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

• This study highlights the role of ERBB3 locus in β-cell apoptosis.
• ERBB3 SNPs associate with β-cell function and metabolic control in T1D.
• ERBB3 SNPs are putatively functional based on various ENCODE regulatory features.
• ERBB3 knockdown decreases basal and cytokine-induced apoptosis.
• ERBB3 and antisense lncRNA NONHSAG011351 are expressed in human islets.

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.