Genetic polymorphisms of interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor {alpha} and risk of gastric cancer in a Chinese population

Wanli Lu1,*, Kaifeng Pan1,*, Lian Zhang1, Dongxin Lin2, Xiaoping Miao2 and Weicheng You1,3

1 Department of Cancer Epidemiology, Peking University School of Oncology, Beijing Institute for Cancer Research, Beijing Cancer Hospital, Beijing 100036, People's Republic of China and 2 Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China

3 To whom correspondence should be addressed Email: weichengyou{at}yahoo.com


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Helicobacter pylori infection and the cytokine-mediated inflammatory responses play important roles in gastric cancer pathogenesis. This case control study was conducted to assess the association between genetic polymorphisms in interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor {alpha} (TNF{alpha}), which are involved in H.pylori infection, and risk of gastric cancer. Genotypes were determined by PCR-based denaturing high-performance liquid chromatography analysis and direct DNA sequencing in 250 incident cases with gastric cancer and 300 controls recruited in Northern China. Serum levels of anti-H.pylori IgG and IgA were measured by enzyme-linked immunosorbent assay to indicate H.pylori infection. We found that the risk of gastric cancer was significantly elevated in subjects with the IL-8-251 AA [adjusted odds ratio (OR) 2.02; 95% confidence interval (CI) 1.27–3.21] or IL-10-1082 G (OR 2.02; 95% CI 1.24–3.29) or TNF{alpha}-308 AG (OR 1.81; 95% CI 1.04–3.14) genotype. An elevated risk of gastric cancer was observed in subjects with H.pylori infection and the IL-8-251 AA genotype (OR 2.54; 95% CI 1.38–4.72) or IL-10-1082 G carriers (OR 2.62; 95% CI 1.42–4.93). An increased OR was also suggested for IL-1B-31 and TNF{alpha}-238, but confidence intervals included the null value. There was no evidence of increased risk for any of the other polymorphisms evaluated. These findings suggest that genetic polymorphisms in IL-8, IL-10 and TNF{alpha} may play important roles in developing gastric cancer in the Chinese population.

Abbreviations: CI, confidence interval; DHPLC, denaturing high-performance liquid chromatography; IL, interleukin; OR, odds ratio; TNF, tumor necrosis factor


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Gastric cancer is the second leading cause of cancer death in the world and particularly prevalent in certain countries including China (1). Helicobacter pylori infection plays a crucial role in gastric cancer pathogenesis (24). Persistent inflammation caused by H.pylori infection induces hypochlorhydria and gastric atrophy, which are two early precursors of gastric cancer development. However, although the prevalence of H.pylori infection ranges from 40 to 80% in humans, only a small proportion (probably <3%) of infected patients develop gastric cancer (4). Genetic variation in genes encoding cytokines and their receptors, which determine the intensity of the inflammatory response to the bacteria, may contribute to individual differences in severity of outcome of H.pylori infection and progression of gastric lesions (5).

Studies in Caucasians showed that genetic polymorphisms of interleukin (IL)-1B (encoding IL-1ß) and IL-1RN (encoding IL-1 receptor antagonist) that may enhance production of IL-1ß were positively associated with hypochlorhydria induced by H.pylori and an increased risk of gastric cancer (6,7). However, results from other studies in Japanese and Chinese do not support this association (8,9). Similarly, inconsistent results also exist in studies on polymorphisms in the IL-10 promoter (9,10). Tumor necrosis factor (TNF){alpha}, a potent pro-inflammatory cytokine, is over-expressed in patients with H.pylori infection (4). It has been shown that carriers of the TNF{alpha}-308 A allele are at high risk for gastric cancer (10,11), whereas the TNF{alpha}-238 A allele seems to have a protective function against the risk of cancers (12). Another cytokine, IL-8, which is a central mediator of the inflammatory response to H.pylori infection, plays a role in the pathogenesis of gastritis (4). In addition, IL-8 may also influence pathways of tumor angiogenesis (13). A common single nucleotide polymorphism in the IL-8 promoter region has been identified and the –251A allele is associated with increased expression of IL-8 (14). Several studies have suggested that the IL-8-251 polymorphism was associated with the risk of prostate cancer, colorectal cancer and Kaposi's sarcoma (1517). However, no study has yet been reported on the role of this IL-8 polymorphism in gastric cancer risk.

