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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 323-328, (2002)
© 2002 American Thoracic Society

Original Article

Antioxidant Gene Polymorphisms and Susceptibility to a Rapid Decline in Lung Function in Smokers

Jian-Qing He, Jian Ruan, John E. Connett, Nicholas R. Anthonisen, Peter D. Paré and Andrew J. Sandford

UBC McDonald Research Laboratories/iCAPTURE Center, St. Paul's Hospital, Vancouver, British Columbia, Canada; Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota; and Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

Correspondence and requests for reprints should be addressed to Dr. A. J. Sandford, UBC McDonald Research Laboratories/iCAPTURE Center, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6 Canada. E-mail: asandford{at}mrl.ubc.ca


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Oxidative stress is believed to play an important role in the pathogenesis of smoking-induced chronic obstructive pulmonary disease. We hypothesized that polymorphisms of antioxidant genes glutathione S-transferase M1 (GSTM1), GSTT1, GSTP1, and heme oxygenase-1 (HMOX1) would be associated with susceptibility to accelerated decline of lung function in smokers. We genotyped 621 subjects (299 rapid decliners [change in forced expiratory volume in 1 second ({Delta}FEV1) = -152 ± 2.5 ml/year] and 322 nondecliners [{Delta}FEV1 = +15 ± 1.5 ml/year]) selected from among smokers followed for 5 years in the National Heart, Lung, and Blood Institute Lung Health Study. Because genotype frequencies were different between ethnic groups, we limited the association study to 594 whites (286 rapid decliners and 308 nondecliners). None of the genotypes studied had a statistically significant effect on decline of lung function when analyzed separately. There was an association between rapid decline of lung function and presence of all three GST polymorphisms (odds ratio [OR] = 2.83; p = 0.03). A combination of a family history of chronic obstructive pulmonary disease with GSTP1 105Ile/Ile genotype was also associated with rapid decline of lung function (OR = 2.20; p = 0.01). However, due to the multiple comparisons that were made, these associations may represent type 1 error. There was no association between HMOX1 (GT)n alleles and the rate of decline in lung function in smokers.

Key Words: obstructive lung diseases • forced expiratory volume • genetic predisposition to disease


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Chronic obstructive pulmonary disease (COPD) is characterized by the progressive development of airflow limitation that is not fully reversible. It encompasses chronic obstructive bronchitis, with obstruction of small airways, and emphysema, with enlargement of air spaces and destruction of lung parenchyma, loss of lung elasticity, and closure of small airways (1). It is generally accepted that cigarette smoking is the most important risk factor for COPD. However, only 10–15% of smokers develop the severe impairment of pulmonary function associated with COPD (2). This phenomenon, together with the familial clustering of patients with early-onset COPD (3) and the differences in the prevalence of COPD among different racial groups, strongly suggests that genetic factors may determine which smokers will develop airflow limitation.

There are two major hypotheses in the pathogenesis of smoke-related COPD (4, 5). One is the protease–antiprotease hypothesis, which states that various proteases break down connective-tissue components, particularly elastin, in lung parenchyma to produce emphysema. This theory could explain the mechanism of development of COPD in {alpha}1-antitrypsin deficiency (6). The other, nonmutually exclusive, hypothesis is the oxidant–antioxidant theory, which proposes that oxidant stress and reactive oxygen species (ROS), resulting from an oxidant/antioxidant imbalance, have important consequences for the pathogenesis of COPD. These include oxidative inactivation of antiproteinases, alveolar epithelial injury, increased sequestration of neutrophils in the pulmonary microvasculature, and gene expression of proinflammatory mediators (7).

