Influence of MHC Class II in susceptibility to Beryllium Sensitization and Chronic Beryllium Diesease

A glutamic acid at residue 69(Glu⁶⁹⁾ in the HLA-DPB1 gene (Glu⁶⁹) 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 Glu⁶⁹ 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 Glu⁶⁹ 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 Glu⁶⁹ alleles. Glu⁶⁹ alieles. Glu⁶⁹ homozygosity was higher in the CBD subjects, while BeS subjects were intermediate and Be-nondiseased lowest. DRBI*01 and DQB1*05 phenotypes were reduced in CBD vs Be-nondiseased subjects, while DRBI*13 and DQBI*06 were associated with CBD in the absence of Glu⁶⁹. Markers of disease severity, including a lower forced vital capacity, diffusion capacity for carbon monoxide, PaO₂ at rest, maximum workload on exercise testing, and a higher arterial-alveolar gradient at rest, were associated with Glu⁶⁹ 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.