Key Words: berylliosis; beryllium; chronic beryllium disease; epidemiology; genetic screening; HLA-DP antigens; HLA-DPB1; occupational exposure

Abbreviations: Arg, arginine; Asp, aspartic acid; BHWCD, beryllium hypersensitivity without clinical disease; CBD, chronic beryllium disease; CI, confidence interval; Glu, glutamic acid; HLA, human leukocyte antigen; Lys, lysine; OR, odds ratio; TNF-, tumor necrosis factor-.

The human leukocyte antigen (HLA) complex comprises closely linked genes located on the short arm of chromosome 6 that include HLA-A, -B, -C, and -D. The HLA-A, -B, and -C loci code for class I molecules. The HLA-D region consists of three primary subregions designated DP, DQ, and DR, and these loci code for class II molecules. A map of chromosome 6p12.3 shows the relative locations of the HLA genes (Figure 1) (1). Both class I and class II molecules are extremely important in immunologic processes, specifically the presentation of foreign and self antigens to the cell surface for T-cell recognition (2). Although the HLA-DP molecule has not been studied as extensively as HLA-DR or HLA-DQ, it shares similar functional characteristics of antigen presentation to the T-cell and induces a strong secondary proliferative response.

Variations encoded in and ß chains of the DP molecule are located at the second exon (3). The helical walls and the ß pleated sheet floor form the peptide binding groove. Polymorphisms are generally restricted to amino acid residues that form this groove and that interact with the peptide or T-cell receptor. These polymorphic residues in the and ß chains account for most of the association of HLA with disease (3). Inheritance of certain alleles may lead to either an absent or a vigorous T-cell response to a given antigen. A strong response protects from some infectious disease, but it can also result in adverse pathologic events (3).

To date, 100 different HLA-DPB1 alleles and 20 HLA-DPA1 alleles have been described (3-10). Certain HLA-DP alleles are thought to play a role in acute graft rejection, pauciarticular juvenile rheumatoid arthritis, and sarcoidosis (11, 12). Among the Japanese, HLA-DPB1*0501 has been found to be associated with opticospinal multiple sclerosis (13, 14). HLA-DP has also been found to be associated with insulin-dependent diabetes mellitus in the Japanese and Indian populations (15, 16). Furthermore, the family of HLA-DPB1 alleles characterized by a glutamic acid residue in the 69th position has been found to be associated with hard metal disease and chronic beryllium disease (17-24). There are 34 such alleles, and it is likely that levels of risk vary by allele. This review will focus on the role of HLA-DPB1 in chronic beryllium disease.

We searched MEDLINE using the keyword "HLA-DP" for papers published between 1993 and 2002. The search was limited to human subjects and the English language. We then identified relevant papers and critically evaluated them for inclusion in or exclusion from the current review. We were specifically interested in identifying population frequencies for those alleles that contain a glutamic acid residue in the 69th position (Table 1) (25-38).

Table 1 reports either the allelic frequency (F), the carrier frequency (C), or both for the HLA-DPB1*02 and non-HLA-DPB1*02alleles reported in different populations. The alleles listed are only those for HLA-DPB1^Glu69 and are not necessarily all of the alleles genotyped. Hardy-Weinberg equilibrium was estimated in four of these studies and was found to be nonsignificant (35-38). Because of the lack of data for the majority of the studies, however, neither Hardy-Weinberg equilibrium nor the frequencies associated with heterozygosity versus homozygosity could be determined (25-38). For this reason, the allelic frequencies, particularly in studies with small populations, might not represent true population frequencies. Furthermore, different laboratory methods probably introduce varying degrees of error. High-resolution allele-specific sequencing data are the most reliable, followed by sequence-specific oligonucleotide probes and dot blot hybridization. Even in light of these limitations, the results indicate that there are considerable differences in the frequency of the HLA-DPB1^Glu69-containing alleles across populations. For example, HLA-DPB1*02 occurred most often in the Tolai people of Papua New Guinea (total F = 0.58), followed by Australian aboriginals from the central desert (F = 0.36) (27, 38). There also appear to be populations in which HLA-DPB1*02 occurs with such a small frequency as to be almost nonexistent. This is true for natives of the Trobriand Islands (F = 0.006) and a large number of Colombian aboriginals (F = 0.00) (29, 38). Similarly, the frequencies for non-HLA-DPB1*02 are also highly variable. HLA-DPB1*1301 occurred with the highest frequency in a Borneo population (F = 0.43) (38). However, the prevalence of this same allele was greatly reduced in a Liberian population (F = 0.03) (35).

