HLA class II DPB1 and DRB1 polymorphisms associated with genetic susceptibility to beryllium toxicity.
Rosenman-KD; Rossman-M; Hertzberg-V; Reilly-MJ; Rice-C; Kanterakis-E; Monos-D
Occup Environ Med 2011 Jul; 68(7):487-493
Objectives: Chronic beryllium disease (CBD) is a hypersensitivity granulomatous pulmonary disease caused by exposure to the metal beryllium (Be2+). 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 DPßE69 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 DPßDE55, 56 and DPßDE84, 85 incrementally increased, although not independently, the risk. The DPßE69 positive alleles with charge -7 or -9 were associated with both CBD and BeS. The polymorphic residues DPßE69, DPßDE55, 56 and DPßDE84, 85 were responsible for the -9 charge and the first two residues for the -7 charge. Conclusions: In the absence of DPßE69, DRßE71 is a risk factor for CBD and BeS. DPßE69 and DRßE71 are adjacent to other amino acids that are also negatively charged, suggesting that the positively charged Be2+ 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.
Biomarkers; Metal-compounds; Metal-fumes; Genes; Genotoxicity; Genetics; Beryllium-disease; Beryllium-compounds; Lung-disorders; Respiratory-system-disorders; Risk-factors; Surveillance-programs; Epidemiology
K D Rosenman, Michigan State University, 117 West Fee Hall, East Lansing, MI 48824, USA
Occupational and Environmental Medicine
Michigan State University