G). The association of these genetic variants with metabolic phenotypes was investigated in 31 PCOS and 18 control women of European ancestry. The insulinogenic index during an oral glucose tolerance test (ΔI30/ΔG30) and insulin secretion rates at the maximal dose during a graded-glucose infusion (ISRmax) were used as indexes of insulin secretion. Endogenous glucose production (EGP) and insulin sensitivity (M/I) were determined during a euglycemic clamp. The disposition index (DI) was calculated using M/I and ΔI30/ΔG30 or ISRmax. Compared with noncarriers (n = 10) and control (n = 10), M/I was decreased (P = 1.1 × 10(-5)) in heterozygous and homozygous PCOS carriers (n = 14) of rs11196236 G and this variant predicted M/I (partial r(2) = 0.34, P = 0.005) in a regression analysis. Postabsorptive EGP tended to be higher (P = 0.040) in heterozygous and homozygous PCOS carriers of the FBN3-associated allele (n = 12), allele 8 of D19S884 (FBN3(+)), compared to PCOS noncarriers (n = 19). PCOS carriers of the rs12255372 T (TCF7L2 Caucasian type 2 diabetes mellitus (T2D) locus) had no significant associated metabolic phenotypes. We conclude that rs11196236 G TCF7L2 variant is associated with peripheral insulin resistance in PCOS but this effect is not seen in control women. The FBN3 risk allele may be associated with changes in basal glucose homeostasis in PCOS. These findings require replication in additional PCOS cohorts.

Aims: The present study examines cognitive function among transcription factor 7-like 2 (TCF7L2) genotype groups in a sample of older adults with cardiovascular disease. Methods: We recruited 111 older adults with diagnosed cardiovascular disease from outpatient cardiology clinics. Neuropsychological tests assessed the following domains of cognitive functioning: global function, attention/executive/psychomotor speed, learning and memory, visuospatial/construction, motor, and language. Genotyping of TCF7L2 single nucleotide polymorphism rs7903146 was conducted to determine membership in the TT, CT, or CC genotype groups. Results: Controlling for diabetes status, participants with the TT genotype of TCF7L2 (n= 12) performed worse on tests of attention/executive function/processing speed than those with the CC (n= 46) and CT (n= 53) genotypes, despite no between-group differences in demographic or medical variables. Conclusions: Older cardiovascular disease patients with the TCF7L2 TT genotype performed worse on tests of attention/executive/ psychomotor speed than CC and CT genotype carriers. Further work using neuroimaging and glucose tolerance indices is needed to clarify underlying mechanisms.

Aims: To test whether the TCF7L2 gene was associated with gestational diabetes, whether the association between TCF7L2 and gestational diabetes was independent of HLA-DQB1*0602 and islet cell autoantibodies, as well as maternal age, number of pregnancies, family history of diabetes and the HLA-DQB1 genotypes, and to test whether the distribution of HLA-DQB1 alleles was affected by country of birth. Methods: We genotyped the rs7903146, rs12255372 and rs7901695 single nucleotide polymorphisms of the TCF7L2 gene in 826 mothers with gestational diabetes and in 1185 healthy control subjects in the Diabetes Prediction in Skane Study. The mothers were also typed for HLA-DQB1 genotypes and tested for islet cell autoantibodies against GAD65, insulinoma-associated antigen-2 and insulin. Results: The heterozygous genotypes CT, GT and TC of the rs7903146 (T is risk for Type 2 diabetes), rs12255372 (T is risk for Type 2 diabetes) and rs7901695 (C is risk for Type 2 diabetes), respectively, as well as the homozygous genotypes TT, TT and CC of the rs7903146, rs12255372 and rs7901695, respectively, were strongly associated with gestational diabetes (P < 0.0001). These associations remained statistically significant after adjusting for maternal age, number of pregnancies, family history of diabetes and HLA-DQ genotypes and were independent of the presence of islet cell autoantibodies. No interaction was observed between TCF7L2 and HLA-DQB1*0602, which was shown to be negatively associated with gestational diabetes in mothers born in Sweden (P = 0.010). Conclusions: The TCF7L2 was associated with susceptibility for gestational diabetes independently of the presence of HLA-DQB1*0602 and islet cell autoantibodies and other factors such as maternal age, number of pregnancies, family history of diabetes and other HLA-DQ genotypes. The HLA-DQB1*0602 was negatively associated with gestational diabetes in mothers born in Sweden.

