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Associations Between Glutathione-S-Transferase Genotypes and Bronchial Hyperreactivity Patients With Di-isocyanate Induced Asthma. A Follow-Up Study

Introduction: Di-isocyanates TDI (toluene di-isocyanate), MDI (diphenylmethane di-isocyanate), and HDI (hexamethylene di-isocyanate) are the most common chemicals causing occupational asthma. Di-isocyanate inhalation has been reported to induce oxidative stress via reactive oxygen and nitrogen speci...

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Autores principales: Leppilahti, Jussi, Majuri, Marja-Leena, Sorsa, Timo, Hirvonen, Ari, Piirilä, Päivi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794415/
https://www.ncbi.nlm.nih.gov/pubmed/31649932
http://dx.doi.org/10.3389/fmed.2019.00220
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author Leppilahti, Jussi
Majuri, Marja-Leena
Sorsa, Timo
Hirvonen, Ari
Piirilä, Päivi
author_facet Leppilahti, Jussi
Majuri, Marja-Leena
Sorsa, Timo
Hirvonen, Ari
Piirilä, Päivi
author_sort Leppilahti, Jussi
collection PubMed
description Introduction: Di-isocyanates TDI (toluene di-isocyanate), MDI (diphenylmethane di-isocyanate), and HDI (hexamethylene di-isocyanate) are the most common chemicals causing occupational asthma. Di-isocyanate inhalation has been reported to induce oxidative stress via reactive oxygen and nitrogen species leading to tissue injury. Glutathione transferases (GSTs) and N-acetyltransferases (NATs) are detoxifying enzymes whose general function is to inactivate electrophilic substances. The most important genes regulating these enzymes, i.e., GSTM1, GSTP1, GSTT1, NAT1, and NAT2 have polymorphic variants resulting in enhanced or lowered enzyme activities. Since inability to detoxify harmful oxidants can lead to inflammatory processes involving activation of bronchoconstrictive mechanisms, we studied whether the altered GST and NAT genotypes were associated with bronchial hyperreactivity (BHR) in patients with di-isocyanate exposure related occupational asthma, irrespective of cessation of di-isocyanate exposure, and adequacy of asthma treatment. Methods: Polymerase chain reaction (PCR) based methods were used to analyze nine common polymorphisms in GSTM1, GSTM3, GSTP1, GSTT1, NAT1, and NAT2 genes in 108 patients with diagnosed occupational di-isocyanate-induced asthma. The genotype data were compared with spirometric lung function and BHR status at diagnosis and in the follow-up examination on average 11 years (range 1–22 years) after the asthma diagnosis. Serum IgE and IL13 levels were also assessed in the follow-up phase. Results: An association between BHR and GSTP1 slow activity (Val105/Val105) genotype was demonstrated in the subjects at the follow-up phase but not at the diagnosis phase. Moreover, the patients with the GSTP1 slow activity genotype exhibited characteristics of Th-2 type immune response more often compared to those with the unaltered GSTP1 gene. Interestingly, all 10 patients with the GSTP1 slow activity genotype had both the GSTM3 slow activity genotype and the unaltered GSTT1 gene. Discussion: The results suggest associations of the low activity variants of the GSTP1 gene with BHR. The fact that these associations came up only at the follow-up phase when the subjects were not any more exposed to di-isocyanates, and used asthma medication, suggest that medication and environmental factors influence the presentation of these associations. However, due to the exploratory character of the study and relatively small study size, the findings remain to be confirmed in future studies with larger sample sizes.
