Genetic polymorphism of GSTM1 and antioxidant supplementation influence lung function in relation to ozone exposure in asthmatic children in Mexico City (original) (raw)
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GSTM1 and GSTP1 and respiratory health in asthmatic children exposed to ozone
European Respiratory Journal, 2006
Acute exposure to ozone has been related to a wide spectrum of health effects in susceptible individuals. Genetic factors may influence interindividual variation in ozone response. The current authors investigated the relationships between common polymorphisms in two genes involved in response to oxidative stress, i.e. glutathione S-transferases M1 (GSTM1) and P1 (GSTP1), and both respiratory symptoms and lung function in response to ozone among childhood asthmatics. A total of 151 asthmatic children, who were participants in a randomised controlled trial of antioxidant vitamin supplementation in Mexico City, were studied. Children were genotyped using PCR methods and followed from October 1998-April 2000. Increases in reported breathing difficulty were associated with ozone exposure in children with GSTM1 null (8%, 95% confidence interval (CI) 1-15%, per 20-ppb increase in 1-h maximum daily average over 7 days) or GSTP1 Valine/Valine (Val/Val) genotypes (14%, 95% CI 5-25%). In children with both GSTM1 null and GSTP1 Val/Val genotypes, the increase in breathing difficulty associated with a 20-ppb increase in ozone exposure was even greater (21%, 95% CI 5-39%). GSTP1 genotypes were not significantly associated with ozone-related lung function changes. In conclusion, asthmatic children with glutathione S-transferase M1 null and glutathione S-transferase P1 Valine/Valine genotypes appear more susceptible to developing respiratory symptoms related to ozone exposure.
Background: We previously reported that asthmatic children with GSTM1 null genotype may be more susceptible to the acute effect of ozone on the small airways and might benefit from antioxidant supplementation. This study aims to assess the acute effect of ozone on lung function ) in asthmatic children according to dietary intake of vitamin C and the number of putative risk alleles in three antioxidant genes: GSTM1, GSTP1 (rs1695), and NQO1 (rs1800566). Methods: 257 asthmatic children from two cohort studies conducted in Mexico City were included. Stratified linear mixed models with random intercepts and random slopes on ozone were used. Potential confounding by ethnicity was assessed. Analyses were conducted under single gene and genotype score approaches. Results: The change in FEF 25-75 per interquartile range (60 ppb) of ozone in persistent asthmatic children with low vitamin C intake and GSTM1 null was −91.2 ml/s (p = 0.06). Persistent asthmatic children with 4 to 6 risk alleles and low vitamin C intake showed an average decrement in FEF 25-75 of 97.2 ml/s per 60 ppb of ozone (p = 0.03). In contrast in children with 1 to 3 risk alleles, acute effects of ozone on FEF 25-75 did not differ by vitamin C intake.
Journal of Allergy and Clinical Immunology, 2009
Glutathione-S-Transferase Mu 1 null genotype has been reported to be a risk factor for acute respiratory disease associated with increases in ambient air ozone. Ozone is known to cause an immediate decrease in lung function and increased airway inflammation. However, it is not known if GSTM1 modulates these ozone responses in vivo in humans Objective-The purpose of this study was to determine if the GSTM1 null genotype modulates ozone responses in humans.
PLoS ONE, 2013
Background: There are limited studies on the role of interaction between exposure to ambient air pollution and glutathione-S-transferase (GST) P1 on the risk of asthma/wheezing among children, which provided suggestive, but inconclusive results. Methods: To assess the joint effect of air pollutants and GSTP1 on asthma/wheezing, we conducted a nationwide crosssectional study of 3,825 children in Taiwan Children Health Study. The studied determinants were three GSTP1 Ile105Val (rs 1695) genotypes (Ile-Ile; Ile-Val and Val-Val) and expoure to ambient air pollutants. We used routine air-pollution monitoring data for ozone (O 3) and particles with an aerodynamic diameter of 2.5 mm or less (PM 2.5). The effect estimates were presented as odds ratios (ORs) per interquartile changes for PM 2.5 and O 3. Findings: In a two-stage hierarchical model adjusting for confounding, the risk of asthma was negatively associated with PM 2.5 (adjusted odds ratio (OR) 0.60; 95% confidence interval (CI) 0.45, 0.82) and O 3 (OR 0.74; 95% CI 0.60, 0.90) among Ile105 homozygotes, but positively associated with PM 2.5 (OR 1.52; 95% CI 1.01, 2.27) and O 3 (OR 1.19; 95% CI 0.91, 1.57) among those with at least one val105 allele (interaction p value = 0.001 and 0.03, respectively). A similar tendency of effect modification between PM 2.5 and O 3 and GSTP1 on wheezing was found. Conclusion: Children who carried Ile105 variant allele and exposed to PM 2.5 and O 3 may be less likely to occurrence of asthma/wheezing.