In the present study, we investigated the genetic polymorphisms of IL-1B, IL-1RN, IL-8, IL-10 and TNF{alpha} with the risk of gastric cancer, and their associations with environmental factors in the risk of gastric cancer.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study subjects
Incident cases with gastric cancer aged 25–81 years were enrolled in this study. A total of 104 gastric cancer cases were identified from a gastric cancer screening program of 3400 adults in Linqu County, Shangdong Province in Northern China between 1994 and 2003 (3), and 146 gastric cancer cases were from the Cancer Hospital, Chinese Academy of Medical Sciences in Beijing between 2001 and 2003. The diagnosis of gastric cancer was established by endoscopic examination and confirmed by histopathology. Each case was interviewed using a questionnaire to obtain information on cigarette smoking and alcohol consumption. All interviews were conducted in the hospital before diagnosis. Controls were randomly selected from the same 3400 screening population in Linqu County in 1994. The selection criteria included no gastric cancer detected by examination, no individual history of cancer and frequency matching to the cases by gender and age (±5 years). A structured questionnaire was developed to seek information on cigarette smoking and alcohol intake and other variables from each participant at the baseline examination in 1994. A 5-ml blood sample was collected from each subject, both case and control. The blood sample was allowed to clot for 30–40 min at room temperature and then centrifuged at 965 g for 15 min. The resulting serum was separated into vials. The clot and serum were stored immediately at –20°C and then moved into a freezer at –70°C within 2 or 3 days after collection. The study was approved by the Institutional Review Board of Peking University School of Oncology.

Genotyping
High molecular weight genomic DNA was isolated by standard proteinase-K digestion and phenol–chloroform extraction from the blood sample. IL-1B-31, IL-1B-511, IL-1RN, IL-8-251, IL-10-1082, TNF{alpha}-308 and TNF{alpha}-238 polymorphisms were analyzed by PCR-based denaturing high-performance liquid chromatography (DHPLC). PCR was accomplished with a 25-µl reaction mixture containing 100 ng of genomic DNA, 1.0 µM of each primer, 0.2 mM of dNTP, 2.0 mM of MgCl2 and 1.0 U Taq DNA polymerase in 1x reaction buffer (Promega, Madison, WI). The primer sequences, PCR annealing temperatures and DHPLC detection methods are listed in Table I. DHPLC analysis was performed on a Transgenomic WAVE System (Transgenomic, Omaha, NE). The detailed genotyping process was described previously (18). Briefly, PCR products for IL-1B-31, IL-1B-511, IL-8-251, TNF{alpha}-308 and TNF{alpha}-238 were denatured for 1 min at 94°C and then gradually re-annealed by decreasing the sample temperature from 94 to 45°C over a period of 30 min to form homo- and/or hetero-duplexes. The PCR products were then applied to the DHPLC column at an optimal oven temperature and eluted with a linear acetonitrile gradient at a flow rate of 0.9 ml/min (Figure 1A). The genotypes revealed by DHPLC analysis were further confirmed by DNA sequencing with ABI Prism 377 DNA Sequencer (Applied Biosystems, Foster City, CA). DHPLC was used to determine the size of IL-1RN PCR products based on the relationship between elution time and base pair number of the fragment. The peaks of IL-1RN PCR products were compared with peaks of known base pairs, resulting from HaeIII digested PUC 18 plasmid on DHPLC under the condition used for DNA sizing at 50°C, to identify variable numbers of an 86-bp tandem repeat in intron 2 of IL-1RN gene. IL-10-1082 genotyping was accomplished by primer extension. The primer designed for primer extension was 5'-CTACTAAGGCTTCTTTGGGA-3'. Samples used for primer extension were first amplified with IL-10-1082 primers and the PCR products were purified with Wizard PCR Preps DNA Purification System (Promega). A 20-µl PCR reaction mixture contained 10 µl purified PCR product, 0.6 µl of 10 µM primer, 0.1 µl of 10 mM dATP, 0.2 µl of 5 mM ddGTP (Amersham Pharmacia Biotech, Piscataway, NJ) and 0.5 U of Thermo Sequenase DNA polymerase (Amersham Pharmacia Biotech, Piscataway, NJ). PCR cycling conditions consisted of an initial denaturation step at 96°C for 1 min, followed by 50 cycles of 96°C for 10 s, 43°C for 15 s, 60°C for 1 min and ending with a final denaturation step at 96°C for 30 s. The primer extension products were then introduced to the DHPLC column at 80°C and detected by UV analysis at 260 nm (Figure 1B).


