Inflammatory cytokine gene polymorphisms and gastric cancer

Authors

  • Don Haeng Lee,

    1. Department of Internal Medicine, Inha University College of Medicine, Center for Advanced Medical Education by BK21 Project, Incheon, Korea
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  • Ki-Baik Hahm

    1. Department of Internal Medicine, Inha University College of Medicine, Center for Advanced Medical Education by BK21 Project, Incheon, Korea
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Professor Ki-Baik Hahm, Digestive Disease Center, Daejin Medical Center Jesaeng Hospital at Bundang and Inha University College of Medicine, 255-2 Seohuyn-dong, Bundang-gu, Seongnam 463-774, Korea. Email: hahmkb@hotmail.com

With the completion of the human genome project and appreciation of the implications of disease-associated single nucleotide polymorphism (SNP) for tailoring medicines, attention is now rapidly shifting towards the study of individual genetic variation in determining clinical diseases.1 SNP is the most abundant source of genetic variation in the human genome, and likely accounts for heritable inter-individual differences in the phenotypes for complex genetic and environmentally determined diseases.2 Identification of disease-associated SNP might allow accurate evaluation of risk ratio, which provides a clue to accurate prediction of disease risk and treatment response.3

Gastric cancer is the second leading cause of cancer death in the world, even though the incidence shows marked variation between countries.4 Incidence rates are especially high in Eastern Asian countries, including Korea, Japan, and China. In addition to being common, gastric cancer ranks highly as a cause of cancer mortality in these countries. The etiology appears to be multifactorial. Host-related genetic and environmental factors are inferred by the geographical, ethnic, and socioeconomic differences in the incidence of gastric cancer. One particularly important factor is the infectious microbe, Helicobacter pylori (H. pylori). Recognition of the importance of H. pylori supports the hypothesis that chronic inflammation might be the basis for gastric carcinogenesis.5 Mechanistically persistent inflammation after H. pylori infection can induce gastric atrophy and ensuing hypochlorhydria, based on which precancerous lesions arise and progress to adenoma or dysplasia.6

The fact that cytokines such as γ-interferon (INF-γ), interleukin-1β (IL-1β), IL-1 receptor antagonist (IL-1RN), and tumor necrosis factor-α (TNF-α) are considerably upregulated during H. pylori infection and that some H. pylori-infected persons develop clinical disease, has stimulated the drive to search for polymorphisms of these and related genes. Polymorphic regions of cytokine genes could alter gene transcription, thereby influencing inflammatory processes in response to H. pylori infection.7 IL-1β and IL-1RN are the cytokine genes studied most extensively for gene polymorphisms. IL-1β gene is an important pro-inflammatory cytokine and a powerful inhibitor of gastric acid secretion.8 Two SNP sites exist in the promoter region at positions −511 and −31, representing C-T and T-C transitions, respectively. These SNP have been shown to be associated with clinical outcomes of H. pylori infection, including gastric ulcer or cancer. Further, within the IL-IRN gene, a variable number of tandem repeats (VNTR) of an 86 bp length in intron 2 have been reported.8 Besides their significant disease associations, these SNP of either IL-1β or IL-1RN appear to impose functional abnormalities. In particular, they promote hypochlorhydria, which favors further colonization of H. pylori, leading to a more severe gastritis and gastric atrophy, after which adenocarcinoma may develop.9

After the first report by El-Omar et al. showing the IL-1β polymorphism is a risk factor for gastric cancer,10,11 many more studies have been published. Furuta et al. also showed that pro-inflammatory IL-1β polymorphisms, IL-1B-511 T, are associated with hypochlorhydria and atrophic gastritis in Japanese people.12 Later, El-Omar reported not only IL-1 gene polymorphism, but also other cytokine polymorphisms, such as IL-10 and TNF-α, increased the risk of non-cardia gastric adenocarcinoma.13 In a study of Mexican people, Garza-Gonzalez et al. showed that among IL-1B-31, IL-1RN, TNF-α-308 gene polymorphisms, only IL-1B-31 is associated with increased risk of distal gastric cancer.14

According to two large meta-analyses published about the association between IL-1 gene polymorphisms and gastric cancer, one involved 25 studies showing that IL-1B-511 T is associated with gastric cancer susceptibility in Caucasians15 and the other involved 39 studies. Both reached the same conclusion, that IL-1B-511 T was associated with an increased risk of gastric cancer. In addition, IL-1RN-2 was also associated with an increased risk of gastric cancer among Caucasians.16

In contrast to these studies showing a positive association between IL-1β and gastric cancer, conflicting results still remain. For example, in studies of Chinese people, IL-1β gene polymorphisms were not associated with gastric cancer risk.17 Another report from Spain also showed no association between variable cytokine gene polymorphisms (IL-1β, IL-1RN, IL-12p40, LTA, IL-10, IL-4 and TGF-β1) and gastric cancer.18 In previous studies of the Korean population, in spite of some reports that pro-inflammatory cytokine gene polymorphisms (IL-1, TNF-α) could be associated with gastric cancer,19 there have been conflicting results.20,21 Shin et al. showed that IL-1B-511, IL-1RN and IL-2 gene polymorphisms were not the determining factor that discriminated gastric ulcer, gastric cancer and duodenal ulcer (unpubl. data). Therefore, although IL-1β and IL-1RN gene polymorphism is generally proven as risk factor in Caucasians, there was no relationship between these cytokine gene polymorphisms and gastric cancer in Korean studies.

In this issue of Journal of Gastroenterology and Hepatology, a further study dealing with polymorphisms of IL-1 and IL-2 genes in Korean patients with gastric cancer is reported. Kim et al. compared the genotypes of IL-1B, IL-1RN and IL-2 gene polymorphisms with risk of gastric ulcer, gastric cancer and duodenal ulcer in Korean patients.21 The age-sex adjusted odds ratios (OR) for IL-1B-511 T genotype relative to the C/C genotype (OR = 0.82, 95% confidence interval [CI] 0.41–1.65), IL-1RN *2 genotype relative to the L/L genotype (OR = 0.85, 95% CI 0.41–1.78) and IL-2-330 T genotype relative to the G/G genotype (OR = 1.94, 95% CI 0.76–4.96) were not increased in gastric cancer. There was also no significant difference in genotypes of these cytokine polymorphisms between study groups (gastric ulcer or duodenal ulcer) and the disease-free control group. In spite of the limitation that the number of H. pylori-positive gastric cancer patients was relatively small (n = 81) in comparison with other studies, it now seems increasingly likely that inflammatory gene polymorphisms do not discriminate between gastric cancer, gastric ulcer and healthy Asian populations, as opposed to their discriminating influence among Western populations.

In summary, as mentioned above, gastric cancer has a multi-factorial pathogenesis and multiple risk factors that include host-related factors, several environmental factors such as diet (nitroso compounds, salt, folate), cigarette smoking, alcohol, and socioeconomic status. Support for a role of genetic polymorphisms is conflicting overall and lacking in some Asian populations. More large scale studies with larger numbers of risk factors are needed. Advancement in high throughput analysis will facilitate the search for SNP present in the whole genome, in addition to cooperative efforts through the International HapMap Project and Global Human Genome Projects. It is hoped that colleagues within and between the major Asian countries where H. pylori and gastric cancer remain among the top three causes of cancer mortality will cooperate to yield much needed mechanistic and prognostic information about gastric cancer, so that it may eventually be prevented as a major cause of death from gastroenterological disease.

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