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Glutathione S-Transferase Variants and Their Interaction with Smoking on Lung Function

The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia; Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota

Correspondence and requests for reprints should be addressed to Andrew J. Sandford, Ph.D., UBC James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6 Canada. E-mail: asandford{at}mrl.ubc.ca

	ABSTRACT

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We studied glutathione S-transferase (GST) polymorphisms in 1,098 whites with the lowest (n = 544, FEV₁ % predicted mean ± SEM = 62.6 ± 0.1) and the highest (n = 554, FEV₁ % predicted mean ± SEM = 91.8 ± 0.1) lung function at the beginning of the Lung Health Study. Homozygosity for GSTP1 105Val was significantly more frequent in the low- than in the high-function group (13.2 vs. 9.3%) (odds ratio = 1.69, 95% confidence interval [CI] = 1.11–2.61, p = 0.016), after adjustment for confounding variables. Subjects with 105Val homozygotes had higher rates of lung function decline in the high-function group (p = 0.017). The frequencies of GSTM1, GSTT1 null genotypes were similar between the high- and low-function groups, but subjects with the GSTT1 null genotype had a faster decline of lung function in the low-function group (p = 0.032). In addition, there was a significant interaction of GSTT1 genotype and pack-years on lung function. When comparing individuals with GSTT1 null genotype with wild type, the adjusted odds ratio was 3.49 (95% CI, 1.48–8.39, p = 0.005) in mild smokers ( 25 pack years). We conclude that GST genotypes are risk factors for rapid decline or low lung function in smokers with mild to moderate airflow obstruction.

Key Words: cigarette smoking • FEV₁ • gene–environment interaction • genetic polymorphism • glutathione S-transferase

Chronic obstructive pulmonary disease (COPD) is defined by the presence of decreased maximal expiratory flow, and the Global Initiative on Obstructive Lung Disease has defined categories of severity that are largely based on the FEV₁ expressed as a percentage of predicted values. Cigarette smoking is the most important environmental factor influencing lung function. Although there is a dose–response relationship between FEV₁ and the extent of cigarette smoking (pack-years and duration of smoking) (1, 2), smoking history accounts for only approximately 15% of the variation in lung function (3). In addition, approximately 5% of subjects with COPD are nonsmokers (4). A number of family and twin studies have documented familial aggregation of FEV₁ even after adjustment for cigarette smoking (5, 6). These observations suggest that genetic factors contribute to lung function through their effect on lung development and/or by influencing susceptibility to the effects of cigarette smoke. The genetic determinants of FEV₁ have received increasing attention (7, 8). However, there have been few studies of gene–smoking interactions other than for the effect of ₁-antitrypsin deficiency alleles on lung function (9).

Oxidative stress, measured as thiobarbituric acid–reactive substances in plasma, has been shown to correlate inversely with FEV₁ percent predicted in a population study (10). Other studies have provided supportive evidence of a role for reactive oxygen species (ROS) released from circulating neutrophils and the development of airflow limitation (11). Antioxidant nutrients have also been associated with preservation of FEV₁ (12, 13). The results of all of these studies suggest oxidant/antioxidant imbalance have important consequences for the pathogenesis of COPD.

The glutathione S-transferases (GSTs) are a family of enzymes that protect against oxidative stress by detoxifying various toxic substrates in tobacco smoke. Several GST polymorphisms have been identified. GSTM1, located on chromosome 1p13.3, has three alleles: GSTM1*0 is a null allele while GSTM1*A, and GSTM1*B alleles encode monomers that form active enzymes. Homozygosity for the common GSTM1 null allele results in a complete lack of GSTM1 activity (14). GSTT1, located on chromosome 22q11.2, has a similar common null genotype (15). GSTP1, located on chromosome 11q13, contains a function changing polymorphism: an AG transition at nucleotide +313 leads to the 105Ile/Val substitution, which has been shown to result in altered catalytic activity (16, 17).

