Opposing Effects of Emphysema, Hay Fever, and Select Genetic Variants on Lung Cancer Risk
Matthew B. Schabath1,
George L. Delclos2,
Marek M. Martynowicz3,4,
Anthony J. Greisinger3,
Charles Lu5,
Xifeng Wu1 and
Margaret R. Spitz1
1 Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
2 Southwest Center for Occupational and Environmental Health, The University of Texas School of Public Health, Houston, TX.
3 Kelsey-Seybold Clinic and Kelsey Research Foundation, Houston, TX.
4 St. Lukes Lung Institute, Houston, TX.
5 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
Received for publication May 25, 2004; accepted for publication October 1, 2004.
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ABSTRACT
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The authors compared histories of nonmalignant respiratory diseases (asthma, bronchitis, emphysema, hay fever, and pneumonia) in 1,553 lung cancer patients and 1,375 healthy controls enrolled in a Texas case-control study from 1995 to 2003. They incorporated data on two biologically relevant polymorphic genes, matrix metalloproteinase-1 and myeloperoxidase. Emphysema was associated with a statistically significant increased lung cancer risk (odds ratio (OR) = 2.87, 95% confidence interval (CI): 2.20, 3.76), while hay fever had a significant protective effect (OR = 0.58, 95% CI: 0.48, 0.70). Odds ratios were consistent after exclusion of respiratory disease diagnoses made up to 10 years before interview. There was little association between other respiratory diseases and lung cancer risk. Among carriers of "protective" genotypes, emphysema was associated with a 1.7-fold increased risk (95% CI: 0.84, 3.50), as compared with the substantially higher risk for persons possessing one (OR = 4.98, 95% CI: 2.94, 8.44) or two (OR = 4.23, 95% CI: 1.84, 9.73) "adverse" genotypes. For hay fever, significantly decreased risks were evident with one (OR = 0.32, 95% CI: 0.21, 0.50) or two (OR = 0.35, 95% CI: 0.19, 0.66) protective genotypes as compared with none (OR = 0.69, 95% CI: 0.30, 1.59). The biologic role of respiratory disease in lung cancer is unclear. Further study may yield new insights for identification of susceptible subgroups.
case-control studies; epidemiology, molecular; genetic predisposition to disease; lung neoplasms; polymorphism, genetic; respiratory tract diseases; smoking; tobacco
Abbreviations:
CI, confidence interval; MMP-1, matrix metalloproteinase-1; MPO, myeloperoxidase; OR, odds ratio.
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INTRODUCTION
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Although cigarette smoking is the predominant risk factor for lung cancer, published studies suggest that respiratory diseases such as asthma, bronchitis, emphysema, hay fever, and pneumonia may also modify lung cancer risk (120). Both cigarette smoking and chronic respiratory diseases result in injury and inflammation that can predispose people to carcinogenesis in affected tissues (21). However, the causal nature of these associations is speculative, since emphysema and, in particular, chronic bronchitis are strongly influenced by smoking (22). Questions also remain about the relation between respiratory disease and lung cancer, since the timing of diagnosis of a respiratory disease such as pneumonia can coincide with or confound the diagnosis of lung cancer. In some instances, the association between respiratory disease and lung cancer is controversial; for asthma and hay fever, there are conflicting epidemiologic data and no proven hypothesis for a role in lung carcinogenesis.
Only a fraction of long-term cigarette smokers will develop lung cancer; therefore, interindividual variation in susceptibility to tobacco carcinogenesis has been postulated (23). This susceptibility may be attributed in part to genetic variations in relevant biologic pathways for lung cancer causation. Two genes that are biologically relevant to both lung cancer etiology and inflammation-related respiratory disease are matrix metalloproteinase-1 (MMP-1) and myeloperoxidase (MPO). We have previously shown that polymorphisms in each gene are associated with lung cancer risk (24, 25).
MMPs are a family of metalloendopeptidases that cleave the protein components of the extracellular matrix and play an essential role in tissue remodeling and repair associated with inflammation. There is growing evidence to support an expanded role of MMPs in creating and maintaining a microenvironment that facilitates initial stages of tumor development (26). MMPs are also up-regulated by tobacco exposure (27), and the MMP family has been suggested to play roles in the pathogenesis of lung cancer (24, 28, 29) and emphysema (3032). MPO is a metabolic/oxidative enzyme found in neutrophils and polymorphonuclear leukocytes. As part of a mediated immune response, neutrophils are recruited and accumulate at the sites of pulmonary inflammation (33), resulting in localized activation of MPO (34, 35). The reactive by-products produced by MPO can react with biologic molecules to produce secondary free radicals (36), DNA damage (37, 38), and increased risk of carcinogenesis (25, 3840). Since both genes have fundamental roles in inflammatory responses, they are biologically relevant to study in relation to both malignant and nonmalignant respiratory diseases.