The glutathione S-transferase (GST) supergene family encodes isoenzymes that appear to be critical in protection against oxidative stress by detoxifying various toxic substrates in tobacco smoke (8). Several families of soluble GSTs have been identified in humans, referred to as {alpha}, µ, {pi}, and {theta} (9). To date, four members of the GST gene family have been found to be polymorphic. One of the µ-class genes is GSTM1. Three alleles have been described for GSTM1: GSTM1*0 is a null allele, whereas GSTM1*A and GSTM1*B encode monomers that form active enzymes. Homozygosity for the GSTM1 null allele results in a complete lack of GSTM1 activity (10). Another polymorphic member of the µ gene family (GSTM3) is biallelic with GSTM3*A and GSTM3*B, differing by a 3-bp deletion in intron 6. The functional consequence of this deletion is unclear. GSTM3*B and GSTM1*A are in linkage disequilibrium. A null polymorphism has also been identified in the GSTT1 gene (11).

The GSTP1 gene contains two polymorphisms; an A->G transition at nucleotide +313, which leads to the Ile105Val amino acid substitution, and a C->T transition at nucleotide +341. In white populations, +313A and +341C are the wild-type alleles and form the GSTP1*A haplotype. The +313G and +341C combination forms the GSTP1*B haplotype, +313G together with +341T form the GSTP1*C haplotype, and +313A with +341T form the GSTP1*D haplotype. The +313 transition has been shown to result in altered catalytic activity (12, 13), though there is no evidence to date of a functional effect of the +341 transition.

The homozygous null GSTM1 genotype has been associated with the pathogenesis of cancer and emphysema (14–16). The null GSTT1 genotype has also been associated with cancer (17). However, Yim and coworkers reported that neither the GSTM1 nor the GSTT1 null alleles were associated with COPD in a Korean population (18). The GSTP1 105Val allele of the exon 5 Ile105Val polymorphism has been associated with lung, breast, bladder, esophageal cancers (10, 13, 19, 20), but its association with COPD was inconsistent (13, 21).

Heme oxygenase-1 (HMOX1) is a key enzyme in heme catabolism that catalyzes the oxidative cleavage of heme, resulting in the release of carbon monoxide, iron, and biliverdin. Biliverdin is subsequently reduced to bilirubin by biliverdin reductase (22). HMOX1 functions as an antioxidant enzyme because locally produced bilirubin works as an efficient scavenger of ROS. The HMOX1 gene (GT)n dinucleotide repeat in the 5'-flanking region shows length polymorphism, and there is evidence that it modulates the level of gene transcription under thermal stress (23). It has also been reported that a high number of (GT)n repeats may reduce HMOX1 inducibility by ROS in cigarette smoke, thereby enhancing susceptibility to the development of pulmonary emphysema (24).

In this study, we investigated whether polymorphisms of the GSTM1, GSTT1, GSTP1, and HMOX1 antioxidant genes were associated with an accelerated rate of decline of forced expiratory volume in 1 second (FEV1) in the Lung Health Study (LHS). The LHS, sponsored by the National Heart, Lung, and Blood Institute, was a clinical trial of smoking intervention and bronchodilator on the progression of COPD (25). This dataset provides an excellent opportunity to test the relationship between antioxidant gene polymorphisms and the rate of decline of FEV1.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Participants
We selected 299 subjects (286 whites and 13 blacks) who had the fastest decline of FEV1 and 322 subjects (308 whites and 14 blacks) who had the slowest decline from 3,216 subjects who continued to smoke during 5 years of follow-up in the LHS study. Spirometry was performed annually over a period of 5 years as previously described (25). Lung function was assessed as FEV1% predicted, i.e., FEV1 adjusted for age, height, and sex (26). The rapid decliners had a mean ± SE decrease in FEV1 -152 ± 2.5 ml/year (FEV1% predicted -4.14 ± 0.05), and the nondecliners had a mean ± SE increase in FEV1 +15 ± 1.5 ml/year (FEV1% predicted +1.08 ± 0.05).

Genotyping
Detection of the GSTM1 and GSTT1 deletions was performed using a multiplex polymerase chain reaction (PCR) described by Yim and coworkers (18). Detection of the A313G (Ile105Val) polymorphism in the GSTP1 gene was performed by a modification of the PCR-restriction fragment length polymorphism method of Ishii and colleagues (21). Template-free controls and known genotype controls were included in each experiment. After amplification, the PCR products were digested for 2 hours at 55°C with five units of BsmAI restriction enzyme. Genotypes were scored without knowledge of the phenotypes by two independent observers.

