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Systematic Evaluation of Genetic Variants in the Inflammation Pathway and Risk of Lung Cancer

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland and ² Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Eric A. Engels, Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, EPS 7076, Rockville, MD 20892. E-mail: engelse{at}exchange.nih.gov.

	Abstract

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Inflammatory responses to environmental exposures, such as tobacco smoke, may play a role in lung carcinogenesis. To test this hypothesis, we studied genetic polymorphisms in the inflammation pathway in relation to lung cancer risk. We evaluated a panel of 59 single nucleotide polymorphisms (SNP) in 37 inflammation-related genes among non-Hispanic Caucasian lung cancer cases (N = 1,553) and controls (N = 1,730) from Houston, Texas. Logistic regression was used to assess associations with lung cancer under a dominant genetic model adjusted for sex, age, and smoking. Haplotypes were estimated with the expectation-maximization algorithm. False-positive report probabilities (FPRP) were calculated for significant associations. Interleukin 1ß (IL1B) C3954T was associated with lung cancer [odds ratio (OR), 1.27; 95% confidence interval (95% CI), 1.10–1.47; FPRP 0.148]. Two IL1A SNPs (C-889T and Ala¹¹⁴Ser) were also related to lung cancer (OR, 1.18–1.22), although FPRPs were higher. One IL1A-IL1B haplotype, containing only the IL1B 3954T allele, was associated with elevated lung cancer risk (OR, 1.80; 95% CI, 1.24–2.61). These associations were stronger in heavy smokers, particularly for IL1B C3954T (OR, 1.59; 95% CI, 1.28–1.97; FPRP 0.004). Lung cancer risk was unrelated to polymorphisms in IL1 receptor or antagonist genes. Associations with lung cancer were also seen for SNPs in granulocyte macrophage colony stimulating factor and peroxisome proliferator-activated factor-, but FPRPs were high. IL1A and IL1B polymorphisms are associated with increased lung cancer risk, especially among heavy smokers. IL1A and IL1B are critical signals in initiating inflammation. Our results suggest that a dysregulated inflammatory response to tobacco-induced lung damage promotes carcinogenesis. [Cancer Res 2007;67(13):6520–7]

	Introduction

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Lung cancer is responsible for 162,000 deaths annually (1). Although tobacco use is the major environmental determinant of lung cancer risk, most smokers never develop lung cancer, and because lung cancer occasionally arises in nonsmokers, other factors are likely important as well.

Inflammation may play a role in the etiology of lung cancer (2–4). Individuals with tuberculosis, HIV infection, or chronic lung infection with Chlamydia pneumoniae seem to have an excess risk of lung cancer independent of tobacco use (5–7). Environmental agents associated with elevated lung cancer risk, such as silica or asbestos, may damage the lung by inducing chronic inflammation. Lung cancer risk is elevated in individuals with emphysema (8), interstitial lung disease (9), and asthma (10), which could similarly reflect effects of the underlying inflammatory disorders. Conversely, use of nonsteroidal anti-inflammatory drugs has been associated with decreased lung cancer risk (11).

In response to microbial agents and various environmental stimuli, macrophages and other cells trigger and sustain inflammation through a complex network of signaling molecules. In the lung, release of toxic oxygen radicals by macrophages and neutrophils participating in the inflammatory response can damage lung epithelial cells and induce DNA mutations. Although an appropriately limited inflammatory response may protect the host, an abnormally prolonged or intense inflammatory response could create a microenvironment that might promote carcinogenesis (2–4).

A few prior studies have examined lung cancer risk in relation to polymorphisms in the genes coding for inflammation pathway signaling molecules, such as interleukin 1ß (IL1B; refs. 12–14), IL1 receptor antagonist (IL1RN; refs. 15, 16), IL6 (13, 17), IL10 (18), cyclooxygenase 2 (17), and tumor necrosis factor (19). These studies have yielded mixed results, and some were limited by small sample size. No large study has systematically assessed lung cancer risk with respect to a range of polymorphisms in inflammation-related genes. In the present case-control analysis, we evaluated lung cancer risk in relation to a large number of candidate polymorphisms in inflammation-related genes.

