title: The genetic and regulatory architecture of ERBB3-type 1 diabetes susceptibility locus.
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.
authors.affiliation: 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.
authors.forename: Simranjeet
authors.initials: S
authors.lastname: Kaur
authors.affiliation: 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.
authors.forename: Aashiq H
authors.initials: AH
authors.lastname: Mirza
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Brorsson
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
authors.forename: Tina
authors.initials: T
authors.lastname: Fløyel
authors.affiliation: Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Pediatrics, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
authors.forename: Joachim
authors.initials: J
authors.lastname: Størling
authors.affiliation: 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.
authors.forename: Henrik B
authors.initials: HB
authors.lastname: Mortensen
authors.affiliation: 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. Electronic address: flemming.pociot.01@regionh.dk.
authors.forename: Flemming
authors.initials: F
authors.lastname: Pociot
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D002648:Child; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding / Q000235:genetics; D051381:Rats; D020893:Receptor, ErbB-3 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016207:Cytokines; D062085:RNA, Long Noncoding; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3
keywords: Apoptosis; Beta cell; CTCF; ERBB3; Type 1 diabetes; lncRNAs