Association of Non-HLA Genes With Type 1 Diabetes

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. Diabetes 54:2482–2486, 2005