The Type I Diabetes Genetics Consortium ‘Rapid Response’ family-based candidate gene study: strategy, genes selection, and main outcome

Julier, Cécile; Akolkar, Beena; Concannon, Patrick; Morahan, Grant; Nierras, Concepcion R.; Pugliese, Alberto

doi:10.1038/gene.2009.99

Cited by 15 publications

(9 citation statements)

References 48 publications

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“…2), a sequence common to all isoforms, has been associated with type-1 diabetes (T1D), 65–68 an autoimmune disease characterized by the degeneration of pancreatic β-islet cells. 69 The resulting Pro-to-Thr conversion is present in all TCF7 variants including the major ΔN-TCF7 variants expressed in activated T lymphocytes, 70 but the functional consequences are not known.…”

Section: Tissue-specific and Cell Context–dependent Expression Anmentioning

confidence: 99%

Cell-Context Dependent TCF/LEF Expression and Function: Alternative Tales of Repression, De-Repression and Activation Potentials

Mao

Byers

2011

Crit Rev Eukar Gene Expr

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Wnt signaling controls cell specification and fate during development and adult tissue homeostasis by converging on a small family of DNA binding factors, the T-cell factor/lymphoid enhancer factor (TCF/LEF) family. In response to Wnt signals, TCF/LEF members undergo a transcriptional switch from repression to activation mediated in part by nuclear β-catenin binding and recruitment of co-activator complexes. In mammals, the specificity and fine tuning of this transcriptional switch is also achieved by the cell-context-dependent expression of four members (TCF7, TCF7L1, TCF7L2, and LEF1) and numerous variants, which display differential DNA binding affinity and specificity, repression strength, activation potential, and regulators. TCF7/LEF1 variants are generated by alternative promoters, alternative exon cassettes, and alternative donor/acceptor splicing sites, allowing combinatorial insertion/exclusion of modular functional and regulatory domains. In this review we present mounting evidence for the interdependency of TCF7/LEF1 variant expression and functions with cell lineage and cell state. We also illustrate how the p53 and nuclear receptor family of transcription factors, known to control cell fate and to inhibit Wnt signaling, may participate in the fine tuning of TCF7/LEF1 repression/activation potentials.

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Section: Tissue-specific and Cell Context–dependent Expression Anmentioning

confidence: 99%

Cell-Context Dependent TCF/LEF Expression and Function: Alternative Tales of Repression, De-Repression and Activation Potentials

Mao

Byers

2011

Crit Rev Eukar Gene Expr

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“…Further, the same DNA samples (as for the MHC Fine Mapping Workshop) from the 2321 ASP families were evaluated for evidence of association of SNPs in selected candidate loci with T1D. These data6,7 appear in this Supplement to Genes and Immunity . The genes that were evaluated and presented here are IL4R ,8 SUMO4 ,9 CTLA4 ,10 IL2RA ,11 PTPN22 ,12 IRS1 and PAX4 ,13 TCF7 ,14 VDR ,15 IL12B ,16 and OAS1 ,17 either by complete tagging of the gene or by characterizing the most associated SNP 7.…”

Section: Research In the T1dgcmentioning

confidence: 99%

Overview of the Type I Diabetes Genetics Consortium

et al. 2009

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The Type I Diabetes Genetics Consortium (T1DGC) is an international, multicenter research program with two primary goals. The first goal is to identify genomic regions and candidate genes whose variants modify an individual’s risk of type I diabetes (T1D) and help explain the clustering of the disease in families. The second goal is to make research data available to the research community and to establish resources that can be used by, and that are fully accessible to, the research community. To facilitate the access to these resources, the T1DGC has developed a Consortium Agreement (http://www.t1dgc.org) that specifies the rights and responsibilities of investigators who participate in Consortium activities. The T1DGC has assembled a resource of affected sib-pair families, parent–child trios, and case–control collections with banks of DNA, serum, plasma, and EBV-transformed cell lines. In addition, both candidate gene and genome-wide (linkage and association) studies have been performed and displayed in T1DBase (http://www.t1dbase.org) for all researchers to use in their own investigations. In this supplement, a subset of the T1DGC collection has been used to investigate earlier published candidate genes for T1D, to confirm the results from a genome-wide association scan for T1D, and to determine associations with candidate genes for other autoimmune diseases or with type II diabetes that may be involved with β-cell function.

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“…Multiple genetic factors have been associated with type 1 diabetes, and these genetic markers may ultimately define individualized strategies for preventing ␤-cell destruction. There now are Ͼ40 genetic loci associated with type 1 diabetes identified by candidate gene approaches and genomewide association studies (26,27 ). Many of the identified genes at these loci are linked to autoimmunity, whereas others appear to be functionally related to ␤-cell survival (28 ).…”

Section: Personalizing Type 1 and Type 2 Diabetesmentioning

confidence: 99%

Personalized Medicine in Diabetes

Malandrino

Smith

2011

Clinical Chemistry

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BACKGROUND:Multiple genes that are associated with the risk of developing diabetes or the risk of diabetes complications have been identified by candidate gene analysis and genomewide scanning. These molecular markers, together with clinical data and findings from proteomics, metabolomics, pharmacogenetics, and other methods, lead to a consideration of the extent to which personalized approaches can be applied to the treatment of diabetes mellitus.CONTENT: Known genes that cause monogenic subtypes of diabetes are reviewed, and several examples are discussed in which the genotype of an individual with diabetes can direct considerations of preferred choices for glycemic therapy. The extent of characterization of polygenic determinants of type 1 and type 2 diabetes is summarized, and the potential for using this information in personalized management of glycemia and complications in diabetes is discussed. The application and current limitations of proteomic and metabolomic methods in elucidating diabetes heterogeneity is reviewed.

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The Type I Diabetes Genetics Consortium ‘Rapid Response’ family-based candidate gene study: strategy, genes selection, and main outcome

Cited by 15 publications

References 48 publications

Cell-Context Dependent TCF/LEF Expression and Function: Alternative Tales of Repression, De-Repression and Activation Potentials

Cell-Context Dependent TCF/LEF Expression and Function: Alternative Tales of Repression, De-Repression and Activation Potentials

Overview of the Type I Diabetes Genetics Consortium

Personalized Medicine in Diabetes

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