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OBJECTIVE - Homozygous loss-of-function mutations in the gene coding for the homeobox transcription factor (TF) PDX1 leads to pancreatic agenesis, whereas heterozygous mutations can cause Maturity-Onset Diabetes of the Young 4 (MODY4). Although the function of Pdx1 is well studied in pre-clinical models during insulin-producing β-cell development and homeostasis, it remains elusive how this TF controls human pancreas development by regulating a downstream transcriptional program. Also, comparative studies of PDX1 binding patterns in pancreatic progenitors and adult β-cells have not been conducted so far. Furthermore, many studies reported the association between single nucleotide polymorphisms (SNPs) and T2DM, and it has been shown that islet enhancers are enriched in T2DM-associated SNPs. Whether regions, harboring T2DM-associated SNPs are PDX1 bound and active at the pancreatic progenitor stage has not been reported so far.
METHODS - In this study, we have generated a novel induced pluripotent stem cell (iPSC) line that efficiently differentiates into human pancreatic progenitors (PPs). Furthermore, PDX1 and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify PDX1 transcriptional targets and active enhancer and promoter regions. To address potential differences in the function of PDX1 during development and adulthood, we compared PDX1 binding profiles from PPs and adult islets. Moreover, combining ChIP-seq and GWAS meta-analysis data we identified T2DM-associated SNPs in PDX1 binding sites and active chromatin regions.
RESULTS - ChIP-seq for PDX1 revealed a total of 8088 PDX1-bound regions that map to 5664 genes in iPSC-derived PPs. The PDX1 target regions include important pancreatic TFs, such as PDX1 itself, RFX6, HNF1B, and MEIS1, which were activated during the differentiation process as revealed by the active chromatin mark H3K27ac and mRNA expression profiling, suggesting that auto-regulatory feedback regulation maintains PDX1 expression and initiates a pancreatic TF program. Remarkably, we identified several PDX1 target genes that have not been reported in the literature in human so far, including RFX3, required for ciliogenesis and endocrine differentiation in mouse, and the ligand of the Notch receptor DLL1, which is important for endocrine induction and tip-trunk patterning. The comparison of PDX1 profiles from PPs and adult human islets identified sets of stage-specific target genes, associated with early pancreas development and adult β-cell function, respectively. Furthermore, we found an enrichment of T2DM-associated SNPs in active chromatin regions from iPSC-derived PPs. Two of these SNPs fall into PDX1 occupied sites that are located in the intronic regions of TCF7L2 and HNF1B. Both of these genes are key transcriptional regulators of endocrine induction and mutations in cis-regulatory regions predispose to diabetes.
CONCLUSIONS - Our data provide stage-specific target genes of PDX1 during in vitro differentiation of stem cells into pancreatic progenitors that could be useful to identify pathways and molecular targets that predispose for diabetes. In addition, we show that T2DM-associated SNPs are enriched in active chromatin regions at the pancreatic progenitor stage, suggesting that the susceptibility to T2DM might originate from imperfect execution of a β-cell developmental program.
Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.
Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.
Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)
Type 2 diabetes (T2D) is up to twice as prevalent among African Americans as Caucasians. Recent genome-wide association studies (GWAS) have identified multiple common genetic risk variants for T2D; however, none of these studies were conducted exclusively among subjects of African ancestry. Investigating these known loci in other populations would be an expedient way to evaluate the generalizability of the current findings. The authors evaluated 29 known T2D loci in a large southeastern US cohort study including 4,288 African Americans (1,554 cases and 2,734 controls) enrolled during 2002-2009. Seven of the 29 single nucleotide polymorphisms (SNPs) examined were found to be associated with T2D risk at P ≤ 0.05, including rs6769511 (IGF2BP2), 2 SNPs in the WFS1 gene (rs4689388 and rs1801214), rs7903146 (TCF7L2), and 3 SNPs in the KCNQ1 gene (rs231362, rs2237892, and rs2237897). Notably, the association for rs7903146 reached the GWAS significance level (P = 3.6 × 10(-8)), with an odds ratio per T allele of 1.32 (95% confidence interval: 1.20, 1.46). Regional analyses using GWAS data from Vanderbilt University's BioVU DNA biobank showed significant associations (P < 0.05) with 9 loci, though no association was observed for the index SNPs reported in European- or Asian-ancestry populations. These results extend some of the recent GWAS findings to African Americans and may guide future efforts to identify causal variants for T2D.
