Interaction of Glutathione S-Transferase M1, T1, and P1 Genes With Early Life Tobacco Smoke Exposure on Lung Function in Adolescents

doi:10.1016/j.chest.2018.08.1079

Chest

Volume 155, Issue 1, January 2019, Pages 94-102

Part of this article has been presented in poster form at the 29th Annual Scientific Conference of the International Society of Environmental Epidemiology (ISEE 2017), September 27, 2017, Sydney, NSW, Australia.

https://doi.org/10.1016/j.chest.2018.08.1079 Get rights and content

Background

Glutathione S-transferase (GST) genes are involved in the management of oxidative stress in the lungs. We aimed to determine whether they modify the associations between early life smoke exposure and adverse lung health outcomes.

Methods

The Melbourne Atopy Cohort study (a high-risk birth cohort) enrolled 620 children and followed them prospectively from birth. We recorded perinatal tobacco smoke exposure, asthma, and lung function at 12 (59%) and 18 years (66%) and genotyped for GSTM1, GSTT1, and GSTP1 (69%).

Results

GST genotypes were found to interact with tobacco smoke exposure on lung function outcomes (P interaction ≤ .05). Only among children with GSTT1 null genotypes was exposure to mother’s, father’s, or parental tobacco smoke in early life associated with an increased risk of reductions in prebronchodilator (BD) FEV₁ and FVC at both 12 and 18 years. These associations were not seen in children with GSTT1 present. Similarly, only among children with GSTM1 null genotypes was exposure to father’s or parental smoking associated with reductions in pre- and post-BD FEV₁ and FVC at 18 years. Only among children with Ile/Ile genotypes of GSTP1 was exposure to mother’s smoking associated with increased risk of reduced FEV₁ at 18 years, but this was not the case among children with Val/Val or Ile/Val genotypes.

Conclusions

Our study provides evidence of interaction between early tobacco smoke exposure and GST genotypes on lung function. Carriers of GST null mutations and GSTP1 Ile/Ile alleles may be more susceptible when exposed to tobacco smoke in early life. These findings support stronger recommendations to protect all infants from tobacco smoke exposure.

Trial Registry

Australian and New Zealand Clinical Trials Registry; No.: ACTRN12609000734268; URL: http://www.anzctr.org.au/

Section snippets

Study Population

Between 1990 and 1994, 620 children were recruited (while in utero) into the MACS (Fig 1). All children had at least one first degree family member with allergic disease. Details of the study have been published elsewhere.¹⁴ Data on exposures and respiratory outcomes for these participants were collected from birth to 18 years of age. MACS initially began as a randomized controlled trial of infant formula on weaning,¹⁵ but has since been followed as an observational cohort. The initial phases

Results

MACS recruited slightly more girls (51.1%) than boys (48.9%). Only 38 (6.1%) were exposed to mother’s smoking, and 112 (18.2%) were exposed to father’s smoking. Overall, 127 (20.5%) were exposed to parental smoking. Spirometry was available for 366 (59%) and 411 (66.3%) at 12 and 18 years, respectively (Fig 1). GSTM1/GSTT1 data were available for 428 participants, and GSTP1 data were available for 429 participants (Table 1).

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

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.