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Table I. Primer sequences, PCR and DHPLC conditions for detection of gene polymorphisms

 


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Fig. 1. Typical elution profiles of DHPLC for different genotypes. (A) Representative DHPLC profiles for different allelic PCR products containing the IL-8-251A/T polymorphism site. At the first DHPLC, the AT genotype (lower panel) was discriminated from homozygous (upper panel). To determine the AA or TT genotype, the second DHPLC was run for the homozygous DNA mixed with a DNA sample known as the AA genotype. The profile of AA genotype was unaltered, while that of the TT genotype changed into the same as the lower panel. (B) DHPLC elution profiles of primer extension. IL-10-1082A/G genotype was determined by retention time of peaks. The GG, AG and AA genotypes were 21, 21/22 and 22 bp, respectively.

 
Helicobacter pylori antibody assays
Detailed serologic assay was described previously (3). Briefly, H.pylori stains cultured from gastric biopsies of five patients in the study subjects were used to provide a local antigen preparation for serology. Serum levels of anti-H.pylori IgG and IgA were measured separately in duplicate with ELISA procedures. Quality-control samples were assayed at Vanderbilt University, Nashville, Tennessee. An individual was determined to be positive for H.pylori infection if the mean optical density for either the IgG or the IgA was >1.0, a cut-off value from the examination of a group of H.pylori-negative persons and reference sera.

Tobacco and alcohol consumption
Participants who reported drinking or smoking during the 1 year before diagnosis for the cases, or up to the date of the interview for controls were classified as current smokers/drinkers. Information collected on the amount of cigarettes smoked per day, the age at which the subjects started smoking and the age at which ex-smokers stopped smoking was used to compute pack-years [(cigarettes per day/20) x (years smoked)]. Because only 10 cases and 12 controls were ex-smokers, they were combined with current smokers for the analysis. Information collected on the frequency of alcohol drinking per week, the age at which the drinkers started drinking and the age at which ex-drinkers stopped drinking was used to derive drinking frequency-years [(times of drinking per week) x (years drinking)]. Because only nine cases and eight controls were ex-drinkers, they were combined with current drinkers for analysis.

Statistical analysis
The Hardy–Weinberg equilibrium equation was used to determine whether the proportion of each genotype obtained was in agreement with the expected values as calculated from allele frequencies. The difference in age between the case and the control groups was evaluated with the Mann–Whitney test. The Pearson's {chi}2 test was used to examine the differences between the case and the control groups in sex, H.pylori infection, smoking and drinking. Odds ratios (ORs) and 95% confidence intervals (CIs) for the polymorphisms under consideration and gastric cancer were computed by unconditional logistic regression, adjusting for age, sex, H.pylori infection, pack-years and drinking frequency-years. We tested the null hypotheses of additivity and multiplicativity and evaluated the departures from additive and multiplicative interaction models. These analyses were carried out with Statistical Analysis System Software (version 6.12; SAS Institute, Cary, NC). Haplotype frequencies and linkage disequilibrium coefficients were estimated using EH (EH-plus) software.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 250 incident patients with gastric cancer and 300 controls were enrolled in this case-control study. Table II shows that the distributions of gender, age, cigarette smoking and alcohol drinking between cases and controls were similar. However, the percentage of H.pylori infection was slightly higher in cases than in controls (70.4 versus 65.0%, P = 0.178). Among the gastric cancer cases, 105 (42%) were intestinal-type, 100 (40%) were diffuse-type and 45 (18%) were mixed-type. Of all gastric cancers, 114 occurred in the antrum, 90 occurred in the corpus, while 46 were found in cardia or unclassified.


