Genetic Markers in Beryllium Hypersensitivity

Stubbs, Jose; Argyris, Elias G.; Lee, Chung Wha; Monos, Dimitri; Rossman, Milton D.

doi:10.1378/chest.109.3_supplement.45s

Cited by 17 publications

(5 citation statements)

References 24 publications

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“…This makes the HLA-DPB1Glu69 marker a very strong candidate as the primary susceptibility gene for disease. Consistent with previous findings [Richeldi et al, 1993;Stubbs et al, 1996], this study shows a strong association between the presence of the HLA-DPB1Glu69 marker and the lung granulomatous reaction to beryllium, i.e., with disease. Because of the small size of the population, the relationship between the marker and sensitization to beryllium in the absence of disease, i.e., a positive blood test without lung granulomas, could not be clarified.…”

Section: Discussionsupporting

confidence: 92%

Interaction of genetic and exposure factors in the prevalence of berylliosis

et al. 1997

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Prevalence of berylliosis, a lung disorder driven by the activation of beryllium-specific T cells, is associated with a major histocompatibility complex (MHC) class II marker (HLADPB1Glu69) and with the type of industrial exposure. We evaluated the interaction between marker and exposure in a beryllium-exposed population in which the prevalence of berylliosis was associated with machining beryllium. The presence of the marker was associated with higher prevalence INTRODUCTIONAvailable models of genetic susceptibility to environmental agents suggest that susceptibility genes may increase the carcinogenic risk of aromatic compounds either at lower [Nakachi et al., 1993] or higher [Cartwright et al., 1992;Kihara et al., 1994] levels of exposure to the agent. In the former case, the environmental factor would predominate in the determination of disease risk at high exposure levels. In this context, genetic screening might not prevent the majority of disease cases; on the contrary, reliance upon genetic screening for disease prevention may lead to relaxed exposure control and to an increased number of disease cases [Van Damme et al., 1995]. In berylliosis, an occupational lung disease caused by exposure to beryllium, both a genetic susceptibility factor, i.e., being a carrier of allelic variants of the HLA-DP gene coding for a glutamate in position 69 of the HLA-DP b 1 chain (HLA-DPB1Glu69) [Richeldi et al., 1993], and industrial process-related risk factors, such as machining beryllium (e.g., drilling, dicing, grinding) [Kreiss et al., 1993], have been identified. Thus, berylliosis represents an ideal model with which to assess the interaction between genetic and environmental factors. Recently, the evaluation of a beryllium worker cohort showed that jobs with higher berylliosis risk were associated with higher beryllium exposures. In this cohort, berylliosis prevalence was 10.6% in machinists, with a median daily weighted average (DWA) exposure of 0.9 µg/m 3 , and 1.2% in nonmachinists, with a median DWA exposure of 0.3 µg/m 3 , suggesting a dose-response relationship between exposure and disease [Kreiss et al., 1996]. This cohort was therefore chosen to assess the role of genetic and exposure factors in INDUSTRIAL MEDICINE 32:337-340 (1997) r 1997 Wiley-Liss, Inc.beryllium disease susceptibility and was evaluated for the carrier status of the HLA-DPB1Glu69 genetic marker. MATERIALS AND METHODSA population of 136 subjects from the workforce (139 workers) of a beryllium ceramics plant in the southwestern United States was enrolled in a genetic marker study after granting informed consent. These workers had been enrolled in a berylliosis surveillance program including interview, blood beryllium-stimulated lymphocyte proliferation (BeLP) test and, for those with abnormal blood BeLP test, bronchoalveolar lavage (BAL) with lung BeLP test and transbronchial biopsy. Six of the 136 individuals were diagnosed with berylliosis based on an abnormal blood BeLP test and an abnormal lung biopsy showing noncaseating granulo...

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Section: Discussionsupporting

confidence: 92%

Interaction of genetic and exposure factors in the prevalence of berylliosis

et al. 1997

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“…A concomitant analysis of genetic linkage between Glu-69 and polymorphic sites within HLA-DRB4 and TNFB demonstrated no association with CBD. (2) In a study of genetic polymorphisms associated with beryllium hypersensitivity, Stubbs et al (31) examined HLA-DRB1, -DRB3, -DRB4, -DRB5, and -DPB1. They observed a significant association between beryllium sensitization and the HLA-DPB1 Glu-69 polymorphism, supporting the observations of Richeldi et al (2) In addition, they observed that five specific polymorphisms in HLA-DRB1 were associated with susceptibility to beryllium sensitization and that four others within the same gene were associated with protection.…”

Section: Other Risk Management Optionsmentioning

confidence: 99%

Risk Estimation and Value‐of‐Information Analysis for Three Proposed Genetic Screening Programs for Chronic Beryllium Disease Prevention

Bartell¹,

Ponce²,

Takaro³

et al. 2000

Risk Analysis

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Genetic differences (polymorphisms) among members of a population are thought to influence susceptibility to various environmental exposures. In practice, however, this information is rarely incorporated into quantitative risk assessment and risk management. We describe an analytic framework for predicting the risk reduction and value-of-information (VOI) resulting from specific risk management applications of genetic biomarkers, and we apply the framework to the example of occupational chronic beryllium disease (CBD), an immune-mediated pulmonary granulomatous disease. One described Human Leukocyte Antigen gene variant, HLA-DP beta 1*0201, contains a substitution of glutamate for lysine at position 69 that appears to have high sensitivity (approximately 94%) but low specificity (approximately 70%) with respect to CBD among individuals occupationally exposed to respirable beryllium. The expected postintervention CBD prevalence rates for using the genetic variant (1) as a required job placement screen, (2) as a medical screen for semiannual in place of annual lymphocyte proliferation testing, or (3) as a voluntary job placement screen are 0.08%, 0.8%, and 0.6%, respectively, in a hypothetical cohort with 1% baseline CBD prevalence. VOI analysis is used to examine the reduction in total social cost, calculated as the net value of disease reduction and financial expenditures, expected for proposed CBD intervention programs based on the genetic susceptibility test. For the example cohort, the expected net VOI per beryllium worker for genetically based testing and intervention is $13,000, $1,800, and $5,100, respectively, based on a health valuation of $1.45 million per CBD case avoided. VOI results for alternative CBD evaluations are also presented. Despite large parameter uncertainty, probabilistic analysis predicts generally positive utility for each of the three evaluated programs when avoidance of a CBD case is valued at $1 million or higher. Although the utility of a proposed risk management program may be evaluated solely in terms of risk reduction and financial costs, decisions about genetic testing and program implementation must also consider serious social, legal, and ethical factors.

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“…The immune response to beryllium appears to depend on an individual's genetic susceptibility. Allelic differences have been shown in the major histocompatibility complex class II molecules human leukocyte antigen-DP 29,30 and human leukocyte antigen-DR 31 in patients with CBD as compared with nondiseased beryllium-exposed individuals. However, it is likely that genetic susceptibility to CBD is multifactorial and that other genes are also involved in regulating the immune response in pathogenesis of this disease.…”

Section: Discussionmentioning

confidence: 99%