The genetic and regulatory architecture of ERBB3-type 1 diabetes susceptibility locus

Mol Cell Endocrinol. 2016 Jan 5:419:83-91. doi: 10.1016/j.mce.2015.10.002. Epub 2015 Oct 9.

Abstract

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.

Keywords: Apoptosis; Beta cell; CTCF; ERBB3; Type 1 diabetes; lncRNAs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cells, Cultured
  • Child
  • Cross-Sectional Studies
  • Cytokines / genetics
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology
  • Female
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Humans
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism
  • Male
  • Polymorphism, Single Nucleotide*
  • RNA, Long Noncoding / genetics
  • Rats
  • Receptor, ErbB-3 / genetics*
  • Receptor, ErbB-3 / metabolism*

Substances

  • Cytokines
  • RNA, Long Noncoding
  • ERBB3 protein, human
  • Receptor, ErbB-3