	Materials and Methods

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Study subjects. The study design has been described previously (20). Briefly, newly diagnosed patients with histologically confirmed lung cancer were recruited at The University of Texas M. D. Anderson Cancer Center (Houston, TX). Controls without a prior history of cancer (except nonmelanoma skin cancer) were recruited from patients attending appointments for routine medical care at the Kelsey-Seybold Clinics, a large multispecialty physician practice in Houston. Controls were frequency matched to cases by age, sex, ethnicity, and smoking status (never, former, current). Questionnaire data included demographic characteristics, prior medical history, and family history of cancer in first-degree relatives. The present study includes only non-Hispanic Caucasians, the major racial/ethnic subgroup of subjects, to control for genetic differences across racial/ethnic populations (21).

The study was approved by institutional review boards at M.D. Anderson and Kelsey-Seybold Clinics. All subjects provided written informed consent for participation.

Genetic polymorphisms and laboratory methods. We selected for genotyping single nucleotide polymorphisms (SNP) in inflammation-related genes that met at least two of three criteria: (a) minor allele frequency of at least 5%; (b) location in the promoter, untranslated region (UTR), or coding region of the gene; and (c) previous report of an association with an inflammatory disorder, lung cancer, or another cancer. Coding SNPs are described according to the amino acid change, whereas other SNPs are described according to the nucleotide change or location in the UTR. All SNPs were genotyped using SNPlex, a technology developed by Applied Biosystems that enables simultaneous genotyping of up to 48 SNPs in a single tube using an oligonucleotide ligation assay. The assay principle and procedures are detailed in the manufacturer's user guide (PN4360858). Briefly, a list of candidate SNPs was submitted to Applied Biosystems, which evaluated the SNPs for suitability for the assay and designed a pool of SNP-specific ligation probes. Genomic DNA was fragmented at 99°C for 10 min, and 37 ng of fragmented DNA was dried down on each well of a 384-well plate. The SNP-specific ligation probes and a universal linker were phosphorylated and ligated together, and the mixture was then treated with exonuclease. Following purification, the probe mixture was added to the genomic DNA, which was amplified by PCR in the presence of biotinylated universal primers. The biotinylated amplicons were denatured and captured on streptavidin-coated plates. To decode the genotype information, single-stranded PCR products were hybridized with a universal set of fluorescent dye-labeled, mobility-modified fragments (Zipchutes, Applied Biosystems), which were then eluted and separated with the Applied Biosystems 3730 Capillary DNA Analyzer. Genotypes were called by Applied Biosystems GeneMapper software, using an analysis template file provided with each custom SNPlex assay.

The variable nucleotide tandem repeat (VNTR) polymorphism in intron 2 of the IL1 receptor antagonist gene (IL1RN) was determined as previously described (22). Briefly, primers (5'-CTCAGCAACACTCCTAT-3' and 5'-TCCTGGTCTGCAGGTAA-3') flanking the 86-bp tandem repeat region were used to amplify a DNA fragment containing the polymorphic region. The PCR conditions were as follows: 94°C for 1 min; 30 cycles of 94°C for 1 min, 60°C for 1 min, and 70°C for 1 min; followed by final extension at 72°C for 5 min. Products were separated by 2% agarose gel electrophoresis. Five different alleles have been reported. The wild-type allele (containing four 86-bp repeats) generated a 410-bp PCR product. The other alleles gave rise to PCR products of 240 bp (two repeats), 325 bp (three repeats), 500 bp (five repeats), and 595 bp (six repeats).

Statistical methods. We compared descriptive characteristics of cases and controls using the ² test and Wilcoxon rank sum test. For each SNP, Hardy-Weinberg equilibrium was assessed among controls using a ² test.

We used logistic regression to assess associations of lung cancer case-control status with each SNP, adjusting for sex, age, and cumulative tobacco exposure. Cumulative tobacco exposure was measured by "logcig-years," where logcig-years = log(cigarettes per day + 1) x duration of smoking in years (23). We focus on SNPs for which there was a statistically significant (P < 0.05) effect in an additive model (i.e., trend in lung cancer risk with increasing copies of the less common, "mutant" allele), and for which there was also a significant association with lung cancer risk for the mutant allele under a dominant model; given the rarity of homozygotes for the mutant allele, these two models could not be distinguished (24). We also examined recessive models, but none of these showed significant associations with lung cancer risk (not shown). In addition, we used logistic regression to compare genotype frequencies in cases and controls with respect to the IL1RN VNTR polymorphism, adjusting for sex, age, and logcig-years.