Individuals who are exposed to beryllium dust or fumes are at risk of lung cancer and a granulomatous lung disease called chronic beryllium disease (CBD) (39-43). Beryllium is atomic number 4 on the periodic table of the elements. Its light weight, stability, and considerable strength make it an ideal element for numerous technological applications. It is extracted from beryl ore or bertrandite and is generally sold as beryllium oxide powder, beryllium alloys, or pure beryllium metal. Beryllium products are used in the aerospace industry, the nuclear power industry, electronics, and the manufacture of dental prostheses (39-41). Exposure to beryllium occurs primarily among workers in beryllium manufacturing plants in which welding, machining, heating, grinding, melting, and pressing of beryllia ceramics may result in the production of respirable beryllium particles (41). However, beryllium exposure and risk of CBD may also occur among secondary users of beryllium products who further adapt them by grinding, welding, or machining, which also results in respirable beryllium particles. Workers in precious metal reclamation and construction workers in beryllium-using facilities are also at risk (44). Currently, it is not known how many persons are or have been exposed to beryllium, although estimates range from a low of 21,233 to a high of 800,000 (44-46). Estimates are important, however, because exposure confers a lifetime risk of CBD.

Since 1960, a series of epidemiologic studies have been conducted to evaluate the excess risks of lung cancer and mortality among beryllium workers (47-58). Although a number of methodological problems plagued many of the earlier studies (59), in 1980 the International Agency for Research on Cancer classified beryllium as a probable human carcinogen (class 2A) (42). This was later revised, and in 1993 beryllium and beryllium compounds were classified as human carcinogens (group 1) (43). However, CBD overshadows lung cancer as a significant problem for beryllium workers.

Morbidity
Exposure to beryllium triggers a cell-mediated, type IV delayed hypersensitivity reaction that results in the proliferation of beryllium-specific T lymphocytes (60, 61). This immunologic response can be monitored in the blood using the beryllium lymphocyte proliferation test, which is used to indicate beryllium sensitization in exposed workers (62-65). Further clinical evaluation is then necessary to determine whether granuloma formation has occurred, resulting in a diagnosis of CBD.

The prevalence of beryllium sensitization among beryllium-exposed workers has been reported to be between 1 percent and 12 percent (Table 2) (63-69). Part of this variation may be a result of the poor reproducibility of the beryllium lymphocyte proliferation test between and within laboratories. Higher prevalence rates are often reported when two laboratories receive split samples than when a single laboratory is used.

Of sensitized persons, 36–100 percent have evidence of granulomatous lung disease (Table 2) (63-69). Currently, it is not known whether all sensitized persons will develop CBD. Individuals with CBD often develop shortness of breath, cough, chest discomfort, fatigue, and weight loss. Severe disease results in pulmonary failure (40, 70). However, in its initial stages, beryllium disease may be asymptomatic. Before the advent of beryllium lymphocyte proliferation test screening and identification of subclinical disease, the average latency period for clinical disease was reported to be 10 years (71). Shorter latency periods are evident with sensitization screening and clinical evaluation of asymptomatic sensitized workers (69).

Mortality
Only a few studies have been conducted to evaluate mortality rates associated with CBD (56-58, 72). Among beryllium-exposed workers, excess mortality has been observed for lung cancer, heart disease, diseases of the respiratory system (e.g., beryllium disease, emphysema, pneumoconiosis), and diseases of the genitourinary system (56-58).

