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In this issue of Occupational and Environmental Medicine, Mehta et al1 describe the potential for SERPINA1 genetic variants to modify the risk of obstructive airways disease associated with workplace inhalation of toxicants. We comment on the research, with an eye toward the ethical considerations for using genetic markers in the workplace.
The association of α 1 antitrypsin (AAT) deficiency with chronic obstructive pulmonary disease (COPD) has been recognised as a clinical entity since 1963.2 AAT is inherited in an autosomal codominant fashion, occurring as the result of phenotypic expression of rare genetic variants of the SERPINA1 gene.3 ,4 Most people with a severe deficiency in AAT are homozygous carriers of the so-called PiMZ allele. A less severe genetic variant, the ‘PiMS’ allele, also increases risk for COPD among homozygous individuals. Of course, the PiMZ and ‘PiMS’ alleles are relatively rare, occurring at a frequency of approximately 2% and 8% in European populations.3–5 The mechanism(s) of action of disease causation continues to be investigated, although early consensus centred upon the protease-antiprotease balance in the lung. More recent studies have implicated a role for an altered inflammatory response, and potentially other mechanisms, that may contribute to the expanding array of consequences of AAT deficiency.3 ,4 ,6–8
Following on from these findings, many authors have hypothesised that heterozygosity for these disease-associated alleles confers susceptibility to respiratory disease. If heterozygosity does confer elevated risk, SERPINA1 PiMZ carriers exposed to respiratory toxicants as a result of their job might be at significantly enhanced risk of lung disease. In fact, there are data suggesting that heterozygosity for the PiMZ allele is associated with …
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