Both genes are polymorphic. MMP-1 has a 1G
2G polymorphism located in a core recognition sequence of the transcription factor-binding site. Promoters containing the 2G allele display significantly higher transcriptional activity than 1G promoters (41). MPO has a G
A polymorphism located in the 5'-untranslated region (42, 43), which results in a decreased affinity for the SP1 transcription factor; thus, promoters with the A allele have decreased transcriptional activity (43).
To shed more light on the role of prior respiratory diseases in lung cancer risk, we used data from a case-control study designed to study genetic susceptibility to lung cancer and incorporated data on polymorphic loci associated with both MMP-1 and MPO genes. To our knowledge, this is the largest case-control study to date to integrate data on prior respiratory diseases with select markers of genetic susceptibility for assessment of lung cancer risk.
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MATERIALS AND METHODS
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Subject recruitment
From August 1995 through June 2003, cases and controls were accrued from an ongoing, previously described molecular epidemiologic study on susceptibility markers for lung cancer (44). There were 1,553 patients with histologically confirmed lung cancer recruited prior to initiation of radiotherapy or chemotherapy from The University of Texas M. D. Anderson Cancer Center. There were no age, gender, ethnic, histologic, or stage restrictions. Healthy controls (n = 1,375) without a previous diagnosis of cancer were recruited from the Kelsey-Seybold Clinics, Houstons largest private multispecialty physician group, which includes a network of 23 clinics and more than 300 physicians. Controls were frequency-matched to the cases on age (±5 years), gender, ethnicity, and smoking status (current, former, and never). All cases and controls were US residents. To date, the overall response rate among both the cases and the controls has been approximately 75 percent. This research was approved by the M. D. Anderson Cancer Center and Kelsey-Seybold institutional review boards.
Collection of epidemiologic data
After study participants signed an informed consent form, a 45-minute personal interview was conducted by research interviewers to obtain information on sociodemographic characteristics, cigarette smoking, medical history, occupation, and select exposures. Participants were asked whether a physician had ever told them that they had asthma, bronchitis, emphysema, pneumonia, and/or hay fever. The age or year of diagnosis was recorded for each positive response. The method used for occupational exposure assessment has been previously described (25, 45, 46).
Genotype assays
Previously described assays were utilized to amplify the polymorphic regions of MMP-1 (24) and MPO (25).
Statistical methods
Analyses were performed using Intercooled Stata 8.0 (Stata Corporation, College Station, Texas). Pearsons
2 test was used to test the differences between cases and controls in terms of gender, ethnicity, smoking status, and occupational exposures. Students t test was used to test differences in mean age, pack-years of cigarette smoking, and years of employment. Odds ratios and 95 percent confidence intervals were calculated as an estimate of the relative risk. Unconditional multivariate logistic regression analysis was performed to control for confounding by age, gender, ethnicity, smoking status, pack-years of smoking, and occupational exposures, where appropriate. Interaction was tested with a multiplicative interaction term included in the multivariate model. All statistical tests were two-sided.
Persons who had smoked at least 100 cigarettes in their lifetime were defined as ever smokers. A former smoker had quit smoking at least 1 year before diagnosis (cases) or before interview (controls). Pack-years were estimated as packs of cigarettes smoked per day x years of smoking.
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RESULTS
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There was no difference between the cases and controls in terms of age, gender, ethnicity, smoking status (ever smokers vs. never smokers), and mean years of employment in asbestos- or wood-dust-related occupations (table 1). Caucasians represented approximately 79 percent of both the cases and the controls. Since the study is ongoing, perfect matching has not yet been achieved. Forty-one percent of the cases were self-reported current smokers and 44 percent were former smokers, as compared with 37 percent and 47 percent, respectively, for the controls (p = 0.051). As ex-pected, the cases were heavier smokers (mean pack-years = 50.1; standard deviation, 31.5) than the controls (mean pack-years = 38.9; standard deviation, 29.1) (p < 0.001). Approximately 13 percent of the cases and 9 percent of the controls self-reported a history of asbestos occupational exposure (p < 0.001), while 13 percent of the cases and 8 percent of the controls reported a history of wood dust occupational exposure (p < 0.001).