are” Summary Type 2 diabetes (T2D) is a chronic degenerative disease that involves the participation of several genetic and environmental factors. The objective of the study was to determine the association of the IRS1 (rs1801278), CAPN10 (rs3792267), TCF7L2 (rs7903146 and rs12255372), and PPARG (rs1801282) gene polymorphisms with T2D, in two different Mexican populations. We conducted a case-control replication study in the state of Guerrero and in Mexico City, with 400 subjects from Guerrero and 1065 from Mexico City. Data were analyzed by logistic regression, adjusting by ancestry, age, gender, and BMI, to determine the association with T2D. Heterozygosity for the Gly972Arg variant of the IRS1 gene showed the strongest association for T2D in both analyzed samples (OR = 2.43, 95% CI 1.12–5.26 and 2.64, 95% CI 1.37–5.10, respectively). In addition, an association of two SNPs of the TCF7L2 gene with T2D was observed in both cities: rs7903146, (for Guerrero OR = 1.98 CI95% 1.02–3.89 and for Mexico OR = 1.94 CI95% 1.31–2.88) and rs12255372 (OR = 1.79 CI95% 1.08–2.97, OR = 1.78 CI95% 1.17–2.71 respectively). We suggest that our results provide strong evidence that variation in the IRS1 and TCF7L2 genes confers susceptibility to T2D in our studied populations.

In the presence of epistasis multilocus association tests of human complex traits can provide powerful methods to detect susceptibility variants. We undertook multilocus analyses in 1924 type 2 diabetes cases and 2938 controls from the Wellcome Trust Case Control Consortium (WTCCC). We performed a two-dimensional genome-wide association (GWA) scan using joint two-locus tests of association including main and epistatic effects in 70,236 markers tagging common variants. We found two-locus association at 79 SNP-pairs at a Bonferroni-corrected P-value = 0.05 (uncorrected P-value = 2.14 × 10⁻¹¹). The 79 pair-wise results always contained rs11196205 in TCF7L2 paired with 79 variants including confirmed variants in FTO, TSPAN8, and CDKAL1, which are associated in the absence of epistasis. However, the majority (82%) of the 79 variants did not have compelling single-locus association signals (P-value = 5 × 10⁻⁴). Analyses conditional on the single-locus effects at TCF7L2 established that the joint two-locus results could be attributed to single-locus association at TCF7L2 alone. Interaction analyses among the peak 80 regions and among 23 previously established diabetes candidate genes identified five SNP-pairs with case-control and case-only epistatic signals. Our results demonstrate the feasibility of systematic scans in GWA data, but confirm that single-locus association can underlie and obscure multilocus findings.

Genome-wide association (GWA) studies have identified around 20 common genetic variants influencing the risk of type 2 diabetes (T2D). Likewise, a number of variants have been associated with diabetes-related quantitative glycaemic traits, but to date the overlap between these genes and variants has been low. The majority of genetic studies have focused on fasting plasma glucose levels; however, this measure is highly variable. We have conducted a GWA meta-analysis of glycated haemoglobin (HbA₁(C) ) levels within three healthy nondiabetic populations. This phenotype provides an estimate of mean glucose levels over 2-3 months and is a more stable predictor of future diabetes risk. Participants were from three isolated populations: the Orkney Isles in the north of Scotland, the Dalmatian islands of Vis, and Korcula in Croatia (total of 1782 nondiabetic subjects). Association was tested in each population and results combined by meta-analysis. The strongest association was with the TCF7L2 gene (rs7903146, P= 1.48 × 10⁻⁷). This is also the strongest common genetic risk factor for T2D but it has not been identified in previous genome-wide studies of glycated haemoglobin.

