The HLA-B∗39 allele increases type 1 diabetes risk conferred by HLA-DRB1∗04:04-DQB1∗03:02 and HLA-DRB1∗08-DQB1∗04 class II haplotypes

To further characterise the effect of the HLA-B∗39 allele on type 1 diabetes risk we assessed its role in different HLA-DR/DQ haplotypes and genotypes using 1764 nuclear families with a diabetic child collected in the framework of the Finnish Paediatric Diabetes Register. HLA assays were based on sequence specific hybridization using lanthanide labelled oligonucleotide probes. Transmissions of major HLA-DR/DQ haplotypes with and without the HLA-B∗39 allele to diabetic index cases were analysed by direct haplotype and allele counting. The HLA-B∗39 allele significantly increased the disease risk conferred by DRB1∗04:04-DQA1∗03-DQB1∗03:02 and (DR8)-DQB1∗04 haplotypes. The same effect was observed on genotype level as disease association for the HLA-B∗39 allele was observed in multiple genotypes containing DRB1∗04:04-DQA1∗03-DQB1∗03:02 or (DR8)-DQB1∗04 haplotypes. Finally we considered the two common subtypes of the HLA-B∗39 allele, B∗39:01 and B∗39:06 and observed their unequal distribution when stratified for specific DR-DQ haplotypes. The risk for type 1 diabetes conferred by certain DR/DQ haplotypes is modified by the presence of the HLA-B∗39 and this confirms the independent disease predisposing effect of the HLA-B∗39 allele. The results can be applied in enhancing the sensitivity and specificity of DR/DQ based screening programs for subjects at disease risk.