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TABLE 1. Distribution of select characteristics of lung cancer cases and healthy controls in a Texas case-control study, 19952003
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Asthma (odds ratio (OR) = 1.25, 95 percent confidence interval (CI): 0.99, 1.57), emphysema (OR = 2.87, 95 percent CI: 2.20, 3.76), and pneumonia (OR = 1.74, 95 percent CI: 1.48, 2.04) were all associated with elevated risks in main-effects models, while hay fever (OR = 0.58, 95 percent CI: 0.48, 0.70) was associated with a significantly reduced risk (table 2). Since symptoms of lung cancer might coincide with or be misdiagnosed as other respiratory diseases, we excluded persons who had been diagnosed with these respiratory diseases within 1, 3, 5, or 10 years prior to the interview. The only main-effects models that remained consistent after these exclusions were emphysema and hay fever. However, there was a borderline-significant protective effect for persons who reported bronchitis more than 10 years before the time of the interview. The elevated odds ratios in the main-effects models for the relations of asthma and pneumonia to lung cancer risk were abolished during this exclusion analysis; this suggests overestimation in the main-effects model due to concomitant disease processes or misdiagnosis. For all analyses, the odds ratios were relatively constant when we excluded occupational exposures in the multivariate models (data not shown).
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TABLE 2. Relation between prior respiratory disease and lung cancer risk in a Texas case-control study, 19952003
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In stratified analyses of smoking subgroups, we further examined the association of both emphysema and hay fever with lung cancer risk (table 3). There was no substantial difference in risk between former smokers (OR = 3.13, 95 percent CI: 2.12, 4.60) and current smokers (OR = 2.56, 95 percent CI: 1.74, 3.77) for a history of emphysema. As expected, there were no never smokers with emphysema. For hay fever, both current and former smokers exhibited statistically significant protective effects (OR = 0.52 (95 percent CI: 0.37, 0.73) and OR = 0.55 (95 percent CI: 0.42, 0.74), respectively) in comparison with never smokers (OR = 0.81, 95 percent CI: 0.53, 1.23). The elevated risk noted for a history of emphysema was markedly reduced in long-term quitters. Among former smokers with emphysema, those who had quit smoking more than 20 years previously (OR = 1.70, 95 percent CI: 0.74, 3.94) were at lesser risk of lung cancer compared with those who had quit 1020 years previously (OR = 2.92, 95 percent CI: 1.54, 5.52) or fewer than 10 years previously (OR = 4.50, 95 percent CI: 2.35, 8.61). The protective effects associated with hay fever were diminished in persons who had quit smoking more than 20 years previously (OR = 0.96, 95 percent CI: 0.59, 1.54) as compared with persons who had quit smoking 1020 years previously (OR = 0.58, 95 percent CI: 0.33, 0.99) or fewer than 10 years previously (OR = 0.32, 95 percent CI: 0.20, 0.53). The lightest smokers with emphysema exhibited the highest risk (OR = 4.03, 95 percent CI: 2.05, 7.91) in comparison with the moderate and heavy smokers (OR = 1.97 (95 percent CI: 0.83, 3.36) and OR = 2.84 (95 percent CI: 1.43, 5.61), respectively). The protective effects of hay fever were strongest in the lightest smokers (OR = 0.30, 95 percent CI: 0.12, 0.75) as compared with moderate and heavy smoking (OR = 0.45 (95 percent CI: 0.24, 0.85) and OR = 0.63 (95 percent CI: 0.40, 0.99), respectively). When persons without a history of either emphysema or hay fever were used as the reference group (OR = 1.0), the risk was elevated for persons who reported a history of emphysema but not hay fever (OR = 2.71, 95 percent CI: 2.00, 3.67) but somewhat attenuated in the presence of hay fever (OR = 1.88, 95 percent CI: 1.06, 3.37). Persons who reported a history of hay fever but not emphysema were at significantly reduced risk of lung cancer (OR = 0.56, 95 percent CI: 0.46, 0.68).
