Cancer Epidemiology Biomarkers & Prevention Vol. 14, 1869-1873, August 2005
© 2005 American Association for Cancer Research
Role of Cytokine Polymorphisms in the Risk of Distal Gastric Cancer Development
Guillermo I. Perez-Perez1,
Elvira Garza-Gonzalez4,
Cynthia Portal2 and
Asalia Z. Olivares3
Departments of 1 Medicine and Microbiology, 2 Microbiology, and 3 Medicine, New York University School of Medicine and 4 Departamento de Microbiologia, Facultad de Medicina, Universidad Autonoma de Nuevo Leon, Nuevo de Leon, Mexico
Requests for reprints: Guillermo I. Perez Perez, 6027W Veterans Affairs Medical Center, 423 East 23rd Street, New York, NY 10010. Phone: 212-263-4101; Fax: 212-263-4108. E-mail: perezg02{at}med.nyu.edu
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Abstract
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We review the current information concerning the role of cytokine polymorphisms and the risk of develop distal gastric cancer in different populations. We have included populations colonized with Helicobacter pylori as well as populations without colonization. We found that the study of polymorphisms alone seems insufficient to assess gastric cancer risk and it is necessary to examine environmental factors in different ethnic groups and geographic areas along with the study of H. pylori strains to define better the risk factors associated with distal gastric cancer.
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Introduction
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Stomach cancer was the most common form of cancer in the world in the 1970s and early 1980s and is now surpassed only by lung cancer. The incidence of gastric cancer shows marked variation among countries in the world (1). Incidence rates are especially high in Japan and other Eastern Asian countries; other areas in the world, including Eastern Europe and parts of Latin America (2), have high incidence rates of gastric cancer as well.
Gastric cancer is a multifactorial disease. Mortality rates for this cancer worldwide have been declining for several decades (3). Despite the decline in distal gastric cancer in many countries of the world, it remains a major public health problem. The number of new cases in the elderly population of both developed and developing countries is rising. It is estimated that more than a million cases per year will occur in the next 10 years (1).
Since 1991, epidemiologic evidence has shown that gastric cancer is associated with Helicobacter pylori colonization (4). However, many studies have shown that even through certain region of the world where nearly 100% of the persons are colonized with H. pylori the risk of developing gastric cancer is not as high as expected, particularly in sub-Sahara Africa and Southeast Asia (5). Bacterial virulence factors such as the cag pathogenicity island, the vacuolating cytotoxin, and others have been associated with higher risk for gastric cancer development particularly in western countries but these associations are less relevant in countries including east Asia and developing countries (6, 7).
Host genetic factors are emerging as determinants of increasing risk for many cancers (8, 9). Cytokines participate in the inflammatory response associated with innate immunity and the acquired immune response. Cytokines such as INF
, interleukin-1ß (IL-1ß), and tumor necrosis factor-
(TNF-) are up-regulated during H. pylori infection. Genes encoding cytokines and related molecules harbor polymorphic regions, which alter gene transcription and thereby influence inflammatory processes in response to infectious disease (10). Polymorphisms in human IL-10, IL-1B, TNF-A, IFN-G, and IL-1 receptor antagonist (IL-1RN) genes have been reported to influence cytokine expression. In gastric cancer, several cytokine polymorphisms, such as IL-1ß, IL-10, TNF-, and others, have been evaluated as risk factors.
IL-1 emcompasses a cluster of genes located on chromosome 2q, the products have an important role in controlling inflammatory response as well as controlling the acidity of the stomach (11). The cluster contains three related genes IL-1A, IL-1B, and IL-1-RN, which encode the proinflammatory cytokines IL-1, IL-1ß, and their endogenous receptor antagonist IL-1ra, respectively (11).
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IL-1B
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Two diallelic polymorphisms in IL-1B have been reported (Fig. 1), each one representing C-T base transitions at positions –511 and –31. IL-1ß is up-regulated in the presence of H. pylori and is important in initiating and amplifying the inflammatory response to this infection. IL-1ß is also a potent inhibitor of gastric acid secretion (12). A biallelic polymorphism at positions –31 and –511 in the promoter of the IL-1B gene have been associated with the development of gastric cancer and its precursors (Table 1; refs. 13-16).
