Reference
Complete the bibliographic reference for the article according to AJE format.

Romieu 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.

Category of HuGE information
Specify the types of information (from the list below) available in the article:

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

Gene-environment interaction

Hypothesis: Asthmatic children genetically lacking in GSTM1 activity might have greater susceptibility to reductions in ozone-associated forced expiratory flow (FEF_25–75), an index of lung function, and greater benefits from antioxidant supplementation (vitamins C and E).

Gene(s)
Identification of the following:

1. Gene name
2. Chromosome location
3. Gene product/function
4. Alleles
5. OMIM #

1. Gene name: GSTM1
2. Chromosome location: 1p1.3
3. Gene product/function: of a broad range of xenobiotics and carcinogens via catalysis of the reaction of glutathione with such organic compounds for detoxification and clearance
4. Alleles: GSTM1
5. OMIM#:138350

Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)

1. Ozone
2. Antioxidant (vitamins C and E) supplementation

Health outcome(s)
Identification of the major health outcome(s) studied

Forced expiratory flow (FEF_25–75), a measure of lung function

1. Case-control
2. Cohort 
3. Cross-sectional
4. Descriptive or case series
5. Clinical trial
6. Population screening

Clinical trial

1. Disease case definition
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants (% of total eligible)

1. Disease case definition: intermittent, mild persistent, moderate persistent, or severe asthma diagnosed by the National Heart, Lung, and Blood Institute classifications (1)
2. Exclusion criteria: none indicated
3. Gender: males and females
4. Race/ethnicity: Mexican
5. Age: mean age 9.2 years (range 6-16 years)
6. Time period: October 1998 to April 2000
7. Geographic location: Mexico City, Mexico
8. Number of participants: N ( % of total eligible ) 158 (98% of those initially enrolled, 2 lost to follow-up)
   

1. Control selection criteria
2. Matching variables
3. Exclusion criteria
4. Gender
5. Race/ethnicity
6. Age
7. Time period
8. Geographic location
9. Number of participants (% of total eligible)

N/A

1. Environmental factor
2. Exposure assessment
3. Exposure definition
4. Number of participants with exposure data (% of total eligible)

Environmental factor: ozone

1. Exposure assessment: 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
2. Exposure definition: maximum 1 hour ozone concentration (on the day before each spirometric test)
3. Number of participants with exposure data: 158 (100% of total eligible)

Environmental factor: antioxidant (vitamins C and E) supplementation

1. Exposure assessment: baseline blood analysis for vitamin C and E levels and at several points during the follow-up period to assess compliance among those in the treatment group
2. Exposure definition: vitamin C (250 mg/day) and vitamin E (50 mg/day) in pill form
3. Number of participants with exposure data: 158 (100% of total eligible)

1. Gene
2. DNA source
3. Methodology
4. Number of participants genotyped (% of total eligible) 

1. Gene: GSTM1
2. DNA source: whole blood or buffy coat
3. Methodology: 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), described elsewhere (2)
4. Number of participants genotyped: N ( % eligible ) 158 (100% of total eligible)
   

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

• See Table 1

Asthmatic children with the GSTM1 null genotype are genetically impaired in their ability to handle oxidative stress and may be more susceptible to the effects of ozone on small airways function; supplementation with the antioxidant vitamins C and E compensated for their genetic susceptibility in this study by significantly mitigating ozone-associated reductions in FEF_25–75.

Strengths:
Biologically plausible, large number of cases, similar genotype prevalence (39%) as prior studies with child populations of Mexican descent (3), effect of population stratification limited due to all subjects being of Mexican ethnicity, clinical trial study design (randomization limits the effects of unknown confounders on results since these factors should be randomly distributed among the treatment and placebo groups, double-blinded, use of placebo, less misclassification due to antioxidant supplementation exposure assignment), forced expiratory flow outcome assessment (conducted at the same time of day and week to limit diurnal variation, standardized and technically sound testing process by one pulmonlogist), potential implications for simple clinical intervention (antioxidant supplementation) regarding a public health issue with great morbidity and associated healthcare-related costs.

Weaknesses:
Unable to stratify by other genotypes that might interact with GSTM1 in relation to ozone response due to small sample size, potential misclassification of ozone exposure since children may not always be exposed to the ozone levels nearest their homes (i.e. during the school day).