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TABLE 3. Stratified analyses of the relations of emphysema and hay fever with lung cancer risk in a Texas case-control study, 19952003
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Overall, the MMP-1 2G/2G genotype was associated with a 1.7-fold increase in lung cancer risk (95 percent CI: 1.35, 2.19) (table 4). The risk associated with the "adverse" 2G/2G genotype was substantially higher in the presence of emphysema (OR = 4.45, 95 percent CI: 2.34, 8.47) as compared with no history of emphysema (OR = 1.75, 95 percent CI: 1.35, 2.27), and the risk was reduced for persons with emphysema and the putatively "protective" 1G genotypes (OR = 2.58, 95 percent CI: 1.63, 4.09). These protective 1G allele genotypes exhibited a greater protective effect in persons with a history of hay fever (OR = 0.32, 95 percent CI: 0.22, 0.49) than in those without such a history (OR = 0.60, 95 percent CI: 0.46, 0.79).
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TABLE 4. Relations between the MMP-1* and MPO* genotypes, prior respiratory disease, and lung cancer risk in a Texas case-control study, 19952003
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Overall, the variant A allele genotypes (G/A + A/A) of MPO were associated with a borderline statistically significant protective effect (OR = 0.83, 95 percent CI: 0.66, 1.03). The risk associated with a history of emphysema was higher in the presence of the putatively "adverse" G/G genotype (OR = 3.73, 95 percent CI: 2.24, 6.21), as compared with persons with the "protective" A allele genotypes with emphysema (OR = 2.03, 95 percent CI: 1.19, 3.49). However, the protective effects of hay fever differed little between the A allele genotypes (OR = 0.49, 95 percent CI: 0.32, 0.76) and the G/G genotype (OR = 0.45, 95 percent CI: 0.31, 0.66).
When the MMP-1 and MPO genotypes were combined (table 5), there was evidence of a gene-dosage effect. Possessing one adverse genotype (MMP-1 2G/2G or MPO G/G) conferred a 1.6-fold (95 percent CI: 1.19, 2.02) increased risk, and possessing both adverse genotypes (2G/2G + G/G) conferred a 2.1-fold (95 percent CI: 1.46, 2.93) increased risk. This pattern was similar for persons without a history of emphysema. However, there were increased risks of over fourfold for persons with a history of emphysema who were carriers of one (OR = 4.98, 95 percent CI: 2.94, 8.44) or two (OR = 4.23, 95 percent CI 1.84, 9.73) adverse genotypes. There was also some evidence of a gene-dosage effect when the MMP-1 and MPO protective genotypes were combined. The protective effects for persons possessing one protective genotype (OR = 0.59, 95 percent CI: 0.45, 0.79) (1G allele or A allele genotype) were enhanced in those with two protective genotypes (OR = 0.48, 95 percent CI: 0.34, 0.68). The protective effect for hay fever was most evident in persons who were carriers of one (OR = 0.32, 95 percent CI: 0.21, 0.50) or two (OR = 0.35, 95 percent CI: 0.19, 0.66) protective genotypes.
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TABLE 5. Relations between number of MMP-1* and MPO* genotypes presumed to exert an adverse or protective influence, prior respiratory disease, and lung cancer risk in a Texas case-control study, 19952003
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DISCUSSION
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In this study, risk of lung cancer was increased among persons with a prior diagnosis of emphysema, while there was a protective effect for lung cancer among those with a prior diagnosis of hay fever. There was little evidence for an etiologic association between lung cancer and other respiratory diseases, including asthma, bronchitis, and pneumonia. Since it is feasible that lung cancer patients seeking health care may have symptoms that are misdiagnosed or attributed to other respiratory disease, we used stratified analyses to exclude respiratory disease diagnoses made within 10 years from the time of the interview. The increased risks in the main-effects models for asthma and pneumonia were attenuated, while the odds ratios remained relatively constant for emphysema and hay fever.
Previous studies have reported increased risk associated with a prior diagnosis of emphysema (17, 18), though not all found statistically significant associations and most did not stratify by time since first diagnosis. Brenner et al. (7) found significantly increased risks in the strata for less than 10 years since diagnosis and slightly elevated risks that were not statistically significant in the strata for more than 10 years since diagnosis. Because smoking is the overwhelming risk factor for emphysema (22), it was not unexpected to find a positive association between emphysema and lung cancer. However, it is also difficult to demonstrate an independent effect of emphysema on lung cancer risk, since they are both strongly linked to the same exposure. By definition, emphysema is a chronic inflammatory condition that leads to fixed narrowing of small airways and alveolar wall destruction (47). The long-standing inflammatory reaction in the bronchi would be accompanied by a continual cycle of injury and repair and therefore could play a key role in lung carcinogenesis (48, 49). Because of a higher rate of cell turnover, the likelihood increases for propagation of genetic errors and subsequent cancer development.
