Genome-wide association study and HLA genotyping for beryllium disease susceptibility in a European descent...

Workplace exposure to beryllium can result in beryllium sensitization (BeS), a cell-mediated immune response that can progress to chronic beryllium disease (CBD), a granulomatous lung disease. DPB1-E69 is highly associated with CBD and BeS, although DRB1-E71 may also be a risk factor in the absence of DPB1-E69.

This study 1) identified novel genetic variants associated with CBD/BeS using a genome-wide association study (GWAS) approach and 2) clarified the role of DRB1-E71 in conjunction with DPB1-E69.

We performed GWAS and HLA analysis on 1626 subjects with BeS, CBD and beryllium exposure without disease.

We found that rs1042140, the first base of the codon that encodes E69, was associated with CBD and BeS. We also found two single nucleotide polymorphisms (SNPs), rs56011217 and rs72636334, near SRIP1 on chromosome 4 associated with CBD and BeS independent of rs1042140. HLA alleles DRB1*04:04 (non E71) and DQB1*06:04 were significantly associated with CBD and BeS independent of rs1042140.

We found both DPB1-E69 and DRB1-E71 carriers have a higher risk of CBD or BeS both independently and jointly, with DPB1-E69 status having higher impact than DRB1-E71 status. DRB1-E71 also increases the risk in subjects without DPB1-E69. Our study also implies that beyond HLA, SRIP1 should be investigated in chronic beryllium disease pathogenesis.