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Figure 1. Schematic illustration of polymorphisms in the IL-1B gene. Allele frequencies of the single-nucleotide polymorphisms (SNP) in the promoter region of the IL-1B gene at positions –511 and –31. SNP -511T (associated with higher IL-1ß secretion) is in complete linkage disequilibrium with –31C. From an eastern European population (19).
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IL-1RN
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The IL-1RN gene has a penta-allelic 86-bp variable number tandem repeat in intron 2, of which allele 2 (IL-1RN*2) is associated with a wide range of chronic inflammatory and autoimmune conditions and enhanced IL-1ß secretion (Fig. 2). The alleles 1, 2, 3, 4, and 5 in IL-1 RN gene, represent four, two, five, three, and six repeats of the 86-bp tandem repeat (see Fig. 2). As described below, the presence of allele 2 has been associated with increased risk of distal gastric cancer and its precursors (14, 15, 17, 18).
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Figure 2. IL-1RN gene has a penta-allelic 86-bp variable number tandem repeat in intron 2, of which the allele 2 (IL-1RA*2) had been associated with enhanced IL-1ß production. Relative frequencies are indicated for each allele. From an eastern European population (19).
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Interactions of IL-1 Polymorphisms and Gastric Cancer
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The first indication of IL-1 polymorphisms and their association with increased risk for gastric cancer was reported by El-Omar et al. (11). El-Omar et al. recently reported that functional polymorphisms in the genes for IL-1ß and its endogenous receptor antagonist (IL-1RN) were associated with increased risk of gastric cancer and its precursors (11, 13). They found also that those polymorphisms were associated with hypochlorhydria. Furthermore, the authors noted that IL-1B –31 and –511 were in almost complete linkage disequilibrium.
Studies from Portugal later confirmed and extend the observations. IL-1B –511*T carriers who were also homozygous for the short allele of IL-1RN 2/2 had an increase gastric carcinoma risk [odds ratio (OR), 3.3; 95% confidence interval (95% CI), 1.3-8.2]. The authors also found that patients with greater risk for gastric carcinoma were those carrying both bacterium and host high-risk genotypes (15). In a second Portuguese study, the authors found that for chronic atrophic gastritis and gastric cancer, the odds of developing disease increased with the number of risk genotypes (17). These studies show that the combination of bacteria and host genotypes can be useful in defining a specific genetic profile associated with high risk for gastric cancer.
The carriage of multiple proinflammatory polymorphisms confers greater risk for the development of distal gastric cancer. This was recently confirmed by El-Omar et al. (12) in a study in which the ORs (95% CIs) increased from 2.8 (1.6-5.1) for one, 5.4 (2.7-10.6) for two, and 27.3 (7.4-99.8) for three or more high-risk genotypes. The same synergistic effect of H. pylori virulence factors and IL-1 polymorphisms was reported in association with the development of severe histologic changes in the gastric mucosa in German patients (19).
The association of IL-1B gene polymorphism and gastric cancer was investigated in high- and low-prevalence regions in China (20). The authors found that IL-1B –511 polymorphism was associated with gastric cancer. This association was less obvious in areas of high prevalence of H. pylori and consequently more gastric cancer. A study from Taiwan has confirmed this observation (21). The study in China did not find complete linkage disequilibrium between IL-1B –511 and –31. The same observation has been reported in a study from Korea (22). In contrast, there are some studies that report a lack of association between IL-1B polymorphisms and gastric cancer. Lee et al. (22) in Korea did not find any association between IL-1B –31 or IL-1RN*2 polymorphisms and increased risk of gastric cancer. Matsukara et al. (18) reported an ethnic difference in the association between the IL-1B polymorphism and gastric atrophy. In the same report, there was no association of the IL-1B polymorphism and the risk of gastric atrophy in Thai and Vietnamese patients.
