HLA-DRB1*04 and susceptibility to type 1 diabetes mellitus in a German/Belgian family and German case-control study

HLA-DR4 is a primary disease association marker in type 1 diabetes mellitus (IDDM). We therefore analyzed the transmission of 228 DR4+ haplotypes in 183 families with an IDDM proband (95 from Germany and 88 from Belgium). In a separate case-control data set, we investigated the HLA-DRB1*04 and DQ allele distribution in 245 IDDM patients and 177 controls from Germany, all DR4 positive. HLA-DRB1*0401 and *0402 linked to DQB1*0302 were significantly more often transmitted to patients in the studied families (81% and 89%) in contrast to DRB1*0401-DQB1*0301 (33%). The case-control study of HLA-DQB1*0302+ individuals revealed -DRB1*0405 to be more frequent in patients with IDDM and HLA-DRB1*0403 and -DRB1*0404 to be less frequent. HLA-DQA1*0102-DQB1*0602 and -DQA1*0501-DQB1*0301 in trans complementation with DRB1*0401-DQB1*0302 were also significantly less frequent in IDDM patients (P<3×10−7 and P<0.02). In conclusion, HLA-DRB1*0403 and -DQB1*0301 alleles in cis as well as protective DQ haplotypes in trans, confer dominant protection against IDDM in a German / Belgian population.