Insulin-dependent diabetes mellitus in non-DR3/non-DR4 subjects

Five to 20% insulin-dependent diabetes mellitus (IDDM) patients do not bear the classical HLA class II DR3 or DR4 susceptibility haplotypes. We have studied the clinical characteristics, anti-islet cell antibodies (Ab) and HLA class II genotypes in 72 non-DR3/non-DR4 Caucasian patients, mainly adults, presenting with clinically typical IDDM. The DRB1*08-DQB1*0402-DQA1*0401 haplotype frequency was increased in the patients compared to 272 non-DR3/non-DR4 controls (OR = 5.9, Pc < 0.005). This association was even stronger in the Ab-positive patients (DRB1*08: OR = 7.2, Pc < 0.005; DQB1*0402: OR = 9.2, Pc < 0.005; DQA1*0401: OR = 9, Pc < 0.02). In those subjects the DRB1*15 allele was less frequent than in controls (OR = 0.1, Pc = 0.05). By contrast, IDDM patients with no Ab showed no particular association with HLA class II allele although they had clinical and metabolic characteristics similar to that of Ab-positive subjects. The genetic basis for IDDM predisposition in the Ab-positive subgroup remains elusive since the DRB1*08-DQB1*0402 haplotype encodes an Asp57-positive DQ beta chain. However, all DR8 patients had a non-Asp57 encoding DQB1 allele on the second haplotype. Thus, trans-complementation leading to peculiar predisposing DQ alpha beta heterodimers may occur. Alternatively, a direct role of the DRB1*08 allele cannot be excluded. These results show that autoimmune type 1 diabetes occurs in non-DR3/non-DR4 subjects, mainly adults. They further support that IDDM, when defined on a clinical basis, encompass different pathogenetic entities.