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Carcinogenesis Advance Access originally published online on March 14, 2007
Carcinogenesis 2007 28(7):1437-1441; doi:10.1093/carcin/bgm030
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Published by Oxford University Press 2007.

Polymorphisms in immunoregulatory genes, smoky coal exposure and lung cancer risk in Xuan Wei, China

Kyoung-Mu Lee1,*, Min Shen1, Robert S. Chapman2, Meredith Yeager1, Robert Welch1, Xingzhou He3, Tongzhang Zheng4, H. Dean Hosgood1,4, Dongyun Yang5, Sonja I. Berndt1, Stephen Chanock1 and Qing Lan1

1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892-7240, USA
2 College of Public Health, Chulalongkorn University, Bangkok 10330, Thailand
3 Institute of Environmental Health and Engineering, Chinese Academy of Preventive Medicine, Beijing 100050, China
4 Yale School of Public Health, Yale University, New Haven, CT 06520, USA
5 USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA

* To whom correspondence should be addressed. Tel: +1 301 594 7485; Fax: +1 301 402 1819; Email: leekyou{at}mail.nih.gov


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Supplementary material
 References
 
We conducted a population-based case–control study in Xuan Wei, China, where lung cancer rates are among the highest in China due to exposure to indoor coal combustion products, to evaluate the association between polymorphisms in immunoregulatory genes and lung cancer risk. A total of 122 incident primary lung cancer cases and 122 individually matched controls were enrolled in Xuan Wei, China. Fifty single-nucleotide polymorphisms (SNPs) in 23 immunoregulatory genes involved in inflammation were genotyped and analyzed by logistic regression to assess the risk of lung cancer. A global test of association for 42 SNPs, which excluded eight SNPs that were in very tight linkage disequilibrium with other SNPs, was statistically significant (P = 0.01), suggesting that overall genetic variation in this pathway contributes to lung cancer risk. In addition, the IL1B –1060TT (i.e. –511TT) genotype was associated with increased lung cancer risk compared with the CC genotype [odds ratio (OR) = 2.27, 95% confidence interval (CI) = 1.05–4.91]. The IL8RA Ex2+860 GC or CC (OR = 0.27, 95% CI = 0.11–0.67), ICAM1 Ex2+100 AT or TT (OR = 0.39, 95% CI = 0.18–0.88) and IL12A Ex7+277 GA or AA (OR = 0.43, 95% CI = 0.22–0.84) genotypes were associated with decreased lung cancer risk. The protective effect of the IL8RA variant was stronger among subjects with high cumulative smoky coal use (≥130 tons) (OR = 0.11, 95% CI = 0.03–0.44; Pinteraction = 0.03). In conclusion, genetic variation in immunoregulatory genes may play an important role in the development of lung cancer in this population.

Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; FDR, false discovery rate; LD, linkage disequilibrium; OR, odds ratio; PAH, polycyclic aromatic hydrocarbon; SNP, single-nucleotide polymorphism


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Supplementary material
 References
 
Lung cancer is one of the leading causes of cancer mortality in the world with an estimated 1.24 million incident cases in 2000 (1). Lung cancer incidence in Xuan Wei County is among the highest in China (27.7 and 25.3 per 100 000 men and women, respectively) and has been causally associated with exposure to indoor smoky coal emissions that contain very high levels of polycyclic aromatic hydrocarbons (PAHs) (2–4).

There is an increasing recognition that inflammatory pathways contribute to malignant transformation including lung cancer development (5,6). Individuals with respiratory diseases associated with chronic inflammation, such as chronic obstructive lung disease and asthma, are at an elevated risk for subsequent lung cancer development (7,8). Activated inflammatory processes may favor lung cancer development by generating reactive oxygen and nitrogen species or by secreting growth stimulatory cytokines, chemokines and pro-angiogenic factors (9). Therefore, polymorphisms in such genes might play a role in lung cancer development. Several epidemiological studies have suggested that the IL1B –580T (i.e. –31T) or –1060T (i.e. –511T) (10,11), IL6 –174C (12), IL10 –1082G (10,13) and COX2 8473C (12) alleles are associated with lung carcinogenesis.