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Table II. Select characteristics and risk factors in patients with gastric cancer and controls

 
The frequencies of the polymorphisms in cases and controls are shown in Table III. The distribution of each of the seven genotypes fitted the Hardy–Weinberg equilibrium law. The genotype frequencies of IL-1RN 2/2, IL-10-1082 GG, TNF{alpha}-308 AA and TNF{alpha}-238 AA were <5%. The distribution of cases and controls was similar with respect to IL-1B-31, IL-1B-511, IL-1RN and TNF{alpha}-238 polymorphisms, respectively. However, the frequencies of three IL-8-251 genotypes in cases (TT, 37.6%; AT, 40.8% and AA, 21.6%) were significantly different from those in controls (TT, 39.7%; AT, 48.0% and AA, 12.3%) ({chi}22 = 8.80; P = 0.012). Multivariate analysis showed that subjects carrying the AA genotype were at a 2-fold elevated risk for gastric cancer (OR 2.02; 95% CI 1.27–3.21) compared with subjects carrying at least one T allele (Table IV). The frequencies of three IL-10-1082 genotypes were significantly different between cases (AA, 80.4%; AG, 17.2% and GG, 2.4%) and controls (AA, 89.3%; AG, 9.7% and GG, 1.0%) ({chi}22 = 8.82; P = 0.012). Since the IL-10-1082 GG homozygotes were rare in our study, it was combined with the AG genotype for subsequent analysis. The OR of developing gastric cancer for IL-10-1082 GG or AG carriers was 2.02 (95% CI 1.24–3.29) compared with the AA genotype (Table IV). Furthermore, the frequencies of three TNF{alpha}-308 genotypes in cases (GG, 85.6%; AG, 14.4% and AA, 0.0%) were also significantly different from those in controls (GG, 91.3%; AG, 8.0% and AA, 0.7%) ({chi}22 = 8.03; P = 0.018). A significantly elevated risk of gastric cancer was seen among TNF{alpha}-308 AG heterozygotes (OR 1.81; 95% CI 1.04–3.14) compared with TNF{alpha}-308 GG homozygotes, whereas the OR for TNF{alpha}-308 AG or AA carriers was 1.67 (95% CI 0.97–2.86; P = 0.065) (data not shown).


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Table III. Genotype frequencies of IL-1ß, IL-1RN, IL-8, IL-10 and TNF{alpha} polymorphisms among gastric cancer patients and controls, and their contributions to the risk of gastric cancer

 

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Table IV. Risk of gastric cancer related to IL-8 and IL-10 genotypes by tobacco smoking, alcohol drinking, histologic type and anatomic site

 
The risks of gastric cancer associated with the IL-8-251 and IL-10-1082 polymorphisms by H.pylori infection, smoking, drinking, histological type and anatomic site are shown in Table IV. Risk of the cancer was more pronounced in subjects who carried the IL-8-251 AA genotype and smoked (OR 2.12; 95% CI 1.13–3.98), drank (OR 3.23; 95% CI 1.64–6.37) or had intestinal-type of gastric cancer (OR 2.34; 95% CI 1.30–4.22). Similar results were observed among subjects having both IL-10-1082 G allele and H.pylori infection (OR 2.16; 95% CI 1.22–3.84), or who smoked (OR 2.31; 95% CI 1.22–4.37) and drank (OR 2.78; 95% CI 1.42–5.45).

The risk of gastric cancer related to IL-8-251 and IL-10-1082 genotypes were further examined with stratification by H.pylori infection. As shown in Table V, the OR of gastric cancer for subjects carrying the IL-8-251 AA genotype or H.pylori infection alone was 2.23 (95% CI 0.99–5.15) or 1.32 (95% CI 0.88–1.97), respectively. However, the OR was elevated in subjects carrying the AA genotype and H.pylori infection (OR 2.54; 95% CI 1.38–4.72). A similar result was observed between IL-10-1082 polymorphism and H.pylori infection. The OR of gastric cancer for subjects carrying the IL-10-1082 GG or AG genotype or H.pylori infection alone was 1.71 (95% CI 0.67–4.37) or 1.22 (95% CI 0.82–1.81), respectively. However, interestingly, the effect of H.pylori infection was evident in the subgroup of GG or AG genotype (OR 2.62; 95% CI 1.42–4.93).


