Non-HLA type 1 diabetes genes modulate disease risk together with HLA-DQ and islet autoantibodies

The possible interrelations between human leukocyte antigen (HLA)-DQ, non-HLA single-nucleotide polymorphisms (SNPs) and islet autoantibodies were investigated at clinical onset in 1-34-year-old type 1 diabetes (T1D) patients (n = 305) and controls (n = 203). Among the non-HLA SNPs reported by the Type 1 Diabetes Genetics Consortium, 24% were supported in this Swedish replication set including that the increased risk of minor PTPN22 allele and high-risk HLA was modified by GAD65 autoantibodies. The association between T1D and the minor AA+ AC genotype in ERBB3 gene was stronger among IA-2 autoantibody-positive patients (comparison P = 0.047). The association between T1D and the common insulin (AA) genotype was stronger among insulin autoantibody (IAA)-positive patients (comparison P = 0.008). In contrast, the association between T1D and unidentified 26471 gene was stronger among IAA-negative (comparison P = 0.049) and IA-2 autoantibody-negative (comparison P = 0.052) patients. Finally, the association between IL2RA and T1D was stronger among IAA-positive than among IAA-negative patients (comparison P = 0.028). These results suggest that the increased risk of T1D by non-HLA genes is often modified by both islet autoantibodies and HLA-DQ. The interactions between non-HLA genes, islet autoantibodies and HLA-DQ should be taken into account in T1D prediction studies as well as in prevention trials aimed at inducing immunological tolerance to islet autoantigens.