University of Oulu

Leppilahti, J., Majuri, M.-L., Sorsa, T., Hirvonen, A., & Piirilä, P. (2019). Associations Between Glutathione-S-Transferase Genotypes and Bronchial Hyperreactivity Patients With Di-isocyanate Induced Asthma. A Follow-Up Study. Frontiers in Medicine, 6.

Associations between glutathione-S-transferase genotypes and bronchial hyperreactivity patients with di-isocyanate induced asthma : a follow-up study

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Author: Leppilahti, Jussi1,2; Majuri, Marja-Leena3; Sorsa, Timo4,5,6;
Organizations: 1Department of Periodontology and Geriatric Dentistry, University of Oulu, Oulu, Finland
2Oulu University Hospital, Oulu, Finland
3Finnish Institute of Occupational Health, Helsinki University, Helsinki, Finland
4epartment of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland
5Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland
6Division of Oral Diseases, Department of Dental Medicine, Karolinska Institute, Huddinge, Sweden
7National Supervisory Authority for Welfare and Health, Valvira, Helsinki, Finland
8Unit of Clinical Physiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.5 MB)
Persistent link:
Language: English
Published: Frontiers Media, 2019
Publish Date: 2020-03-26


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 GSTP1 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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Series: Frontiers in medicine
ISSN: 2296-858X
ISSN-E: 2296-858X
ISSN-L: 2296-858X
Volume: 6
Article number: 220
DOI: 10.3389/fmed.2019.00220
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Funding: PP had received a grant from the Nummela Sanatorium Foundation for this study in September 13th, 2012. The grant was received for laboratory and publication costs.
Copyright information: © 2019 Leppilahti, Majuri, Sorsa, Hirvonen and Piirilä. 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.