Glutamic acid decarboxylase 65 and islet cell antigen 512/IA-2 autoantibodies in relation to human leukocyte antigen class II DR and DQ alleles and haplotypes in type 1 diabetes mellitus.

The frequencies of autoantibodies against glutamic acid decarboxylase 65 (GAD65) and islet cell antigen (ICA) 512/IA-2 (512/IA-2) are functions of the specific human leukocyte antigen (HLA) in type 1 diabetes mellitus (T1D). We investigated the association of HLA class II (DR and DQ) alleles and haplotypes with the presence of GAD and IA-2 autoantibodies in T1D. Autoantibodies were tested in 88 Tunisian T1D patients and 112 age- and gender-matched normoglycemic control subjects by enzyme immunoassay. Among T1D patients, mean anti-GAD antibody titers were higher in the DRB1030101 allele (P < 0.001), together with the DRB1030101/DQB10201 (P < 0.001) and DRB1040101/DQB10302 (P = 0.002) haplotypes, while lower anti-GAD titers were associated with the DRB1070101 (P = 0.001) and DRB1110101 (P < 0.001) alleles and DRB1070101/DQB10201 (P = 0.001) and DRB1110101/DQB1030101 (P = 0.001) haplotypes. Mean anti-IA-2 antibody titers were higher in the DRB1040101 allele (P = 0.007) and DRB1040101/DQB10302 (P = 0.001) haplotypes but were lower in the DRB1110101 allele (P = 0.010) and the DRB1110101 (P < 0.001) and DRB1110101/DQB1030101 (P = 0.025) haplotypes. Multinomial regression analysis confirmed the positive association of DRB1030101 and the negative association of DRB1110101 and DQB1030101, along with the DRB1070101/DQB10201 and DRB1110101/DQB1030101 haplotypes, with anti-GAD levels. In contrast, only the DRB1040101/DQB1*0302 haplotype was positively associated with altered anti-IA-2 titers. Increased GAD65 and IA-2 antibody positivity is differentially associated with select HLA class II alleles and haplotypes, confirming the heterogeneous nature of T1D.