We observed significant associations with lung cancer case-control status for several SNPs in interleukin 1 (IL1A) and IL1B, both located in a 60-kb region on chromosome 2q13 (see Results). We therefore calculated D' as a measure of pairwise linkage disequlibrium (LD) for SNPs in this region. IL1A-IL1B haplotypes were estimated using the expectation-maximization algorithm (Helixtree, version 5.0.7, Golden Helix). Haplotypes estimated with at least 95% certainty were considered known and were included in the analysis, and haplotypes occurring at <1% frequency were grouped together. Because each subject had two haplotypes (one on each chromosome), we doubled the data (i.e., considering the haplotype as the unit of analysis) to conduct an unadjusted logistic regression analysis of the association between haplotypes and case-control status (24). For IL1A-IL1B haplotypes that showed a significant association with lung cancer, we then returned to an analysis in which the subject was the unit of analysis, using logistic regression to evaluate associations with paired haplotypes (i.e., diplotypes), adjusting for sex, age, and logcig-years. A dominant model (comparing individuals with one or two copies of the haplotype of interest versus those with zero copies) seemed to fit best.

In stratified analyses, we used logistic regression to examine associations of selected SNPs or diplotypes with lung cancer case-control status for subgroups of subjects defined by sex, age, smoking status, history of emphysema or hay fever, or family history of lung cancer. We also tested for interactions (polymorphism x stratification variable) using appropriate logistic regression models. Similarly, we examined associations between these polymorphisms and specific histologic subtypes and stages of non–small cell lung cancer, comparing each subgroup of cases against the entire group of controls.

Because we evaluated associations with multiple SNPs and haplotypes, some associations would arise by chance. To correct for multiple comparisons, we calculated the false-positive report probability (FPRP) for those associations observed to be statistically significant in the overall analysis or which seemed to differ within subgroups in the stratified analyses (25). The FPRP is the probability that the observed association is a false positive (i.e., the result of chance). FPRP depends on the observed result, the prior probability of an association, and the study's power to detect an association. For these calculations, we assumed prior probabilities for associations with lung cancer status under a dominant model of 0.01 for each SNP and 0.001 for each haplotype. The calculations further assume that the power is to detect, under the dominant model, an odds ratio (OR) of 1.3 for SNPs in the overall study population, 1.6 for haplotypes in the overall population or SNPs in subsets of the population, and 2.0 for haplotypes in subsets of the population. In accordance with Wacholder et al. (25), we considered FPRP <0.200 to indicate a noteworthy association (i.e., unlikely to be due to chance).

	Results

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Study subjects. Characteristics of the non-Hispanic Caucasians lung cancer cases (N = 1,553) and controls (N = 1,730) are presented in Table 1 . By design, the proportions of current and former smokers were similar in cases and controls, although as expected, cases reported greater cumulative tobacco exposure than controls (median 46 versus 40 pack-years, P < 0.0001). As reported previously for a subset of these subjects (26), cases were significantly more likely than controls to report a physician-diagnosed history of emphysema and less likely to report a physician-diagnosed history of hay fever. Family history of lung cancer in a first-degree relative was more common in cases than controls. The most common histologic type of lung cancer was adenocarcinoma, followed by squamous cell carcinoma, and most cancers presented at advanced stage (Table 1).

Results for the multiallelic VNTR polymorphism in IL1RN, also on 2q13, are presented in Table 3 . Alleles 4 and 2 were most common (73.4% and 23.7% of alleles, respectively). The overall distribution of IL1RN genotypes was similar in cases and controls (P = 0.91; Table 3).

