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Carcinogenesis Advance Access originally published online on August 2, 2006
Carcinogenesis 2007 28(1):118-123; doi:10.1093/carcin/bgl130
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Published by Oxford University Press 2006

Polymorphisms in Th1-type cell-mediated response genes and risk of gastric cancer

L. Hou1,*, E.M. El-Omar2, J. Chen1, P. Grillo3, C.S. Rabkin1, A. Baccarelli3,4, M. Yeager5, S.J. Chanock1,5, W. Zatonski6, L.H. Sobin7, J. Lissowska6, J.F. Fraumeni, Jr1 and W.H. Chow1

1 Division of Cancer Epidemiology and Genetics, National Cancer Institute 6120 Executive Boulevard, EPS 8123, Bethesda, MD 20852-7242, USA
2 Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen Foresterhill, Aberdeen, AB25 2ZD, UK
3 Molecular and Genetic Epidemiology Center—Epidemiology Unit, Department of Occupational, Clinical and Preventive Medicine, IRCCS Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, I-20122 Milan, Italy
4 EPOCA Research Center for Clinical, Occupational and Environmental Epidemiology, Department of Occupational Medicine, University of Milan I-20122 Milan, Italy
5 Core Genotyping Facility, Advanced Technology Center, National Cancer Institute Gaithersburg, MD 20892, USA
6 Division of Cancer Epidemiology and Prevention, Cancer Center and M.Sklodowska-Curie Institute of Oncology 02-781 Warsaw, Poland
7 Department of Hepatic and Gastrointestinal Pathology, Armed Forces Institute of Pathology Washington, DC, 20306, USA

*To whom correspondence should be addressed. Tel: +1 301-451-5031 Fax: +1 301 402 4489; Email: lifangh2{at}mail.nih.gov


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Helicobacter pylori infection, the dominant risk factor for gastric cancers, has been shown to elicit T helper type 1 (Th1) polarized immunological responses. We conducted a population-based study of 305 gastric cancer cases and 427 age- and gender-matched controls in Warsaw, Poland, to evaluate the association with several variants in genes responsible for Th1-cell-mediated response. Genotyping was performed on genomic DNA by TaqManTM assays to determine TNFA (–308 G>A, –417 G>A, –555 G>A, –1036 C>T, –1042 C>A, –1210 T>C), IL1A (–889 C>T), IFNGR2 (Ex7-128 T>C, Ex2-34 C>G and Ex2-16 A>G) and IL12A (IVS2-798 T>A, IVS2-701 C>A and Ex7+277 G>A) polymorphisms. We used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for sex, age, education and smoking status. Out of six single nucleotide polymorphisms (SNPs) tested in TNFA, gastric cancer risk was significantly associated with the TNFA (–308 G>A) polymorphism, with ORs of 1.4 (95% CI: 1.0–2.0) for the G/A and 2.5 (95% CI: 1.3–4.9) for the A/A genotype carriers, when compared with the more frequent genotype (G/G) (P-trend < 0.001). Among the three tested SNPs in the IFNGR2 gene, only the Ex7-128C>T polymorphism was associated with increased risk, with ORs of 1.5 (95% CI: 1.0–2.3) for T/C and 1.7 (95% CI: 1.1–2.7) for C/C carriers when compared with T/T carriers (P-trend = 0.01). Subjects carrying both IFNGR2 Ex7-128 C/C and TNFA –308 A/A genotypes had the highest risk (OR = 5.5, 95% CI: 1.5–19.4), although the interaction was not statistically significant. IL1A (–889 C>T) and the three examined IL12A variants were unrelated to gastric cancer risk. Our findings suggest that two Th1-related polymorphisms (TNFA –308 A>G and IFNGR2 Ex7-128 C>T) may increase the risk of gastric cancer.