Effects of antioxidant enzyme polymorphisms on ozone-induced lung function changes
European Respiratory Journal, 2007
Chronic exposure to ozone (O 3) can cause changes in lung function that may reflect remodelling of small airways. It is likely that antioxidant enzyme function affects susceptibility to O 3. The aim of the present study was to determine whether polymorphisms in antioxidant enzyme (GSTM1, GSTP1 and NQO1) genes affect the risk of lung function changes related to chronic exposure to O 3. In total, 210 young adults who participated in a previous study, which showed a relationship between lifetime exposure to O 3 and decreased lung function, were genotyped. Multivariable linear regression was used to model sex-specific associations between genotypes and O 3-related lung function changes, adjusting for height, weight, lifetime exposure to nitrogen dioxide and particles with a 50% cutoff aerodynamic diameter of 10 mm, and self-identified race/ethnicity. The GSTM1-null/NQO1 Pro187Pro-combination genotype was significantly associated with increased risk of an O 3-related decrease in mean forced expiratory flow between 25-75% of forced vital capacity in females (parameter estimate¡SE-75¡35 mL?s-1), while the GSTP1 Val105 variant genotypes were significantly associated with greater risk of an O 3-related decrease in mean forced expiratory flow at 75% of forced vital capacity in males (-81¡31 mL?s-1). GSTM1-null status was not significantly associated with any O 3-related changes in lung function in either sex. The current authors conclude that the effects of antioxidant enzyme gene polymorphisms on the risk of decreased lung function related to chronic exposure to ozone may be modified by sexspecific factors.
Glutathione-S-transferase (GST) P1, GSTM1, exercise, ozone and asthma incidence in school children
Thorax, 2009
Background-Because asthma has been associated with exercise and ozone exposure, an association likely mediated by oxidative stress, we hypothesized that GSTP1, GSTM1, exercise and ozone exposure have interrelated effects on asthma pathogenesis. Methods-We examined associations of the well characterized null variant of GSTM1 and four SNPs that characterized common variation in GSTP1 with new-onset asthma in a cohort of 1,610 school children. Children's exercise and ozone-exposure status were classified using participation in team sports and community-specific ozone levels, respectively. Results-A two SNP model (rs6591255, rs1695 [Ile105Val]) best captured the association between GSTP1 and asthma. Compared to children with common alleles for both the SNPs, the risk of asthma was lower for those with the Val allele of Ile105Val (HR 0.60, 95% CI 0.4, 0.8) and higher for the variant allele of rs6591255 (HR 1.40, 95%CI 1.1-1.9). Asthma risk increased with level of exercise among ile 105 homozygotes but not among those with at least one val 105 allele (interaction p-value=0.02). Risk was highest among ile 105 homozygotes who participated in ≥3 sports in the highozone communities (HR: 6.15, 95%CI: 2.2-7.4). GSTM1 null was independently associated with asthma and showed little variation with air pollution or GSTP1 genotype. These results were consistent in two independent fourth-grade cohorts in the study population recruited in 1993 and 1996. Conclusion-Children who inherit a val 105 variant allele may be protected from the increased risk of asthma associated with exercise, especially in high-ozone communities. GSTM1 null genotype was associated with increased risk of asthma.
American Journal of Respiratory and Critical Care Medicine, 2003
Nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase (NQO1) and glutathione S-transferase (GST) M1 are phase II enzymes important in response to oxidative stress, such as occurs during exposure to ozone. We examined the relationship between functionally significant polymorphisms in NQO1 (Pro187Ser) and GSTM1 (homozygous deletion) and asthma risk in children with high lifetime exposure to ozone. We enrolled children with asthma from the allergy referral clinic at a public pediatric hospital in Mexico City, together with their parents. We assayed for the Pro187Ser polymorphism in NQO1 using a polymerase chain reaction-restriction fragment length polymorphism assay and for the presence of GSTM1 by polymerase chain reaction among 218 case-parent triads. We did not find strong evidence of an association between NQO1 genotype alone and asthma risk. However, among subjects with homozygous deletion of GSTM1, carriers of a serine allele were at significantly reduced risk of asthma compared with Pro/Pro homozygotes (relative risk ϭ 0.4; 95% confidence interval, 0.2-0.8). The p value for difference in relative risk for NQO1 by GSTM1 genotype ϭ 0.013. These data are consistent with a protective effect of the NQO1 Ser allele in this population of GSTM1-null children with high ozone exposure.