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Interactions of IL-1B Polymorphisms with Other Diseases
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The IL-1B polymorphisms –511 and IL-1RN 2/2 have been associated with esophagitis in patients who are not colonized with H. pylori. Koivurova et al. (23) reported that the simultaneous carriage of those two polymorphisms is significantly associated with esophagitis. Garcia-Gonzalez et al. (24) confirmed that the same IL-1B and IL-1RN polymorphisms that are associated with high risk of distal gastric adenocarcinoma are associated with a reduced risk of duodenal ulcer.
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Tumor Necrosis Factor-A
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TNF- is one of the proinflammatory cytokines highly expressed in H. pylori gastritis and a potent inhibitor of gastric acid secretion (25, 26). Although several polymorphisms have been reported in the TNF-A promoter, the majority of studies have been focused on the G/A polymorphism at position –307 (Fig. 3), because most of the other polymorphisms are functionally silent. Several studies found a higher concentration of TNF- in patients with the polymorphism at position –307 with malignant tumors (27, 28).
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Figure 3. Schematic illustration of TNF-A polymorphism. Allele frequencies from an eastern European population.
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As noted above, TNF- is a proinflammatory cytokine, which is a mediator of the immune response in H. pylori and shares many biological activities with IL-1 (26). Apparently, the TNF region is crucial in the complex genetic predisposition to H. pylori colonization in certain patient subgroups. Kunstmann et al. (29) reported that TNF-A –307 wild type is associated with duodenal ulcer in female patients independent of H. pylori status. The functional promoter polymorphism in this gene not only plays an important role in H. pylori–induced gastritis but also doubles the risk of non-cardia gastric cancer without any association with the risk of esophageal or cardia gastric cancer (12). Almost identical results were reported by Machado et al. (17). The authors found that carriers of TNF-A –307A* allele have an increased risk of gastric cancer with an OR of 1.9 (95% CI, 1.3-2.7).
In contrast, some studies did not find an association between TNF-A –307 polymorphism and gastric cancer. Zambon et al. (30) in Italy studied 210 controls and 475 patients with esophageal or gastric cancer. Their results suggested that TNF-A –307 might be involved in favoring H. pylori infection and the inflammatory response of the infected gastric mucosa but not favoring precancerous intestinal metaplasia or non-cardia gastric cancer. A recent report from Korea also indicated that not only TNF-A –307 but also four other polymorphisms (–1031, –863, –857, and –238) have no association with gastric cancer (31). The differences in polymorphism profile were not statistically significant between gastric cases and controls.
Whereas in some in vitro studies, allele A of this single nucleotide polymorphism was associated with heightened TNF- secretion, other studies did not find such a correlation. Rad et al. (32) studied the influence of the TNF-A –307 polymorphism on mucosal cytokine expression and they show no significant differences in TNF- level between different allele carriers. These results suggest that this polymorphism may not influence cytokine expression. However, it is important to extend the number of studies in this area to confirm or refute these findings.
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IL-10
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Inflammatory reactions are an essential component of host defense mechanisms, but prolonged or excessive inflammation is deleterious; therefore, the inflammatory process must be tightly regulated. The key regulators of inflammation are the cytokines, proinflammatory (IL-1ß and TNF-) and the anti-inflammatory (IL-10). The possible roles of proinflammatory cytokine in gastric cancer were noted above; anti-inflammatory cytokines also play a role. In the IL-10 gene promoter, single nucleotide polymorphisms at positions –1082 (G/A), –819 (C/T), and –592 (C/A) have been reported to produce three main haplotypes: GCC, ACC, and ATA (refs. 9, 32; Fig. 4).
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Figure 4. Schematic illustration of IL-10 polymorphisms. Allele frequencies from German and southern European populations.