Abbreviations: CIs, confidence intervals; IFN, interferon; IL, interleukin; ORs, odds ratios; SNPs, single nucleotide polymorphisms; Th1, T helper type 1; TNF, tumor necrosis factor


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Helicobacter pylori infection is a major risk factor for gastric cancer (1–3). The infection usually causes chronic gastritis, but only a small proportion of the infected subjects develop peptic ulcers or gastric cancer (1,4). The nature of the host immune response may contribute to the different outcomes of H.pylori infection (3,5,6). It has been demonstrated that H.pylori infection triggers T helper type 1 (Th1) cell-mediated response induced by interleukin 12 (IL12) and characterized by high production of interferon-{gamma} (IFN-{gamma}), IL1-{alpha}, tumor necrosis factors (TNFs) and IL2 (3,7). Th1 cells have been found in T-cell clones specific for H.pylori isolated from infected gastric tissue (8). The Th1-polarized response activates macrophages to produce pro-inflammatory cytokines, helps in eliminating the bacteria, increases the release of gastrin, and by inhibiting acid secretion it promotes the development of gastric atrophy and its stepwise progression to cancer. In addition, by increasing apoptosis of normal gastric epithelial cells and mucosal damage (3,6,7,9,10), the Th1 cell-mediated response further promotes the process of gastric atrophy and carcinogenesis (11,12).

In recent years, increasing attention has been paid to the role of Th1 pathway in H.pylori-related gastric diseases (3,6,10). A number of polymorphisms in cytokine genes, including Th1-related genes, have been identified and related to differences in cytokine production or function (13,14). In the present study, we examined 13 polymorphisms in five Th1-related genes in relation to gastric cancer risk in a Polish population.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Study design
The present population-based case–control study of gastric cancer was carried out in Warsaw, Poland, between 1994 and 1996. The study population has been described in detail previously (5,15,16). Residents aged 21–79 years and newly diagnosed with gastric cancer (ICD-O 151) were identified by collaborating physicians in each of the 22 hospitals serving the study area. All diagnoses were pathologically confirmed by study pathologists. Controls were randomly selected from a computerized registry of Warsaw residents who were healthy at the time of interview and frequency-matched to cases by sex and 5 year age groups. The registry was updated monthly, and the completeness of registration was estimated to be nearly 100%.

Detailed information on lifetime tobacco use, alcohol consumption, family history of gastric cancer, childhood living conditions, demographic background, history of selected medical conditions and medication use, lifetime occupational history and usual diet before 1990 was recorded during a personal interview, after written consent was obtained. Among the 464 gastric cancer cases and 480 controls identified for the study, genomic DNA was obtained from 305 (65.7%) cases and 427 (90.0%) controls (16).

Genotyping assays
In total, 13 single nucleotide polymorphisms (SNPs) in five Th1-related genes were assessed. The 13 SNPs were selected on the basis of evidence reported in the literature regarding the function and disease association of each SNP and the characteristics of the polymorphisms (non-synonymous and promoter SNPs). Synonymous SNPs in coding and non-coding regions were also selected to improve the coverage of the candidate genes. Eleven of the 13 SNPs were tested by TaqManTM assays (Applied Biosystems, Foster City, CA) at the Core Genotyping Facility (CGF), National Cancer Institute, National Institutes of Health (NIH), including five SNPs in TNFA [–417G>A (rs361525), 555G>A (rs1800750), –1036 C>T (rs1799724), –1042 C>A (rs1800630) and –1210 T>C (rs1799964)], three SNPs in IFNGR2 [Ex7-128 T>C (rs1059293), Ex2-34C>G (T58R) (rs4986958) and Ex2-16A>G (Q64R) (rs9808753)] and three SNPs in IL12A [IVS2-798 T>A (rs582054), IVS2-701 C>A (rs582537) and Ex7+277 G>A (rs568408)]. Assays were validated and optimized as described in the SNP500 Cancer website (17). Assay-specific primer/probe concentrations and thermocycling conditions for these polymorphisms are also available on the website (http://snp500cancer.nci.nih.gov). For each genotype, as a lab internal quality control, four human DNA controls (Coriell DNA) as well as no template controls were run with study samples. Approximately 8% blind quality control samples from two individuals were interspersed with the study samples, showing >99% concordance. Genotyping data for each tested SNP were successfully obtained for ≥95% of the subjects. The two remaining SNPs, IL1A (–889 C>T; rs1800587) and TNFA (–308 G>A; rs1800629), were also assessed by 5'-nuclease polymerase chain reaction assays (TaqMan) using methods as described previously (5,18) at the Viral Epidemiology Section, Science Applications International Corporation-Frederick, NIH. The sequences of the primers and probes used for these three SNPs are provided in Table I.