BACKGROUND - Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI.
METHODS AND RESULTS - We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10(-6) to denote statistical significance.
RESULTS - In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10(-7)) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10(-5)) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10(-3); rs290481, p=8.88×10(-5)). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance.
CONCLUSIONS - Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
OBJECTIVE - Common genetic variants in GCK and TCF7L2 are associated with higher fasting glucose and type 2 diabetes in nonpregnant populations. However, their associations with glucose levels from oral glucose tolerance tests (OGTTs) in pregnancy have not been assessed in a large sample. We hypothesized that these variants are associated with quantitative measures of glycemia in pregnancy.
RESEARCH DESIGN AND METHODS - We analyzed the associations between variants rs1799884 (GCK) and rs7903146 (TCF7L2) and OGTT outcomes at 24-32 weeks' gestation in 3,811 mothers of European (U.K. and Australia) and 1,706 mothers of Asian (Thailand) ancestry from the HAPO cohort. We also tested associations with offspring birth anthropometrics.
RESULTS - The maternal GCK variant was associated with higher fasting glucose in Europeans (P = 0.001) and Thais (P < 0.0001), 1-h glucose in Europeans (P = 0.001), and 2-h glucose in Thais (P = 0.005). It was also associated with higher European offspring birth weight, fat mass, and skinfold thicknesses (P < 0.05). The TCF7L2 variant was associated with all three maternal glucose outcomes (P = 0.03, P < 0.0001, and P < 0.0001 for fasting and 1-h and 2-h glucose, respectively) in the Europeans but not in the Thais (P > 0.05). In both populations, both variants were associated with higher odds of gestational diabetes mellitus according to the new International Association of Diabetes and Pregnancy Study Groups recommendations (P = 0.001-0.08).
CONCLUSIONS - Maternal GCK and TCF7L2 variants are associated with glucose levels known to carry an increased risk of adverse pregnancy outcome in women without overt diabetes. Further studies will be important to determine the variance in maternal glucose explained by all known genetic variants.
There is a known inverse association between type 2 diabetes (T2D) and prostate cancer (PrCa) that is poorly understood. Genetic studies of the T2D-PrCa association may provide insight into the underlying mechanisms of this association. We evaluated associations in the Atherosclerosis Risk in Communities study between PrCa and nine T2D single nucleotide polymorphisms from genome-wide association studies of T2D (in CDKAL1, CDKN2A/B, FTO, HHEX, IGF2BP2, KCNJ11, PPARG, SLC30A8, and TCF7L2) and four T2D single nucleotide polymorphisms from pre-genome-wide association studies (in ADRB2, CAPN10, SLC2A2, and UCP2). From 1987 to 2000, there were 397 incident PrCa cases among 6,642 men ages 45 to 64 years at baseline. We used race-adjusted Cox proportional hazards models to estimate associations between PrCa and increasing number of T2D risk-raising alleles. PrCa was positively associated with the CAPN10 rs3792267 G allele [hazard ratio (HR) 1.20; 95% confidence interval (CI), 1.00-1.44] and inversely associated with the SLC2A2 rs5400 Thr110 allele (HR, 0.85; 95% CI, 0.72, 1.00), the UCP2 rs660339 Val55 allele (HR, 0.84; 95% CI, 0.73, 0.97) and the IGF2BP2 rs4402960 T allele (HR, 0.79; 95% CI, 0.61-1.02; blacks only). The TCF7L2 rs7903146 T allele was inversely associated with PrCa using a dominant genetic model (HR, 0.79; 95% CI, 0.65-0.97). Further knowledge of T2D gene-PrCa mechanisms may improve understanding of PrCa etiology.
