TNF polymorphism and bronchoalveolar lavage cell TNF-α levels in chronic beryllium disease and beryllium sensitization

Background

Beryllium stimulates TNF-α from chronic beryllium disease (CBD) bronchoalveolar lavage (BAL) cells.

Objective

We sought to relate TNF polymorphisms to beryllium-stimulated TNF-α production, to the development of CBD, and to the risk of more severe CBD over time.

Methods

We recruited 147 patients with CBD, 112 beryllium-sensitized subjects, and 323 control subjects; genotyped 5 TNF promoter polymorphisms; and measured beryllium-stimulated and unstimulated BAL cell TNF-α production from a subset of subjects.

Results

Beryllium-stimulated, but not beryllium-unstimulated, BAL cell TNF-α production was significantly increased in patients with CBD compared with that seen in those only sensitized (P = .0002). Those subjects with the TNF –857T allele and the only haplotype (haplotype 4) containing this allele demonstrated significantly lower unstimulated BAL cell TNF-α production compared with that seen in noncarriers (P = .009). Patients with CBD alone and combined with sensitized subjects carrying the TNF haplotype 1 compared with those without this haplotype had significantly increased beryllium-stimulated BAL cell TNF-α levels (P = .02). We found no significant association between patients with CBD, sensitized subjects, and control subjects with any of the TNF promoter polymorphisms or haplotypes. A greater decrease in Pao₂ at maximum exercise was noted in patients with CBD with the −1031C allele (P = .03) and with haplotypes other than the TNF haplotype 1 (P = .01), 3 (from 5) of which contain the −1031C allele.

Conclusions

The −857T allele and haplotype 1 are associated with BAL cell TNF-α production, indicating a potential role of TNF promoter variants in regulation of TNF production in sensitized subjects and patients with CBD.

Clinical implications

TNF promoter variants are not risk factors for CBD or sensitization.

Key words: TNF-α, chronic beryllium disease, beryllium sensitization, berylliosis, genetics, polymorphism, bronchoalveolar lavage

Abbreviations used: BAL, Bronchoalveolar lavage, Be, Beryllium, BeLPT, Beryllium lymphocyte proliferation test, BeS, Beryllium sensitized, CBD, Chronic beryllium disease, NF, Nuclear factor, Pao₂m, Pao₂ at maximal exercise, SNP, Single nucleotide polymorphism