As of 1993, 36 percent of the persons registered in the United Kingdom Beryllium Case Registry had died from respiratory failure associated with beryllium disease (72). A similar study utilizing data from the United States Beryllium Case Registry (71, 73-75) reported that 62 percent of eligible persons had died. The primary cause of death in this cohort was reported as "pneumoconioses, other respiratory disease," a classification often used for beryllium disease (56). However, ascertainment problems may affect both the United Kingdom Beryllium Case Registry and the United States Beryllium Case Registry, resulting in inaccuracy in mortality rates. For example, prior to the advent of the beryllium lymphocyte proliferation test, it was difficult to distinguish beryllium disease from other granulomatous lung diseases, particularly sarcoidosis. Furthermore, some CBD patients may have been excluded from the registry because they were not actively sought out for registration or because their physicians did not recognize CBD or refer them for registration (71-75).

In 2001, Wang et al. (21, 22) once again utilized allele-specific polymerase chain reaction to evaluate the frequency of HLA-DPB1 in 25 beryllium-sensitized persons (without CBD) and to further characterize persons with and without CBD. Twenty of the persons with CBD and 70 of the controls in this study had participated in the previous study (21). The additional controls were beryllium-exposed workers who had a negative beryllium lymphocyte proliferation test. When the presence or absence of HLA-DPB1^Glu69 was evaluated, sensitized persons were significantly more likely to carry at least one HLA-DPB1^Glu69 allele in comparison with the control group (88 percent vs. 37 percent; OR = 12.3, 95 percent CI: 3.5, 42.7; p < 0.0001). Haplotype analysis identified 30 percent of persons with CBD as being homozygous for HLA-DPB1^Glu69, as compared with 24 percent of the sensitized persons and only 3 percent of the controls (p < 0.001). When the frequency of non-HLA-DPB1*0201 alleles was evaluated, sensitized persons were more likely to have at least one non-HLA-DPB1*0201 allele than controls (52 percent vs. 13 percent; p < 0.001) but had such an allele less often than persons with CBD (52 percent vs. 80 percent; not significant). When the specific non-HLA-DPB1*0201 alleles were examined, HLA-DPB1*1701occurred most often in both sensitized persons (16 percent) and persons with CBD (30 percent) in comparison with the control group (2 percent) (p < 0.01) (21, 22).

The results of this last study (22) will help in clarifying the natural history of CBD. However, concerns about the population under study also warrant further evaluation and verification of these findings. These concerns include composition of the CBD case, sensitized, and control groups and the small sample size. For example, five of the sensitized persons in the most recent study conducted by Wang et al. (22) had previously been analyzed as controls (21); 10 of the beryllium-sensitized persons did not have signs of respiratory impairment, but none were clinically evaluated for granulomatous lung disease; and two of the sensitized persons in the most recent study were not known to have been occupationally exposed to beryllium.

Using the same methods as Richeldi et al. (19, 20), Saltini et al. (23) conducted a study that analyzed the presence and absence of specific HLA-DPB1 alleles in 22 persons with CBD, 23 persons with beryllium sensitivity (without CBD), and 93 control samples. HLA-DPB1^Glu69 was significantly associated with persons with CBD in comparison with both the control group and the sensitized group. HLA-DPB1*0501 occurred more often, though not significantly, among the sensitized in comparison with both persons with CBD and controls (11 percent in the sensitized vs. 2 percent among persons with CBD and controls). The prevalence of HLA-DPB1*0201 was increased, also not significantly, in the CBD cases as compared with the controls (27 percent vs. 17 percent). Although frequencies were not significantly different, a number of non-HLA-DPB1*0201 alleles were also observed to appear more often in the CBD cases than in the controls (23). These included HLA-DPB1*0601, HLA-DPB1*0901, HLA-DPB1*1001, HLA-DPB1*1701, and HLA-DPB1*1901.