Summary The aim of this study was to validate the single nucleotide polymorphisms (SNPs) of four candidate genes (TCF7L2, HHEX, KCNJ11 ,a ndADIPOQ) related to type 2 diabetes (T2D) in an endogamous population of north India; the Aggarwal population, having 18-clans. This endogamous population model was heavily supported by recent land mark work and we also verified the homogeneity of this population by clan-based stratification analysis. Two SNPs (rs4506565; rs7903146) in TCF7L2 were found to be significant (p-value = 0.00191; p-value = 0.00179, respectively), and odds ratios of 2.1 (dominant-model) and 2.0 (recessive-model) respectively, were obtained for this population. The TTT haplotype in the TCF7L2 gene was significantly associated with T2D. Waist-Hip ratio (WHR), systolic blood pressure (SBP), and age were significant covariates for increasing risk of T2D. Single-SNP, combined-SNPs and haplotype analysis provides clear evidence that the causal mutation is near to or within the significant haplotype (TTT) of the TCF7L2 gene. In spite of a culturally-learned sedentary lifestyle and fat-enriched dietary habits, WHR rather than body-mass-index emerged as a robust predictor of risk for T2D in this population.

Type 2 diabetes (T2D) is influenced by diverse environmental and genetic risk factors. Metabolic syndrome (MS) increases the risk of cardiovascular disease and diabetes. We analysed 14 cases of polymorphisms located in 10 candidate loci, in a sample of patients with T2D and controls from Mexico City.We analysed the association of 14 polymorphisms located within 10 genes (TCF7L2, ENPP1, ADRB3, KCNJ11, LEPR, PPARgamma, FTO, CDKAL1, SIRT1 and HHEX) with T2D and MS. The analysis included 519 subjects with T2D defined according to the ADA criteria, 389 with MS defined according to the AHA/NHLBI criteria and 547 controls. Association was tested with the program ADMIXMAP including individual ancestry, age, sex, education and in some cases body mass index (BMI), in a logistic regression model.The two markers located within the TCF7L2 gene showed strong associations with T2D (rs7903146, T allele, odd ratio (OR) = 1.76, p = 0.001 and rs12255372, T allele, OR = 1.78, p = 0.002), but did not show significant association with MS. The non-synonymous rs4994 polymorphism of the ADRB3 gene was associated with T2D (Trp allele, OR = 0.62, p = 0.001) and MS (Trp allele, OR = 0.74, p = 0.018). Nominally significant associations were also observed between T2D and the SIRT1 rs3758391 SNP and MS and the HHEX rs5015480 polymorphism.Variants located within the gene TCF7L2 are strongly associated with T2D but not with MS, providing support to previous evidence indicating that polymorphisms at the TCF7L2 gene increase T2D risk. In contrast, the non-synonymous ADRB3 rs4994 polymorphism is associated with T2D and MS.

Background Although variants in the transcription factor 7-like 2 (TCF7L2) gene are consistently associated with impaired fasting glucose (IFG) in Caucasians, data from large population-based studies of African Americans are lacking. Moreover, few studies have investigated the effects of TCF7L2 on IFG in the context of metabolic risk factors for diabetes. Methods We investigated the association between the TCF7L2 rs7903146 polymorphism and incident IFG defined as fasting serum glucose levels of 100–125 mg/dL (5.6–6.9 mmol/L) in 1377 African American and 5152 Caucasian participants without diabetes and IFG at intake who participated in the Atherosclerosis Risk in Communities (ARIC) Study from 1987 to1989 and were followed for 9 years. Results Incident IFG was identified in 810 (58.8%) African American and 2652 (51.5%) Caucasian participants. Compared to homozygous CC Caucasian individuals, heterozygous CT [hazard ratio (HR) = 1.09 (95% CI = 1.03–1.15)] and homozygous TT [1.18 (1.05–1.33)] individuals had significantly higher risk of developing IFG over 9-year follow-up. The association between rs7903146 and IFG risk was stronger in Caucasians with obesity [HRCTvs.CC = 1.28 (1.12, 1.47); HRTTvs.CC = 1.65 (1.25, 2.17)] or high triglycerides [HRCTvs.CC = 1.31(1.10, 1.56); HRTTvs.CC = 1.72 (1.21, 2.43)]. No association of the TCF7L2 rs7903146 polymorphism and incident IFG was noted in African Americans. Conclusions Our study replicates the association between rs7903146 and IFG risk in a population-based, longitudinal cohort of Caucasians but not in African Americans. For the first time, our study provides evidence for interactions between TCF7L2 and metabolic risk factors on the occurrence of IFG in Caucasians. Copyright © 2010 John Wiley & Sons, Ltd.

