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  • br Conflict of interest br Acknowledgement br Exposure to

    2022-05-25


    Conflict of interest
    Acknowledgement
    Exposure to tobacco smoke in early life has been found to increase the risk of developing asthma and lung function deficits in adolescence and adulthood., , , , However, not all children exposed to tobacco smoke in early life develop asthma, which suggests differences in genetic susceptibility. There is increasing interest in genetic polymorphisms involved in oxidative stress pathways. One of the major enzymatic regulators of oxidative stress in the body is through glutathione S-transferase (GST) enzymes encoded by GST genes. GST enzymes are involved in the detoxification of a variety of foreign chemicals, including several reactive tobacco metabolites and reactive oxygen species., , Three major GST enzymes are encoded by the , , and genes. Deficiencies in the enzyme activity in and are typically caused by deletion of the genes (null genotypes), whereas the most studied variant contains two polymorphisms: an A→G transition at codon 105, which leads to the ile105val amino MK2 Inhibitor IV substitution., Substituting Ile for Val significantly lowers GST enzyme activity. However, a 2010 systematic review including 22 studies did not support a substantial direct role of GST genetic polymorphisms in the development of asthma. The authors instead suggested the possibility of a gene-environment interaction influencing the risks of asthma and impaired lung function. However, there are a limited number of longitudinal studies focusing on gene-environment interactions and measuring outcomes at different time periods in older children and adolescents, especially concerning the effect on lung function. We aimed to investigate the relationship between GST genes and early life tobacco smoke exposure and their interaction on asthma and lung function at 12 and 18 years of age in the Melbourne Atopy Cohort Study (MACS). We have previously found in this cohort that early life tobacco MK2 Inhibitor IV smoke exposure was associated with asthma and lung function impairment at 18 years in girls. We now investigate the potential for GST gene (, , and ) polymorphisms to modify these associations. Materials and Methods
    Discussion In this study, we found evidence that individuals with GSTM1 and GSTT1 null genotypes were more susceptible to reduced FEV1 and FVC at 18 years when exposed in early life to second-hand smoke. Similar associations were found for lung function at 12 years of age for early life smoke exposure and GSTT1. Although the trend was similar for asthma outcomes, interactions between the effects of GST genes and parental smoking were not significant. The relevance of GST deficiency for lung function impairment and respiratory symptoms in children exposed to oxidative inhalants has been suggested by previous epidemiologic studies.20, 21, 22 The Perth Infant Asthma Follow-up cohort investigated infant lung function at 12 months and found evidence for an interaction between smoke exposure in utero and GSTT1 genes. Kabesch et al conducted a cross-sectional study of schoolchildren and found evidence suggesting increased susceptibility for asthma/wheeze in children with GSTM1/GSTT1 null; however, the interactions were not significant. Our findings in a prospective birth cohort strengthen this growing body of evidence on this association up to late adolescence. These findings are supported by strong biologic plausibility. Exposure to early life tobacco smoke, especially before 2 years of age, can damage the rapidly growing alveolar cells and stimulate inflammatory responses that may lead to development of impaired lung function and asthma in later life.1, 2, 23 GST genes generate enzymes that detoxify and catalyze the conjugation of glutathione with oxidant substrates, including tobacco-derived substances. Through this mechanism, they may reduce inflammation and lung injury when exposed to oxidative stress. Therefore, this may lead to impaired lung function when an individual has a GST gene deficiency (null genotype) or a reduction in enzymatic activity associated with genetic polymorphisms.