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Weiyue Ding, Li Xu, Lejun Zhang, Zhijie Han, Qinghua Jiang, Zhe Wang, Shuilin Jin
BACKGROUND: Large scale association studies have found a significant association between type 2 diabetes mellitus (T2DM) and transcription factor 7-like 2 (TCF7L2) polymorphism rs7903146. However, the quality of data varies greatly, as the studies report inconsistent results in different populations. Hence, we perform this meta-analysis to give a more convincing result. METHODS: The articles, published from January 1st, 2000 to April 1st, 2017, were identified by searching in PubMed and Google Scholar...
March 7, 2018: BMC Medical Genetics
Andreas W Berger, Katja Raedler, Cord Langner, Leopold Ludwig, Nektarios Dikopoulos, Karl F Becker, Julia Slotta-Huspenina, Michael Quante, Daniel Schwerdel, Lukas Perkhofer, Alexander Kleger, Eugen Zizer, Franz Oswald, Thomas Seufferlein, Alexander Meining
Background and objective: Current surveillance strategies for colorectal cancer following polypectomy are determined by endoscopic and histopathological factors. Such a distinction has been challenged. The present study was designed to identify molecular parameters in colonic polyps potentially defining new sub-groups at risk. Methods: One hundred patients were enrolled in this multicentre study. Polyps biopsies underwent formalin-free processing (PAXgene, PreAnalytiX) and targeted next generation sequencing (38 genes (QIAGEN), NextSeq 500 platform (Illumina))...
March 2018: United European Gastroenterology Journal
V Chedid, P Vijayvargiya, P Carlson, K Van Malderen, A Acosta, A Zinsmeister, M Camilleri
BACKGROUND: Weight loss in response to the long-acting GLP-1 receptor (GLP1R) analog, liraglutide, is correlated with delay in gastric-emptying (GE). The aim of this pilot study was to assess whether specific genetic variants in GLP1R or TCF7L2 are associated with delayed GE and weight loss in obese patients treated with liraglutide or the short-acting GLP-1 agonist, exenatide. METHODS: We evaluated in obese individuals the associations of genetic variations of GLP1R (rs6923761) and TCF7L2 (rs7903146) on GE T1/2 and weight from two trials that evaluated separately exenatide, 5 μg BID for 30 days, or liraglutide, 3 mg daily for 5 weeks...
February 28, 2018: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
Jinfeng Xiang, Qiangsheng Hu, Yi Qin, Shunrong Ji, Wenyan Xu, Wensheng Liu, Si Shi, Chen Liang, Jiang Liu, Qingcai Meng, Dingkong Liang, Quanxing Ni, Jin Xu, Bo Zhang, Xianjun Yu
Patients with pancreatic ductal adenocarcinoma have much worse prognoses, and much effort has been directed toward understanding the molecular biological aspects of this disease. Accumulated evidence suggests that constitutive activation of the Wnt/β-catenin signalling contributes to the oncogenesis and progression of pancreatic cancer. Transcription factor 7-like2/transcription factor 4 (TCF7L2/TCF4), a β-catenin transcriptional partner, plays a vital role in the Wnt/β-catenin signalling pathway. In the present study, we investigated the clinicopathological significance of TCF7L2 in pancreatic cancer...
February 23, 2018: Cell Death & Disease
Jeremy W Prokop, Nan Cher Yeo, Christian Ottmann, Surya B Chhetri, Kacie L Florus, Emily J Ross, Nadiya Sosonkina, Brian A Link, Barry I Freedman, Candice J Coppola, Chris McDermott-Roe, Seppe Leysen, Lech-Gustav Milroy, Femke A Meijer, Aron M Geurts, Frank J Rauscher, Ryne Ramaker, Michael J Flister, Howard J Jacob, Eric M Mendenhall, Jozef Lazar
Background Interpreting genetic variants is one of the greatest challenges impeding analysis of rapidly increasing volumes of genomic data from patients. For example, SHROOM3 is an associated risk gene for CKD, yet causative mechanism(s) of SHROOM3 allele(s) are unknown. Methods We used our analytic pipeline that integrates genetic, computational, biochemical, CRISPR/Cas9 editing, molecular, and physiologic data to characterize coding and noncoding variants to study the human SHROOM3 risk locus for CKD. Results We identified a novel SHROOM3 transcriptional start site, which results in a shorter isoform lacking the PDZ domain and is regulated by a common noncoding sequence variant associated with CKD (rs17319721, allele frequency: 0...