The polymorphisms of GSTM1, T1, and P1 have been associated with cancers of the lung, bladder, breast, and colon (18). The GSTM1 null genotype was reported to be associated with emphysema (19). The GSTP1 105Ile allele has been associated with COPD in the Japanese population (20). However, Yim and colleagues reported that none of the GSTM1, GSTT1, and GSTP1 polymorphisms were associated with COPD in a Korean population (21, 22).

We recently reported that decline of lung function in smokers with mild to moderate air flow obstruction was not associated with any of the genotypes for GSTs when analyzed separately, but there was an association between rapid decline of lung function and the presence of the combination of the GSTM1 null, GSTT1 null, and GSTP1 150Ile/Ile genotype (OR = 2.83, p = 0.03) in this population (23). A combination of a family history of COPD with GSTP1 105Ile/Ile genotype was also associated with rapid decline of lung function (OR = 2.20, p = 0.01) (23). In contrast, Gilliland and colleagues showed that homozygosity for the GSTP1 105Val or GSTM1 null alleles was associated with deficits in lung function growth in children (24). To the best of our knowledge, there is no report of GST gene polymorphisms and their interaction with smoking on lung function in adults.

We hypothesized that FEV₁ % predicted in smokers with mild to moderate air flow obstruction from the Lung Health Study (LHS) cohort would be influenced by GSTM1, T1, and P1 polymorphisms, and there would be an interaction of these genotypes with cigarette smoking. The LHS, sponsored by the National Heart, Lung, and Blood Institute, was a clinical trial of smoking intervention and bronchodilator treatment on the progression of COPD (25). This dataset provides an excellent opportunity to explore the associations of gene polymorphisms and their interactions with cigarette exposure on FEV₁ % predicted. Some of the results of these studies have been previously reported in the form of an abstract (26).

	METHODS

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Study Participants
Study subjects were selected from among the participants of the LHS of the National Heart, Lung, and Blood Institute. A total of 5,887 smokers aged 35–60 years with spirometric evidence of mild to moderate lung function impairment were recruited from 10 North American medical centers. The lung function was assessed as FEV₁ % predicted, that is, FEV₁ adjusted for age, height, sex, and race (25).

From this cohort, we have previously selected the 303 and the 324 individuals with the highest and the slowest rate of decline of lung function among continuous smokers during the first 5 years of follow-up (27). In this study, of those who remained, we selected 500 individuals who had the highest postbronchodilator FEV₁ % predicted (high lung function group) and 500 individuals who had the lowest postbronchodilator FEV₁ % predicted (low lung function group) at the start of the LHS. Arbitrary cut off points of FEV₁ % predicted 88.9% or more and 67.0% or less were used for the high and low lung function groups, respectively. Because 153 individuals from our previous study had baseline lung function within one of these categories, they were included in the present study. Thus, a total of 1,153 subjects were eligible, and of these individuals, 48 were either black or of another ethnic group. Of the remaining 1,105 whites, there were 1,098 DNA samples available. There were 544 and 554 individuals in the high and low lung function groups, respectively.

Genotyping
Detection of the GSTM1 and GSTT1 deletions was performed using a multiplex PCR described by Yim and colleagues (21). Detection of the 313A/G (105Ile/Val) polymorphism in the GSTP1 gene was performed by a PCR-RFLP method of Ishii and colleagues (20). Template-free controls and known genotype controls were included in each experiment.