To determine the length of the (GT)n repeats in the HMOX1 promoter region, PCR products were generated using a fluorescently labeled forward primer (5'-ATCAAGTCCCAAGGGGACAG-3') and an unlabeled reverse primer (5'-ACAGCTGATGCCCACTTTCT-3'), which were designed according to the published sequence (27). The PCR was performed over 30 cycles of 20 seconds at 94°C, 10 seconds at 60°C, and 20 seconds at 72°C with 3 mM MgCl2. After PCR, products were mixed with an internal standard (Rox-350, Applied Biosystems, Mississauga, ON). Alleles were separated by a laser-based automated DNA sequencer (ABI PRISM 3,700). The sizes of the fluorescence-labeled PCR products were calculated from a standard curve made from the internal standard. DNA samples with known HMOX1 (GT)n repeats were included in each experiment as positive controls (repeat numbers of 23, 27, 30, 38). Ten samples with HMOX1 homozygous (GT)n genotypes were confirmed by direct sequencing.

Data Analysis
The frequencies of the alleles and genotypes between ethnic groups were compared by {chi}2 analyses for 2 x 2 contingency tables. Odds ratios (OR) and 95% confidence intervals (CI) were calculated as previously described (28). The associations were analyzed by binary logistic regression to adjust for potential confounding factors. The outcome was a dichotomous variable, that is, rapid decliner or nondecliner. Potential confounding factors included in the analysis were smoking history (expressed as pack years), age, sex, initial level of lung function (prebronchodilator FEV1% predicted), and responsiveness to methacholine. The latter variable was expressed as a two-point dose–response slope as previously described (29). Only age, smoking history, and responsiveness to methacholine were included as covariates in the final models, because sex and initial level of lung function were not significant predictors of the outcome variable. p Values less than 0.05 were considered significant. Hardy–Weinberg equilibrium was tested using the Arlequin software package (30). All other tests were performed using the JMP Statistics software package (SAS Institute Inc., Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The numbers of (GT)n repeats in the HMOX1 gene showed a trimodal distribution, with three main peaks located at 23, 30, and 37 GT repeats (Figure 1) . Therefore, we divided the alleles into three subclasses according to the numbers of (GT)n repeats as described by Yamada and colleagues (24). Alleles with less than 27 GT repeats were designated as "Class S," alleles with GT repeats between 27 and 32 were designated as "Class M," and alleles with GT repeats more than or equal to 33 were designated as "Class L." In addition, the study subjects were divided into two groups according to their HMOX1 genotypes as described previously (24): "Group I" were individuals with one or two Class L alleles, and "Group II" were individuals without a Class L allele.



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  		Figure 1. Frequency distribution of the numbers of (GT)n repeats of the HMOX1 gene in the total subjects (n = 617).

 
The genotype/allele frequencies in the two ethnic groups are given in Table 1 . Because of allele/genotype frequency differences between ethnic groups, we limited our association study to whites, of which we had the largest number of subjects. The characteristics of the white subjects are shown in Table 2 . We were unsuccessful in obtaining genotypic data on GSTM1 and GSTT1 in four participants, GSTP1 in seven participants, and HMOX1 in nine participants; the analyses include 590, 587, and 585 participants for GSTM1 and GSTT1, GSTP1, and HMO1 gene polymorphisms, respectively. The HMOX1 polymorphism was in Hardy–Weinberg equilibrium in the white population (p = 0.32). However, for the GSTP1 polymorphism, there was a slight excess of heterozygotes (p = 0.03). Because heterozygous individuals could not be distinguished from homozygous wild-type individuals for the GSTM1 and GSTT1 polymorphisms, we were unable to determine whether they were in Hardy–Weinberg equilibrium.