Diabet. Med. 27, 701–704 (2010) Abstract Aims We previously demonstrated the presence of two different populations among adult-onset autoimmune diabetes (latent autoimmume diabetes of adults; LADA) having high or low titre of antibodies to glutamic acid decarboxylase (GADA). The transcription factor 7-like 2 (TCF7L2) gene has been recognized as the major gene associated with Type 2 diabetes. The aim of the present study was to evaluate whether the phenotypic heterogeneity of LADA based on GADA titre is associated with TCF7L2 polymorphisms. Methods Two hundred and fifty patients identified as LADA, divided into two subgroups with low (≤ 32 arbitrary units) or high (> 32 units) GADA titre, 620 subjects with Type 2 diabetes [from the Non-Insulin Requiring Autoimmune Diabetes (NIRAD) study cohort of 5330 subjects] in addition to 551 consecutive cases of Type 1 diabetes and 545 normoglycaemic subjects were analysed for the rs12255372 and rs7903146 polymorphisms of the TCF7L2 gene using Taqman. Results The genotype and allele distributions of the two polymorphisms revealed similar frequencies in subjects with low GADA titre and Type 2 diabetes. High GADA titre, Type 1 diabetes and controls also showed comparable frequencies. A significant increase of GT/TT genotypes of the rs12255372 single-nucleotide polymorphism (SNP) and CT/TT genotypes of the rs7903146 SNP was observed in low GADA titre and Type 2 diabetes compared with high GADA titre, Type 1 diabetes and controls (P ≤ 0.04 for both comparisons). The risk alleles of both variants were increased in low GADA titre and Type 2 diabetes compared with high GADA titre, Type 1 diabetes and control subjects (P

Summary Context 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. Objective 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. Subjects A total of 246 Caucasian short children born SGA, with a median age of 7·8 years. Outcome measures 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). Results 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 × insulin sensitivity), which is an estimate of beta cell function, was not associated with genotype and did not change during GH treatment. Conclusion The TCF7L2 rs7903146 polymorphism is not associated with the change in insulin secretion during GH treatment in short SGA children.

Background: We previously reported that the fasting serum insulin level was significantly lower in Japanese patients than in Korean and Chinese patients, and showed evidence that a difference in the dietary component would be one of the most influential factors for the ethnic difference. However, it is well known that type 2 diabetes mellitus (T2DM) results from the interaction between genetic predispositions and environmental risk factors. Therefore, we investigated ethnic differences by focusing on gene polymorphism, possibly related to T2DM in Japanese, Korean, and Chinese subjects. Methods: Data sources included MEDLINE and EMBASE between January 2001 and October 2008. We conducted a search for articles containing minor allele frequency (MAF) in the gene polymorphisms of peroxisome proliferator-activated receptor-γ (PPARG), inward-rectifying potassium channel Kir6.2 (KCNJ11), Calpain 10 (CAPN10), and transcription factor 7-like 2 (TCF7L2). The pooled odds ratio was calculated by using a fixed-effects model with the Mantel–Haenszel method after confirming statistical evidence of homogeneity across the ethnicities using the Breslow–Day test. Results: The Breslow–Day test revealed that there were no statistically significant differences between ethnicities in pooled odds ratios for the gene polymorphisms in PPARG (P = 0.828), KCNJ11 (P = 0.194), CAPN10 (P = 0.090), and TCF7L2 (P = 0.376). Also, pooled odds ratios of each gene polymorphism in East Asians were 0.645 for PPARG (P = 0.000), 1.168 for KCNJ11 (P = 0.000), 0.967 for CAPN10 (P = 0.759), and 1.386 for TCF7L2 (P = 0.000). Conclusion: The results of this study and our previous studies suggest that behavioral and environmental risk factors have a more significant impact on ethnic difference in East Asian patients with T2DM compared with genetic predispositions.