We have previously linked smoky coal exposure with risk of both chronic obstructive pulmonary disease (COPD) (14) and lung cancer (4) in Xuan Wei, and have shown that COPD itself is a risk factor for lung cancer in this population (4). Further, experimental studies have shown that PAHs are capable of elevating the expression level of a key pro-inflammatory cytokine (i.e. IL-8) in a lung epithelial cell line (15,16) and of causing lung cancer risk in laboratory animals (17). We therefore hypothesized that genetic polymorphisms in important immunoregulatory genes, many of which play a role in the inflammatory process, might be the susceptibility factors for lung cancer. To test this hypothesis, we conducted an analysis of 50 genetic polymorphisms in 23 immunoregulatory genes in a series of lung cancer patients and matched controls from Xuan Wei, China.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Supplementary material
 References
 
Study population
This population-based case–control study of lung cancer in Xuan Wei has been described previously (18). Briefly, 122 newly diagnosed lung cancer cases from five regional hospitals and 122 controls individually matched on sex, age (±2 years), village and type of fuel currently used for cooking and home heating were selected from March 1995 through March 1996. The criteria for inclusion as a lung cancer case were positive histology or cytology results (105 cases, 86.1%) or clinically diagnosed cases who died within a 1 year period (17 cases, 13.9%). Cell-type information was available on 35 cases, which included 24 non-small cell carcinoma, 3 small cell carcinoma and 8 others. Within 2 weeks after the diagnosis and recruitment of each lung cancer case, a control was selected randomly from the list of household registrants from the same villages in which the lung cancer patients lived. A standardized structured questionnaire was used to obtain information on demographic characteristics, lifetime use of different types of coal, tobacco smoking, family history of lung cancer and personal medical history. The participation rate was 98% for cases and 100% for controls. For the protection of the human subjects, this international research study was conducted according to the guidelines of the World Medical Association Declaration of Helsinki. All the subjects in this study signed a consent form. The research protocol was approved by an Environmental Protection Agency Human Subjects Research Review Official.

Genotyping
DNA was extracted from sputum samples using phenol–chloroform extraction (19) and genotyped by real-time polymerase chain reaction on an ABI 7900HT sequence detection system as described on the SNP500 website (http://snp500cancer.nci.nih.gov) at the Core Genotyping Facility of the National Cancer Institute. Of the 122 cases and 122 controls, genotyping was available from 119 cases and 113 controls. Fifty single-nucleotide polymorphisms (SNPs) in 23 genes (CCR5, ICAM1, IFNG, IFNGR2, IL1A, IL1B, IL1RN, IL4, IL4R, IL5, IL8, IL8RA, IL8RB, IL10, IL10RA, IL12A, IL12B, IL13, IL16, LTA, MIF, TGFB, and TNF) were genotyped. The SNPs were selected based on the criteria of having minor allele frequencies >5% from the SNP500 database (20) and if possible having laboratory evidence of function or prior association with human diseases including cancer (21) (Table I). More than 96% of all DNA samples were successfully genotyped for all SNPs except IFNG –1615C>T (92%), IL4R Ex10+300A>C (E400A) (93%) and Ex11+828A>G (Q576R) (94%). Concordance rates between quality control samples were 99–100% for all assays. Eight of the 50 SNPs [i.e. IL1A Ex1+12C>T, IL1B –580C>T (–31C>T), IL4 IVS3–9A, IL8 IVS1–204C>T, IL8 IVS1+230G>T, IL10 –6653A>C, IL10 Ex5+210C>T and IL13 Ex4+98A>G (Q144R)] were found to be in very tight linkage disequilibrium (LD) (i.e. r2 > 0.95) with other SNPs in the same gene [IL1A Ex5+21G>T (A114S), IL1B –1060T>C (–511T>C), IL4 IVS2–1443A>C, IL8 –351A>T, IL10 –7334T>C, IL10 IVS1–286G>T and IL13 IVS3–24T>C, respectively]. Thus, these eight SNPs were excluded from the global test of association and the false discovery rate (FDR) test, described below.


