We found few differential effects on lung function for

We found few differential effects on lung function for exposure to mother’s and father’s smoking in relation to GSTM1 and GSTT1. However, effects related to mother’s or father’s smoking may differ because mothers tend to spend greater amounts of time with young children and mothers may also smoke during pregnancy. This exposure in utero is thought to have different effects on the child than second-hand smoke exposure after birth. Although there was a suggestion that mothers smoking had a greater effect on lung function for children with GSTT1 null genotypes and fathers smoking for GSTM1 null genotypes, we were unable to draw definitive conclusions. The slight differences we observed may simply be because of lack of power associated with the small numbers of smoking mothers. We did not find significant associations with asthma. Nicotine exposure in utero/early life may cause a global reduction in both FEV1 and FVC rather than preferentially affecting FEV1 as is the usual scenario for people with asthma. Another possible reason could be that SB 747651A dihydrochloride is a dichotomous outcome, whereas lung function is a continuous outcome, leading to less power to detect an effect with asthma. A cross-sectional study investigating interactive effect between GST genes and passive smoking also found little effect on childhood asthma for GSTM1/GSTT1 null groups although their sample size was > 3,000. We found that among children with GSTM1 present, those exposed to father’s smoking in early life had an increased risk of improved lung function (FVC) compared with those unexposed. This result was inconsistent and unexpected. It is possible that this finding may be related to the small numbers of children exposed to both tobacco smoke and genotype. This contrary finding may also be because of compensation by other antioxidant genes or networks which are more successful at detoxifying substances other than tobacco smoke. There is evidence from two studies that a polymorphism (Ser187) of an alternative antioxidant enzyme, quinone oxidoreductase 1, provides a protective effect among GSTM1 null subjects.26, 27 An alternative hypothesis is that tobacco smoke exposure in early life may induce upregulation of GST enzymes through DNA methylation changes. These improved oxidation defenses may then protect the lung from oxidative threats in the environment (other than tobacco smoke) that are also related to lung function. There is no conclusive support of this hypothesis in the literature. Studies examining the GSTP1 105 variant reported that associations vary depending on the specific risk alleles of GSTP1.28, 29, 30 Similar to our findings, some research exploring second-hand smoke has found no evidence of GSTP1 interaction on asthma outcomes,31, 32, 33 but studies investigating lung function were limited. We found no evidence of interaction for GSTP1 genes with early life smoking and lung function impairment or asthma (interaction P > .10) One explanation may be because of the small numbers limiting our power to find associations. A further reason might be because the effect of GSTP1 genes on allergy risk and lung function varies for different pollutants. For instance, enzymes encoded by Val genotypes have a sevenfold greater catalytic efficiency for polycyclic aromatic hydrocarbon diol epoxides but a threefold lower efficiency for 1-chloro-2,4-dinitrobenzene than those with Ile genotypes.34, 35 Careful measurement and definitions of pollutant exposures may be necessary before these relationships become clear.
Conclusions We found evidence that the impact of early life tobacco smoke exposure on reducing adolescent lung function was modified by GST gene polymorphisms, particularly GSTT1. These interactions may help to explain the inconsistent effects seen when either tobacco smoke exposure or GST genotypes were investigated alone for their effects on respiratory health.
Acknowledgments Author contributions: At the 18-year follow-up, S. C. D., M. J. A., and A. J. L. were all involved with acquiring funding and/or establishing study directions and protocols. J. H. coordinated the blood collection and DNA genotyping at the 18-year follow-up. X. D. led the analysis and interpretation of the data with support from S. C. D., C. J. L., G. B., N. T. W., and J. L. P. X. D. wrote the initial draft of the manuscript, which was critically revised for important content by all the authors. All authors approved the final version of the article.