Evidence that HLA class I and II associations with type 1 diabetes, autoantibodies to GAD and autoantibodies to IA-2, are distinct

Abstract

Objective: A major feature of type 1 diabetes is the appearance of islet autoantibodies before diagnosis. However, although the genetics of type 1 diabetes is advanced, the genetics of islet autoantibodies needs further investigation. The primary susceptibility loci in type 1 diabetes, the HLA class I and II genes, are believed to determine the specificity and magnitude of the autoimmune response to islet antigens. We investigated the association of glutamic acid decarboxylase autoantibodies (GADA) and insulinoma-associated antigen-2 autoantibodies (IA-2A) with the HLA region.

Research design and methods: Associations of GADA and IA-2A with HLA-DRB1, HLA-DQB1, HLA-B, HLA-C, HLA-A, MICA, and 3,779 single nucleotide polymorphisms (SNPs) were analyzed in 2,531 childhood-onset case subjects (median time since diagnosis 5 years). All analyses were adjusted for age-at-diagnosis and duration of diabetes.

Results: GADA and IA-2A were associated with an older age-at-diagnosis (P < 10(-19)). For GADA, the primary association was with HLA-DQB1 (P = 9.00 × 10(-18)), with evidence of a second independent effect in the HLA class I region with SNP, rs9266722 (P = 2.84 × 10(-6)). HLA-DRB1 had the strongest association with IA-2A (P = 1.94 × 10(-41)), with HLA-A*24 adding to the association, albeit negatively (P = 1.21 × 10(-10)). There was no evidence of association of either IA-2A or GADA with the highly type 1 diabetes predisposing genotype, HLA-DRB1*03/04.

Conclusions: Despite genetic association of type 1 diabetes and the islet autoantibodies localizing to the same HLA class II genes, HLA-DRB1 and HLA-DQB1, the effects of the class II alleles and genotypes involved are quite different. Therefore, the presence of autoantibodies is unlikely to be causal, and their role in pathogenesis remains to be established.

FIG. 1.

GADA positivity association map. A: Association of SNPs used in the T1DGC Illumina experiment (using ∼1,218 type 1 diabetic case subjects) and the WTCCC Affymetrix experiment (using ∼1,056 case subjects) and the classical loci (using between 2,408 and 1,275 type 1 diabetic case subjects; Table 2) with GADA positivity. The top SNPs from both the WTCCC and T1DGC experiments are in linkage disequilibrium with HLA-DRB1*03 (r² = 0.85 and D’ = 1.00 with rs502055 and r² = 1.00 and D’ =1.00 with rs2187668). B: Association of SNPs and genes with GADA positivity conditional on HLA-DQB1 genotypes.

FIG. 2.

IA-2A positivity association map. A: Association of SNPs used in the T1DGC Illumina experiment (using ∼1,215 type 1 diabetic case subjects) and the WTCCC affymetrix experiment (using ∼1,051 case subjects) with IA-2A and the classical loci (using between 2,399 and 1,268 type 1 diabetic case subjects). The most associated SNP, rs9275572, is in LD with HLA-DRB1*03 (r² = 0.72, D’ = 1.00). B: Association of SNPs and classical genes with IA-2A, conditional on HLA-DRB1 alleles. The most associated SNP, rs9258750, is in LD with the HLA-A*24 allele (r² = 0.55, D’ = 0.99).