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Major histocompatibility locus genetic markers of beryllium sensitization and disease

¹ Division of Respiratory Diseases of the University of Rome "Tor Vergata" at the National Institute for Infectious Diseases (INMI), Spallanzani Hospital, Rome, Italy. ² Division of Pneumology, Policlinico, Modena, Italy. ³ Laboratory of Clinical Pathology, INMI, Spallanzani Hospital, and the Dept of Cell Biology, University of "Tor Vergata", Rome, Italy. ⁴ Tissue Typing Laboratory, University Hospital Maastricht, Maastricht, the Netherlands. ⁵ Pulmonary and Intensive Care, Cleveland Clinic Foundation, Cleveland, OH, USA. ⁶ Medical Dept, Brush Wellman Inc., Elmore, OH, USA. ⁷ Biostatistics Unit, IRCCS San Matteo, Pavia, Italy

CORRESPONDENCE: C. Saltini, Divisione di Malattie Respiratorie, Ospedale L. Spallanzani-I.R.C.C.S., via Portuense, 292 00149, Roma, Italy. Fax: 39 0655170413

Keywords: berylliosis, genetic susceptibility, human leukocyte antigen-DPGlu69, human leukocyte antigen-DR, tumour necrosis factor-;

Received: December 12, 2000
Accepted June 10, 2001

This work was supported by grants DE-FG02-93ER61714 and ER61714-1004058 0000196 from the Dept of Energy of the USA and grant 99060855594 from MURST, Italy.

Hypersensitivity to beryllium (Be) is found in 1–16% of exposed workers undergoing immunological screening for beryllium disease using the beryllium lymphocyte proliferation test (BeLPT). However, only 50% of BeLPT-positive workers present with lung granulomas (i.e. berylliosis). As berylliosis is associated with the human leukocyte antigen (HLA)-DP supratypic marker DPGlu69, the authors asked whether this marker is differentially associated with disease presentation.

A population of 639 workers from a beryllium factory undergoing BeLPT screening was evaluated in a nested case-control study for the prevalence of HLA-DPGlu69, the HLA-DPB1, HLA-DQ and HLA-DR alleles and of the biallelic tumour necrosis factor (TNF)-; polymorphism TNF-;-;308 in 23 individuals presenting as "sensitized" (i.e. BeLPT-positive without lung granulomas) and in 22 presenting as "diseased" (i.e. BeLPT-positive with granulomas in the lung biopsy).

The HLA-DPGlu69 marker was associated with "disease" (odds ratio (OR) 3.7, p=0.016, 95% confidence interval (CI) 1.4–10.0), whilst the high TNF-; production-related TNF-;-;308*2 marker was associated with both a positive BeLPT (OR 7.8, corrected p<0.0001, 95% CI 3.2–19.1) with no difference between "sensitization" and "disease". Furthermore, the HLA-DRArg74 marker was associated with "sensitization" without disease (OR 3.96, p=0.005, 95% CI 1.5–10.1).

The data indicate that tumour necrosis factor-;, human leukocyte antigen-DR and human leukocyte antigen-DP markers play different roles in beryllium sensitization and granuloma formation in beryllium-exposed workers.

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