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  		TABLE 1. Prevalence of genetic polymorphisms between whites and blacks

 

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  		TABLE 2. Characteristics of 594 white participants in the study groups*

 
The prevalence of the GSTM1 null and GSTP1 AA genotypes in rapid decliners was similar to that found in nondecliners (Table 3) . Although the prevalence of the GSTT1 null genotype in rapid decliners (30.4%) was slightly higher than that found in nondecliners (25.1%), the difference was not significant, even after adjustment for the significantly different baseline values (age, pack-years, response to methacholine) (Table 3). Previous studies have shown that it is combinations of GST polymorphisms rather than individual genotypes that show associations with lung cancer (31). In our study, the proportion of subjects with a combination of the GSTM1 null, GSTT1 null, and GSTP1 AA genotype was significantly greater in rapid decliners (5.4%) than in nondecliners (2.3%); adjusted OR = 2.83; 95% CI = 1.11–7.18; p = 0.03. However, the proportion of subjects with a combination of any two of those three polymorphisms was not significantly different between rapid decliners and nondecliners (Table 4) .


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  		TABLE 3. Frequency of gst genotypes in the study groups

 

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  		TABLE 4. Frequency of gst genotype combinations in the study groups

 
We (32) and others (33) have shown that a combination of specific genotypes and a family history of COPD were more strongly associated with rate of decline of lung function than the genetic risk factor alone. The frequencies of GSTM1 null, GSTT1 null, or GSTP1 AA genotypes combined with a family history of COPD in the rapid decliners and nondecliners are shown in Table 5 . In the rapid decliner group, the frequency of GSTM1 null combined with a family history of COPD was similar to that in the nondecliner group. However, the frequency of GSTT1 null combined with a family history of COPD was significantly higher among rapid decliners (10.3%) than nondecliners (4.9%) (unadjusted OR = 2.22; 95% CI = 1.17–4.24; p = 0.02). However, after adjustment for age, smoking history, and methacholine responsiveness, the significance between the two groups disappeared (OR = 1.59; 95% CI = 0.79–3.26; p = 0.19). The frequency of GSTP1 AA genotype with a family history of COPD was also significantly higher in rapid decliners (12.1%) than in nondecliners (6.9%) (OR = 1.85; 95% CI = 1.05–3.28; p = 0.03). After adjustment, the difference between the two groups was still significant (OR = 2.20; 95% CI = 1.20–4.02; p = 0.01). A family history of COPD was defined as a first-degree relative who had chronic bronchitis or emphysema. Family history alone was not associated with the rate of decline of lung function (OR = 1.28; p = 0.17).


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  		TABLE 5. Distribution of gst genotypes combined with family history of copd

 
It is possible that methacholine responsiveness could be a more appropriate outcome variable than rate of decline of lung function in this study. For example, a deficiency in antioxidant defenses could result in airway hyperresponsiveness, which then leads to accelerated decline in lung function. Alternatively, a reduction in the level of antioxidants could directly contribute to loss of lung function via, e.g., inactivation of {alpha}1-antitrypsin or direct damage to alveolar epithelial cells. The latter was the rationale for investigating these genes, but it is difficult to discount the former. To investigate this we determined whether those risk factors identified in the analysis of rate of decline of lung function, namely a combination of all GST polymorphisms and a combination of GSTP1 AA and a family history of COPD, were associated with methacholine responsiveness. However, neither risk factor was significantly associated with methacholine responsiveness (data not shown).

An important point to address is whether there is an interaction between these antioxidant polymorphisms and the amount of cigarettes smoked, which is related to the level of exposure to oxidants. We have tested potential gene x environment interactions by adding the appropriate term into the regression analyses. Neither the combination of all GST polymorphisms nor a combination of GSTP1 AA and a family history showed a significant interaction with smoking history (data not shown).

There may be a concern that the regression analysis was unable to adequately adjust the results for the differences in baseline variables, e.g., age, smoking history, etc. Therefore, we have analyzed the data to determine whether there were any significant differences in the baseline values between those with the risk factor combinations (all three GSTs or GSTP1 + family history) and those without. There were no significant differences between these groups (data not shown).

