Influence of MHC class II in susceptibility to beryllium sensitization and chronic beryllium disease.
A glutamic acid at residue 69(Glu(69)) in the HLA-DPB1 gene (Glu(69)) is associated with chronic beryllium disease (CBD) and possibly beryllium sensitization (BeS). This study tested the hypothesis that MHC class II polymorphisms are important in susceptibility to BeS and CBD and that the Glu(69) variant is related to markers of disease severity. Genomic DNA was obtained from BeS (n = 50), CBD (n = 104), and beryllium-exposed nondiseased (Be-nondiseased) (n = 125) subjects. HLA-DPB1, -DRB1, and -DQB1 genotypes were determined by (sequence-specific primers) PCR. Disease severity was assessed by pulmonary function and exercise testing. A higher frequency of the DPB1 Glu(69) gene was found in CBD and BeS compared with the Be-nondiseased subjects, with odds ratios of 10.1 for CBD vs Be-nondiseased and 9.5 for BeS vs Be-nondiseased. The majority of BeS and CBD subjects displayed non-0201 Glu(69) alleles. Glu(69) homozygosity was higher in the CBD subjects, while BeS subjects were intermediate and Be-nondiseased lowest. DRB1*01 and DQB1*05 phenotypes were reduced in CBD vs Be-nondiseased subjects, while DRB1*13 and DQB1*06 were associated with CBD in the absence of Glu(69). Markers of disease severity, including a lower forced vital capacity, diffusion capacity for carbon monoxide, PaO(2) at rest, maximum workload on exercise testing, and a higher arterial-alveolar gradient at rest, were associated with Glu(69) homozygosity. We conclude that DPB1 Glu69 is a marker of sensitization and not specific for disease. Glu(69) homozygosity acts as a functional marker associated with markers of CBD severity.
Maier
Lisa A
LA
Department of Medicine, Hollis Laboratory of Occupational and Environmental Health, Division of Environmental and Occupational Health Sciences, National Jewish Medical and Research Center, Denver, CO 80206, USA. maierL@njc.org
McGrath
Dierdre S
DS
Sato
Hiroe
H
Lympany
Penny
P
Welsh
Ken
K
Du Bois
Roland
R
Silveira
Lori
L
Fontenot
Andrew P
AP
Sawyer
Richard T
RT
Wilcox
Eric
E
Newman
Lee S
LS
D000328:Adult; D000368:Aged; D001607:Berylliosis / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D001608:Beryllium / Q000009:adverse effects / Q000276:immunology*; D016022:Case-Control Studies; D002908:Chronic Disease; D000939:Epitopes / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018698:Glutamic Acid / Q000235:genetics; D006680:HLA Antigens / Q000235:genetics*; D006682:HLA-DP Antigens / Q000235:genetics; D059868:HLA-DP beta-Chains; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D059826:HLA-DRB3 Chains; D059845:HLA-DRB4 Chains; D059847:HLA-DRB5 Chains; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D007114:Immunization; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012720:Severity of Illness Index
D000939:Epitopes; D006680:HLA Antigens; D006682:HLA-DP Antigens; D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D059826:HLA-DRB3 Chains; D059845:HLA-DRB4 Chains; D059847:HLA-DRB5 Chains; D000949:Histocompatibility Antigens Class II; D018698:Glutamic Acid; D001608:Beryllium