Tnf Polymorphism and Bronchoalveolar Lavage Cell Tnf-Alpha Levels in Chronic Beryllium Disease and Beryllium Sensitization

Background: Beryllium stimulates TNF-alpha from chronic beryllium disease (CBD) bronchoalveolar lavage (BAL) cells. Objective: We sought to relate TNF polymorphisms to beryllium-stimulated TNF-a 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-a production from a subset of subjects.Results: Beryllium-stimulated, but not beryllium-unstimulated, BAL cell TNF-a 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-alpha production compared with that seen in noncarriers (P = .009). Patients with CBD alone and combined with sensitized subjects carrying the TNF haplotype I compared with those without this haplotype had significantly increased beryllium-stimulated BAL cell TNF-a 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 I (P = .01), 3 (from 5) of which contain the - 1031 C allele. Conclusions: The -857T allele and haplotype I are associated with BAL cell TNF-alpha 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.