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A study104 of US children aged 6–10 years showed an association between maternal smoking and reduced lung function, which was more common in children whose mothers were carriers of a GSTM1 deletion (and thus had no functional enzyme). An Australian study105 also showed that carriers of null mutations in glutathione S-transferase genes and GSTP1 genes with Ile/Ile alleles have an increased likelihood of developing lung function deficits by early-to-late adolescence when exposed to tobacco smoke in early life. Animal models have also shed light on the adverse respiratory effects of prenatal and early-life exposure to smoke.
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Thus, we speculated that seasonal difference in effects of individual PAHs in PM2.5 exposure on lung function may be related to spending more time on the outdoor environment which likely increase their exposure to traffic emission in warm season. Recent studies suggested that individuals with spending more time on moderate-vigorous physical activity may increase PM2.5 deposited in the lungs, induced oxidative stress and inflammation response, leading to impairment of lung function (Dai et al., 2019; Duecker et al., 2018; Xu et al., 2018). Besides, after entering the body, PAHs can affect lung function by inducing oxidative stress and airway inflammation (Kuang et al., 2020).
Personal exposure to fine particulate matter (PM_2.5)-bound polycyclic aromatic hydrocarbons (PAHs) can cause serious adverse health effects. However, limited information is available on the impact of a mixture of PAHs in air-borne PM_2.5 on lung function. We conducted a repeated-measures pilot study for four seasons during the period of 2014–2015, monitored the concentrations of 13 PAHs in PM_2.5 samples from the outdoor and indoor microenvironments using a gas chromatograph-mass spectrometry, estimated inhaled dose of PM_2.5-bound PAHs based on the outdoor and indoor PM_2.5-bound PAHs concentrations as well as individual time-activity diary, and analyzed independent and joint effects of PM_2.5-bound 13 PAHs on lung function by linear mixed effect (LME) and Bayesian kernel machine regression (BKMR) models, respectively. LME models indicated the negative association of phenanthrene or benzo[a]pyrene with forced expiratory volume in 1 s (FEV1) or forced vital capacity (FVC) in warm season. BKMR models revealed that an overall negative association of the mixture of 13 PAHs in PM_2.5 with FVC, FEV1, PEF or MVV values in warm season but only overall negative association of the mixture of 13 PAHs in PM_2.5 with MVV values in cold season. In warm season, young adults with higher exposure to certain PAHs or the mixture of 13 PAHs in PM_2.5 showed significant impairment in lung function, implying that health risk assessment of the mixture of PAHs in PM_2.5 attributed to PM_2.5 from traffic emission.
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Total doubling of days of acetaminophen use was associated with increased risk of asthma for people with Ile/Ile genotypes, and individuals with GSTM1 null and GSTT1 present genotypes were at risk of lower lung function by the age of 18 years when given acetaminophen for nonrespiratory indications, compared with those with GSTM1 present/GSTT1 null genotypes. In a previous analysis of this cohort, we found little evidence of a main association between GSTM1/T1 null genotypes for either lung function or current asthma, except that we found some evidence that carriers of GSTP1 with Ile/Ile genotypes were at an increased risk of reduced post-BD FVC at 18 years compared with those with Ile/Val or Val/Val.24 However, in the current analysis, we found some evidence of the effect of an interaction between acetaminophen use from birth to age 2 years and GST genotype on the risks of asthma and reduced lung function up to age 18 years.
Although the impact of early life acetaminophen on asthma risk is still not clear, potential interactions with glutathione S-transferase (GST) genes due to reduced antioxidant function in particular polymorphisms, and possible impact on lung function, have never been investigated in adolescents.
We aimed to investigate associations between early life acetaminophen use and adolescent asthma and lung function and to assess potential interactions by GST polymorphisms.
Acetaminophen use was recorded 18 times up to age 2 years (n = 575 [92.7%]). Participants were genotyped for GST polymorphisms (GSTM1/T1/P1) (n = 429 [69.2%]). Asthma and lung function were measured at 12 (n = 365 [58.9%]) and 18 years (n = 413 [66.6%]). Regression models assessed associations and interactions.
Doubling of days of acetaminophen use was associated with reduced prebronchodilator FEV₁/forced vital capacity (β coefficient, −0.10; 95% CI, −0.19 to −0.01) and midexpiratory flow (−0.09; 95% CI, −0.18 to 0) at 18 years, but this association was not found when restricted for nonrespiratory reasons, suggesting confounding by indication. However, in children with GSTM1 null and GSTT1 present, increasing acetaminophen use for nonrespiratory reasons was associated with reduced FEV₁ and midexpiratory flow at 18 years (interaction between GSTM1/T1 and acetaminophen P < .05). Increased acetaminophen use was associated with asthma at 18 years for children with GSTP1 Ile/Ile (odds ratio, 1.66; 95% CI, 1.07 to 2.57), but not other GSTP1 genotypes.
These novel findings need to be investigated for consistency in other studies but suggest that children carrying risk genotypes may be susceptible to respiratory consequences from acetaminophen use.
Early-Life Exposure to Oral Antibiotics and Lung Function Into Early Adulthood
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We found no evidence that children with GST null polymorphisms were at increased risk of adverse lung function outcomes with increasing antibiotic exposure in early life. We have previously reported from this cohort30 and older cohorts14 that children with GSTT1 null polymorphisms are at increased risk of asthma if exposed to increased oxidative stress from other sources, including traffic-related air pollution; in addition, carriers of GSTP1 ile/ile genotypes are more susceptible to the impact of passive smoke exposure in early life on lung function outcomes.13 One of the mechanisms by which early-life antibiotic exposure could affect lung function is by induction of airway oxidative stress.
Although there is ongoing debate regarding the impact of early postnatal exposure to antibiotics on the development of asthma, the possibility that antibiotic exposure may impair lung function has not previously been examined. Furthermore, it is unclear if specific types of antibiotics may have a greater effect, or if children with genetic mutations in the oxidative stress response glutathione S-transferase (GST) superfamily may be at greater risk.
Parent-reported data of childhood antibiotic use from birth to 2 years, including type and indication, were collected from a birth cohort of 620 infants with a family history of allergy. Spirometry was performed at age 12 and 18 years, and results are presented as z scores. Participants were genotyped for GST-P, GST-M, and GST-T polymorphisms. Linear regression models were used to investigate the associations while adjusting for confounding factors.
Neither increasing days of exposure nor earlier exposure to antibiotics was associated with reduced FEV₁ (at 18 years, per doubling of days of exposure = –0.03 z score units; 95% CI, –0.11 to 0.04) or FVC (< 0.01; 95% CI, –0.08 to 0.07). There was no evidence that GST-risk polymorphisms (M1, P1, and T1) increased susceptibility, and specific types of antibiotics also did not increase risk of lung function deficits.
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The interaction effects of coke oven emissions exposure and metabolic enzyme Gene variants on total antioxidant capacity of workers
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Citation Excerpt :
This study also found that the T-AOC of GSTM1 (-) was lower than that of GSTM1 (+) in exposed group, indicated that GSTM1 (-) may be the promote factor of oxidative damage in COEs exposure. The interactions of gene-environment play a decisive role in the phenotype and genotype of many complex diseases (Dai et al., 2019; Wang et al., 2019). Long-term exposure to PAHs may result in a significant increase in the level of reactive oxygen free radicals in the GSTM1 (-) individual.
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536 coke oven workers and 238 healthy controls were recruited. T-AOC of plasma was determined with kit. Five polymorphic loci of GSTT1 (+/-), GSTM1 (+/-), GSTP1 rs1695, CYP2E1 rs6413432 and CYP2E1 rs3813867 were detected by polymerase chain reaction and restriction fragment length polymorphism.
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: FUNDING/SUPPORT: This study was funded by the National Health and Medical Research Council of Australia, VicHealth, The Asthma Foundation and Nestle Australia. X. D., S. C. D., G. B., J. L. P., A. J. L., and C. J. L. are funded by the National Health and Medical Research Council of Australia; and G. B. and J. L. P. were funded by the Centre for Air Quality & Health Research and Evaluation of Australia in 2016-2017, and are funded by the National Health and Medical Research Council of Australia in 2018.

