Glutathione S-transferase and N-acetyltransferase genotypes and asbestos-associated pulmonary disorders

Our plain-English summary of Glutathione S-transferase and N-acetyltransferase genotypes and asbestos-associated pulmonary disorders, by A. Hirvonen, S.T. Saarikoski, K. Linnainmaa, et al (Journal of the National Cancer Institute, 1996).

The study

• Authors: A. Hirvonen, S.T. Saarikoski, K. Linnainmaa, K. Koskinen, K. Husgafvel-Pursiainen, K. Mattson, H. Vainio
• Journal: Journal of the National Cancer Institute
• Published: 1996;88(24):1853-6
• Cited by: 127 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Humans vary in their ability to metabolize endogenous and exogenous compounds. Glutathione S-transferases (GSTs) and N-acetyltransferases (NATs) are enzymes involved in the detoxification of hazardous agents. The GSTM1 and GSTT1 genes exhibit null (i.e., deletion) polymorphisms; in specific individuals, homozygous deletion (i.e., both copies lost) of these genes can be detected. Polymorphism of the NAT2 gene results in slow and fast acetylators of potentially toxic substances. The GSTM1-null and the NAT2 slow-acetylator genotypes have been associated with increased risks for the development of environmentally induced cancers.

Purpose: We assessed whether homozygous GSTM1-null or GSTT1-null genotypes or the NAT2 slow-acetylator genotype were associated with increased risks for the development of malignant and nonmalignant asbestos-related pulmonary disorders in a cohort of Finnish construction workers.

Methods: The study population consisted of 145 asbestos insulators who were classified as having been exposed to high levels of asbestos; 69 of these individuals had no pulmonary disorders (control subjects), and 76 had either malignant mesothelioma (n = 24) or nonmalignant pulmonary disorders, such as asbestosis and/or pleural plaques (n = 52). Lymphocyte DNA and the polymerase chain reaction were used to determine the GSTM1, GSTT1, and NAT2 genotypes of the study subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) estimating the relative risks of disease associated with specific genotypes were calculated from 2 x 2 tables by use of Fisher's exact method.

Results: Risks for the development of asbestos-related pulmonary disorders were not affected significantly by homozygous deletion of the GSTM1 or GSTT1 genes. However, the risk of developing both malignant and nonmalignant pulmonary disorders for individuals with a NAT2 slow-acetylator genotype was more than twice that observed for those with a NAT2 fast-acetylator genotype (OR = 2.3; 95% CI = 1.1-4.7); the risk of developing malignant mesothelioma for NAT2 slow acetylators was increased almost fourfold (OR = 3.8; 95% CI = 1.2-14.3). Individuals who lacked the GSTM1 gene and possessed a NAT2 slow-acetylator genotype had a risk of developing malignant and nonmalignant pulmonary disorders that was approximately fivefold greater than that observed for those who had the GSTM1 gene and a NAT2 fast-acetylator genotype (OR = 5.1; 95% CI = 1.6-17.6); these individuals had a fourfold increased risk of developing nonmalignant pulmonary disorders (OR = 4.1; 95% CI = 1.1-17.2) and an eightfold increased risk of developing malignant mesothelioma (OR = 7.8; 95% CI = 1.4-78.7) when compared with the same reference group.

Conclusions: Individuals with homozygous deletion of the GSTM1 gene and a NAT2 slow-acetylator genotype who are exposed to high levels of asbestos appear to have enhanced susceptibility to asbestos-related pulmonary disorders.

In plain English

This Finnish study compared inherited variants of three detoxification genes (GSTM1, GSTT1 and NAT2) among 145 asbestos insulators. All were classified as highly exposed and came from about 1500 construction workers in a health-screening survey. Of the 145, 69 had no pulmonary disorders on chest x-rays, 24 had malignant mesothelioma, and 52 had asbestosis and/or pleural plaques. Lacking the GSTM1 or GSTT1 gene was not significantly linked to disease. NAT2 results were available for 75 workers with disorders and 68 without; the slow-acetylator genotype was found in 69% and 50% of them respectively (odds ratio 2.3, 95% confidence interval 1.1 to 4.7). Among the mesothelioma patients it was 79% (odds ratio 3.8, 1.2 to 14.3). Workers who lacked GSTM1 and were slow acetylators were compared with workers who had GSTM1 and were fast acetylators. Their odds ratios were 7.8 (1.4 to 78.7) for mesothelioma, 4.1 (1.1 to 17.2) for nonmalignant disorders and 5.1 (1.6 to 17.6) for any disorder. The authors concluded that highly exposed people with this combination appear to have enhanced susceptibility to asbestos-related pulmonary disorders. They noted that the study was relatively small.