Statistical Analysis
The differences in genotype frequency between the high and low lung function groups were analyzed by logistic regression to adjust for potential confounding factors–cigarette exposure (pack-years), age, sex, and research center. Because it has been argued that airway hyperresponsiveness is either a risk factor predisposing some smokers to develop COPD or an independent outcome of smoking (28), we performed logistic regression analyses using models with or without methacholine responsiveness as a confounding factor. Methacholine responsiveness was expressed as a two-point dose–response slope (29). The associations of genotype with rate of decline of lung function during 5 years of follow-up were analyzed by multiple linear regressions to adjust for potential confounding factors. The associations of genotype with methacholine responsiveness were analyzed by Wilcoxon test because these values were not normally distributed even after different transformations. To examine the interaction of genotype and smoking, interaction terms between genotype and pack-years were entered into the regression models. Hardy-Weinberg equilibrium was tested using the Arlequin software package (30). The demographic variables in the two groups were compared by chi-square tests for categoric variables and by t test for continuous variables; p values less than 0.05 were considered significant. All tests were performed using the JMP statistics software (SAS Institute, Inc., Cary, NC) except those specifically mentioned.

	RESULTS

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Of the 1,098 subjects, we were unsuccessful in obtaining genotypic data on GSTM1 in 1 participant, GSTT1 in 2 participants, and GSTP1 in 29 participants. Therefore, the analyses include 1,097, 1,096, and 1,069 participants for the GSTM1, GSTT1, and GSTP1 gene polymorphisms, respectively. There were no significant demographic differences (age, sex, pack-years, and methacholine responsiveness) between those with and without genotypic data in the high lung function group (> 98% participation rate) and the low lung function group (> 95% participation rate).

According to the Global Initiative on Obstructive Lung Disease standard (31), all subjects in the high lung function group have mild COPD, and all subjects in the low-function group have moderate COPD. In 153 individuals from our previous genetic association study of rate of lung function decline (23), 22 are fast decliners but are in the high lung function group, and 21 are slow decliners but are in the low-function group. The demographic characteristics for the groups are shown in Table 1 . There were significant differences in several potential confounding factors between high and low lung function groups. Therefore, the associations of genotypes and lung function were analyzed by logistic regression to adjust for those factors.

Low lung function was associated with the homozygous GSTP1 105Val genotype when compared with genotypes containing at least one 105Ile allele both before and after adjustment for confounding factors not including methacholine responsiveness (Table 2) . After adjustment, this association was seen under a recessive model and a codominant model with odds ratio (OR) = 1.69, p = 0.017, and OR = 2.01, p = 0.017, respectively (Table 2). However, after adjustment for confounding factors, including methacholine responsiveness, the significance disappeared with p values of 0.088 for both genetic models. No difference in the frequencies of GSTM1 genotypes was observed between low and high lung function groups (Table 2). There was a borderline association of GSTT1 genotype with lung function (OR = 1.32, p = 0.066), but after adjustment for confounding factors including or not including methacholine responsiveness, the association became less significant (Table 2).

He (23) and others (32) 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. In this study, the frequencies of GSTM1 null, GSTT1 null, GSTP1 105Ile/Ile, or 105Val/Val genotypes combined with a family history of COPD were similar in both groups (data not shown).

We evaluated genotype–smoking interaction by entering an interaction term of genotype^*pack-years along with the aforementioned confounding factors not including methacholine responsiveness into the regression models. The interaction term between genotype and pack-years was not statistically significant for GSTT1, M1, and P1 polymorphisms (p = 0.23–0.35). However, if methacholine responsiveness was included as a confounding factor in the models, the interaction term of GSTT1*pack-years was of borderline significance (p = 0.058). To examine further the potential interaction of genotype and smoke exposure and to avoid potential misclassification of smoking exposure, we classified smokers into three discrete categories based on criteria from the literature (33, 34): mild ( 25 pack-years), moderate (25–55 pack-years), and heavy ( 55 pack-years) smokers. The interaction term between genotype and smoking exposure grouped in this way (pack-years coded as mild, moderate, and heavy in the regression model) was statistically significant for the GSTT1 polymorphism (p = 0.038). The homozygous GSTT1 null genotype was a risk factor for low lung function in mild smokers in both unadjusted analysis (OR = 3.60, 95% confidence interval [CI] = 1.78–7.26, p = 0.0002) and adjusted analysis not including methacholine responsiveness as a confounding factor (OR = 3.49, 95% CI = 1.48–8.39, p = 0.005) or that including methacholine responsiveness as a confounding factor (OR = 4.28, 95% CI = 1.71–10.96, p = 0.002) (Center E was excluded from this analysis because the regression model was unstable if this center was included) (Table 3) . No genotype–smoking interactions were observed for GSTM1 and GSTP1 polymorphisms for lung function (data not shown).