The association between hay fever and lung cancer is controversial, and there are two distinct and contradictory hypotheses (10). Some studies suggest that the protective effects are attributed to enhanced immune surveillance, resulting in a stimulated immune system that is better at detecting and destroying malignant cells (10, 11, 1316). One could also speculate that antiinflammatory agents used to treat hay fever could contribute to this protection. Conversely, other studies suggest that chronic immune stimulation leads to random prooncogenic mutations in actively dividing stem cells and an increased risk of cancer (10, 17). In support of our findings, Osann (11) reported a borderline-significant lower risk for lung cancer among women with hay fever and asthma combined (OR = 0.5, 95 percent CI: 0.3, 1.0) and a further reduction in risk among younger women (OR = 0.2, 95 percent CI: 0.0, 0.7). Cockcroft et al. (13) also noted a significantly lower frequency of hay fever in patients with endodermal malignancies (lung, gut, bladder, and prostate) as compared with controls (6.4 percent vs. 13.2 percent; p < 0.005). Vena et al. (14) reported decreased risks of oral, lung, larynx, and digestive and urinary system cancers in men with a history of hives and other allergies. Conversely, Talbot-Smith et al. (10) and, in a later study, Osann et al. (12) found no significant association between hay fever and lung cancer risk.
Of particular interest was the joint effect of emphysema and hay fever. In the absence of a history of hay fever, the risk associated with emphysema was 2.7, a risk of the same magnitude seen in the main-effects model for emphysema. This risk was attenuated for persons who also reported a history of hay fever (OR = 1.9). Conversely, in the absence of emphysema, persons reporting a history of hay fever were at significantly reduced lung cancer risk (OR = 0.56) of the same magnitude as in the main-effects models for hay fever (OR = 0.58). These novel findings require confirmation in larger analyses, since only 41 cases and 18 controls self-reported both diseases.
Pneumonia has been associated with increased risk of lung cancer (1, 3, 5, 79); however, most studies did not stratify by time since diagnosis. Lung cancer may be initially misdiagnosed as pneumonia, and pneumonia may be a complication of lung cancer (e.g., postobstructive pneumonia). In our study, the elevated lung cancer risk associated with pneumonia steadily declined over time to no apparent risk upon stratified analysis, suggesting that persons with pneumonia-like symptoms were misdiagnosed prior to their lung cancer diagnosis. Consistent with our findings, Brenner et al. (7) found a sixfold increased risk of lung cancer in persons diagnosed with pneumonia within 5 years of lung cancer onset but no apparent risks for persons diagnosed 5 or more years prior to the diagnosis of cancer.
Our data further confirm the findings of previous studies that the elevated lung cancer risk associated with emphysema is diminished with increasing length of smoking cessation (23, 50), although there was no overall difference in risk in our analysis for current versus former smokers. There was no statistical interaction between pack-years of smoking and emphysema, probably because of the limited number of current smokers among controls with emphysema in each stratum.
The interaction between smoking and hay fever was unexpected. The greatest protection from hay fever was in former smokers who had quit more recently and current smokers who reported lighter smoking histories. Persons with hay fever were slightly less likely to be smokers or to have been exposed to asbestos or wood dust (data not shown); however, this difference was small and could not account for the substantial protective effects noted. Although these data suggest that the interaction between smoking and hay fever confers a protective effect, we caution against any overinterpretation of these findings, since the interplay between smoking, hay fever, and lung cancer is not known.
Previous studies have shown that polymorphisms in the CYP1A1 (51), GSTM1 (52, 53), and mEPHX (54) genes are weakly associated with susceptibility to emphysema, but no data have been published exploring genetic susceptibility, hay fever, and lung cancer risk. We included data on MMP-1 and MPO because of their biologic interaction with smoking and their roles in the inflammatory process.
