title: HLA class II DPB1 and DRB1 polymorphisms associated with genetic susceptibility to beryllium toxicity.
abstract: OBJECTIVE
  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 DPβE69 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 DPβDE55, 56 and DPβDE84, 85 incrementally increased, although not independently, the risk. The DPβE69 positive alleles with charge -7 or -9 were associated with both CBD and BeS. The polymorphic residues DPβE69, DPβDE55, 56 and DPβDE84, 85 were responsible for the -9 charge and the first two residues for the -7 charge.
  
  
  CONCLUSIONS
  In the absence of DPβE69, DRβE71 is a risk factor for CBD and BeS. DPβE69 and DRβE71 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.
authors.affiliation: Michigan State University, 117 West Fee Hall, East Lansing, MI 48824, USA. rosenman@msu.edu
authors.forename: K D
authors.initials: KD
authors.lastname: Rosenman
authors.forename: M
authors.initials: M
authors.lastname: Rossman
authors.forename: V
authors.initials: V
authors.lastname: Hertzberg
authors.forename: M J
authors.initials: MJ
authors.lastname: Reilly
authors.forename: C
authors.initials: C
authors.lastname: Rice
authors.forename: E
authors.initials: E
authors.lastname: Kanterakis
authors.forename: D
authors.initials: D
authors.lastname: Monos
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001607:Berylliosis / Q000235:genetics*; D001608:Beryllium / Q000633:toxicity; D002908:Chronic Disease; D005260:Female; D020022:Genetic Predisposition to Disease; D006682:HLA-DP Antigens / Q000235:genetics*; D059868:HLA-DP beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic
chemical_list: D006682:HLA-DP Antigens; D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D001608:Beryllium