Genetic Polymorphism of GSTM1 and Antioxidant Supplementation
Influence Lung Function in Relation to Ozone Exposure
in Asthmatic Children in Mexico City
http://www.cdc.gov/genomics/hugenet/ejournal/GSTM1.htm
Colleen Bradley
Rollins School of Public Health
Emory University
The Health Outcome
Asthma is an inflammatory lung condition characterized by repeated episodes of reversible airway constriction; it is the most common chronic disease among children (1). In 2001, 6.3 million children (8.7% of US non-institutionalized children) had an asthma diagnosis (2). Asthma accounts for 14 million missed days of school and $3.2 billion in treatment-related costs annually in children younger than 18 years of age; in addition, the number of children dying from asthma increased threefold from 1976 to 1996 (3).
Asthma has both genetic and environmental components. Certain environmental triggers, such as cockroaches, dust mites, furry pets, mold, tobacco smoke, and ozone, can induce airway inflammation and subsequent asthma symptoms (3, 4). Ozone is a powerful oxidant and toxic air pollutant; ozone-related lung damage can be mitigated by antioxidants present in the fluid compartment of the lungs (4). Glutathione transferases (GSTs) protect cells against damage from oxygen radicals such as those produced by ozone by conjugating them with glutathione so that they may be eliminated from the body. There is substantial variability with regards to the effects of ozone on lung function. Genetic susceptibility by the GSTM1 null genotype, a common homozygous deletion polymorphism of the GSTM1 gene, may reduce the body's capability to respond to oxidative stress imposed by ozone (5).
This paper describes the association between GSTM1 genotype and ozone-related lung function assessed by forced expiratory flow ( FEF 25–75), as well as the effects of antioxidant supplementation (vitamins C and E) by GSTM genotype.
The Finding
Romieu et al. analyzed the relationship of GSTM1 genotype with lung function and response to vitamin C and E in a study of 158 Mexican children with asthma who participated in a clinical trial of antioxidant supplementation. Asthma was classified as intermittent, mild persistent, moderate persistent, or severe based upon National Heart, Lung, and Blood Institute criteria (6). FEF 25–75 was assessed twice weekly during the 12-week follow-up period; tests were conducted at the same time of day and week to limit diurnal variation and involved a standardized and technically sound testing process by one pneumologist. All subjects were genotyped using DNA extracted from whole blood or buffy coat using a differential polymerase chain reaction to distinguish subjects with homozygous deletion of GSTM1 (GSTM1 null genotype) from those with either one or two copies of the gene (GSTM1 positive genotype) (7). Ozone exposure was assessed via ultraviolet photometry at Mexican government air monitoring stations (located within 5 km of each subject's residence), and each subject was assigned values from the closest monitoring station; exposure was assigned as the maximum 1-hour ozone concentration on the day before each spirometric test. Blood levels of vitamins C and E were assessed at baseline and at several points during follow-up to assess compliance.
The GSTM1 null genotype was present in 39% of children, similar genotype prevalence as prior studies with child populations of Mexican descent (8). Among the placebo group, ozone levels were significantly and inversely associated with FEF 25–75 in children with the GSTM1 null genotype (FEF 25–75 decrement of –2.9%, p=0.01); no such association was observed for children with the GSTM1 positive genotype receiving placebo, and this effect was stronger in children with moderate and severe asthma (FEF 25–75 decrement of –4.7%, p=0.002). Children receiving antioxidants had no statistically significant ozone-related reductions in FEF 25–75 regardless of genotype. The beneficial effects of antioxidant supplementation were observed in children with the GSTM1 null genotype (FEF 25–75 difference of 2.7% between the placebo and supplement groups, p=0.09); supplementation among those with the GSTM1 positive phenotype had a small but non-statistically significant positive effect, and the beneficial effects of antioxidants were more evident among children with moderate and severe asthma (FEF 25–75 difference of 4.4% between the placebo and supplement groups, p=0.04).
Romieu et al concluded that the GSTM1 null genotype was associated with greater susceptibility to ozone-related reductions in FEF 25–75; antioxidant supplementation (vitamins C and E) mitigated the effects of genetic susceptibility among children with asthma.
The results of this study provide potentially important implications for a simple clinical intervention for a public health problem associated with high morbidity and healthcare costs. A biologically plausible mechanism of action exists to explain the finding that antioxidant supplementation can mitigate the effect of ozone exposure on asthma. Furthermore, the results indicate that children with the GSTM1 null genotype, who are genetically susceptible to harmful ozone-related oxygen radicals, will benefit most from this treatment. The study methods were strong, accounting for population stratification by including only Mexican children in the study. The clinical trial design allows for better control of confounding through randomization, limits investigator bias through double-blinding, and limits the effect of misclassification of exposure on study results. These study results are promising; however, it is important that they be replicated in populations of different ethnicities and age structures. This study was unable to examine other genotypes that might in tera ct with GSTM1 in relation to ozone response because of sample size; larger intervention trials are needed to study additional glutathione S-transferase and other gene polymorphisms and their in tera ctions with ozone and other environmental asthma triggers.
References
- Asthma FAQ
- National Center for Health Statistics, Fast Stats A-Z: Asthma
- Asthma's Impact on Children and Adolescents
- Mudway IS, et al. Ozone and the lung: a sensitive issue. Mol Aspect Med 2000;21:1-48.
- Romeiu I, et al. Genetic polymorphism of GSTM1 and antioxidant supplementation influence lung function in relation to ozone exposure in asthmatic children in Mexico City . Thorax 2004;59:8-10.
- US Department of Health and Human Services. NIH/NLBI. Asthma management and prevention: a pocket guide for physicians and nurses. NIH Publication No. 96-3659B;1998.
- Bell DA, et al. Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen-metabolism gene glutathione S-tranderase (GSTM1) that increases susceptibility to bladder cancer. J Natl Cancer Inst 1993;85:1159-64.
- Gilliland FD, et al. Effects of glutathione S-transferase M1, T1, and P1 on childhood lung function growth. Am J Respir Crit Care Med 2002;166:710-6
| Page last reviewed: June 8, 2007 (archived document) Page last updated: November 2, 2007 Content Source: National Office of Public Health Genomics |