Using the five SNPs in IL1A and IL1B, we identified 15 haplotypes, seven of which were estimated to be present in at least 1% of cases and controls (Table 4 ). The overall distribution of haplotypes differed between cases and controls (P = 0.004). As shown in Table 4, two haplotypes were associated with increased lung cancer risk compared with the w-w-w-w-w haplotype: the w-w-m-w-w haplotype, in which the only mutant allele was IL1B 3954T (OR, 1.80; 95% CI, 1.25–2.59), and the m-m-m-w-w haplotype, in which mutant alleles in IL1A Ala¹¹⁴Ser and IL1A C-889T were present with IL1B 3954T (OR, 1.18; 95% CI, 1.00–1.39). In an analysis of IL1A-IL1B diplotypes in relation to lung cancer risk, we found that possessing one or two copies of w-w-m-w-w, or one or two copies of m-m-m-w-w, was associated with increased lung cancer risk compared with other diplotypes (OR, 1.80; 95% CI, 1.24–2.61 and OR, 1.26; 95% CI, 1.05–1.51, respectively, adjusted for age, sex, and logcig-years).

Associations with these SNPs and haplotypes did not vary according to subtype or stage of non–small cell lung cancer (Table 5).

False-positive report probabilities. Table 6 shows FPRP estimates for selected results. In the analyses including all lung cancer cases and controls, only the association for IL1B C3954T yielded a FPRP below 0.200 (FPRP 0.148), suggesting that this association is unlikely to represent a false-positive result. Associations for other SNPs showed substantially higher FPRPs, in the range 0.429 to 0.854. For associations with IL1A-IL1B haplotypes, the associations also yielded high FPRPs (0.878–0.925; Table 6).

	Discussion

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Our study systematically evaluated associations with a wide range of polymorphisms in inflammation-related genes. The strongest finding was the observed associations of polymorphisms in IL1A and IL1B with lung cancer, especially among older individuals and those with a history of heavy smoking. IL1A and IL1B are secreted by macrophages and other cells in response to microbial infection or tissue damage. Together with tumor necrosis factor , they act as critical signals in the initiation of acute inflammation (27). IL1A and IL1B also induce stromal cells to secrete proteases and angiogenic molecules, which could facilitate tumor invasion (27). We did not find associations with lung cancer risk for polymorphisms in IL1R1 (coding for the IL1 receptor) or IL1RN (IL1 receptor antagonist), two other components of the IL1 signaling pathway.

Individuals heterozygous or homozygous for the mutant allele at IL1B C3954T had an increased risk of lung cancer (OR, 1.27; 95% CI, 1.10–1.47). This association manifested a low FPRP, indicating that the finding was unlikely due to chance. Although the C3954T SNP in exon 5 of IL1B is synonymous (i.e., it does not result in an amino acid change in the IL1B protein), it may affect levels of gene transcription or translation. The relevance of this SNP was supported by Pociot et al. (28), who described a dose-response increase in IL1B secretion by monocytes with increasing copy number of the mutant allele; one explanation may be that IL1B C3954T is in LD with another polymorphism that affects IL1B expression. In addition, some research groups (29, 30), although not all (31), have reported that individuals possessing the IL1B C3954T polymorphism manifest elevated levels of C-reactive protein, an acute phase protein secreted by the liver during acute inflammation. One recent case-control study in China examined the association between lung cancer and IL1B C3954T (14); although results were negative, the study was limited by low statistical power (n = 119 cases). The IL1B C3954T polymorphism has been associated with risk of cervical dysplasia (32) and mortality after pancreatic cancer diagnosis (33). Some studies also found this polymorphism associated with risk of gastric cancer (34).

Our finding of an association of lung cancer risk with the IL1B C3954T polymorphism supports the hypothesis that heightened production of IL1B in response to inflammatory stimuli or lung damage may promote carcinogenesis. We did not find associations with lung cancer status for two SNPs in the IL1B promoter (Table 2). Two small case-control studies have shown an association between IL1B C-511T and lung cancer risk (12, 14), but previous results for IL1B T-31C have been inconsistent (12–14).

We also found increased lung cancer risk among individuals homozygous or heterozygous for the mutant alleles of two IL1A SNPs, C-889T and Ala¹¹⁴Ser. These SNPs were in complete LD (D' = 1.000), so it was not possible to determine which was more relevant for lung cancer. We are unaware of data relating the IL1A SNPs to differences in the level of expression or function of IL1A. The change in amino acids coded for by the Ala¹¹⁴Ser polymorphism is not predicted to have a strong effect on IL1A function (SIFT score 0.38, PolyPhen score 1.3).