We analyzed the association of genotypes with the rate of decline of lung function during five years of follow-up in the high and low lung function groups separately by multiple linear regression models adjusted for confounding factors such as age, smoking history (pack-years), cigarettes smoked per day during follow-up, and methacholine responsiveness. Subjects with homozygous 105Val had higher rates of lung function decline in the high lung function group but not in the low lung function group (Table 4) . In a codominant model, homozygosity for 105Val was associated with the fastest decline of lung function, whereas homozygosity for 105Ile had the least decline of lung function (p = 0.017). In dominant and recessive model for 105Val, similar associations were found after adjustment for confounding factors (p = 0.022 for both models) (Table 4). There was no difference of the rate of decline of lung function between GSTM1 genotypes. However, there was a significant association of GSTT1 genotype with the rate of decline of lung function in the low lung function group but not in the high lung function group. The GSTT1 null genotype was associated with a faster decline of lung function, with p = 0.032 after adjustment for confounding factors.

We also evaluated genotype–smoking interaction for the decline of lung function by entering an interaction term of genotype x pack-years (either as continuous or categoric valuables) along with the aforementioned confounding factors into the regression models: no genotype–smoking interaction was found.

Finally, we analyzed the association of methacholine responsiveness with genotypes. We did not find associations between genotypes with methacholine responsiveness in high or low lung function groups; there was also no association after stratification by sex in both groups (data not shown).

	DISCUSSION

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The LHS cohort provides an excellent opportunity to explore the effects of gene polymorphisms, gene–gene interactions, and interaction of genotype with cigarette exposure on severity of lung function impairment in smokers with airflow obstruction. First, the lung function measurements in this cohort were carefully standardized and monitored using a high-quality control program to control for multiple factors that were known to increase intraindividual variability of FEV₁ and FVC results, and thus, the data were very reliable (35). Second, complete clinical information and longitudinal lung function measurements were obtained during five years of follow-up. Third, a detailed smoking history was obtained using a modified American Thoracic Society Division of Lung Diseases questionnaire (36). Fourth, there was reasonable sample size in each group we studied. We had excellent power to detect an association of a risk allele for low lung function in smokers: 80% power at a significance level of 5% to detect a 1.7-fold or greater increased risk of low lung function for a risk allele/genotype with prevalence of 10% or more given the size of our study.

Previously, we have examined this cohort using the rate of decline of lung function as a phenotype for genetic studies (37). Different environmental factors and genes may contribute to lung function as a percentage of predicted at one point in time. FEV₁ increases to a maximal at age 20–25 years, is stable for 5–10 years, and then declines throughout the remainder of adulthood (38–40). Low lung function at the initiation of the LHS could come about because of a low level of maximal lung function (i.e., decreased rate of lung or airway growth during development), an earlier onset of the expected decline in lung function, and/or an accelerated decline of lung function before recruitment into the study. In this study, we used FEV₁ % predicted at the start of the LHS as the phenotype because this phenotype incorporates all of these factors.

In the logistic regression models, we used two sets of confounding factors. One set was age, sex, research center, and smoking history, and the second was the aforementioned plus methacholine responsiveness. The rationale was that if airway hyperresponsiveness is an outcome of smoking secondary to smoking-related airway inflammation, airway narrowing, and/or wall thickening (41), it should not be regarded as a confounding factor for FEV₁ independent of smoking and should not be corrected for. However, if airway hyperresponsiveness is an independent host risk factor predisposing some smokers to develop COPD (28, 42, 43), it should be regarded as a confounding factor for FEV₁ and should be corrected for.

