Differential susceptibilities to chronic beryllium disease contributed by different Glu(69) HLA-DPB1 and-DPA1 alleles

Chronic beryllium disease (CBD) is associated with the allelic substitution of a Glu(69) in the HLA-DPB1 gene, Although up to 97% of CBD patients may have the Glu(69) marker, about 30-45% of beryllium-exposed, unaffected indi viduals carry the same marker. Because CBD occurs in only 1-6% of exposed w orkers, the presence of Glu(69) does not appear to be the sole genetic fact or underlying the disease development. Using two rounds of direct automated DNA sequencing to precisely assign HLA-DPB1 haplotypes, we have discovered highly significant Glu(69)-containing allele frequency differences between the CBD patients and a beryllium-exposed, nondiseased control group. Indiv iduals with DPB1 Glu(69) in both alleles were almost exclusively found in t he CBD group (6/20) vs the control group (1/75), Whereas most Glu(69) carri ers from the control group had a DPB1 allele *0201 (68%), most Glu(69) carr iers from the CBD group had a non-*0201 DPB1 Glu(69)-carrying allele (84%), The DPB1 allele *0201 was almost exclusively (29/30) associated with DPA1 *01 alleles, while the non-*0201 Glu(69)-containing DPB1 alleles were close ly associated with DPA1 *02 alleles (26/29), Relatively rare Glu(69)-contai ning alleles *1701, *0901, and *1001 had extremely high frequencies in the CBD group (50%), as compared,vith the control group (6.7%). Therefore, the most common Glu(69)-containing DPB1 allele, *0201, does not seem to be a ma jor disease allele, The results suggest that it is not the mere presence of Glu(69), per se, but specific Glu(69)-containing alleles and their copy nu mber (homozygous or;heterozygous) that confer the greatest susceptibility t o CBD in exposed individuals.