title: Associations of polymorphisms in non-HLA loci with autoantibodies at the diagnosis of type 1 diabetes: INS and IKZF4 associate with insulin autoantibodies.
abstract: OBJECTIVE
  More than 50 loci outside the human leukocyte antigen (HLA) region have been confirmed to affect type 1 diabetes (T1D) risk but their effect on β-cell autoimmunity is poorly defined. We analyzed the association of 35 single nucleotide polymorphism (SNP) markers previously associated with T1D with the presence of disease-predictive autoantibodies at the time of T1D diagnosis.
  
  
  METHODS
  The study cohort comprised 1554 children diagnosed with T1D before the age of 15 yr. The associations between various genotypes and positivity for antibodies against islet cells [islet cell antibodies (ICA)], insulin [insulin autoantibodies (IAA)], glutamic acid decarboxylase (GADA), islet antigen 2 (IA2A), and zinc transporter 8 (ZnT8A) were analyzed.
  
  
  RESULTS
  INS gene polymorphism rs689 and IKZF4 polymorphism (rs1701704) were strongly associated with IAA positivity at the time of T1D diagnosis (p = 0.000004 and 0.00044, respectively). The presence of the T1D-risk conferring INS AA genotype was associated with IAA. In contrast, the presence of the susceptible C allele of the IKZF4 marker was inversely associated with IAA. The INS and IKZF4 polymorphisms were not significantly associated with ICA, GADA, IA2A, or ZnT8A positivity.
  
  
  CONCLUSIONS
  Both INS and IKZF4 polymorphisms modified the probability of IAA positivity at time of T1D onset but the inverse association of IKZF4 risk allele with IAA suggests that the IKZF4 polymorphism is involved in a pathway of β-cell autoimmunity alternate to the route characterized by IAA and development of T1D in early childhood. The IKZF4 gene encodes Eos, which is implicated to play an important role in Treg programming where this gene might exert its influence on T1D risk.
authors.affiliation: Immunogenetics Laboratory, University of Turku, Turku, Finland; Department of Pediatrics, Turku University Hospital, University of Turku, Turku, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Lempainen
authors.forename: T
authors.initials: T
authors.lastname: Härkönen
authors.forename: Ap
authors.initials: A
authors.lastname: Laine
authors.forename: M
authors.initials: M
authors.lastname: Knip
authors.forename: J
authors.initials: J
authors.lastname: Ilonen
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D007223:Infant; D007330:Insulin Antibodies / Q000235:genetics* / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D001323:Autoantibodies; C551264:IKZF4 protein, human; D007330:Insulin Antibodies; C024211:islet cell antibody; D051740:Ikaros Transcription Factor
keywords: IKZF4; INS; insulin autoantibodies; single nucleotide polymorphism; type 1 diabetes