HLA-DPB1 *E69 and Chronic Beryllium Disease
PUBLISHED: April 10, 2003
AUTHORS: Ainsley Weston, Kathleen Kreiss, Michael Andrew, Erin McCanlies

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GENE

HLA-DPB1 is located on chromosome 6p12.3 and codes for Human Leukocyte Antigen, a Major Histocompatibility Class II (MHCII) molecule. MHCII molecules are heterodimeric, having a and ß chains, DPB1 codes for the ß chain. These molecules are responsible for initiation of the immune response through antigen presentation to T cells.

PREVALENCE OF GENE VARIANTS

There are 103 known variants of HLA-DPB1 (Table 1). The supratypic marker HLA-DPB1^*E69, coding for glutamic acid at the 69th residue of the mature protein, is found in 34 of those variants. The allelic frequency of the supratypic marker HLA-DPB1^*E69 is highly variable occuring in: <1% of some Amerindian tribes, 20-25% of Caucasian-Americans and African-Americans, >40% of Chinese. In Asia-Oceana it varies between <1% and >55%. Frequencies are typically based on studies of 20-150 individuals (1).

DISEASE BURDEN

Chronic Beryllium Disease (CBD) is caused by exposure to beryllium (Be), in the form of particles of BeO, BeF, other Be-salts, Be-metal, or Be-alloy. It has been estimated that approximately 1-12% of workers in the primary industry are immunologically sensitized to beryllium. Of those, 36-100% develop CBD (2). There is evidence that certain tasks, such as machining which has a relatively high exposure, pose greatest risk of CBD (3). Data from 5 molecular epidemiological case-control studies have shown odds ratios for CBD among HLA-DPB1^*E69 positive beryllium-workers to be between 4 and 80. Studies in general were hampered by small numbers (6-33 cases, 44-121 controls). Genotyping used several different methods, from oligonucleotide hybridization to high resolution DNA sequencing.

INTERACTIONS

Attempts to estimate gene-gene and gene-environment interactions have relied on too few study subjects. However, there is a suggestion that there are interactions of HLA-DPB1^*E69 with: HLA-DPB1^*R74, TNF-a-308*2, and high exposure tasks in the beryllium industry (4,5).

LABORATORY TESTS

Identification of HLA-DPB1^*E69 is facile and can be accomplished by reliable molecular methods, such as RFLP (6). However, because of the relatively high carrier frequency of this supratypic marker among Caucasian-Americans and African-Americans (30-40%) compared with the relatively low CBD prevalence among US beryllium-workers (1-5%), its positive predictive value (PPV) is probably too low to have a significant impact on CBD burden through genetic testing. Although the data required to calculate a true PPV for this marker do not yet exist, we have estimated the PPV to be between 7 and 14% (6).

POPULATION TESTING

The positive public health impact of genetic research on HLA-DPB1 and CBD will be accomplished, not through genetic testing, but rather the development of better research tools (animals genetically modified with human genes), development of post-exposure interventions, and development of an exposure limit that protects all workers irrespective of their genotype (6). We are aware that a major U.S. beryllium manufacturing company has conducted a limited pilot project in which applicants for employment were offered the opportunity for anonymous genetic testing through an independent academic center. To better understand the ethical and legal issues surrounding workplace genetic testing, the company has discussed this pilot project in several conference settings. The ethical issues concerning genetic information in relation to employment requires that beryllium workers be educated about the risks and benefits associated with obtaining genetic test results.

REFERENCES

1. McCanlies E, Kreiss K, Andrew M, et al. HLA-DPB1 and chronic beryllium disease: A HuGE review. Am. J. Epidemiology 157:388-398, 2003.
2. Kreiss K, Mroz M, Zhen B, et al. Risks of beryllium disease related to work processes at a metal alloy, and oxide production plant. Occup. Environ. Med. 54:605-612, 1997.
3. Kreiss K, Mroz M, Newman et al. Machining risk of beryllium disease and sensitization with medium exposures below 2 micrograms/m³ . Am. J. Ind. Med. 30:16-25, 1996.
4. Richeldi L, Kreiss K, Mroz M, et al. Interaction of genetic and exposure factors in the prevalence of berylliosis. Am. J. Ind. Med. 32:337-340, 1997.
5. Saltini C, Richeldi L, Losi M, et al. Major histocompatibility locus genetic markers of beryllium sensitization and disease. Eur. Respir. J. 18:677-684, 2001.
6. Weston A, Ensey J, Kreiss K, et al. Racial differences in prevalence of a supratypic HLA-genetic marker immaterial to pre-employment testing for chronic beryllium disease. Am. J. Ind. Med. 41:457-465, 2002.
   

WEBSITES

1. European Bioinformatics Institute IMGT/HLA Database 
2. Beryllium Support Group

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