title: Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3.
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.
authors.affiliation: Department of Clinical Medicine, University of Bergen, N-5020 Bergen, Norway.
authors.forename: Anja
authors.initials: A
authors.lastname: Ragvin
authors.forename: Enrico
authors.initials: E
authors.lastname: Moro
authors.forename: David
authors.initials: D
authors.lastname: Fredman
authors.forename: Pavla
authors.initials: P
authors.lastname: Navratilova
authors.forename: Øyvind
authors.initials: Ø
authors.lastname: Drivenes
authors.forename: Pär G
authors.initials: PG
authors.lastname: Engström
authors.forename: M Eva
authors.initials: ME
authors.lastname: Alonso
authors.forename: Elisa
authors.initials: E
authors.lastname: de la Calle Mustienes
authors.forename: José Luis
authors.initials: JL
authors.lastname: Gómez Skarmeta
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Tavares
authors.forename: Fernando
authors.initials: F
authors.lastname: Casares
authors.forename: Miguel
authors.initials: M
authors.lastname: Manzanares
authors.forename: Veronica
authors.initials: V
authors.lastname: van Heyningen
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
authors.forename: Pål R
authors.initials: PR
authors.lastname: Njølstad
authors.forename: Francesco
authors.initials: F
authors.lastname: Argenton
authors.forename: Boris
authors.initials: B
authors.lastname: Lenhard
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Becker
mesh_terms: D000818:Animals; D017124:Conserved Sequence; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009765:Obesity / Q000235:genetics*; D010179:Pancreas / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D055751:SOXC Transcription Factors / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics
chemical_list: C078492:HHEX protein, human; D018398:Homeodomain Proteins; C501598:IRX3 protein, human; D007328:Insulin; C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; D014157:Transcription Factors