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Rad et al. (32) have recently shown that carriers of the IL-10 –1082G, –819C, and –592C alleles had higher mucosal IL-10 mRNA than ATA haplotype carriers. These results confirmed the relevance of IL-10 polymorphisms in the down-regulation of the inflammatory response. El-Omar et al. have recently reported that certain polymorphisms in anti-inflammatory cytokine genes, such as IL-10, were associated with more than doubling of the risk of non-cardia gastric cancer (12). Patients homozygous for the hypoactive IL-10 alleles IL-10 –1082A and IL-10 –592A, as well as for the "low IL-10" haplotype ATA (IL-10 –1082A, IL-10 –819T, and IL-10 –592A) had significantly increased risks of non-cardia gastric cancer.
Garza-Gonzalez et al. (33) studied the potential role of IL-10 polymorphisms in gastric cancer patients. They found no association between IL-10 polymorphisms (–592 and –1082) and gastric cancer in a very small study (33 gastric cancer cases and 25 controls).
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Association Between Multiple Polymorphisms and Gastric Cancer Risk
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The combination of multiple proinflammatory polymorphisms and some anti-inflammatory polymorphisms conferred greater risk for gastric cancer as illustrated in Table 2 (12). The association of IL-10, an anti-inflammatory cytokine, with proinflammatory cytokines such as Il-1ß and TNF- may be explained by the role of IL-10 in down-regulating the proinflammatory cytokines. In addition, some reports suggest an important role for cytokine expression in the level of the inflammatory response observed in vivo (34).
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Table 2. Frequencies (%) and age-, sex-, and race-adjusted ORs for the association of inflammatory polymorphisms in IL-1B, IL-1RN, IL-10, and TNF-A with non-cardia gastric cancer
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In contrast, the number of inflammatory cytokine polymorphisms was not statistically significantly associated with the risk of esophageal squamous cell carcinoma, adenocarcinoma of the esophagus, or gastric cardia cancer. ORs for carriage of three or four inflammatory genotypes were 0 (95% CI, 0-10.5), 1.3 (95% CI, 02-8.0), and 3.6 (95% CI, 0.8-16.7), respectively.
Other cytokine polymorphisms have been recently described, including IL-8 –251, Thr399Ile, and TLR-4 Asp299Gly and are currently under study for their role in cytokine level and cancer risk.
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Effect of Cytokine Polymorphisms and H. pylori Status
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An interesting finding in the El-Omar study (12) was the association between cytokine polymorphisms and H. pylori–seropositive status. Tables 3 and Table 4show clearly that the ORs are higher in H. pylori– and CagA-positive patients than in the whole population studied in Table 2. This observation has been confirmed in patients with severe histologic changes in the gastric mucosa (20).
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Table 3. Estimated ORs for the association of cytokine polymorphisms in seropositve patients to H. pylori and CagA antigen preparations
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Table 4. H. pylori and CagA status-adjusted ORs for the association of inflammatory polymorphisms with non-cardia gastric cancer
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The study of Figueiredo et al. (15) is probably the most complete study that shows that the pattern of bacterial and host genotypes may determine risk of developing distal gastric cancer (Table 5). Bacterial status and genotype were determined by PCR and not by serology. The study concentrated on two of the major virulence factors in H. pylori vacA and cagA. In particular, the authors were able to assess the s1 and m1 regions of vacA that have been associated with the most severe H. pylori–related disease outcome. Overall, the findings suggest that it is possible to define a disease risk profile combining host and bacterial genotypes in distal gastric cancer, which may be useful in prevention programs.
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Table 5. Combination of H. pylori and IL-1B genotype in non-atrophic gastritis and non-cardia gastric cancer patients
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Table 6 summarizes the association of different cytokine polymorphisms, H.pylori carriage, and gastric pathologies.
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Conclusions
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It is clear that colonization with H. pylori increases the risk of developing distal gastric cancer and perhaps there are further additive effects on risk if specific host cytokine polymorphisms coincide with specific bacterial genotypes. We have presented some of the most recent evidence for these associations. Furthermore, the combination of more virulent H. pylori strains and the expression of specific cytokine polymorphisms contribute to an increasing risk of developing distal gastric cancer. We have mentioned that there is a need for more studies in different geographic regions of the world and in a wide diversity of ethnic populations to explore whether colonization with virulent H. pylori strains and expression of cytokine polymorphisms contribute to an increased risk of developing distal gastric adenocarcinoma. As Furuta et al. mentioned in a recent editorial (35), the study of polymorphisms alone seems insufficient to assess gastric cancer risk and they suggest examining environmental factors in different ethnic groups and geographic areas along with the study of H. pylori strains. Studies of this type may be required to determine the most important risk factors associated with distal gastric cancer in a particular region of the world.