In this study, we found that the homozygous GSTP1 105Val genotype was associated with low lung function both before and after adjustment for confounding factors not including methacholine responsiveness. Gilliland and colleagues recently reported that children who were homozygous GSTP1 105Val had slower lung function growth than children with at least one 105Ile allele (24). There are several possible explanations for the association of the homozygous GSTP1 105Val genotype with low lung function in smokers. First, the GSTP1 105Val and 105Ile isoenzymes differ significantly in their ability to metabolize specific substrates. Although the 150Val isoenzyme is more active than the 150Ile isoenzyme for some substrates (44, 45), the 105Val isoenzyme is threefold less effective when 1-chloro-2,4-dinitrobenzene is the substrate (16, 45). Thus, if a substance such as 1-chloro-2,4-dinitrobenzene has an influence on lung maturation, individuals with a homozygous GSTP1 105Val genotype will be at risk for low lung function in adulthood. Second, the major GST protein in human lung tissue is GSTP1, and it was shown that GST enzyme activity for 1-chloro-2,4-dinitrobenzene was significantly lower in normal human lung tissue in individuals who have the 105Val enzyme (46). Third, Ryberg and colleagues showed that individuals with the GSTP1 105Val/Val genotype had a significantly higher lung DNA adduct level than individuals with GSTP1 105Ile/Ile (47). They reasoned that this could explain the association between GSTP1 150Val/Val and risk of lung cancer (OR = 1.9, p = 0.035) (47). We believe that this also could explain the association between this genotype and low lung function.

Furthermore, our study is different from other genetic association studies of COPD in that the two groups we studied are patients with mild and moderate COPD. Therefore, we are studying the genetic determinants of progression of airflow obstruction rather than genetic determinants of initiation of airflow obstruction in smokers. The genetics of COPD susceptibility and COPD severity may be different, as has been proposed in inflammatory bowel disease (48). Some genes may only contribute to disease susceptibility and some genes may only contribute to disease severity, whereas some genes may contribute to both. It is more important to determine whether polymorphisms are associated with COPD severity because once a subset of patients is identified it may be possible to target more aggressive and effective therapeutic approaches to that group.

The observation that the association of the homozygous GSTP1 105Val genotype with low lung function disappeared after adjusting for confounding factors including methacholine responsiveness suggests that the genotypes may influence lung function through their effect on airway reactivity (49, 50). However, homozygosity for GSTP1 105Val was protective against asthma, and its prevalence significantly decreased with increasing severity of airflow obstruction and bronchial hyperresponsiveness (51), seemingly contradicting this explanation. We did not find any associations of genotypes of GSTP1, GSTT1, and GSTM1 with methacholine responsiveness in the high or low lung function groups. This could be due to the design of this study. Because we were primarily interested in polymorphisms that affect the baseline of lung function, we selected cases and control subjects from those with the highest or lowest baseline of lung function at the beginning of the LHS. The distribution of methacholine responsiveness was not normally distributed even after different transformations in our study subjects, whereas its log transformation was normally distributed in the entire LHS cohort (28), suggesting that the distribution in this study is related to subject selection. Therefore, this could have masked a real association between the GST polymorphisms and methacholine responsiveness. Different design strategies would be required to study associations of polymorphisms with airway responsiveness.

There was a significant interaction of GSTT1 genotype and smoking exposure when confounding factors, including methacholine responsiveness, were entered into the regression models. Cigarette smoking modified the associations between the GSTT1 polymorphism and low lung function: there was significant association of GSTT1 null genotype with low lung function in individuals who had low cigarette smoke exposure, but no such association existed in moderate and heavy smokers. A possible explanation for this interaction could be that in heavy smokers the dose of toxic substrates was so great that it overwhelmed the effects of the GSTT1 null genotype. In milder smokers, the relative deficiency of metabolic activity of the null genotype may be unmasked. In addition, smoking itself reduces GST activity in the lung, and this decrease is likely to be greater in those who smoke more (52). The results of several studies have shown a similar genotype–exposure interaction for environmentally induced cancers: genetic susceptibility is most readily identifiable for those with low or very low exposure to the causative carcinogen (33, 34, 53, 54).