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Table V. Risk of gastric cancer associated with the IL-8 and IL-10 genotypes by H.pylori infection

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In the present study, we investigated the association between a panel of five genes and risk of gastric cancer in a Chinese population. We found that subjects who carried the IL-8-251 AA genotype had an increased risk for gastric cancer. To our best knowledge, this is the first study investigating the impact of the IL-8 polymorphism on susceptibility to gastric cancer.

Some studies have suggested that the IL-8-251AA genotype was associated with an increased risk of prostate cancer and Kaposi's sarcoma (15,17), and a decreased risk of colorectal cancer (16). However, the role of this IL-8 polymorphism in gastric cancer risk has not been investigated so far. Our study provides evidence that the IL-8-251 polymorphism may play an important role in the development of gastric cancer.

IL-8 has potent activity in the activation and migration of neutrophils and, therefore, may play an important role in H.pylori-associated gastric inflammation. It is possible that increased IL-8 might amplify the inflammatory response to H.pylori by recruiting neutrophils and monocytes, and thus results in an advanced degree of gastritis, ultimately predisposing to the development of gastric cancer (4). Moreover, the expression of IL-8 directly correlates with gastric peritumoral cellular infiltrates (19), hypostatic migration of tumor cells (20) and angiogenesis of gastric cancer (13,21).

Studies in vitro have shown that the IL-8-251 A allele tended to be associated with increased IL-8 production by lipopolysacharide-stimulated whole blood (14). Our study suggested that subjects with genetically determined higher levels of IL-8 production might have a higher risk of gastric cancer. We also found that the association between the IL-8 AA genotype and gastric cancer risk appeared to be more pronounced in intestinal-type gastric cancer, which is an end result of multistage transformation of gastric mucosa over many years (4). Whether the IL-8 polymorphism is associated with pre-cancerous lesions of atrophic gastritis, intestinal metaplasia and dysplasia needs further investigation.

IL-10 has emerged as a potent immunosuppressive cytokine by down-regulating the expression of Th1 cytokines and co-stimulatory molecules and this gene is highly polymorphic. The association of the A to G substitution at position –1082 of the IL-10 gene promoter with increased transcription of IL-10 has been shown in vitro (22). The IL-10 genotype may influence predisposition to a number of solid tumors, but the current disease association data are confusing and often contradictory. Some studies have described an association between the IL-10-1082 G allele and decreased susceptibility to cancers (10,15). The mechanism for this may be via the ability of IL-10 to down-regulate synthesis of IL-1ß, TNF{alpha} and vascular endothelial growth factor. However, other studies drew an opposite conclusion (9,23,24). Our results are consistent with that reported in Taiwan (9). One suggestive explanation for these intriguing findings is that IL-10 generally protects the host against inflammation after toxin-induced injury, but physiologically inadequate responses related to IL-10 after systemic injury may render the host susceptible to malignant change.

Previous studies in Linqu County indicated that H.pylori infection, cigarette smoking and low levels of dietary vitamin C were environmental risk factors for gastric cancer (3,25). Our study observed an elevated risk for IL-8-251 AA genotype and gastric cancer in subjects without H.pylori infection, but the CIs included the null value. The data suggested that the IL-8 polymorphism might be an independent risk factor for the pathogenesis of gastric cancer. Moreover, the risk of gastric cancer associated with this polymorphism was further slightly elevated in subjects with H.pylori infection, but there was no evidence of an interaction between the IL-8 polymorphism and H.pylori infection in our study (P = 0.60 for multiplicative model). Similarly, the risk of gastric cancer associated with IL-10-1082G carriers was elevated in subjects with H.pylori infection. However, there was a moderate departure from an additive relationship between IL-8 polymorphism and H.pylori infection, with a relative risk due to the interaction of 0.69 and a synergy index of 1.74. Further studies with a large sample size are needed to elucidate the interaction between IL-8 and IL-10 polymorphisms and H.pylori infection.

