Differential susceptibilities to chronic beryllium disease contributed by different Glu⁶⁹ HLA-DPB1 and -DPA1 alleles

Chronic beryllium disease (CBD) is associated with the allelic substitution of a Glu⁶⁹ in the HLA-DPB1 gene. Although up to 97% of CBD patients may have the Glu⁶⁹ marker, about 30-45% of beryllium-exposed, unaffected individuals carry the same marker. Because CBD occurs in only 1- 6% of exposed workers, the presence of Glu⁶⁹ does not appear to be the sole genetic factor underlying the disease development. Using two rounds of direct automated DNA sequencing to precisely assign HLA-DPB1 haplotypes, we have discovered highly significant Glu⁶⁹-containing allele frequency differences between the CBD patients and a beryllium-exposed, nondiseased control group. Individuals with DPB1 Glu⁶⁹ in both alleles were almost exclusively found in the CBD group (6/20) vs the control group (1/75). Whereas most Glu⁶⁹ carriers from the control group had a DPB1 allele *0201 (68%), most Glu⁶⁹ carriers from the CBD group had a non-*0201 DPB1 Glu⁶⁹-carrying allele (84%). The DPB1 allele *0201 was almost exclusively (29/30) associated with DPA1 *01 alleles, while the non-*0201 Glu⁶⁹-containing DPB1 alleles were closely associated with DPA1 *02 alleles (26/29). Relatively rare Glu⁶⁹- containing alleles *1701, *0901, and *1001 had extremely high frequencies in the CBD group (50%), as compared with the control group (6.7%). Therefore, the most common Glu⁶⁹-containing DPB1 allele, *0201, does not seem to be a major disease allele. The results suggest that it is not the mere presence of Glu⁶⁹, per se, but specific Glu⁶⁹-containing alleles and their copy number (homozygous or heterozygous) that confer the greatest susceptibility to CBD in exposed individuals.