Rossman et al. (24) recently published information on the genetics of beryllium sensitization and CBD. The study population consisted of 137 persons who had been referred to the Hospital of the University of Pennsylvania for clinical evaluation of CBD. Fifty-five of the participants had a positive beryllium lymphocyte proliferation test and were designated as having beryllium hypersensitivity. Upon clinical examination, 25 out of 55 were determined to have CBD and 30 out of 55 were defined as having beryllium hypersensitivity without clinical disease (BHWCD). The control group consisted of 82 beryllium-exposed persons. None had positive beryllium lymphocyte proliferation test results, although 10 had abnormal chest radiographs. HLA-DPB1 genotyping was conducted on all of the samples, and the frequencies of alleles were compared across the groups with and without disease (24). HLA-DQB1 and HLA-DRB1 were also evaluated but not in conjunction with HLA-DPB1, so they will not be discussed here.

HLA-DPB1^Glu69 appeared more often in persons with BHWCD (90 percent) and persons with CBD (84 percent) than in those without disease (48 percent). The highest odds ratio for disease was associated with BHWCD and HLA-DPB1^Glu69 (OR = 9.9, 95 percent CI: 2.8, 35.3). When the frequency of HLA-DPB1^Glu69 among persons with BHWCD was compared with the frequency among persons with CBD, there was no significant difference. When specific HLA-DPB1^Glu69 alleles were evaluated, none remained significant after adjustment for multiple comparisons.

The presence of lysine at position 11 (HLA-DPB1^Lys11) and the presence of aspartic acid at position 55 (HLA-DPB1^Asp55) were significantly associated with beryllium hypersensitivity, but this association remained significant only in the presence of HLA-DPB1^Glu69. Furthermore, there was no difference between the frequencies of HLA-DPB1^{-Glu69 -Lys11} and HLA-DPB1^{-Glu69 -Asp55} among persons with CBD or persons with BHWCD. It was concluded that HLA-DPB1^Glu69 was the most important epitope in the development of beryllium hypersensitivity, but it could not be used to predict whether someone would develop CBD.

While all of the studies conducted found that HLA-DPB1^Glu69 is associated with CBD, they differed in terms of the relative importance placed on the role of the HLA-DPB1*0201 alloforms in CBD (19-24). Furthermore, it is of interest that while Wang et al. (22) and Rossman et al. (24) found a relation between HLA-DPB1^Glu69 and beryllium sensitization, Saltini et al. (23) did not report this relation. This discrepancy might be a result of the different methods used to determine HLA haplotypes or differences between the populations under study. Future studies should formally address the differences observed across these studies.

The overall meaning of the reviewed studies described in Tables 2 and 3 must be considered with some caution, because of sample populations known to overlap and with the potential to overlap. For example, Stange et al. (67) included beryllium cases previously identified by Kreiss et al. (63, 65). Similarly, Henneberger et al. (69) included beryllium-exposed workers previously studied by Kreiss et al. (66) (Table 2). Although the studies presented in Table 3 appear to be independent, there is potential for overlap across the populations studied by Rossman et al. (24) and Saltini et al. (23) (Table 3). Overlap among these studies does not change the general interpretation of these results with respect to the range of prevalence and the estimates of association. However, it could affect the generalizablity of the results, since the estimates of association may not be entirely statistically independent.

