Exposure and genetics increase risk of beryllium sensitisation and chronic beryllium disease in the nuclear weapons industry

Abstract

Objectives Beryllium sensitisation (BeS) and chronic beryllium disease (CBD) are caused by exposure to beryllium with susceptibility affected by at least one well-studied genetic host factor, a glutamic acid residue at position 69 (E69) of the HLA-DPβ chain (DPβE69). However, the nature of the relationship between exposure and carriage of the DPβE69 genotype has not been well studied. The goal of this study was to determine the relationship between DPβE69 and exposure in BeS and CBD. Methods Current and former workers (n=181) from a US nuclear weapons production facility, the Y-12 National Security Complex (Oak Ridge, Tennessee, USA), were enrolled in a case–control study including 35 individuals with BeS and 19 with CBD. HLA-DPB1 genotypes were determined by PCR-SSP. Beryllium exposures were assessed through worker interviews and industrial hygiene assessment of work tasks. Results After removing the confounding effect of potential beryllium exposure at another facility, multivariate models showed a sixfold (OR 6.06, 95% CI 1.96 to 18.7) increased odds for BeS and CBD combined among DPβE69 carriers and a fourfold (OR 3.98, 95% CI 1.43 to 11.0) increased odds for those exposed over an assigned lifetime-weighted average exposure of 0.1μg/m3. Those with both risk factors had higher increased odds (OR 24.1, 95% CI 4.77 to 122). Conclusion DPβE69 carriage and high exposure to beryllium appear to contribute individually to the development of BeS and CBD. Among workers at a beryllium-using facility, the magnitude of risk associated with either elevated beryllium exposure or carriage of DPβE69 alone appears to be similar.

Chronic Beryllium Disease, HLA-DPB1, and the DP Peptide Binding Groove

“…Their numbers of people studied were small (19 persons with CBD and 34 who were beryllium exposed), so their study was limited in what relationships they could evaluate. More recently, Van Dyke et al (17, 18) found this same relationship in a larger population-based study even after taking into account the increased risk associated with exposure.…”

“…All study subjects were white. Some of the subjects in this study were included in prior smaller studies of CBD and BeS risk related to E69 (8, 10, 17, 18), although some subjects were only included in this study.…”

Genetic susceptibility to beryllium: a case–referent study of men and women of working age with sarcoidosis or other chronic lung disease

“…Suggested occupational risk factors include metal working industries (from an ecological study in Switzerland)4 and exposure to insecticides 2. No clear gene–environmental interaction has been reported for sarcoidosis, contrasting strongly with the highly elevated risk of chronic beryllium disease (CBD) in those with a glutamic acid residue coded for in codon 69 (Glu69) in the HLA-DPB1 gene 5. Given that CBD is clinically and pathologically indistinguishable from sarcoidosis, it is reasonable to hypothesise that genetic variation in the presentation of one or more (as yet unknown) antigens may be causal also in sarcoidosis.…”

“…The health effects of exposure have largely been investigated in the USA in the nuclear industry 5. Importantly, no clear dose–response relationship has been found between exposure and CBD, although there is an assumption that sensitisation to beryllium depends on intensity of exposure and perhaps also duration and/or latency 6.…”

Beryllium: a paradigm for occupational lung disease and its prevention

“…In this issue of the journal, Van Dyke and colleagues have shown that the supra-typic genetic marker, HLA-DPB1(E69), has an additive and independent contribution with beryllium exposure to cell-mediated beryllium sensitisation and chronic beryllium disease in a cohort at a US nuclear weapons plant 1. This finding of statistical independence between required beryllium exposure and genetic characteristics is quantitatively consistent with an earlier finding in a small beryllia ceramics operation,2 and is extended by a concurrent publication in a second, larger nuclear weapons plant population 3.…”