title: Chronic beryllium disease, HLA-DPB1, and the DP peptide binding groove.
abstract: Multiple epidemiologic studies demonstrate associations between chronic beryllium disease (CBD), beryllium sensitization (BeS), and HLA-DPB1 alleles with a glutamic acid residue at position 69 (E69). Results suggest that the less-frequent E69 variants (non-*0201/*0202 alleles) might be associated with greater risk of CBD. In this study, we sought to define specific E69-carrying alleles and their amino acid sequences in the DP peptide binding groove, as well as their relationship to CBD and BeS risk, using the largest case control study to date. We enrolled 502 BeS/CBD subjects and 653 beryllium-exposed controls from three beryllium industries who gave informed consent for participation. Non-Hispanic white cases and controls were frequency-matched by industry. HLA-DPB1 genotypes were determined using sequence-specific primer PCR. The E69 alleles were tested for association with disease individually and grouped by amino acid structure using logistic regression. The results show that CBD cases were more likely than controls to carry a non-*02 E69 allele than an *02 E69, with odds ratios (95% confidence interval) ranging from 3.1 (2.1-4.5) to 3.9 (2.6-5.9) (p < 0.0001). Polymorphic amino acids at positions 84 and 11 were associated with CBD: DD versus GG, 2.8 (1.8-4.6), p < 0.0001; GD versus GG, 2.1 (1.5-2.8), p < 0.0001; LL versus GG, 3.2 (1.8-5.6), p < 0.0001; GL versus GG, 2.8 (2.1-3.8), p < 0.0001. Similar results were found within the BeS group and CBD/BeS combined group. We conclude that the less frequent E69 alleles confer more risk for CBD than does *0201. Recent studies examining how the composition and structure of the binding pockets influence peptide binding in MHC genes, as well of studies showing the topology of the TCR to likely bind DPB1 preferentially, give plausible biological rationale for these findings.
authors.affiliation: National Jewish Health, Denver, CO 80206, USA. silveiral@njhealth.org
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Silveira
authors.forename: Erin C
authors.initials: EC
authors.lastname: McCanlies
authors.forename: Tasha E
authors.initials: TE
authors.lastname: Fingerlin
authors.forename: Michael V
authors.initials: MV
authors.lastname: Van Dyke
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Mroz
authors.forename: Matthew
authors.initials: M
authors.lastname: Strand
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fontenot
authors.forename: Natalie
authors.initials: N
authors.lastname: Bowerman
authors.forename: Dana M
authors.initials: DM
authors.lastname: Dabelea
authors.forename: Christine R
authors.initials: CR
authors.lastname: Schuler
authors.forename: Ainsley
authors.initials: A
authors.lastname: Weston
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Maier
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D001607:Berylliosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001608:Beryllium / Q000009:adverse effects / Q000737:chemistry*; D016022:Case-Control Studies; D002908:Chronic Disease; D005260:Female; D059868:HLA-DP beta-Chains / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D018836:Inflammation Mediators / Q000009:adverse effects / Q000737:chemistry; D008297:Male; D011110:Polymorphism, Genetic / Q000276:immunology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000473:pathology; D055672:Static Electricity
chemical_list: D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D018836:Inflammation Mediators; D001608:Beryllium