Genetic susceptibility to asbestos-related fibrotic pleuropulmonary changes

Our plain-English summary of Genetic susceptibility to asbestos-related fibrotic pleuropulmonary changes, by M.K. Kukkonen, S. Hämäläinen, S. Kaleva, et al (The European Respiratory Journal, 2011).

The study

• Authors: M.K. Kukkonen, S. Hämäläinen, S. Kaleva, T. Vehmas, M.S. Huuskonen, P. Oksa, H. Vainio, P. Piirilä, A. Hirvonen
• Journal: The European Respiratory Journal
• Published: 2011;38(3):672-8
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The objective of this study was to determine whether genetic polymorphisms in enzymes that metabolise oxidative agents modify the individual susceptibility to developing asbestos and smoking-related pleuropulmonary changes. Nine polymorphisms of six genes (EPHX1, GSTM1, GSTM3, GSTP1, GSTT1 and NAT2) were genotyped from 1,008 Finnish asbestos-exposed workers. The genotype data were compared to signs of lung fibrosis and pleural thickenings, as well as with total lung capacity, single-breath diffusing capacity of the lung for carbon monoxide (D(L,CO)) and specific diffusing capacity (expressed as D(L,CO) per unit of alveolar volume (V(A))). The GSTT1 deletion polymorphism was associated with fibrotic changes (p=0.003), and decreased D(L,CO) (p=0.02) and D(L,CO)/V(A) (p=0.002), and the GSTM1 deletion polymorphism was associated with the greatest thickness of pleural plaques (p=0.009). On further analysis, the GSTT1 null genotype was found to pose over a three-fold risk for severe fibrotic changes (OR 3.12, 95% CI 1.51-6.43), and around two-fold risks for decreased D(L,CO) (OR 1.77, 95% CI 1.06-2.95) and D(L,CO)/V(A) (OR 2.37, 95% CI 1.33-4.23). In addition, the GSTM1 null genotype showed an elevated risk (OR 1.36, 95% CI 1.03-1.80) for thicker pleural plaques. Our data suggest that inherited detoxification capacity may affect the development and severity of asbestos and smoking-related nonmalignant pulmonary changes.

In plain English

This Finnish study asked whether inherited differences in six genes for enzymes that break down harmful and oxidative chemicals (EPHX1, GSTM1, GSTM3, GSTP1, GSTT1 and NAT2) were linked to non-cancer lung and pleural changes. It included 1,008 asbestos-exposed workers (992 men) from two screening studies, done in 1996–1997 and 2003–2004. Workers had high-resolution CT scans and lung function tests. The analyses were adjusted for age, sex, smoking and years of asbestos exposure. Workers lacking the GSTT1 gene (the "null" genotype) had higher odds of severe lung fibrosis on CT (odds ratio 3.12, 95% CI 1.51–6.43). They also had higher odds of reduced lung diffusing capacity. Workers lacking GSTM1 had higher odds of pleural plaques 5 mm or thicker (OR 1.36, 95% CI 1.03–1.80). Only the GSTT1–fibrosis link was statistically significant in both original study groups. The authors concluded that GSTT1 deletion is associated with severe pulmonary fibrosis and that GSTM1 deletion may have a role in pleural plaques. They cautioned that the many comparisons may have produced false-positive findings and that the results need replication.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Case-only genetic association study combining data from two earlier screening studies of asbestos-exposed workers. A general-population group was used only to compare gene frequencies, not as a statistical reference group.
• Who was studied: 1,008 Finnish asbestos-exposed workers (992 males, 16 females). The first group was recruited in the Helsinki area in 1996–1997. The second group was recruited in Helsinki, Tampere and Turku in 2003–2004, with 178 repeat participants excluded. The demographic reference group was 2,105 Finnish Caucasians from south-western Finland.
• Exposure: Occupational asbestos exposure, measured in years; fiber types and products are not specified. The study examined nine polymorphisms in six enzyme genes, with smoking (pack-years) as a covariate. No lung fibre measurements were made.
• Main results:
  • Severe fibrosis (CT score 2 or more): GSTT1 null workers had an adjusted OR of 3.12 (95% CI 1.51–6.43). The null genotype was found in 21 of 91 workers (23.1%) with severe changes and 24 of 222 (10.8%) with no radiological changes. For mild changes the OR was 1.20 (95% CI 0.73–1.95).
  • GSTT1 null workers had higher odds of decreased diffusing capacity (below 74% predicted). For single-breath DLCO the OR was 1.77 (95% CI 1.06–2.95); for DLCO/VA it was 2.37 (95% CI 1.33–4.23).
  • GSTM1 null workers had higher odds of pleural plaques 5 mm or thicker (OR 1.36, 95% CI 1.03–1.80). The association with plaque extent of 100 square centimetres or more (OR 1.27, 95% CI 0.98–1.65) was of borderline statistical significance.
  • When the two original study groups were analysed separately, only the GSTT1 deletion and fibrotic changes association was statistically significant in both.
  • No statistically significant associations were found between the GSTP1 polymorphism and nonmalignant pulmonary changes.
  • No significant combined effects were seen for any of the gene combinations studied.
• The authors' conclusion: The authors concluded that GSTT1 deletion is associated with severe pulmonary fibrosis and that GSTM1 deletion may have a role in the development of pleural plaques. They suggested that polymorphisms in these enzyme genes may be involved in asbestos-induced nonmalignant lung diseases and their severity.
• Limitations the authors state:
  • Patients were enrolled in three cities over two separate studies, four different CT scanners were used, and seven radiologists read the images.
  • Because many comparisons were made, some associations may be false positives. The results should be treated with caution until replicated in another population.
  • The general-population reference group had no asbestos exposure history or clinical data. It could therefore serve only as demographic referents, not as a reference group in statistical analyses.

Topics

Medical terms in this study, explained in our Lexicon: Fibrosis, Pleural Thickening, Total Lung Capacity (TLC), Diffusing Capacity (DLCO), Pleural Plaques.

Related studies

• Genes involved in innate immunity associated with asbestos-related fibrotic changes — M.K. Kukkonen, T. Vehmas, et al. (2014)
• Pleural malignant mesothelioma, genetic susceptibility and asbestos exposure — M. Neri, R. Filiberti, et al. (2005)
• Role of NAT2 deficiency in susceptibility to lung cancer among asbestos-exposed individuals — S.T. Saarikoski, M. Reinikainen, et al. (2000)
• Glutathione S-transferase and N-acetyltransferase genotypes and asbestos-associated pulmonary disorders — A. Hirvonen, S.T. Saarikoski, et al. (1996)
• Genetic susceptibility to malignant pleural mesothelioma and other asbestos-associated diseases — M. Neri, D. Ugolini, et al. (2008)
• Decline in annual lung function in workers exposed to asbestos with and without pre-existing fibrotic changes on chest radiography — T. Nakadate (1995)

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