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  		Table I. Fifty SNPs in twenty-three immunoregulatory genes genotyped in this study

 
Statistical analysis
Ever-smokers were defined as subjects who smoked at least one cigarette per day for 6 months or longer. Cut-off points for smoky coal use (tons) and tobacco smoking (pack-years) were estimated using the distribution of lifetime cumulative use in controls (<130 versus ≥130 tons and <25 versus ≥25 pack-years, respectively). Hardy–Weinberg equilibrium for each SNP was tested with a Pearson’s {chi}2 or an exact test if any of the cell counts was less than five.

To assess the global significance of the association between SNPs tested in the immunoregulatory pathway and lung cancer risk, we used the whole-model likelihood ratio {chi}2 statistic (22), comparing the logistic regression model that included all 42 SNPs as main effects (i.e. variant allele-containing genotypes versus homozygotes of the common allele) against the null model that included none of the SNPs.

Genotype data for each SNP were then analyzed with the homozygote of the common allele as the reference group. Because genotype data were not available for all cases and controls, unconditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for the association between lung cancer risk and respective SNP, adjusted for age, sex, smoking status and cumulative smoky coal use. ORs are not provided for the main effect analyses of genotypes where there were fewer than five subjects in any cell, but are provided for the stratified analysis (Table IV) where cells contain as few as three subjects, so that interactions with smoky coal exposure could be presented with all SNPs that showed significant main effects. FDR values were calculated using the Benjamini–Hochberg method (23). Results from the dominant models from the main effects of the 42 SNPs (i.e. variant allele-containing genotypes versus homozygotes of the common allele) for lung cancer were assessed as one set by the FDR method.

Haplotype analyses were conducted for selected genes with two or more SNPs using the haplo.stat package (http://mayoresearch.mayo.edu/mayo/research/schaid_lab/software.cfm), which uses an expectation–maximization algorithm to estimate haplotypes from genotype data (24), in the R program (version 2.2.1: http://www.r-project.org). Haplotype block structure was evaluated with the program Haploview (http://www.broad.mit.edu/mpg/haploview; Whitehead Institute, Cambridge, MA). An unconditional logistic regression model was used to estimate the effect of each haplotype by fitting an additive model, adjusted for sex, age, smoking and smoky coal use. The overall difference in haplotype frequencies between cases and controls was assessed using a global score test.

Stratified analyses by cumulative smoky coal use were conducted to evaluate effect modification. Interactions between each genotype that showed significant main effects and smoky coal use were tested on a multiplicative scale by adding product term of binary variables, genotype (minor allele-containing genotypes versus wild-type homozygotes) and cumulative smoky coal use (<130 versus ≥130 tons), into the logistic regression model.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Supplementary material
 References
 
Characteristics of the 119 cases and 113 controls are presented in Table II. Demographic characteristics, including age and sex were very similarly distributed in the two groups. Cumulative smoky coal use but not smoking was associated with an increased risk of lung cancer, which is consistent with a previous study in Xuan Wei (18).


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  		Table II. Distribution of demographic features in lung cancer cases and controls

 
All genotype frequencies were consistent with Hardy–Weinberg equilibrium in the control group (P > 0.05). A global test of all 42 SNPs was statistically significant (P = 0.01), suggesting that genetic variation in immunoregulatory genes may be an important risk factor for lung cancer in this population.

Four of the 42 SNPs tested were associated with lung cancer risk in this study (Table III). The IL1B –1060TT (–511TT) genotype was associated with increased lung cancer risk compared with the CC genotype (OR = 2.27, 95% CI = 1.05–4.91). The IL8RA Ex2+860 GC or CC, ICAM1 Ex2+100 AT or TT and IL12A Ex7+277 GA or AA genotypes were associated with decreased lung cancer risk (OR = 0.27, 95% CI = 0.11–0.67; OR = 0.39, 95% CI = 0.18–0.88 and OR = 0.43, 95% CI = 0.22–0.84, respectively). When the dose–response effect was evaluated, all four alleles, IL1B –1060T (–511T), IL8RA Ex2+860C, ICAM Ex2+100T and IL12A Ex7+277A, showed significant dose–response effects on the risk of lung cancer (Ptrend ≤ 0.04). The FDR value for the strongest association in this study (IL8RA Ex2+860 GC or CC) was 0.18 when taking into account all SNPs tested for association with risk of lung cancer.