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spelling pubmed-67944152019-10-24 Associations Between Glutathione-S-Transferase Genotypes and Bronchial Hyperreactivity Patients With Di-isocyanate Induced Asthma. A Follow-Up Study Leppilahti, Jussi Majuri, Marja-Leena Sorsa, Timo Hirvonen, Ari Piirilä, Päivi Front Med (Lausanne) Medicine Introduction: Di-isocyanates TDI (toluene di-isocyanate), MDI (diphenylmethane di-isocyanate), and HDI (hexamethylene di-isocyanate) are the most common chemicals causing occupational asthma. Di-isocyanate inhalation has been reported to induce oxidative stress via reactive oxygen and nitrogen species leading to tissue injury. Glutathione transferases (GSTs) and N-acetyltransferases (NATs) are detoxifying enzymes whose general function is to inactivate electrophilic substances. The most important genes regulating these enzymes, i.e., GSTM1, GSTP1, GSTT1, NAT1, and NAT2 have polymorphic variants resulting in enhanced or lowered enzyme activities. Since inability to detoxify harmful oxidants can lead to inflammatory processes involving activation of bronchoconstrictive mechanisms, we studied whether the altered GST and NAT genotypes were associated with bronchial hyperreactivity (BHR) in patients with di-isocyanate exposure related occupational asthma, irrespective of cessation of di-isocyanate exposure, and adequacy of asthma treatment. Methods: Polymerase chain reaction (PCR) based methods were used to analyze nine common polymorphisms in GSTM1, GSTM3, GSTP1, GSTT1, NAT1, and NAT2 genes in 108 patients with diagnosed occupational di-isocyanate-induced asthma. The genotype data were compared with spirometric lung function and BHR status at diagnosis and in the follow-up examination on average 11 years (range 1–22 years) after the asthma diagnosis. Serum IgE and IL13 levels were also assessed in the follow-up phase. Results: An association between BHR and GSTP1 slow activity (Val105/Val105) genotype was demonstrated in the subjects at the follow-up phase but not at the diagnosis phase. Moreover, the patients with the GSTP1 slow activity genotype exhibited characteristics of Th-2 type immune response more often compared to those with the unaltered GSTP1 gene. Interestingly, all 10 patients with the GSTP1 slow activity genotype had both the GSTM3 slow activity genotype and the unaltered GSTT1 gene. Discussion: The results suggest associations of the low activity variants of the GSTP1 gene with BHR. The fact that these associations came up only at the follow-up phase when the subjects were not any more exposed to di-isocyanates, and used asthma medication, suggest that medication and environmental factors influence the presentation of these associations. However, due to the exploratory character of the study and relatively small study size, the findings remain to be confirmed in future studies with larger sample sizes. Frontiers Media S.A. 2019-10-09 /pmc/articles/PMC6794415/ /pubmed/31649932 http://dx.doi.org/10.3389/fmed.2019.00220 Text en Copyright © 2019 Leppilahti, Majuri, Sorsa, Hirvonen and Piirilä. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Leppilahti, Jussi
Majuri, Marja-Leena
Sorsa, Timo
Hirvonen, Ari
Piirilä, Päivi
Associations Between Glutathione-S-Transferase Genotypes and Bronchial Hyperreactivity Patients With Di-isocyanate Induced Asthma. A Follow-Up Study
title Associations Between Glutathione-S-Transferase Genotypes and Bronchial Hyperreactivity Patients With Di-isocyanate Induced Asthma. A Follow-Up Study
title_full Associations Between Glutathione-S-Transferase Genotypes and Bronchial Hyperreactivity Patients With Di-isocyanate Induced Asthma. A Follow-Up Study
title_fullStr Associations Between Glutathione-S-Transferase Genotypes and Bronchial Hyperreactivity Patients With Di-isocyanate Induced Asthma. A Follow-Up Study
title_full_unstemmed Associations Between Glutathione-S-Transferase Genotypes and Bronchial Hyperreactivity Patients With Di-isocyanate Induced Asthma. A Follow-Up Study
title_short Associations Between Glutathione-S-Transferase Genotypes and Bronchial Hyperreactivity Patients With Di-isocyanate Induced Asthma. A Follow-Up Study
title_sort associations between glutathione-s-transferase genotypes and bronchial hyperreactivity patients with di-isocyanate induced asthma. a follow-up study
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794415/
https://www.ncbi.nlm.nih.gov/pubmed/31649932
http://dx.doi.org/10.3389/fmed.2019.00220
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