February 23, 2018: Journal of the American Society of Nephrology: JASN
N M Phani, M Vohra, P Adhikari, S K Nagri, U Shashikiran, S C D'Souza, P R R Kalluri, K Satyamoorthy, P S Rai
BACKGROUND: Several SNPs were identified through GWAS for their association with type 2 diabetes which has implications to pancreatic β-cell physiology. OBJECTIVE: We aimed to study the role of risk alleles of TCF7L2, KCNJ11, CDKN2A, CDKAL1, IGF2BP2, SLC30A8 and KCNQ1 along with pharmacokinetic variants in response to sulfonylureas. METHOD: We performed a prospective study on 209 newly diagnosed subjects; treatment naive T2D subjects were recruited...
February 22, 2018: Current Molecular Medicine
Xianming Wang, Michael Sterr, Ingo Burtscher, Shen Chen, Anja Hieronimus, Fausto Machicao, Harald Staiger, Hans-Ulrich Häring, Gabriele Lederer, Thomas Meitinger, Filippo M Cernilogar, Gunnar Schotta, Martin Irmler, Johannes Beckers, Martin Hrabě de Angelis, Michael Ray, Christopher V E Wright, Mostafa Bakhti, Heiko Lickert
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...
January 30, 2018: Molecular Metabolism
Lavanya M Iyer, Sankari Nagarajan, Monique Woelfer, Eric Schoger, Sara Khadjeh, Maria Patapia Zafiriou, Vijayalakshmi Kari, Jonas Herting, Sze Ting Pang, Tobias Weber, Franziska S Rathjens, Thomas H Fischer, Karl Toischer, Gerd Hasenfuss, Claudia Noack, Steven A Johnsen, Laura C Zelarayán
Chromatin remodelling precedes transcriptional and structural changes in heart failure. A body of work suggests roles for the developmental Wnt signalling pathway in cardiac remodelling. Hitherto, there is no evidence supporting a direct role of Wnt nuclear components in regulating chromatin landscapes in this process. We show that transcriptionally active, nuclear, phosphorylated(p)Ser675-β-catenin and TCF7L2 are upregulated in diseased murine and human cardiac ventricles. We report that inducible cardiomyocytes (CM)-specific pSer675-β-catenin accumulation mimics the disease situation by triggering TCF7L2 expression...
January 31, 2018: Nucleic Acids Research
Qianghua Xia, Sumei Lu, Julian Ostrovsky, Shana E McCormack, Marni J Falk, Struan F A Grant
TCF7L2 is located at one of the most strongly associated type 2 diabetes loci reported to date. We previously reported that the most abundant member of a specific protein complex to bind across the presumed causal variant at this locus, rs7903146, was poly [ADP-ribose] polymerase type 1 (PARP-1). We analyzed the impact of PARP-1 inhibition on C. elegans health in the setting of hyperglycemia and on glucose-stimulated GLP-1 secretion in human intestinal cells. Given that high glucose concentrations progressively shorten the lifespan of C...
February 2018: Aging and Disease
Rujikorn Rattanatham, Nongnuch Settasatian, Chatri Settasatian, Nisa Decharatchakul, Ingkarat Sarutipaiboon, Sakda Kanyalert, Nuthatai Boonpalit
No abstract text is available yet for this article.
August 2017: Atherosclerosis
Xin Wang, Peijie Lin, Joshua W K Ho
BACKGROUND: It has been observed that many transcription factors (TFs) can bind to different genomic loci depending on the cell type in which a TF is expressed in, even though the individual TF usually binds to the same core motif in different cell types. How a TF can bind to the genome in such a highly cell-type specific manner, is a critical research question. One hypothesis is that a TF requires co-binding of different TFs in different cell types. If this is the case, it may be possible to observe different combinations of TF motifs - a motif grammar - located at the TF binding sites in different cell types...