The prevalence of HMOX1 alleles and genotypes was not different between the fast decliners and nondecliners (Table 6) . Analysis of the L allele or I genotype combined with a positive family history of COPD showed that there were no significant differences between the two groups (data not shown).


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  		TABLE 6. Allele/genotype frequencies of the microsatellite polymorphism in the HMOX1 gene

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
There is no doubt that cigarette smoking is the major risk factor for COPD, and there is a genetic susceptibility to this complex genetic disorder (6). Potential susceptibility genes include those regulating the protease–antiprotease and oxidant–antioxidant interactions. Although there have been many studies in experimental animals and humans that support a role for imbalances in oxidant–antioxidant systems in the pathogenesis of smoking-induced COPD (34), there have been relatively few studies that investigated the role of polymorphisms of antioxidant genes in COPD. In particular, there have been no studies to evaluate the association of antioxidant gene polymorphisms and the rate of decline of lung function. In the present study, we have investigated whether polymorphisms of the GSTP1, GSTM1, GSTT1, and HMOX1 antioxidant genes were associated with the rate of decline of lung function in smokers.

In the present study, none of the polymorphisms of GSTM1, GSTT1, and GSTP1 had a statistically significant effect on the decline of lung function when studied separately. We found the prevalences of GSTM1 and GSTP1 genotype were different among whites and African Americans. The prevalences of GSTM1 null, GSTT1 null, and GSTP1 AA genotype in the white nondecliners group (50.2, 25.1, and 39.0%, respectively) were comparable to those observed previously for other white populations (14, 17, 35). Several studies have been conducted to test for associations of GST polymorphisms and COPD. A weak association has been reported to exist between null GSTM1 and emphysema in combination with lung cancer (OR = 2.1) (16) and severe chronic bronchitis in heavy smokers (OR = 2.8) (36) in whites. However, this association between GSTM1 and COPD was not confirmed in a Korean population, and no association between GSTT1 and COPD was found (18). The results of previous studies of the GSTP1 AA genotype and COPD are contradictory. One group of investigators demonstrated that the AA genotype was associated with COPD in a Japanese population (OR = 3.5) (21). However, in another study, an increased frequency of the GG genotype was observed in patients with COPD (12.7%) compared with control subjects (6.6%), although the difference was not significant (p = 0.233) (13). These inconsistencies may be due to different ethnic groups and different selection criteria for the study subjects.

In a complex polygenic disease such as COPD, it is likely that genetic susceptibility is dependent on the action of several gene polymorphisms operating in concert. Polymorphisms in individual gene may impart only a small relative risk of COPD, and it is likely that the cumulative effect of many polymorphisms will be important in its pathogenesis. We analyzed the genotypes of the GSTT1, GSTM1, and GSTP1 genes in four different combinations, based on a biologically plausible scenario, to determine whether these combined genotypes were associated with rate of decline of lung function. A significant association was observed for concurrent deletion of the GSTM1, GSTT1 genes, and presence of homozygous GSTP1 AA (OR = 2.83, p = 0.03). This association could be explained by the fact that tobacco smoke is known to contain multiple substrates for GSTM1, GSTT1, and GSTP1. Individuals having a defective genotype for more than one of these genes would therefore be at greater risk for smoking-induced decline in lung function than those having a defective genotype for only one gene. Moreover, the GSTP1 AA genotype may be less protective against xenobiotics in tobacco smoke (21). Similar results were also observed in polymorphisms of GST genes and susceptibility to cervical and lung cancer (31, 37).