Diabetes mellitus arises from defects in insulin secretion or action, or both. In pancreatic islets, insulin production is linked with zinc transport mediated by zinc transporter ZnT-8, a product of the SLC30A8 gene. Therefore, altered activity of ZnT-8 is expected to be associated with impaired glucose-induced insulin response and promote progression from glucose intolerance to diabetes. Recent findings do emerge with a role of SLC30A8 in diabetes. Genome-wide association scans for type 2 diabetes (T2D) susceptibility loci revealed and then replicated a highly significant association between the R allele of the R325W variant of SLC30A8 (marker rs13266634) and susceptibility to T2D in Caucasians. A role of ZnT-8 as a new major self-antigenic determinant in type 1 diabetes (T1D) was found. Marker rs13266634 was also shown to modulate anti-ZnT-8 self-antibody specificity in islet autoimmunity. Hence, these findings suggest for a dual role of SLC30A8 in diabetes, which is consisted in conferring genetic susceptibility to T2D and being a major islet self-antigen in T1D as well. Here we characterize an emerging role of ZnT-8 in diabetes and discuss potential mechanisms of its involvement in the etiology of both forms of diabetes.

To investigate candidate genes involved in human type 2 diabetes (T2D) for obesity-related phenotypes in pigs. Statistical association analyses of genes with fat deposition were realized in a pig reference family constructed by two breeds, Berkshire and Yorkshire. Extensive sequencing was then attempted to discover the causative polymorphism. Genes implied in human T2D development, TCF7L2, WFS1, FTO, SLC30A8, and GCKR, were mapped on Sus scrofa chromosomes 14, 8, 6, 4, and 3, respectively. Only TCF7L2 was significantly associated with five fat traits in pigs. Further investigation demonstrated that one haplotype (HapB), but not the HapA (homologous to the region for human T2D susceptibility where single-nucleotide polymorphism (SNP) rs7903146 is located), is significantly associated with the fat-related traits. In HapB, two SNPs in TCF7L2 exon 8 and intron 10 are significantly associated with five fat traits, and may be in linkage disequilibrium with the causative variant with additive effects on all four backfat traits, and the total lipid percentage. Pigs of genotype TT for the SNP in exon 8 have only one transcript isoform (the one without exon 4), and lower backfat depth. Candidate gene analyses could provide novel ideas about how these genes function in T2D susceptibility in human, and support that the pig can be a suitable model for human obesity and T2D research. Further replication of this research in other pig populations should be considered, so that the possibility of utilizing these genetic markers in pig breeding or in animal model research can be explored.

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is considered an important regulator of T-cell activation. Polymorphisms within the PTPN22 gene have been suggested to confer susceptibility to autoimmune endocrine disorders. To evaluate the impact of a functional variation in the PTPN22 gene in type 1 (T1D) and type 2 diabetes (T2D), the PTPN22 C1858T single nucleotide polymorphism (SNP) was studied in the population of Estonian origin, including 170 T1D patients, 244 T2D patients and 230 controls. Using two methods for PTPN22 C1858T detection in parallel, we found that not only T1D but also T2D is associated with the PTPN22 1858T allele. The role of PTPN22 gene in the pathogenesis of T2D is yet unclear and needs further investigation.

We report a patient born to consanguineous parents as a further example of a recently described phenotype comprising neonatal diabetes, intestinal atresias and gall bladder agenesis. Other reports have described cases with overlapping patterns including malrotation, biliary atresia and pancreatic hypoplasia (e.g. as described by Martínez-Frías). We propose that these cases may represent variations of the same syndrome. It is likely that this disorder is inherited as an autosomal recessive trait. Our case is the first to have neonatal diabetes without a demonstrable structural pancreatic abnormality, showing that a deficit in pancreatic function is involved. We sequenced genes with a recognized role in monogenic forms of diabetes, including KCNJ11, ABCC8, GCK, IPF1, HNF1beta, NeuroD1 and TCF7L2, as well as a novel candidate gene, HNF6, known to be involved in hepatobiliary and pancreatic development, but did not identify mutations.