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  		Table III. Main effect of selected SNPs of immunoregulatory genes on lung cancer risk in Xuan Wei, China

 
Among other SNPs, as shown in the supplementary table (available at Carcinogenesis Online), IL4 Ex1–168 TC or CC was associated with reduced lung cancer risk (OR = 0.57, 95% CI = 0.33–0.98). However, the trend test was not statistically significant (Ptrend = 0.06). No other SNPs showed significant associations with lung cancer.

Stratified analysis suggested that at least one of these associations was modified by the level of cumulative smoky coal use (Table IV). The protective effect of IL8RA Ex2+860 GC or CC was greater in high smoky coal users (≥130 tons) (OR = 0.11, 95% CI = 0.03–0.44) than in low smoky coal users (<130 tons) (OR = 0.70, 95% CI = 0.19–2.51) (Pinteraction = 0.03), although the number of subjects in some cells was relatively small. Further, the effect of ICAM1 Ex2+100 AT or TT was stronger among high smoky coal users (≥130 tons) and the effects of IL1B –1060 (–511) CT or TT and IL12A Ex7+277 GA or AA were stronger among low smoky coal users. However, tests for interaction were not statistically significant. There was no evidence that effects differed between men and women. Haplotype analysis did not reveal associations beyond what was apparent in the single-SNP analyses (data not shown).


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  		Table IV. Genotype distributions of selected SNPs stratified by cumulative smoky coal use

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Supplementary material
 References
 
We investigated the association between lung cancer and 42 SNPs in 23 genes involved in inflammation. Variants in IL1B, IL8RA, ICAM1 and IL12A showed significant associations with lung cancer risk, and one association was modified by smoky coal use.

The association between the IL1B –1060T (–511T) allele and lung cancer risk found in this study (Ptrend = 0.04) is consistent with the results of Zienolddiny et al. (10). These authors found that the CT genotype increased the risk of non-small cell lung cancer in Norwegians by 1.91-fold and the TT genotype increased by 2.51-fold compared with CC genotype. The IL1B –580C (–31C) allele, which is in tight LD with –1060T (–511T) (D' = 1.0 and r2 = 1.0), also showed a moderate dose–response relationship with lung cancer risk in our study (Ptrend = 0.08). The IL1B haplotype, composed of the T allele at –1060 (–511) and the C allele at –580 (–31), was significantly associated with increased LPS-induced pro-inflammatory IL-1ß protein secretion (25,26). Thus, either allele or another variant in LD with this haplotype might intensify the inflammatory response, thereby increasing the risk of lung cancer.

The amino acid change at the IL8RA Ex2+860C>G (S276T) is located in the extracellular domain (27) and may result in modification of a chemokine receptor located on monocytes which is involved in the binding of pro-inflammatory chemokine IL-8 to mediate the attraction and activation of neutrophils (28). In a genome-wide screen, the chromosome region of IL8RA and IL8RB was linked to total serum IgE levels in asthma patients (29) and spirometric phenotypes for early-onset COPD (30). In a recent study, a significant association was found between the IL8RA M31C polymorphism and COPD in adults and asthma in children (31).

As noted previously, we found evidence that the IL8RA Ex2+860 GC or CC genotype was more strongly associated with decreased risk of lung cancer among subjects who had used relatively high levels of smoky coal in their household (Table IV). The biologic plausibility of this finding is supported by the observation that the expression levels of pro-inflammatory cytokine IL8 are increased when pulmonary cells are exposed to PAHs (15,16). The IL8RA Ex2+860C allele results in an amino acid change from serine to threonine in the extracellular domain, and may have functional implications, particularly at higher levels of PAH exposure. However, the finding needs to be interpreted cautiously, the association needs to be replicated, and the functionality of this SNP, as well as other SNPs in LD, needs to be evaluated.