In a previous study, MZ heterozygotes of the {alpha}1-antitrypsin ({alpha}1-AT) gene were shown to have an increased rate of decline of lung function only if they also had a family history of lung disease (asthma, bronchitis, or emphysema) (38). We also demonstrated that the associations of the {alpha}1-AT MZ genotype and the microsomal epoxide hydrolase His113/His139 haplotype with rate of decline of lung function were stronger when the subjects had a family history of COPD (32). In the present study, we analyzed the associations of different combinations of genotypes and family history of COPD. We found that the combination of homozygous GSTP1 AA and family history of COPD also increases the risk of rapid decline of lung function in smokers (OR = 2.20, p = 0.01), suggesting an interaction with other familial risk factors. It is possible that these other familial factors could be the {alpha}1-AT and microsomal epoxide hydrolase risk factors we previously identified in this study group. Unfortunately, there were too few individuals who had the GSTP1 AA genotype as well as one of these previously identified risk factors to determine if there was an interaction between them.

In view of the lack of Hardy–Weinberg equilibrium shown by the GSTP1 polymorphism, the associations reported here need to be interpreted with caution. Lack of Hardy–Weinberg equilibrium could be due to many factors, and of particular concern to this study would be population stratification and the accompanying risk of type 1 error. We have genotyped this study group for 30 polymorphisms in total including the four reported here (including 17 unpublished polymorphisms). Three of these are null alleles where it is not possible to test for Hardy–Weinberg equilibrium. Of the remaining 27, only one polymorphism (other than GSTP1) was found not to be in Hardy–Weinberg equilibrium (32). However, these markers were not specifically chosen to detect population stratification in a "genomic control" strategy (39, 40) but were other candidate polymorphisms. Therefore, these polymorphisms are not ideally suited to test for population stratification.

Population stratification would be expected to produce an excess of homozygosity, i.e., the Wahlund effect, whereas we detected a slight excess of heterozygotes. Possible explanations for an excess of heterozygotes may be overdominance or nonrandom mating (e.g., negative assortative mating). Neither of these explanations seems particularly likely and the lack of Hardy–Weinberg equilibrium may simply be due to sampling variation. Nevertheless, given this concern, and the multiple comparisons that we have made, it is important to regard these data as hypothesis generating rather than as evidence that these polymorphisms are true risk factors for a rapid decline in lung function.

We demonstrated that there is no association of the HMOX1 promoter (GT)n polymorphism with the rate of decline of lung function. The study by Yamada and coworkers in a Japanese population suggested that the larger size of a (GT)n repeat in the HMOX1 gene promoter, the lower the HMOX1 inducibility by ROS in cigarette smoke (24). They reasoned that this explained the association between a large GT repeat size and pulmonary emphysema in their study (24). There are several possible reasons for the lack of reproducibility between our study and that of Yamada and coworkers. First, emphysema can develop because of reduced maximally achieved lung function, an earlier age of onset of decline, or an accelerated rate of decline. In this study, to reduce the phenotypic heterogeneity and increase the power of the study, we used of rate of decline of lung function rather than emphsema as a phenotype. Second, this lack of reproducibility might result from differences between the study subjects such as race, age etc. Third, the association in the Japanese may not be due to HMOX1 (GT)n polymorphism but due to linkage disequilibrium with a nearby gene—this linkage disequilibrium may not be present in whites.

In conclusion, we have analyzed polymorphisms in several antioxidant genes and their association with the rate of decline of lung function in smokers. When studied separately, none of the GST genotypes had a statistically significant effect on lung function decline. However, when genotype combinations were analyzed, concurrent deletion of the GSTT1 and GSTM1 genes together with the presence of the GSTP1 AA genotype carried an increased risk for accelerated decline of lung function in smokers. In addition, the combination of homozygous GSTP1 AA and a family history of COPD was associated with an increased risk of decline of lung function. The combined effects of GST genotype may, at least partly, explain the conflicting results from studies on association between the GST genotype and COPD. Finally, we were unable to demonstrate that there was an association of the 5'-flanking polymorphism in the HMOX1 gene with the rate of the decline of lung function in smokers.


   Acknowledgments
 
This study was supported by grants from the Canadian Institutes of Health Research. The Lung Health Study was supported by contract N01-HR-46002 from the Division of Lung Diseases of the National Heart, Lung, and Blood Institute.

Received in original form November 27, 2001; accepted in final form March 16, 2002


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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
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