Objectives Human leukocyte antigen-DP beta 1 (HLA-DPB1) with a glutamic acid at the 69th position of the ß chain (E69) genotype and inhalational beryllium exposure individually contribute to risk of chronic beryllium disease (CBD) and beryllium sensitisation (BeS) in exposed individuals. This retrospective nested case–control study assessed the contribution of genetics and exposure in the development of BeS and CBD.
Methods Workers with BeS (n=444), CBD (n=449) and beryllium-exposed controls (n=890) were enrolled from studies conducted at nuclear weapons and primary beryllium manufacturing facilities. Lifetime-average beryllium exposure estimates were based on workers’ job questionnaires and historical and industrial hygienist exposure estimates, blinded to genotype and case status. Genotyping was performed using sequence-specific primer-PCR. Logistic regression models were developed allowing for over-dispersion, adjusting for workforce, race, sex and ethnicity.
Results Having no E69 alleles was associated with lower odds of both CBD and BeS; every additional E69 allele increased odds for CBD and BeS. Increasing exposure was associated with lower odds of BeS. CBD was not associated with exposure as compared to controls, yet the per cent of individuals with CBD versus BeS increased with increasing exposure. No evidence of a gene-by-exposure interaction was found for CBD or BeS.
Conclusions Risk of CBD increases with E69 allele frequency and increasing exposure, although no gene by environment interaction was found. A decreased risk of BeS with increasing exposure and lack of exposure response in CBD cases may be due to the limitations of reconstructed exposure estimates. Although reducing exposure may not prevent BeS, it may reduce CBD and the associated health effects, especially in those carrying E69 alleles.
- occupational health
- genetic predisposition to disease
- lung diseases
Data availability statement
No data are available. Individual participant data is not available.
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JC and MMM are joint first authors.
Contributors JC and MMM analysed the data and wrote the manuscript. LAM and TEF conceived the idea for the study, provided DNA samples, patient information and oversaw the conduct of the study. LAM, CS, ECM, KDR and MR provided DNA samples, patient information, exposure data and critically contributed to the interpretation of results. MVD, AM, MAV, CR provided industrial hygiene data, exposure estimates and analysed the exposure data. DM and LAM provided genotyping and interpretation. All authors contributed to the interpretation of the results, revisions of the manuscript and approved the final version for submission.
Funding NIH Grants: P01 ES11810-06A1 and UL1 TR000154 from NIH/NCATS.
Disclaimer The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the National Institute for Occupational Safety and Health, Centres for Disease Control and Prevention.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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