Given the close physical proximity of IL1A and IL1B and the observed LD between SNPs in these genes, we evaluated associations of IL1A-IL1B haplotypes with lung cancer risk (Table 4). Lung cancer risk was substantially elevated among individuals who had at least one copy of the w-w-m-w-w haplotype (OR, 1.80; 95% CI, 1.24–2.61). Because this haplotype contains only the mutant allele of IL1B C3954T, which is synonymous, its association with elevated lung cancer risk might be due to LD with an unmeasured risk polymorphism nearby on chromosome 2q13. Interestingly, the m-m-m-w-w haplotype, which included mutant alleles at the two linked SNPs in IL1A, was actually associated with a lower level of risk (OR, 1.26; 95% CI, 1.05–1.51), and haplotypes that included only the mutant alleles in IL1A (but not the mutant allele of IL1B C3954T) were not associated with increased lung cancer risk (Table 4). These observations suggest that the IL1A SNPs do not affect lung cancer risk themselves, but rather are associated with lung cancer through their LD with IL1B C3954T.

Notably, we found especially strong associations with lung cancer risk for the IL1A and IL1B polymorphisms among heavy smokers (ORs 1.38–1.59). Likewise, the IL1A-IL1B haplotype w-w-m-w-w was associated with markedly elevated risk among both heavy smokers and older subjects. The interpretation of these finding is uncertain, but they are consistent with the possibility that the effects of IL1A and IL1B polymorphisms are subtle and manifest in pulmonary damage only after prolonged or heavy exposure to tobacco smoke. Our analyses also suggested that polymorphisms in IL1A may be important in influencing lung cancer risk among individuals with emphysema. However, the high FPRPs for associations with IL1A SNPs in this subgroup suggest chance could also be an explanation.

In addition, we found associations with lung cancer risk for polymorphisms in GM-CSF and PPARD. GM-CSF regulates macrophage and neutrophil function during inflammatory reactions (35). Blockade of GM-CSF signaling reduces airway inflammation and hyperresponsiveness in mouse models of environmentally induced lung damage and asthma (36, 37). The mutant allele at GM-CSF Ile¹¹⁷Thr, which we found associated with increased lung cancer risk, has previously been linked to an elevated risk for atopic asthma (38). PPARD is a member of the family of peroxisome proliferator-activator receptors, which act as nuclear transcription factors to regulate lipid metabolism and inflammation (39). Although the associations of lung cancer risk with SNPs in GM-CSF and PPARD may have a plausible basis, the FPRP values for the associations were high.

A strength of our study was the large number of lung cancer cases and controls, and the availability of supporting data on lung cancer subtype and important covariates, such as smoking behavior and medical history. Another major strength was our systematic evaluation of a large number of known polymorphisms in inflammation-related genes, which facilitated comprehensive assessment of this pathway. The inclusion of a large number of polymorphisms was also a potential weakness because it raises the possibility that some statistically significant associations were due to chance alone. To mitigate this problem, we have presented FPRP statistics for all significant results and emphasize results where the FPRP is below 0.200 (25). Another potential limitation is the use of controls from a physician practice instead of the general population, but it is unlikely that control selection biased our analyses of genetic polymorphisms (20). By including only non-Hispanic Caucasian subjects, we reduced the likelihood that population stratification materially affected the results (21). In addition, we had no data on use of nonsteroidal anti-inflammatory drugs, which might modify the effects of these polymorphisms.

In conclusion, our results concerning IL1B C3954T, and to a lesser extent the IL1A polymorphisms, support a role for inflammation in the etiology of lung cancer. These associations were modest in magnitude, but they suggest that, in the setting of heavy or prolonged exposure to tobacco or other agents, an aberrant inflammatory response may promote lung damage, eventually leading to lung cancer. Future studies may focus on identifying additional polymorphisms within the IL1 locus, characterizing their function, and assessing their relationship with lung cancer risk.

	Acknowledgments

 
Grant support: National Cancer Institute grants CA55769, CA70609, and CA 111646; the Department of Defense grant DAMD17-02-1-0706; the Flight Attendants Medical Research Institute; the M. D. Anderson Specialized Programs of Research Excellence grant CA070907; and the Intramural Research Program of the National Cancer Institute (E.A. Engels).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank Dr. Christopher Amos (The University of Texas M. D. Anderson Cancer Center) for helpful statistical advice.

Received 1/29/07. Revised 4/13/07. Accepted 4/27/07.

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