The transcription factor 7-like 2 (TCF7L2) has been recently associated with diabetes risk, and it may exert its effect through metabolic syndrome (MetS)-related traits and be subjected to modification by environmental factors. We investigated the effect of single nucleotide polymorphisms (SNP), rs7903146 and rs12255372, within the TCF7L2 locus on postprandial lipemia and other MetS-related traits and their modulation by dietary fat. Data were collected from 1083 European Americans participating in the Genetics of Lipid Lowering Drugs and Diet Network Study. Carriers of the minor T allele at the C/T rs7903146 SNP had higher fasting plasma glucose (P = 0.012), lower homeostasis model assessment of beta cell function (P = 0.041), higher plasma VLDL (P = 0.035), and lower large LDL particle (P = 0.007) concentrations and higher risk of MetS (P = 0.011) than CC individuals. Moreover, we identified significant interactions between this SNP and PUFA intake modulating fasting VLDL particle concentrations (P = 0.016) and postprandial triglycerides (TG) (P = 0.028), chylomicrons (P = 0.025), total VLDL (P = 0.026), and large VLDL (P = 0.018) concentrations. Thus, only T allele carriers with a PUFA intake > or = 7.36% of energy had elevated fasting plasma VLDL concentrations and postprandial TG-rich lipoproteins. These variables did not differ in T allele carriers and noncarriers in the low-PUFA intake group. Moreover, these significant interactions were due exclusively to (n-6) PUFA intake. In summary, high (n-6) PUFA intakes (> or = 6.62% of energy intake) were associated with atherogenic dyslipidemia in carriers of the minor T allele at the TCF7L2 rs7903146 SNP and may predispose them to MetS, diabetes, and cardiovascular disease.
Canonical Wnt signaling is mediated by a molecular "switch" that regulates the transcriptional properties of the T-cell factor (TCF) family of DNA-binding proteins. Members of the myeloid translocation gene (MTG) family of transcriptional corepressors are frequently disrupted by chromosomal translocations in acute myeloid leukemia, whereas MTG16 may be inactivated in up to 40% of breast cancer and MTG8 is a candidate cancer gene in colorectal carcinoma. Genetic studies imply that this corepressor family may function in stem cells. Given that mice lacking Myeloid Translocation Gene Related-1 (Mtgr1) fail to maintain the secretory lineage in the small intestine, we surveyed transcription factors that might recruit Mtgr1 in intestinal stem cells or progenitor cells and found that MTG family members associate specifically with TCF4. Coexpression of beta-catenin disrupted the association between these corepressors and TCF4. Furthermore, when expressed in Xenopus embryos, MTG family members inhibited axis formation and impaired the ability of beta-catenin and XLef-1 to induce axis duplication, indicating that MTG family members act downstream of beta-catenin. Moreover, we found that c-Myc, a transcriptional target of the Wnt pathway, was overexpressed in the small intestines of mice lacking Mtgr1, thus linking inactivation of Mtgr1 to the activation of a potent oncogene.
A new p53 family member, p73, and its isoform DeltaNp73 are increasingly recognized in cancer research as important players in tumorigenesis, as well as in chemotherapeutic drug sensitivity. Despite substantial structural similarities to p53, accumulating evidence suggests that p53 and p73 may play different roles in human tumorigenesis. In this study, we have investigated the role of p73 and DeltaNp73 in upper gastrointestinal tumorigenesis. Our results indicate that p73 and DeltaNp73 are frequently overexpressed in >60% of primary adenocarcinomas of the stomach and esophagus. We have demonstrated that this overexpression can lead to the suppression of p73 transcriptional and apoptotic activity in gastrointestinal cells. Moreover, it induces beta-catenin up-regulation and T-cell factor/lymphocyte enhancement factor-dependent transcription. Wild-type p53, but not mutant p53, can inhibit this effect. Our results demonstrate a novel mechanism for activation of beta-catenin in gastrointestinal tumors and support the concept that overexpression of p73 isoforms can play an important role in tumorigenesis.