January 19, 2018: BMC Genomics
Polina V Popova, Alexandra A Klyushina, Lyudmila B Vasilyeva, Alexandra S Tkachuk, Yana A Bolotko, Andrey S Gerasimov, Evgenii A Pustozerov, Ekaterina N Kravchuk, Alexander Predeus, Anna A Kostareva, Elena N Grineva
We hypothesized that the association of certain lifestyle parameters with gestational diabetes mellitus (GDM) risk would depend on susceptibility loci. In total, 278 Russian women with GDM and 179 controls completed questionnaires about lifestyle habits (food consumption, physical activity and smoking). GDM was diagnosed according to the criteria of the International Association of Diabetes and Pregnancy Study Groups. Maternal blood was sampled for genotyping single-nucleotide polymorphisms (SNPs) in MTNR1B (rs10830963 and rs1387153), GCK (rs1799884), KCNJ11 (rs5219), IGF2BP2 (rs4402960), TCF7L2 (rs7903146 and rs12255372), CDKAL1 (rs7754840), IRS1 (rs1801278) and FTO (rs9939609)...
December 19, 2017: Oncotarget
Shylaja Srinivasan, Varinderpal Kaur, Bindu Chamarthi, Katherine R Littleton, Ling Chen, Alisa K Manning, Jordi Merino, Melissa K Thomas, Margo Hudson, Allison Goldfine, Jose C Florez
OBJECTIVE: The 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 METHODS: We genotyped rs7903146 in 608 individuals without diabetes and recorded biochemical data before and after one dose of glipizide (5 mg) on visit 1, and a 75-g oral glucose tolerance test (OGTT) performed after administration of metformin 500 mg twice daily over 2 days...
January 11, 2018: Diabetes Care
Marica Franzago, Federica Fraticelli, Daniela Marchetti, Claudio Celentano, Marco Liberati, Liborio Stuppia, Ester Vitacolonna
AIM: Gestational diabetes mellitus (GDM) is the most frequent metabolic disorder in pregnancy and it can be considered a silent risk associated to T2DM and CVD later in life. The aim of this study was to investigate the association of clinical parameters with nine single nucleotide polymorphisms (SNPs) involved with nutrients and metabolism in women with or without GDM in order to identify potential routine clinical markers for early prevention. METHODS: Nine gene variants associated with nutrients and metabolism, namely PPARG2 rs1801282 (C>G); PPARGC1A rs8192678 (C>T); TCF7L2 rs7903146 (C>T); LDLR rs2228671 (C>T); MTHFR rs1801133 (C>T); APOA5 rs662799 (T>C); GCKR rs1260326 (C>T); FTO rs9939609 (T>A); MC4R rs17782313 (T>C) were genotyped in 104 GDM cases and 124 controls using High Resolution Melting (HRM) analysis...
January 8, 2018: Diabetes Research and Clinical Practice
Xi Chen, Ayala Iriscilla, Chris Shannon, Marcel Fourcaudot, Nikhil K Acharya, Christopher P Jenkinson, Sami Heikkinen, Luke Norton
The gene encoding for transcription factor 7-like 2 (TCF7L2) is the strongest type 2 diabetes (T2DM) candidate gene discovered to date. The TCF7L2 protein is a key transcriptional effector of the Wnt/β-catenin signaling pathway, which is an important developmental pathway that negatively regulates adipogenesis. However, the precise role that TCF7L2 plays in the development and function of adipocytes remains largely unknown. Using a combination of in vitro approaches, we first show that TCF7L2 protein is increased during adipogenesis in 3T3-L1 cells and primary adipocyte stem cells (ASC), and that TCF7L2 expression is required for the regulation of Wnt signaling during adipogenesis...
