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

Abstract

ABSTRACTThe 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 theDRB1*030101allele (P< 0.001), together with theDRB1*030101/DQB1*0201(P< 0.001) andDRB1*040101/DQB1*0302(P= 0.002) haplotypes, while lower anti-GAD titers were associated with theDRB1*070101(P= 0.001) andDRB1*110101(P< 0.001) alleles andDRB1*070101/DQB1*0201(P= 0.001) andDRB1*110101/DQB1*030101(P= 0.001) haplotypes. Mean anti-IA-2 antibody titers were higher in theDRB1*040101allele (P= 0.007) andDRB1*040101/DQB1*0302(P= 0.001) haplotypes but were lower in theDRB1*110101allele (P= 0.010) and theDRB1*110101(P< 0.001) andDRB1*110101/DQB1*030101(P= 0.025) haplotypes. Multinomial regression analysis confirmed the positive association ofDRB1*030101and the negative association ofDRB1*110101andDQB1*030101, along with theDRB1*070101/DQB1*0201andDRB1*110101/DQB1*030101haplotypes, with anti-GAD levels. In contrast, only theDRB1*040101/DQB1*0302haplotype 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.