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  		Table I Sequences of primers and probes used for TNFA–308 G/A and IL1A (–889 C>T)

 
Statistical analysis
Hardy–Weinberg equilibrium in controls was tested using the asymptotic Pearson's {chi}2-test. For all genotypes, the homozygote of the common allele was used as the referent. For TNFA, IFNGR2 and IL12A, in which more than one SNP was genotyped, we also evaluated gastric cancer risk associated with their haplotypes. The HaploView software was used to assess the pair-wise linkage disequilibrium (LD) between the markers within each gene (19). Haplotypes were reconstructed from genotype data by means of Phase software (Version 2.1) (http://www.stat.washington.edu/stephens/software.html). For TNFA and IL12A, the most common haplotype was set as the referent. Since the most common haplotype in IFNGR2 contained the ‘at-risk’ allele (C allele) in Ex7-128 C>T locus, we used the most frequent haplotype (CAT) among those containing the T allele in this locus as the referent. The omnibus test was performed to assess the global difference in haplotype frequencies between cases and controls using the Stata 9.0 (Stata Corporation, College Station, TX). The Fisher's exact test was used to assess the difference in the distributions of categorical variables between cases and controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for gastric cancer in association with genotypes and haplotypes. Multiplicative gene–gene interactions were examined by testing the significance of a cross-term between two SNP genotype scores in a logistic regression model. All ORs were adjusted for age, gender, education and smoking. Further adjustment for other potential confounding variables, including family history of gastric cancer, pack-years of cigarette smoking, intake of fruits and vegetables, H.pylori infection and use of ulcer medications, did not meaningfully affect the risks. All statistical analyses were conducted using the Stata 9.0 (Stata Corporation, College Station, TX) statistical package. All tests were two-sided at the 0.05 significance level.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Gastric cancer cases and controls had comparable age and gender distributions (Table II). However, cases tended to have lower education (P = 0.004) and were more likely to be current smokers (P < 0.001) and to report a first-degree family history of stomach cancer (P < 0.001). The majority of gastric cancers were of the intestinal type (67.5%). The most common site of tumor origin was the distal stomach (73.1%).


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  		Table II Distribution of selected demographic and clinical characteristics in gastric cancer cases and controls

 
Among controls, genotype distribution for each of the 13 assessed SNPs was in Hardy–Weinberg equilibrium. Among the six SNPs in TNFA, gastric cancer risk was significantly associated with the TNFA (–308 G>A) polymorphism, with ORs of 1.4 (95% CI: 1.0–2.0) for the G/A genotype carriers and 2.5 (95% CI: 1.3–4.9) for the A/A genotype carriers, when compared with the more frequent G/G genotype carriers (P for trend < 0.001) (Table III). In addition, carriers of the CC genotype of TNFA (–1210) had significantly elevated risk (OR = 2.4, 95% CI: 1.1–5.3) relative to TT carriers. Among the three SNPs in IFNGR2, the Ex7-128 T>C polymorphism was significantly associated with the risk of gastric cancer, with ORs of 1.5 (95% CI: 1.0–2.2) for T/C carriers and 1.7 (95% CI: 1.1–2.7) for C/C carriers when compared with T/T carriers (P for trend = 0.01). The other two SNPs in IFNGR2 were unrelated to risk. No clear association with risk was observed for the IL1A (–889 C>T) promoter polymorphism. None of the three SNPs tested in IL12A (IVS2-798 A>T, IVS2-701 A>C and Ex7 + 277 A>G) was significantly related to risk.


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  		Table III Gastric cancer risk and polymorphisms in genes on Th1-type cell-mediated immune response pathway

 
We examined whether the associations of the 13 tested SNPs with gastric cancer risk were modified by other risk factors and tumor characteristics, including age, smoking, alcohol consumption, Lauren classification, tumor grade, site of tumor origin, metastasis status and H.pylori infection status. Stratification by these factors produced comparable results (data not shown).