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Chest

Original Research: AsthmaInteraction of Glutathione S-Transferase M1, T1, and P1 Genes With Early Life Tobacco Smoke Exposure on Lung Function in Adolescents

Background

Methods

Results

Conclusions

Trial Registry

Section snippets

Study Population

Results

Discussion

Conclusions

Acknowledgments

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Environ Toxicol Pharmacol

Biochem Biophys Res Commun

The effects of second-hand and direct exposure to tobacco smoke on asthma and lung function in adolescence

Paediatr Respir Rev

Effects of early onset asthma and in utero exposure to maternal smoking on childhood lung function

Am J Respir Crit Care Med

In utero and postnatal maternal smoking and asthma in adolescence

Epidemiology

A longitudinal-study of the effects of parental smoking on pulmonary-function in children 6-18 years

Am J Respir Crit Care Med

Glutathione S-transferase polymorphisms and their biological consequences

Pharmacology

Interactive effects of antioxidant genes and air pollution on respiratory function and airway disease: a HuGE review

Am J Epidemiol

Association of GST genes polymorphisms with asthma in tunisian children

Mediators Inflamm

Polymorphism at the glutathione S-transferase GSTP1 locus. A new marker for bronchial hyperresponsiveness and asthma

Am J Respir Crit Care Med

Antioxidant gene polymorphisms and susceptibility to a rapid decline in lung function in smokers

Am J Respir Crit Care Med

MRP2 and GSTP1 polymorphisms and chemotherapy response in advanced non-small cell lung cancer

Cancer Chemother Pharmacol

Glutathione-S-transferase genes and asthma phenotypes: a Human Genome Epidemiology (HuGE) systematic review and meta-analysis including unpublished data

Int J Epidemiol

Early smoke exposure is associated with asthma and lung function deficits in adolescents

J Asthma

Cohort Profile: Melbourne Atopy Cohort study (MACS)

Int J Epidemiol

Original Research: Asthma
Interaction of Glutathione S-Transferase M1, T1, and P1 Genes With Early Life Tobacco Smoke Exposure on Lung Function in Adolescents