HLA class II DPB1 and DRB1 polymorphisms associated with genetic susceptibility to beryllium toxicity

Objectives Chronic beryllium disease (CBD) is a hypersensitivity granulomatous pulmonary disease caused by exposure to the metal beryllium (Be(2+)). Our objective was to extend current knowledge of the genetics of beryllium disease by examining all HLA-DPB1 and HLA-DPR1 gene polymorphisms and the interactions between them. Methods DNA-based typing of HLA-DPB1 and HLA-DRB1 loci at the allele level was performed on 65 CBD, 44 beryllium sensitised (BeS) but without CBD and 288 non-affected, beryllium exposed controls. Results The DP beta E69 residue regardless of zygosity, but particularly if present on non-*0201 alleles, was of primary importance for the development of CBD and BeS, while other negatively charged residues DP beta DE55, 56 and DP beta DE84, 85 incrementally increased, although not independently, the risk. The DP beta E69 positive alleles with charge -7 or -9 were associated with both CBD and BeS. The polymorphic residues DP beta E69, DP beta DE55, 56 and DP beta DE84, 85 were responsible for the -9 charge and the first two residues for the -7 charge. Conclusions In the absence of DP beta E69, DR beta E71 is a risk factor for CBD and BeS. DP beta E69 and DR beta E71 are adjacent to other amino acids that are also negatively charged, suggesting that the positively charged Be(2+) modifies the local environment of the epitopes in a way that promotes interactions between peptides and T cells and results in CBD. Finally, the protective effect of the DPB1*0201 positive haplotype may involve particular polymorphisms outside of the DPB1 gene.