Ozone, Oxidant Defense Genes, and Risk of Asthma during Adolescence
American Journal of Respiratory and Critical Care Medicine, 2008
Rationale: Although oxidative stress is a cardinal feature of asthma, the roles of oxidant air pollutants and antioxidant genes Heme oxygenase1 (HMOX1), catalase (CAT) and manganese superoxide dismutase (MNSOD) in asthma pathogenesis have yet to be determined. Objective: We hypothesized that the functional polymorphisms of HMOX1 ((GT) n repeat), CAT (-262C>T-844C>T) and MNSOD-(Ala-9Val) are associated with new onset asthma, and the effects of these variants vary by exposure to ozone, a potent oxidant air pollutant. Method: We assessed this hypothesis in a population-based cohort of non-Hispanic (N=1,125) and Hispanic-White (N=586) children who resided in 12 California communities and who were followed annually for 8 years to ascertain new onset asthma. Measurements: Air pollutants were continuously measured in each of the study communities during the 8 years of study follow-up. Main Result: HMOX1 'short' alleles (< 23 repeats) were associated with a reduced risk for new onset asthma among non-Hispanic Whites (Hazard ratio(HR) 0.64, 95% CI 0.41-0.99). This protective effect was largest in children residing in low-ozone communities (HR 0.48, 95% CI 0.25-0.91) (interaction p-value=0.003). Little evidence for an association with HMOX1 was observed among Hispanic children. In contrast, Hispanic children with a variant of the CAT-262 'T' allele (CT or TT) had an increased risk for asthma (HR 1.78, p-value=0.01). The effects of these polymorphisms were not modified by personal smoking or secondhand-smoke exposure. 4 Conclusions: Functional promoter variants in CAT and HMOX1 showed ethnic-specific associations with new onset asthma. Oxidant gene protection was restricted to children living in low-ozone communities.
Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy, 2004
Background Polymorphisms at the glutathione S-transferase (GST) P1 locus were associated with asthma-related phenotypes and bronchial hyper-responsiveness. Objective This study investigated whether GSTP1 genotypes and outdoor air pollution were interactive risk factors on childhood asthma. Methods Four hundred and thirty-six subjects were recruited for oral mucosa samplings from 2853 fourth-to ninth-grade schoolchildren from three districts with different air pollution levels in southern Taiwan. PCR-based assays were performed by oral mucosa DNA to determine GSTP1 genotypes. We also conducted a nested case-control study comprising 61 asthmatic children and 95 controls confirmed by International Study of Asthma and Allergies in Childhood questionnaire results and methacholine challenge test. Multiple logistic regression was used to adjust for potential confounding factors. Results All participants were homozygous at the Ala-114 locus. Although only a marginally significant association existed between the frequency of homozygosity at the Ile-105 locus and asthma when air pollution was not considered, we found a significant gene-environmental interaction between GSTP1-105 alleles and air pollution after adjusting for confounders (P 5 0.035). Specifically, we found that compared with participants carrying any Val-105 allele in low air pollution, those who are Ile-105 homozygotes in high air pollution district had a significantly increased risk of asthma (adjusted odds ratio (AOR) 5 5.52, 95% confidence interval (CI) 5 1.64-21.25). Compared with participants carrying any Val-105 allele, in high air pollution district, children with Ile-105 homozygotes had a significantly increased risk of asthma (AOR 5 3.79, 95% CI 5 1.01-17.08), but those who carried two Ile-105 alleles in low or moderate air pollution districts did not show similar tendencies. The risk of asthma also revealed a clear dose-response relationship with outdoor air pollution in children with Ile-105 homozygotes. Conclusion Our result suggests a gene-environmental interaction between GSTP1-105 genotypes and outdoor air pollution on childhood asthma.
Ozone exposure, antioxidant genes, and lung function in an elderly cohort: VA Normative Aging Study
Background: Ozone exposure is known to cause oxidative stress. We investigated the acute effects of ozone (O 3 ) on lung function in the elderly, a suspected risk group. We then investigated whether genetic polymorphisms of antioxidant genes (heme oxygenase-1 [HMOX1] and glutathione S-transferase pi [GSTP1]) modified these associations. Methods: We studied 1,100 elderly men from the Normative Aging Study whose lung function (forced vital capacity [FVC] and forced expiratory volume in one second [FEV1]) was measured every 3 years from 1995-2005. We genotyped the GSTP1 Ile105Val and Ala114Val polymorphisms and the (GT)n repeat polymorphism in the HMOX1 promoter, classifying repeats as short (n<25) or long (n≥ 25). Ambient O 3 was measured continuously at locations in the Greater Boston area. We used mixed linear models, adjusting for known confounders. Results: A 15 ppb increase in O 3 during the previous 48 hours was associated with a 1.25% decrease in FEV1 (95% CI: -1.96%, -0.54%). This estimated effect was worsened with either the presence of a long (GT)n repeat in HMOX1 (-1.38%, 95% CI: -2.11%, -0.65) or the presence of an allele coding for Val105 in GSTP1 (-1.69%, 95% CI: -2.63%, -0.75). A stronger estimated effect of O 3 on FEV1 was found in subjects carrying both the GSTP1 105Val variant and the HMOX1 long (GT)n repeat (-1.94%, 95% CI: -2.89%, -0.98%). Similar associations were also found between FVC and ozone exposure. Conclusions: Our results suggest that ozone has an acute effect on lung function in the elderly, and the effects may be modified by the presence of specific polymorphisms in antioxidant genes.