Association of non-HLA genes with type 1 diabetes autoimmunity

Diabetes. 2005 Aug;54(8):2482-6. doi: 10.2337/diabetes.54.8.2482.

Abstract

Approximately 50% of the genetic risk for type 1 diabetes is attributable to the HLA region. We evaluated associations between candidate genes outside the HLA region-INS, cytotoxic T-lymphocyte-associated antigen (CTLA)-4, interleukin (IL)-4, IL-4R, and IL-13 and islet autoimmunity among children participating in the Diabetes Autoimmunity Study in the Young (DAISY). Children with persistent islet autoantibody positivity (n = 102, 38 of whom have already developed diabetes) and control subjects (n = 198) were genotyped for single nucleotide polymorphisms (SNPs) in the candidate genes. The INS-23Hph1 polymorphism was significantly associated with both type 1 diabetes (OR = 0.30; 95% CI 0.13-0.69) and persistent islet autoimmunity but in the latter, only in children with the HLA-DR3/4 genotype (0.40; 0.18-0.89). CTLA-4 promoter SNP was significantly associated with type 1 diabetes (3.52; 1.22-10.17) but not with persistent islet autoimmunity. Several SNPs in the IL-4 regulatory pathway appeared to have a predisposing effect for type 1 diabetes. Associations were found between both IL-4R haplotypes and IL-4-IL-13 haplotypes and persistent islet autoimmunity and type 1 diabetes. This study confirms the association between the INS and CTLA-4 loci and type 1 diabetes. Genes involved in the IL-4 regulatory pathway (IL-4, IL-4R, IL-13) may confer susceptibility or protection to type 1 diabetes depending on individual SNPs or specific haplotypes.

Publication types

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

MeSH terms

  • Adolescent
  • Antigens, CD
  • Antigens, Differentiation / genetics
  • Autoimmunity / genetics*
  • CTLA-4 Antigen
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1 / immunology*
  • Female
  • Genotype
  • Haplotypes
  • Humans
  • Infant
  • Insulin / genetics
  • Interleukin-13 / genetics
  • Interleukin-4 / genetics
  • Islets of Langerhans / immunology*
  • Male
  • Polymorphism, Single Nucleotide / genetics*
  • Receptors, Interleukin-4 / genetics

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Insulin
  • Interleukin-13
  • Receptors, Interleukin-4
  • Interleukin-4