We have previously shown that the GSTP1 105Ile/Ile genotype combined with a family history of COPD was associated with rapid decline of lung function (23). We also demonstrated that the combination of GSTP1 105Ile/Ile with GSTTT1 null and GSTM1 null genotypes was associated with a rapid decline (23). We were unable to replicate the former observation but did replicate the latter, albeit only in the high lung function group. The lack of concordance between the two studies may reflect the different subject selection criteria or different methods of analysis. The previous study group contained individuals at the extremes of the distribution for rate of decline of lung function and therefore may have been enriched for susceptibility genes, making genetic associations with rate of decline easier to find. Furthermore, in our previous study, rate of decline was used as a dichotomized variable, but we were unable to repeat this strategy for these analyses. Thus, the two studies are not directly comparable.

Population stratification could have led to false-positive results in our study. Although we limited our analysis to whites, there could be genetically distinct subgroups in this population because the participants were selected from 10 North American centers, especially because different centers had different percentages of individuals in the low lung function group. However, it is reasonable to assume that the associations we observed were not artifacts from population stratification because the GSTP1 polymorphism in this study was in Hardy-Weinberg equilibrium and the allele frequency of GSTP1 polymorphism was the same as that reported (65–67.5%) in non-Hispanic whites or whites in seven of nine cohorts in the United States and the United Kingdom (17, 24, 46, 55–60). Two of those cohorts had approximately 2,000 subjects (24, 55), and thus, the allele frequency estimates should be accurate. There were only 32 participants in the LHS who identified themselves as "Hispanic white," and therefore, more than 99% of our participants were non-Hispanic whites. The phenomenon of different centers contributing different percentages of individuals to the low lung function group could be explained, at least partly, by the differences in environment factors such as smoking history.

In this report, we demonstrate that the results of association studies could be different depending on which confounding factors were corrected for in the regression models, as reviewed by Vineis and McMichael (61). This illustrates the importance of comprehensive phenotypic data collection to adjust effectively for potential confounding factors in an association study. Similarly, it is important to consider confounding factors when comparing the results of different association studies.

Because of the multiple comparisons that we have made, the associations of GSTP1 with baseline of lung function or rate of decline of lung function would not be significant at the 5% level if corrected for the multiple comparisons. In addition, the association of low lung function with GSTT1 null genotype in the low cigarette exposure group came from a subgroup analysis rather than the primary analysis. Therefore, it is important to regard these data as hypothesis generating rather than as evidence that these polymorphisms are true risk factors for a low baseline lung function and a rapid decline of lung function in smokers with mild to moderate airflow obstruction.

In summary, this is the first report to show interactions between a GSTT1 polymorphism and cigarette smoking in influencing lung function. We demonstrated the GSTT1 null genotype is associated with a higher risk of low lung function in mild smokers and is associated with rapid decline of lung function in low baseline lung function group. We found that homozygosity for GSTP1 105Val was associated with low lung function, and it is also associated with a fast decline of lung function in high baseline lung function group. We conclude that lung function and lung function decline are affected by GST polymorphisms and that there is a significant interaction with cigarette smoking in this cohort of individuals. Clearly, further study of the interaction between GST genotype and cigarette smoking is warranted.

	Acknowledgments

 
The authors thank Kelly Burkett and Jean Shin for consulting in the statistical analysis.

	FOOTNOTES

 
Supported by grants from the Canadian Institutes of Health Research and National Institutes of Heath Grant 5R01HL064068-04 and by contract N01-HR-46002 from the Division of Lung Diseases of the National Heart, Lung, and Blood Institute (The Lung Health Study).

Conflict of Interest Statement: J-Q.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.E.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; N.R.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; P.D.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.J.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form December 23, 2003; accepted in final form May 20, 2004

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