Major histocompatibility locus genetic markers of beryllium sensitization and disease

Abstract

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)-;α polymorphism TNF-;α-;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-;α production-related TNF-;α-;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-;α, human leukocyte antigen-DR and human leukocyte antigen-DP markers play different roles in beryllium sensitization and granuloma formation in beryllium-exposed workers.

Electrostatic Potential on Human Leukocyte Antigen: Implications for Putative Mechanism of Chronic Beryllium Disease

“…HLA-DPB1*E69 and BeS. However, elimination of the BeS data reported by Saltini et al (2001) from our analyses did not change the overall ranking. All of the reports described were case-control studies, and we remain ignorant of many facets of the natural history of CBD, especially as it pertains to the progression from BeS to disease.…”

“…Moreover, we are unaware of the impact of any potential allele misclassification, which is suggested by the growing numbers of haplotypes reported since 1999. Regarding the ranking of alleles with respect to BeS (Table 1), we considered the possibility of bias, potentially introduced by the data reported by Saltini et al (2001), as, unlike those of Wang et al (2001) and Rossman et al (2002), these data did not show an association between inheritance of kT/e, respectively. The solvent-accessible surface is displayed in white.…”

“…The results of this work are useful for interpreting the molecular recognition in MHC class II proteins and for investigating their interactions with Be 2+ . Previous studies have suggested Glu β69 as an important genetic marker for conferring susceptibility to CBD (Díaz et al 1998;Fontenot et al 2000;Lombardi et al 2001;Potolicchio et al 1999;Richeldi et al 1993Richeldi et al , 1997Rossman et al 2002;Saltini et al 2001;Wang et al 1999Wang et al , 2001). More recent studies have led some investigators to suggest that the charged residues Asp β55 and Glu β56 might also contribute to the recognition of HLA-DP by T cells (Díaz et al 1998;Fontenot et al 2000;Potolicchio et al 1999).…”

“…Histidine and cysteine residues were assumed to be neutral. b ORs calculated from pooled data reported by Rossman et al (2002), Saltini et al (2001), and Wang et al (1999). c Could not be deduced from Wang et al (1999Wang et al ( , 2001).…”

Some implications of genetic biomarkers in occupational epidemiology and practice

“…Richeldi et al (36) have reported an 85-fold (95% CI 10.9-3578.0) risk of chronic beryllium disease for workers with an HLA-DPB1 coding for glutamic acid (Glu-69) in the 69th position. Subsequent studies confirmed this relationship (37)(38)(39); however, the risk ratios were lower. The question in this scenario is whether prospective employees in a beryllium manufacturing plant should be screened for Glu 69 variant prior to employment.…”