Cigarette smoking is an established risk factor of gastric cancer (3,25). Although alcohol drinking is an established risk factor for cancers of the upper aerodigestive tract, the evidence for an association with gastric cancer is weak (26). However, studies have demonstrated that smoking and drinking may influence the production of cytokines (27,28). Therefore, smoking and drinking may interact with cytokine genotypes to enhance gastric inflammation. In the present study, we found that the presence of both risk genotype and smoking or drinking significantly elevated the risk of the cancer. However, the interaction between the two genotypes and individual smoking and drinking habits failed to reach the statistical significance in our study (data not shown).

Previous studies have described an association between the TNF{alpha}-308 A allele and increased risk to gastric cancer (10,11). These findings are consistent with our results in the present study and support the critical role of TNF{alpha} in tumor promotion. In a case-control study in Korea (12), the TNF{alpha}-238A genotype was associated with a reduced risk of gastric cancer. However, our study suggested a non-significantly elevated risk for the TNF{alpha}-238 AG genotype and gastric cancer. The variant genotypes of TNF{alpha} are rare in the Asian population, which could possibly explain this inconsistency (9,29), and limitation of the statistical power may significantly affect the conclusions of these two studies. Linkage disequilibrium analysis showed that the two polymorphisms we investigated in TNF{alpha} were not tightly linked and there was no significant difference in haplotype distribution between cases and controls in our study.

IL-1B and IL-1RN polymorphisms have been shown to be associated with the risk of gastric cancer in the Caucasian population (6,7). However, the results could not be reproduced in studies in Japanese (8) and Taiwanese (9). Our results are consistent with those reported in Japanese and Taiwanese but not those in Caucasians. We found that the frequencies of the IL-1B-511 genotypes in our control population (CC, 22.3%, CT, 54.4% and TT, 23.3%) were significantly different (P < 0.05) from those in the Caucasian population (CC, 50.6%, CT, 38.7% and TT, 10.7%) (6). In addition, differences in the frequencies of IL-1B-31, IL-10-1082 and TNF{alpha}-308 polymorphisms were also seen between our study population and a reported Caucasian population (6). In our study population, haplotype analysis with the IL-1B-31 and IL-1B-511 polymorphisms suggested these polymorphisms might be tightly linked, in accord with the earlier study (30).

Our study has some limitations. Potential drawbacks such as selection bias may have occurred as some of our cases were from hospital whereas the controls were from the Linqu general population. However, the distribution of the controls was frequency matched to the cases on sex, age, drinking and smoking status. The fact that genotype frequencies among the control population fit the Hardy–Weinberg law further supports the randomness of our control selection. Moreover, the frequencies of the IL-1B, IL-1RN, IL-8, IL-10 and TNF{alpha} genotypes in cases of Linqu and Beijing hospital were similar, e.g. the frequencies of three IL-8-251 genotypes in cases from Linqu (TT, 38.5%, AT, 40.4% and AA, 21.1%) were similar with cases from Beijing hospital (TT, 37.0%, AT, 41.1% and AA, 21.9%). The data indicated that the use of Linqu controls was appropriate for these two groups of cases. In addition, H.pylori is genetically a highly diverse bacteria and the virulence of H.pylori is related to different subtypes. However, anti-CagA antibodies are not available in our study. Finally, the number of participants in our study is relatively small and thus failure to detect associations between some genotypes and gastric cancer risk might be due to limited statistical power.

In conclusion, to our knowledge, this study is the first one to indicate that the IL-8-251 polymorphism increases the genetic susceptibility of gastric cancer in a Chinese population. IL-10-1082 and TNF{alpha}-308 polymorphisms could also contribute to individual susceptibility to gastric cancer. The study further indicates that a significant difference exists in the distribution of genotypes in different ethnic groups.


    Notes
 
* W.L. and K.P. contributed equally to this work. Back


    Acknowledgments
 
This work was supported by Grants from the National High Technology R&D Program (2002BA711A06), the State Key Basic Research Program (G1998051203) and Beijing Municipal Commission for Science and Technology (H0209-20030130).


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received September 13, 2004; revised October 27, 2004; accepted November 21, 2004.





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