Utilizing a series of 2 x 2 tables extracted from a 2 x 4 table, Saltini et al. (23) evaluated the risk of sensitization or CBD in the presence of either one or a combination of the genes HLA-DPB1^Glu69, tumor necrosis factor- (TNF-)-308*2, and HLA-DR^Arg74. HLA-DR^Arg74 was independently associated with sensitization (OR = 4.0, 95 percent CI: 1.5, 10.1), while HLA-DPB1^Glu69 was found to be associated with CBD (OR = 3.7, 95 percent CI: 1.4, 10.0) but not with sensitization. TNF--308*2 was associated with a positive beryllium lymphocyte proliferation test result (OR = 7.8, 95 percent CI: 3.2, 19.1), regardless of disease status. When gene combinations were evaluated, the risk of sensitization was increased in the presence of both TNF--308*2 and HLA-DR^Arg74. The risk of sensitization was also reportedly higher among persons who were HLA-DPB1^Glu69-positive but HLA-DR^Arg74-negative (23). However, scrutiny of the tabulated data revealed that sensitization was associated with HLA-DR^Arg74-positive, HLA-DPB1^Glu69-negative persons. TNF--308*2 was independently associated with CBD (OR = 4.0; p < 0.05), but in the presence of HLA-DPB1^Glu69, this risk was even greater (OR = 9.7; p < 0.05). Interestingly, neither HLA-DPB1^Glu69 alone nor HLA-DR^Arg74 alone, nor both in combination, was associated with CBD. This may have been an effect of the small sample sizes created in the construction of the 2 x 4 tables. The extent to which these analyses may have been affected by the use of different laboratory methods to determine the presence of the TNF--308*2, HLA-DPB1^Glu69, and HLA-DR^Arg74 alleles is unknown. However, these results demonstrate that genes other than HLA-DPB1^Glu69 or genes acting in conjunction with HLA-DPB1^Glu69 may play a role in the risks of both sensitization and disease.

Ethical issues surrounding the use of genetic information as a screening tool in the workplace include employment discrimination and insurance discrimination (76). These concerns have become particularly relevant given that current, former, and prospective beryllium-industry workers are being genetically characterized in research studies for HLA-DPB1^Glu69. In addition, while the odds associated with CBD in the presence of HLA-DPB1 ^Glu69 are quite high, because the population prevalence of HLA-DPB1^Glu69 is also high, the cross-sectional predictive value is relatively low (77).

The positive predictive value has typically been defined as the probability that an individual will have a disease given that the diagnostic test is positive. It is a function of test sensitivity, test specificity, and disease prevalence (78). For example, using the odds ratio of 23 obtained by Wang et al. (21), a population prevalence of 40 percent for HLA-DPB1^Glu69, and a prevalence of disease among beryllium workers of 5 percent, the positive predictive value is only 11.7 percent (77). Thus, HLA-DPB1 ^Glu69 does not fulfill the screening criteria outlined by Khoury et al. (79).

The positive predictive value can also be defined longitudinally. This definition is based on disease incidence rather than on prevalence, and it can be interpreted as the probability that an exposed individual will develop the disease subsequent to screening, given that he or she has a positive screening test (78). While prospective employees might be able to use longitudinal risk information, the disease incidence data required to estimate this risk are not yet available. The utility of risk information for people already exposed to beryllium is even less clear, since CBD risk remains even after exposure cessation. Currently, it is not known whether workers can lower their risk by leaving the industry or whether genetic characterization of sensitized or CBD cases has prognostic implications. Continued research will be important in the identification of other high-risk genes, gene-exposure interactions, and gene-gene interactions that may improve personal risk assessment and help in determining whether specific genes or alleles are more valuable as prognostic indicators. Regardless, prospective, current, and former beryllium workers must be educated about the risks and benefits associated with obtaining their genetic screening results.

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• Table 1
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• Agency for Toxic Substances and Disease Registry (ATSDR): Public Health Statement for Beryllium
• Agency for Toxic Substances and Disease Registry (ATSDR): ToxFAQs for Beryllium
  
• US Environmental Protection Agency (EPA), Technology Transfer Network Air Toxics Web site: Beryllium compounds
• US Department of Labor, Occupational Safety and Health Administration (OSHA): Safety and Health Topics-- Beryllium
• CDC, National Institute of Occupational Safety and Health (NIOSH): Electronic Library of Construction Occupational Safety  and Health (eLOCOSH)-- Beryllium

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