ERBB3 型 1 型糖尿病易感性位点的遗传与调控结构
The genetic and regulatory architecture of ERBB3-type 1 diabetes susceptibility locus.
作者信息
Kaur Simranjeet, Mirza Aashiq H, Brorsson Caroline A, Fløyel Tina, Størling Joachim, Mortensen Henrik B, Pociot Flemming
机构信息
Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Center for Non-coding RNA in Technology and Health, University of Copenhagen, Denmark.
出版信息
Mol Cell Endocrinol. 2016 Jan 5;419:83-91. doi: 10.1016/j.mce.2015.10.002. Epub 2015 Oct 9.
The study aimed to explore the role of ERBB3 in type 1 diabetes (T1D). We examined whether genetic variation of ERBB3 (rs2292239) affects residual β-cell function in T1D cases. Furthermore, we examined the expression of ERBB3 in human islets, the effect of ERBB3 knockdown on apoptosis in insulin-producing INS-1E cells and the genetic and regulatory architecture of the ERBB3 locus to provide insights to how rs2292239 may confer disease susceptibility. rs2292239 strongly correlated with residual β-cell function and metabolic control in children with T1D. ERBB3 locus associated lncRNA (NONHSAG011351) was found to be expressed in human islets. ERBB3 was expressed and down-regulated by pro-inflammatory cytokines in human islets and INS-1E cells; knockdown of ERBB3 in INS-1E cells decreased basal and cytokine-induced apoptosis. Our data suggests an important functional role of ERBB3 and its potential regulators in the β-cells and may constitute novel targets to prevent β-cell destruction in T1D.
该研究旨在探讨ERBB3在1型糖尿病（T1D）中的作用。我们研究了ERBB3的基因变异（rs2292239）是否会影响T1D患者残余β细胞功能。此外，我们检测了ERBB3在人胰岛中的表达、ERBB3基因敲低对胰岛素分泌型INS-1E细胞凋亡的影响以及ERBB3基因座的遗传和调控结构，以深入了解rs2292239可能导致疾病易感性的机制。rs2292239与T1D儿童的残余β细胞功能和代谢控制密切相关。发现与ERBB3基因座相关的lncRNA（NONHSAG011351）在人胰岛中表达。ERBB3在人胰岛和INS-1E细胞中表达，并受到促炎细胞因子的下调；在INS-1E细胞中敲低ERBB3可降低基础凋亡和细胞因子诱导的凋亡。我们的数据表明ERBB3及其潜在调节因子在β细胞中具有重要的功能作用，可能构成预防T1D中β细胞破坏的新靶点。
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