Received 12/ 3/04;
accepted 1/ 3/05.
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References
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|---|
- Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J. Cancer incidence in five continents. Vol VII. Scientific Publication No. 143. Lyon (France): WHO, IARC; 1997.
- Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin 1999;49:33–64.[Abstract/Free Full Text]
- Parsonnet J. Helicobacter pylori and gastric carcinoma. In: Parsonnet, editor. Microbes and malignancy as a causes of human cancer. New York: Oxford University Press; 1999. p. 372–408.
- IARC. Working Group on the evaluation of carcinogenic risk to humans infection with Helicobacter pylori. In: IARC, editor. IARC monograph on the evaluation of carcinogenesis risks to humans. IARC Scientific Publications No. 61. Lyon: IARC; 1994. p. 177–241.
- Holcome C. Helicobacter pylori. The African enigma. Gut 1992;33:429–31.[Free Full Text]
- Blaser MJ, Perez-Perez GI, Kleanthous H, et al. Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res 1995;55:2111–5.[Abstract/Free Full Text]
- Covacci A, Telford JL, Del Guidice G, Parsonnet J, Rappuoli R. Helicobacter pylori virulence and genetic geography. Science 1999;284:1328–33.[Abstract/Free Full Text]
- Bidwell J, Keen L, Gallagher G, et al. Cytokine gene polymorphism in human disease: on-line databases, Supplement 1. Genes Immun 2001;2:61–70.[CrossRef][Medline]
- Ponder BA. Cancer genetics. Nature 2001;411:336–41.[CrossRef][Medline]
- Hurme M, Lahdenpohja N, Santtila S. Gene polymorphisms of interleukin-1 and 10 in infectious and autoimmune diseases. Ann Med 1998;30:469–73.[Medline]
- El-Omar EM, Carrington M, Chow WH, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 2000;404:398–402.[CrossRef][Medline]
- El-Omar EM, Rabkin CS, Gammon MD, et al. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 2003;124:1193–201.[CrossRef][Medline]
- Furuta T, El-Omar EM, Xiao F, Shirai N, Takashima M, Sugimurra H. Interleukin 1ß polymorphisms increase risk of hypochlorhydria and atrophic gastritis and reduce risk of duodenal ulcer recurrence in Japan. Gastroenterology 2002;123:92–105.[CrossRef][Medline]
- El-Omar EM. The importance of interleukin 1ß in Helicobacter pylori associated disease. Gut 2001;48:743–7.[Free Full Text]
- Figueiredo C, Machado JC, Pharoah P, et al. Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst 2002;94:1680–7.[Abstract/Free Full Text]
- Hwang IR, Kodama T, Kikuchi S, et al. Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1 production in Helicobacter pylori infection. Gastroenterology 2002;123:1793–803.[CrossRef][Medline]
- Machado JC, Pharoah P, Sousa S, et al. Interleukin 1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma. Gastroenterology 2001;121:823–9.[CrossRef][Medline]
- Matsukura N, Yamada S, Kato S, et al. Genetic differences in interleukin-1 ß polymorphisms among four Asian populations: an analysis of the Asian paradox between H. pylori infection and gastric cancer incidence. J Exp Clin Cancer Res 2003;22:47–55.[Medline]
- Rad R, Prinz C, Neu B, et al. Synergistic effect of Helicobacter pylori virulence factors and interleukin-1 polymorphisms for the development of severe histological changes in the gastric mucosa. J Infect Dis 2003;188:272–81.[CrossRef][Medline]
