| Literature DB >> 20080751 |
Anja Ragvin1, Enrico Moro, David Fredman, Pavla Navratilova, Øyvind Drivenes, Pär G Engström, M Eva Alonso, Elisa de la Calle Mustienes, José Luis Gómez Skarmeta, Maria J Tavares, Fernando Casares, Miguel Manzanares, Veronica van Heyningen, Anders Molven, Pål R Njølstad, Francesco Argenton, Boris Lenhard, Thomas S Becker.
Abstract
Genome-wide association studies identified noncoding SNPs associated with type 2 diabetes and obesity in linkage disequilibrium (LD) blocks encompassing HHEX-IDE and introns of CDKAL1 and FTO [Sladek R, et al. (2007) Nature 445:881-885; Steinthorsdottir V, et al. (2007) Nat. Genet 39:770-775; Frayling TM, et al. (2007) Science 316:889-894]. We show that these LD blocks contain highly conserved noncoding elements and overlap with the genomic regulatory blocks of the transcription factor genes HHEX, SOX4, and IRX3. We report that human highly conserved noncoding elements in LD with the risk SNPs drive expression in endoderm or pancreas in transgenic mice and zebrafish. Both HHEX and SOX4 have recently been implicated in pancreas development and the regulation of insulin secretion, but IRX3 had no prior association with pancreatic function or development. Knockdown of its orthologue in zebrafish, irx3a, increased the number of pancreatic ghrelin-producing epsilon cells and decreased the number of insulin-producing beta-cells and glucagon-producing alpha-cells, thereby suggesting a direct link of pancreatic IRX3 function to both obesity and type 2 diabetes.Entities:
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Year: 2009 PMID： 20080751 PMCID： PMC2818943 DOI： 10.1073/pnas.0911591107
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205