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Closed Access item Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3

Authors:Ragvin, Anja
Moro, Enrico
Fredman, David
Navratilova, Paula
Drivenes, Øyvind
Engström, Pär G.
Alonso, M. Eva
Calle-Mustienes, Elisa de la
Gómez-Skarmeta, José Luis
Tavares, María J.
Casares, Fernando
Manzanares, Miguel
Heyningen, Verónica van
Molven, Anders
Njølstad, Pål R.
Argenton, Francesco
Lenhard, Boris
Becker, Thomas S.
Keywords:hb9, hlxb9, nkx2.2, Pancreatic islet development, Pancreatic peptides, Diabetes mellitus, Insulin, Obesity
Issue Date:22-Dec-2009
Publisher:National Academy of Sciences (U.S.)
Citation:Proceedings of the National Academy of Sciences of the USA 107(2): 775-780 (2009)
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 β-cells and glucagon-producing α-cells, thereby suggesting a direct link of pancreatic IRX3 function to both obesity and type 2 diabetes.
Description:6 páginas, 3 figuras, 4 tablas. This article contains supporting information online at www.pnas.org/cgi/content/full/0911591107/DCSupplemental.
Publisher version (URL):http://dx.doi.org/10.1073/pnas.0911591107
E-ISSNmetadata.dc.identifier.doi = DOI:1091-6940
Appears in Collections:(CABD) Artículos

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