January 9, 2018: Diabetes
Yun Hu, Ping Shi, Ke He, Yun-Qing Zhu, Fan Yang, Min Yang, Bang-Shun He, Xiao-Ming Mao
BACKGROUND: The TCF7L2 (transcription factor 7 like 2) gene is strongly associated with type 2 diabetes (T2D) risk. However, many people without the TCF7L2 at-risk allele develop T2D. The aim of this study was to investigate altered Tcf7l2 DNA methylation and gene expression caused by high-fat diets (HFDs). METHODS: C57BL/6 mice were fed either a HFD or normal diet for 8 weeks and intraperitoneal glucose tolerance tests were performed. Pancreatic islets were sorted for bisulfite sequencing PCR to determine DNA methylation status...
January 4, 2018: Diabetes/metabolism Research and Reviews
Hao Qiu, Xunting Lin, Weifeng Tang, Chao Liu, Yu Chen, Hao Ding, Mingqiang Kang, Shuchen Chen
Single nucleotide polymorphisms (SNPs) in energy metabolism related gene may be key agents in the development of human malignancies. In this study, we aimed to examine the association of transcription factor 7-like 2, Leptin (LEP) and LEP receptor (LEPR) polymorphisms with esophageal squamous cell carcinoma (ESCC). A total of 507 ESCC cases and 1,496 controls were enrolled. We found that LEPR rs6588147 AA genotype was associated with ESCC risk (AA vs. GG/GA: adjusted OR=1.90, 95%CI=1.00-3.61, P=0.049). In the stratified analyses, LEPR rs6588147 G>A polymorphism increased the risk of ESCC (<63 years subgroup: AA vs...
December 12, 2017: Oncotarget
M R Marshall, N Paneth, J A Gerlach, L M Mudd, L Biery, D P Ferguson, J M Pivarnik
Several studies have suggested that maternal lifestyle during pregnancy may influence long-term health of offspring by altering the offspring epigenome. Whether maternal leisure-time physical activity (LTPA) during pregnancy might have this effect is unknown. The purpose of this study was to determine the relationship between maternal LTPA during pregnancy and offspring DNA methylation. Participants were recruited from the Archive for Research on Child Health study. At enrollment, participants' demographic information and self-reported LTPA during pregnancy were determined...
January 9, 2018: Journal of Developmental Origins of Health and Disease
Snehangshu Kundu, Muhammad Akhtar Ali, Niklas Handin, Narendra Padhan, Jimmy Larsson, Maria Karoutsou, Kenneth Ban, Jacek R Wiśniewski, Per Artursson, Liqun He, Mats Hellström, Tobias Sjöblom
BACKGROUND: The Ras pathway genes KRAS, BRAF, or ERBBs have somatic mutations in ~ 60% of human colorectal carcinomas. At present, it is unknown whether the remaining cases lack mutations activating the Ras pathway or whether they have acquired mutations in genes hitherto unknown to belong to the pathway. METHODS: To address the second possibility and extend the compendium of Ras pathway genes, we used genome-wide transposon mutagenesis of two human colorectal cancer cell systems deprived of their activating KRAS or BRAF allele to identify genes enabling growth in low glucose, a Ras pathway phenotype, when targeted...
January 4, 2018: Genome Medicine
Lina Sakhneny, Eleonor Rachi, Alona Epshtein, Helen C Guez, Shane Wald-Altman, Michal Lisnyansky, Laura Khalifa-Malka, Adina Hazan, Daria Baer, Avi Priel, Miguel Weil, Limor Landsman
Polymorphism in TCF7L2, a component of the canonical Wnt signaling pathway, has a strong association with β-cell dysfunction and type 2 diabetes through a yet to be defined mechanism. β-Cells rely on cells in their microenvironment, including pericytes, for their proper function. Here, we show that Tcf7l2 activity in pancreatic pericytes is required for β-cell function. Transgenic mice in which Tcf7l2 was selectively inactivated in their pancreatic pericytes exhibited impaired glucose tolerance due to compromised β-cell function and glucose-stimulated insulin secretion...
December 15, 2017: Diabetes
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