MMP-1 is thought to be involved in tumor initiation, development, invasion, and metastasis by altering the cellular tumor microenvironment (26). The 2G allele promoters have higher transcriptional activity than 1G promoters, resulting in more aggressive extracellular matrix degradation and thereby facilitating tumor development. At present, no data have shown a role for MMPs in hay fever, but previous studies suggest that MMP-1 is active in the airways and lung tissue of persons with emphysema and that continued MMP-1 expression contributes to tissue breakdown in emphysema patients (55, 56). Previously, our research group (24) found a significant association between the 2G/2G genotype and lung cancer risk (OR = 1.76). In this analysis, the MMP-1 genotypes appeared to have an impact in both conditions. The risk associated with emphysema was increased 4.5-fold among persons with the 2G/2G genotypes, as compared with an odds ratio of 2.58 in the presence of the 1G allele genotypes. The protective effect of hay fever was greater in carriers of the 1G allele genotypes as compared with the 2G/2G genotype.
Since the MPO polymorphism is associated with decreased transcriptional activity (43), one can hypothesize that there are less activation of carcinogens, enzyme-mediated DNA damage, and free radical production and that the protective effects would be more evident in persons exposed to tobacco mutagens or with an inflammation-related disease. At present, no data exist on the role of MPO in emphysema; however, previous studies suggested that MPO is involved in the inflammatory process of hay fever (5760). Previously, we reported a significantly reduced risk of lung cancer in Caucasian smokers with the A allele genotypes (OR = 0.63) (61). In this analysis, the A allele genotypes were associated with a borderline-significant reduced risk. Persons with emphysema were afforded some reduction in risk in the presence of the A allele genotypes of MPO. However, there was no difference in the protective effect of hay fever by the MPO genotypes. Overall, the joint effects of respiratory diseases and genetic susceptibility were less than additive but greater than the effects for either factor alone, which suggests independent risk factors acting together to moderately increase lung cancer risk.
Further analyses of gene-dosage effects (table 5) demonstrated that the risk associated with emphysema was substantially enhanced (increased over 4.2-fold) in the presence of one or more risk genotypes. Similarly, the protective effect of hay fever was enhanced in carriers of one or more protective genotypes. One possible explanation for these data may be that in the presence of emphysema, a destructive inflammatory condition, or the absence of hay fever, a putative enhancer of immune surveillance, the increased extracellular matrix degradation associated with the MMP-1 2G/2G genotype substantially increases lung cancer risk, while the decrease of deleterious enzyme activities associated with the MPO A allele genotypes reduces risk further in the presence of hay fever and the absence of emphysema.
Limitations and sources of bias should be considered. Misclassification and recall bias of exposure are of particular concern. Respiratory disease diagnoses were self-reported, and participants may not have been able to differentiate between diseases. Since cigarette smoking is the main risk factor for both chronic bronchitis and emphysema (22), some studies combine both diagnoses (i.e., reflected as chronic obstructive pulmonary disease) to assess lung cancer risk. Our questionnaire asked about "bronchitis" but did not specify "chronic bronchitis," limiting our ability to combine the two diseases and raising concern about disease misclassification and any possible association with lung cancer (i.e., the protective effects among persons diagnosed with bronchitis more than 10 years from the time of the interview). Furthermore, we were not able to validate the self-reported prior respiratory diseases. A limited sample size contributed to the nonsignificant gene-disease interactions and prohibited tests for three-way interactions. When relatively large independent effects are observed, as in this study, a sample size in the range of 1,5005,000 case-control pairs would be necessary to detect departures from additive interaction, with an alternative hypothesis of multiplicative interaction (62). Therefore, these novel findings require further research in larger studies.
In summary, after accounting for smoking and occupational exposures, we found that the risk of lung cancer was increased among persons with emphysema, and hay fever was associated with a protective effect. There were no statistically significant interaction terms for respiratory disease and markers of genetic susceptibility, but the data suggest moderate effect modification, which was greater than additive in some instances. Because cancer is a multigenic disease, a single genotype may have only a small-to-moderate independent effect on the disease phenotype, yet in aggregate with multiple biologically relevant genotypes, history of respiratory conditions, and deleterious exposures, it may reveal a more accurate representation of lung cancer risk.
The biologic role of nonmalignant respiratory diseases in lung cancer remains understudied. Further study including an assessment of genetic variants in the entire inflammatory pathway may yield new insights into the mechanisms of lung tumorigenesis and identification of highly susceptible subgroups.
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ACKNOWLEDGMENTS
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This study was supported by National Cancer Institute grants CA 55769, CA 86390, and CA 70907. Dr. Schabath was also supported, in part, by a cancer prevention fellowship (National Cancer Institute grant R25 CA 57730).
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NOTES
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Correspondence to Dr. Margaret R. Spitz, Department of Epidemiology, Unit 189, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 (e-mail: mspitz{at}mdanderson.org). 
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