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: Comparison of gene variants (genotypes) between highly exposed asbestos workers with and without asbestos-related pulmonary disorders. Diseased workers were compared with exposed workers who had no disease. Odds ratios were calculated from 2 x 2 tables.
• Who was studied: 145 asbestos insulators in Finland, taken from a cohort of about 1500 construction workers recruited for a health-screening survey at the Finnish Institute of Occupational Health. Of these, 69 had no pulmonary disorders detectable on chest x-rays. 24 had malignant mesothelioma; these patients were admitted to Helsinki University Central Hospital between 1985 and 1993. 52 had asbestosis and/or pleural plaques.
• Exposure: Work as asbestos insulators, with all workers classified in the high asbestos-exposure group. The fiber type is not named. Known years of asbestos exposure were 1-9 years (29 workers), 10-19 years (17), 20-29 years (54) and 30 years or more (45).
• Main results:
  • Lacking the GSTM1 or GSTT1 gene (null genotype) did not significantly change the risk of asbestos-related pulmonary disorders. The GSTM1-null genotype was more frequent among mesothelioma patients (67%) and workers with nonmalignant disorders (58%) than among workers without disorders (46%). These differences were not statistically significant.
  • NAT2 genotypes were reported for 68 workers without disorders, 75 with any disorder, 51 with nonmalignant disorders and 24 with mesothelioma.
  • The NAT2 slow-acetylator genotype was found in 69% of workers with any pulmonary disorder and 50% of workers without disorders (OR = 2.3; 95% CI = 1.1-4.7).
  • Among the malignant mesothelioma patients, 79% had the NAT2 slow-acetylator genotype (OR = 3.8; 95% CI = 1.2-14.3, compared with workers without disorders).
  • For nonmalignant disorders (asbestosis and/or pleural plaques) alone, the NAT2 slow-acetylator odds ratio in Table 1 was 1.8 (95% CI 0.8-4.2).
  • NAT2 slow acetylators lacking GSTM1 were compared with fast acetylators who had GSTM1. For malignant mesothelioma, the odds ratio was 7.8 (95% CI 1.4-78.7).
  • In the same comparison, the odds ratio was 4.1 (95% CI 1.1-17.2) for nonmalignant pulmonary disorders. It was 5.1 (95% CI 1.6-17.6) for any of the disorders studied.
  • The authors checked correlations between the genotypes and age, smoking pack-years, smoking duration and duration of asbestos exposure. These ranged from -0.05 to 0.12. The authors judged them negligible and did not adjust the odds ratios for these factors.
• The authors' conclusion: The authors concluded that people who lack the GSTM1 gene, have a NAT2 slow-acetylator genotype and are exposed to high levels of asbestos appear to have enhanced susceptibility to asbestos-related pulmonary disorders.
• Limitations the authors state:
  • The authors stated that the study size is relatively small.

Topics

Medical terms in this study, explained in our Lexicon: Glutathione (GSH), Homozygous Deletion, Insulator, Malignant Mesothelioma, Pleural Plaques, Odds Ratio, confidence interval, Relative Risk.

Related studies

• Pooled analysis of NAT2 genotypes as risk factors for asbestos-related malignant mesothelioma — M. Betti, M. Neri, et al. (2009)
• Polymorphism of glutathione S-transferase M1 and lung cancer risk among African-Americans and Caucasians in Los Angeles County, California — S.J. London, A.K. Daly, et al. (1995)
• Genetic polymorphism for glutathione-S-transferase mu in asbestos cement workers — K. Jakobsson, A. Rannug, et al. (1994)
• Polymorphisms of glutathione-S-transferase M1 and manganese superoxide dismutase are associated with the risk of malignant pleural mesothelioma — S. Landi, F. Gemignani, et al. (2007)
• Manganese superoxide dismutase genotypes and asbestos-associated pulmonary disorders — A. Hirvonen, J. Tuimala, et al. (2002)
• Are glutathione S transferases involved in DNA damage signalling? Interactions with DNA damage and repair revealed from molecular epidemiology studies — M. Dusinska, M. Staruchova, et al. (2012)

Browse more research in Journal of the National Cancer Institute, or return to medical research.