Transcription factor 7-like 2 (TCF7L2) is a high mobility group -box containing protein that is a critical member of the Wnt/β-catenin signaling pathway. In addition to its recently recognized role in diabetes, aberrant TCF7L2 expression has been implicated in cancer through regulation of cell proliferation and apoptosis by c-MYC and cyclin D. It has been hypothesized that germline variants within the TCF7L2 gene previously associated with diabetes may affect cancer risk through the Wnt/β-catenin signaling pathway. Specifically, the same risk allele of single nucleotide polymorphism (SNP) rs12255372 that is associated with diabetes (T allele) has recently been associated with an increased risk of breast cancer. Here, we investigated associations between rs12255372 and prostate cancer risk among 597 cases and 548 controls from a population-based study. We also evaluated prostate cancer progression/recurrence and prostate-specific mortality among these cases under long-term surveillance. The risk allele was associated with cancer progression/recurrence after primary treatment [hazard ratio (HR) =1.48, 95% confidence interval (CI) =1.01-2.19), but this association was attenuated when the model was further adjusted for Gleason score and tumor stage. There were no associations between this SNP and the risk of developing disease or prostate cancer-specific mortality. Our findings suggest that this variant in the TCF7L2 gene may enhance tumor progression or metastasis, but it does not contribute significantly to tumor initiation. These findings are of clinical importance for identification of patients that may develop more aggressive/recurrent disease after primary treatment.

Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes Grant et al. (2006) Nature Genetics 38: 320–323 Combining information from common type 2 diabetes risk polymorphisms improves disease prediction Weedon et al. (2006) PLoS Medicine 3: e374 A genome-wide association study identifies novel risk loci for type 2 diabetes Sladek et al. (2007) Nature 445: 881–885

In 1988 the task of identifying Type 2 diabetes genes was described as a nightmare. For the next 17 years this proved to be largely correct. In the meantime the prevalence of Type 2 diabetes rose sharply due to non-genetic factors, compounding the problem of trying to find genes. Despite a huge amount of effort, progress was disappointing and only two genes, PPARG and KCNJ11, were confirmed beyond doubt as Type 2 diabetes risk factors in multiple studies. The reasons for this have been well documented and mainly consist of the use of inappropriate levels of statistical inference given the many hundreds of thousands of potential risk polymorphisms in the genome and their small effect sizes. The good news is that these problems are now surmountable and prospects for finding many more genes are bright. This year saw the identification of a third gene, TCF7L2, that has a greater impact on risk than the first two and provided important lessons for Type 2 diabetes genetic studies. The most important of these lessons was that previously unsuspected genes may be involved. In this review I discuss why this year is the start of a new era in our understanding of Type 2 diabetes genes and how this may lead to improved patient care.

Multiple genome-wide scans in different populations have linked the chromosome 12q24 region, known as NIDDM2 (non-insulin-dependent-diabetes, locus 2), to type 2 diabetes. Within NIDDM2 we examined the PSMD9 (proteasome modulator 9/Bridge-1) gene that encodes a PDZ-domain transcriptional coactivator of insulin production. Our goal was to identify a potential contribution of the PSMD9 gene to type 2 diabetes in Italians. We directly sequenced the entire gene PSMD9 in Italian type 2 diabetes patients (n = 237) and controls subjects (n = 215) and performed an association study with the identified gene variants. We found five single nucleotide polymorphisms (SNPs), A17V, IVS1+nt29, IVS3+nt460, IVS3+nt437, and E197G, which are not associated with disease in our case-control study. Furthermore, we identified two PSMD9 gene variants in type 2 diabetes patients, which produced nonconservative amino acid substitutions S143G and N166S within the PDZ domain and two other gene variants. Three out of four of these variants are absent from the control subjects screened. We propose that the three PSMD9 gene variants (S143G, N166S and G > A at IVS3+nt102), absent in control subjects, contribute rarely to late-onset type 2 diabetes in Italians. In fact, the frequency rate of such variants in unrelated cases equals 0.016. We may not exclude that PSMD9 gene variants may contribute, either commonly or rarely, to an increased risk of type 2 diabetes in other populations.

Multiple genes are involved in the susceptibility to autoimmune type 1 diabetes. The immunoreceptor programmed cell death-1 (PDCD-1), an inhibitory costimulatory molecule regulating peripheral tolerance, was reported to play a role in the development of type 1 diabetes, making the human PDCD-1 gene, PDCD1, as a candidate for disease susceptibility. In this article, we sequenced all 5 exons and exon–intron junctions of PDCD1 in Japanese subjects, and found 10 sequence variants. Preliminary data suggested no association of these polymorphisms with type 1 diabetes. These sequence variants are valuable for further studies to clarify contribution of PDCD1 to susceptibility to type 1 diabetes.