Department of Clinical Medicine, University of Bergen, N-5020 Bergen, Norway.
Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):775-80. doi: 10.1073/pnas.0911591107. Epub 2009 Dec 22.
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.
全基因组关联研究确定了与 2 型糖尿病和肥胖相关的非编码单核苷酸多态性（SNP），这些 SNP 位于 HHEX-IDE 和 CDKAL1 内含子以及 FTO 的连锁不平衡（LD）块中[Slade 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]。我们表明，这些 LD 块包含高度保守的非编码元件，并与转录因子基因 HHEX、SOX4 和 IRX3 的基因组调节块重叠。我们报告称，与风险 SNP 处于 LD 的人类高度保守的非编码元件可驱动转基因小鼠和斑马鱼内胚层或胰腺中的表达。HHEX 和 SOX4 最近都与胰腺发育和胰岛素分泌的调节有关，但 IRX3 与胰腺功能或发育没有先前的关联。在斑马鱼中敲低其同源物 irx3a，增加了产生胃饥饿素的胰腺 ε 细胞的数量，减少了产生胰岛素的 β 细胞和产生胰高血糖素的 α 细胞的数量，这表明胰腺 IRX3 功能与肥胖和 2 型糖尿病直接相关。