Analyses of gene–gene interactions showed an OR of 4.8 (95% CI: 1.3–17.4) for carriers of the TNFA (–308 A/A) and IFNGR2 (Ex7-128 T/C) genotypes and an OR of 5.5 (95% CI:1.5–19.4) for carriers of the TNFA (–308 A/A) and IFNGR2 (Ex7-128 C/C) genotypes when compared with carriers of the TNFA (–308 G/G) and IFNGR2 (Ex7-128 T/T) genotypes. However, the interaction was not statistically significant (P = 0.41) (Table IV).


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  		Table IV Gastric cancer risk by TNFA (–308 G>A) and IFNGR2 (Ex7-128C>T)a

 
We conducted haplotype analyses on the TNFA, IFNGR2 and IL12A genes in which more than one SNP was evaluated. Omnibus score tests showed that the global difference in haplotype frequencies between cases and controls was significant for TNFA (P = 0.04) and IFNGR2 (P = 0.03), but not for IL12A (P = 0.12). Unconditional logistic regression analyses showed that the TCCGAG haplotype containing the ‘at-risk’ A allele at the position of –308 G>A in TNFA conferred an increased risk (OR = 1.48, 95% CI: 1.1–1.98) when compared with the most frequent haplotype (TCCGGG). The CAC haplotype containing the ‘at-risk’ C allele at the position of –128C>T in IFNGR2 was associated with an increased risk (OR = 1.40, 95% CI: 1.11–1.78) when compared with the CAT haplotype. The CAT was the most frequent haplotype among those containing the T allele at Ex7-128C>T. We did not observe any meaningful results in the analysis of IL12 haplotypes (Table V).


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  		Table V Gastric cancer risk by haplotypes in TNFA, IL12 and IFNGR2

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The cellular immune response to H.pylori infection is an important determinant of damage to the gastric mucosa (7,9,10). T lymphocytes generated in response to H.pylori infection predominantly show the Th1 cell phenotype (20). Co-culture of naive T cells with H.pylori-pulsed dendritic cells significantly enhanced TNF-{alpha}, IFN-{gamma} and IL2 secretion (21). TNF-{alpha} is upregulated early in H.pylori colonization of the gastric mucosa and induces the transcription of other pro-inflammatory cytokines and chemokines, amplifying the inflammatory cascade against the infection (22). TNF-{alpha} also inhibits gastric acid secretion, induces cell apoptosis and promotes epithelial cell damage (23–25). Furthermore, TNF-{alpha} and other Th1 cytokines have a direct inhibitory effect on gastric acid secretion, predisposing to gastric inflammation and atrophy (5). Among inbred mice, the C57BL/6 strain mounts a stronger Th1 mucosal immune response to H.pylori infection than other strains, and is also more prone to develop gastric atrophy with H.pylori infection (4). Since gastric atrophy and hypochlorhydria are considered precancerous conditions (1,26), Th1-polarized immune response may play a critical role in gastric carcinogenesis.

In our study, two polymorphisms in two key Th1-related genes, TNFA (–308 G>A) and IFNGR2 (Ex7-128C>T), were linked to gastric cancer risk. The risk was particularly elevated among subjects who carried both the TNFA (–308 AA) and IFNGR2 (Ex7-128 CC) genotypes. Previous epidemiological studies of the relationship of TNFA –308 to gastric cancer risk have yielded inconsistent results, with some studies reporting an increased risk among carriers of the A allele (18,27) while others revealed a null association (28–30). The three positive studies (including our current study) were from Caucasian populations, whereas the negative studies were from two Asian and one Hispanic population. It is possible that variations in the frequency of the A allele between the different ethnic groups could explain the diverse results (18,27–32). It is also conceivable that the –308 A allele is functional only in the context of a haplotypic profile that is inherited differently between ethnic groups (33). Finally, variations in predominant H.pylori strains, prevalence of infection in the population and genotyping methodologies might have contributed to the different results. Of note, it has been reported that the TNFA –308 A allele increases the expression of TNFA (34). The resulting alteration in the immune response due to the higher production of TNF-{alpha} may confer susceptibility to H.pylori infection-related gastric diseases (35,36).