- Zeng Z-R, HuP-J, Hu S, et al. Association of interleukin IL-1B gene polymorphism and gastric cancers in high and low prevalence regions in China. Gut 2003;52:1684–9.[Abstract/Free Full Text]
- Chen A, Li C-N, Hsu P-I, et al. Risks of interleukin-1 genetic polymorphisms and Helicobacter pylori infection in the development of gastric cancer. Aliment Pharmacol Ther 2004;20:203–11.[CrossRef][Medline]
- Lee S-G, Kim B, Choi W, Lee I, Choi J, Song K. Lack of association between pro-inflammatory genotypes of the interleukin-1 (IL-1B –31 C/+ and IL-1RN *2/*2) and gastric cancer/duodenal ulcer in Korean population. Cytokine 2003;21:167–71.[CrossRef][Medline]
- Kolvurova OP, Karhukorpi JM, Koistinen PO, et al. IL-1RN 2/2 genotype and simultaneous carriage of genotypes IL-1RN 2/2 and IL-1B –511 T/T associated with oesophagitis in Helicobacter pylori negative patients. Scand J Gastroenterol 2003;38:1217–22.[Medline]
- Garcia-Gonzalez MA, Lanas A, Savelkoul PHM, et al. Association of interleukin-1 gene family polymorphisms with duodenal ulcer disease. Clin Exp Immunol 2003;134:525–31.[CrossRef][Medline]
- Noach LA, Basma NB, Jansen J, Hoek FJ, van Deventer SJ, Tytgat GN. Mucosal tumor necrosis factor-a, interleukin-1b, and interleukin-8 production in patients with Helicobacter pylori infection. Scand J Gastroenterol 1994;29:425–9.[Medline]
- Beales IL, Calam J. Interleukin-1ß and tumor necrosis factor- inhibit acid secretion in cultured rabbit parietal cells by multiple pathways. Gut 1998;42:227–34.[Abstract/Free Full Text]
- Forones NM, Mandowsky SV, Lourenco LG. Serum levels of interleukin-2 and tumor necrosis factor- correlate to tumor progression in gastric cancer. Hepatogastroenterology 2001;48:1199–201.[Medline]
- Izutani R, Katoh M, Asano S, Ohyanagi H, Hirose K. Enhanced expression of manganese superoxide dismutase mRNA and increased TNF mRNA expression by gastric mucosa in gastric cancer. World J Surg 1996;20:228–33.[CrossRef][Medline]
- Kunstmann E, Epplen C, Elitok E, et al. Helicobacter pylori infection and polymorphisms in the tumor necrosis region. Electrophoresis 1999;20:1756–61.[CrossRef][Medline]
- Zambon C-F, Basso D, Navaglia F, et al. Increased risk of non cardia gastric cancer associated with pro-inflammatory cytokine gene polymorphism. Gastroenterology 2004;126:382–3.[CrossRef][Medline]
- Lee S-G, Kim B, Yook J-H, Oh S-T, Lee I, Song K. TNF/LTA polymorphisms and risk for gastric cancer/duodenal ulcer in Korean population. Cytokine 2004;28:75–82.[Medline]
- Rad R, Dossumbekova A, Neu B, et al. Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and host specific colonisation during Helicobacter pylori infection. Gut 2004;53:1082–9.[Abstract/Free Full Text]
- Garza-Gonzalez E, Bosques-Padilla FJ, El-Omar E, et al. Role of polymorphic IL-1B, IL-1RN, and TNF-A genes in distal gastric cancer in Mexico. Int J Cancer 2005;114:237–41.[CrossRef][Medline]
- Peek RM, Miller GG, Tham KT, Perez-Perez GI, Zhao X, Atherton JC, Blaser MJ. Heightened inflammatory response and cytokine expression in vivo to cagA+ Helicobacter pylori strains. Lab Invest 1995;71:760–70.
- Furata T, Shirai N, Sugimoto M. Controversy in polymorphisms of interleukin-1ß in gastric cancer risks. J Gastroenterol 2004;39:501–3.[CrossRef][Medline]
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Abstract
Introduction