ICAM1 functions as an intercellular adhesion molecule 1 (CD54). Mice deficient in ICAM1 had impaired lymphocyte recruitment to the lung, less airway hyper-responsiveness and less lung inflammation than healthy controls (32). An amino acid change from lysine to methionine caused by the ICAM1 Ex2+100A>T (K56M) polymorphism evaluated in this study might affect the adhesive function of ICAM1. The fact that two other ICAM1 polymorphisms (rs5030382:K469E and rs1799969:G241R) have been associated with cutaneous melanoma and breast and prostate cancer risk supports the importance of genetic variation in this gene for cancer (33,34).

IL12 is an inducer of differentiation of T helper cells toward Th1 and induces natural killer cells and T cells to produce IFN-{gamma}. IL12 gene polymorphisms have been associated with risk of autoimmune diabetes (35) and atopic and non-atopic asthma (36). One of two recent studies that have evaluated the association between IL12A polymorphisms and gastric cancer found that the frequency of non-cardia gastric cancer was higher in patients with the IL12A –504TT genotype (OR = 2.38) (37). The other study, however, found no association between three IL12A polymorphisms (IVS2–798A>T, IVS2–701A>C and Ex7+277A>G) and gastric cancer (38). The association between the IL12A polymorphism (Ex7+277A>G) and lung cancer found in this study should be replicated in a larger study.

These findings from this study suggest that genetic variation in immunoregulatory genes involved in inflammation may play a role in lung carcinogenesis in this population. There is evidence that variants in other genes, such as GSTM1, may also play a role in the etiology of lung cancer in populations exposed to indoor pollution from fuel combustion products, as shown in this population (18) and in a recent meta-analysis (39). These findings suggest that further evaluation of genetic susceptibility in populations exposed to indoor air pollution from fuel combustion products may be worthwhile.

A strength of this study is that we evaluated SNPs in a total of 23 genes that play a role in the immune and inflammatory process. It is noteworthy that a global test of association for all SNPs evaluated was significant, suggesting overall that genetic variation in these pathways may contribute to risk of lung cancer in this population. To our knowledge, this is the first study to report a number of these associations with lung cancer. Further, our study is one of the few investigations that have evaluated genetic susceptibility in a population where lung cancer is caused in great part by exposure to coal combustion emissions, and we carried out an extensive exposure assessment so that lifetime use of smoky coal could be analyzed.

However, our study has several limitations. The primary limitation of our study is the small sample size and, as a consequence, low statistical power to detect effects. In addition, a small sample size has an increased likelihood of producing false-positive findings, particularly if the risk factor has a low prior probability (40). Interactive effects found between SNPs in immunoregulatory genes and smoky coal use also need cautious interpretation. Therefore, it is important to attempt to replicate the findings in other studies of lung cancer in populations exposed to indoor air pollution from coal or other fuels. We note that a new, substantially larger study of lung cancer among women in Xuan Wei and adjacent regions is currently in progress and will provide an opportunity in the future to evaluate and extend these findings.

In conclusion, the results of this study suggest that genetic variation in immunoregulatory genes may play a role in the development of lung cancer in this population, and that some of these effects might be modified by cumulative smoky coal use. These findings need to be replicated in other populations exposed to indoor fuel combustion products and extended by the analysis of additional genetic variants in these and other genes that play a role in the inflammatory pathway.


   Supplementary material
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Supplementary material
References
 
Supplementary table can be found at http://carcin.oxfordjournals.org/


   Acknowledgments
 
The authors are grateful to the study subjects who participated in the study.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Supplementary material
 References
 

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Received December 11, 2006; revised February 5, 2007; accepted February 5, 2007.


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M. Ter-Minassian, R. Zhai, K. Asomaning, L. Su, W. Zhou, G. Liu, R. S. Heist, T. J. Lynch, J. C. Wain, X. Lin, et al.
Apoptosis gene polymorphisms, age, smoking and the risk of non-small cell lung cancer
Carcinogenesis, November 1, 2008; 29(11): 2147 - 2152.
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