IFNGR2 is an important receptor of the IFN-{gamma} pathway. Like TNF-{alpha}, IFN-{gamma} may also promote H.pylori-induced apoptosis of gastric epithelial cells by several mechanisms, such as by sensitizing epithelial cells towards Fas-induced apoptosis, by inducing major histocompatibility complex class II molecules that may enhance the adherence of H.pylori to epithelial cells and consequent apoptosis (37) and by upregulating TNF-{alpha} receptors (7). It has been shown that IFN-{gamma}-producing T cells are prominent in H.pylori-infected gastric mucosa (38), particularly in H.pylori-infected biopsies (7). In addition, IFN-{gamma} knockout mice infected with H.pylori were found to be protected from gastric atrophy (4,8), suggesting that IFN-{gamma} secretion may play an important role in gastric carcinogenesis. To date, no studies have been conducted to evaluate polymorphisms in either the IFNG gene or its receptor genes in relation to gastric cancer risk.

IL12 initiates Th1 polarization in response to H.pylori infection (3), and several polymorphisms in IL12 have been associated with gastric cancer risk among H.pylori-infected individuals (39). Production of IL1-{alpha} increases after H.pylori infection (3), and IL1A (–889 C>T) polymorphism has been associated with gastric atrophy or cancer in previous investigations (40,41). However, in our study, IL1A (–889 C>T) and the three examined IL12A SNPs were not related to gastric cancer risk.

The risk of gastric cancer was highest among carriers of both the TNFA (–308) A/A and the IFNGR2 (Ex7-128) C/C genotypes. This finding needs to be confirmed since it may be a chance occurrence owing to the limited number of cases in subgroup analyses. Haplotypes containing ‘at-risk’ alleles in both TNFA and IFNGR2 genes significantly increased the risk for gastric cancer, although a chance finding cannot be excluded because of the lack of experimental evidence and incomplete SNP coverage in these two genes.

Our study has the advantage of relatively high participation rates and being population-based. Misclassification was minimal owing to the high reproducibility and accuracy of genotyping. However, since we examined only 13 SNPs, even though they included synonymous and non-synonymous SNPs in coding regions, as well as SNPs in promoter and non-coding regions, the small number of selected SNPs may not provide a comprehensive picture of Th1 pathway-related polymorphisms. It is possible that associations between gastric cancer risk and the polymorphisms of TNFA (–308 G>A) or IFNGR2 (Ex7-128C>T) merely reflect the influence of other alleles that are in LD. Further studies are planned to investigate a broader range of candidate polymorphisms in Th1-related genes. Furthermore, the number of cases in our study had limited statistical power to detect a haplotype effect and gene–gene interactions, increasing the likelihood of false-positive (42) or false-negative associations.

Another potential limitation was the relatively low rate of blood donation among cases (65.7%). However, we found no significant difference in selected demographic or lifestyle characteristics between cases with and without genotype data. Finally, we might have underestimated the prevalence of H.pylori infection among cases in our study owing to clearance of H.pylori colonization with tumor progression (42–44). However, our genotyping findings remain robust, with no meaningful alterations in the results following adjustment for H.pylori status or in sensitivity analyses excluding H.pylori negative controls and/or cases.

In conclusion, our findings suggest that two Th1-related polymorphisms (TNFA –308 A>G and IFNGR2 Ex7-128 C>T) may increase the risk of gastric cancer, and that a Th1 cell-mediated response to H.pylori infection plays an important role in gastric carcinogenesis. Further studies with larger sample size and more comprehensive SNP selection are needed to fully examine the role of Th1 genes in gastric carcinogenesis.


   Acknowledgments
 
This research was supported in part by the Intramural Research Program of the NIH, NCI, Division of Cancer Epidemiology and Genetics.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received March 1, 2006; revised June 16, 2006; accepted July 11, 2006.


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