INTERLEUKIN-10 GENOTYPES ASSOCIATE WITH THE RISK OF GASTRIC CARCINOMA IN TAIWANESE CHINESE Ming-Shiang WU 1 , Chun-Ying WU 2 , Chien-Jen CHEN 3 , Ming-Tsan LIN 4 , Chia-Tung SHUN 5 and Jaw-Town LIN 1 * 1 Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital Taipei, Taiwan 2 Department of Internal Medicine, Taichung Veteran General Hospital, Taichung, Taiwan 3 Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan 4 Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan 5 Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan The association of cytokine genotypes with gastric carci- noma (GC) may be influenced by environmental factors and varies among different populations. Few studies have ad- dressed the impact of different cytokine genotypes on the development and progression of GC. We analyzed 11 func- tional polymorphisms in tumor necrosis factor- (TNF-), interleukin (IL)-1, IL-4 and IL-10 genes in 220 Taiwanese Chi- nese with GC and in 230 healthy controls. The risk of geno- types was adjusted with confounding environmental risks. Our results revealed that the frequency of Helicobacter pylori infection [odds ratio (OR) 1.7, 95% confidence interval (CI) 1.19 –2.56], cigarette smoking (OR 2.02, 95% CI 1.38 –2.95) and high IL-10 producer genotype (OR 2.67, 95% CI 1.29 – 5.50) was significantly increased in the entire GC patients. Among different subtypes of GC, a higher risk of developing diffuse type (OR 1.64, 95% CI 1.01–2.67) or cardia cancer (OR 2.44, 95% CI 1.13–2.67) was observed for the CT/CC geno- type of IL-4 at the position 590, whereas the high IL-10 producer genotype was significantly linked with the risk of cardia cancer (OR 3.21, 95% CI 1.06 –9.73) or advanced stage (OR 2.29, 95% CI 1.12– 4.64). No association was noted be- tween GC and controls in the distribution of IL-1 and TNF- genotypes. Logistic regression analyses revealed that H. py- lori infection (OR 1.7, 95% CI 1.14 –2.52), cigarette smoking (OR 1.87, 95% CI 1.27–-2.96) and IL-10 genotype (OR 2.54, 95% CI 1.24 –5.61) are independent risks for GC. Independent effects of IL-10 genotype, H. pylori infection and cigarette smoking indicate that carcinogenesis of GC is influenced by a variety of host and environmental factors. © 2003 Wiley-Liss, Inc. Key words: gastric carcinoma; cytokine genotype; Helicobacter py- lori; cigarette smoking; single nucleotide polymorphism Gastric carcinoma (GC) is a common and complex multifacto- rial disease in which environmental and host-related factors inter- act. 1 Helicobacter pylori infection and cigarette smoking are among important environmental risks for GC. However, only a small portion of H. pylori-infected patients or cigarette smokers develop GC, indicating that additional factors must be involved in determining the fate after exposure to environmental factors. 2,3 Recently, studies of twins, familial clustering, ethnic differences and human leukocyte antigen (HLA) genes have provided evi- dence that host factors play a significant role in the pathogenesis of GC. 4,5 Specifically, the host response to environmental triggers, rather than bacteria or environmental factors per se, may be responsible for the outcome of disease. 6 In the multistage model of gastric carcinogenesis, gastric in- flammation is a prerequisite for the development of GC. 7 Accord- ingly, factors involved in initiation and regulation of the inflam- matory response may confer susceptibility to or protection against GC. In this respect, cytokines that play a crucial role in regulating inflammation are potential candidates for correlating with such variation. The in vitro maximal capacity to produce different cytokines varies among different individuals. Family studies indi- cate that much of this variability is genetically determined. 8 Such interindividual differences can be attributed to several molecular mechanisms, including single nucleotide polymorphisms (SNPs) in the coding or promoter regions of cytokine or cytokine receptor genes. These polymorphisms may affect the overall expression and secretion of cytokines. The observed genetically determined dif- ferences in cytokine production in inflammatory response might account for some of the heterogeneity of infectious diseases. 8,9 For H. pylori infection, tumor necrosis factor alpha (TNF-) and interleukin (IL)-1 are 2 prototypic proinflammatory cytokines that have been implicated in the pathogenesis of GC and H. pylori-associated diseases. 10 –13 Multiple polymorphisms have been found in both TNF- and IL-1 gene clusters. Two polymorphisms located in the TNF- promoter (-238 and -308 positions) have been studied. 10,11 The expression of TNF--308 A allele is a risk factor for duodenal ulcer, 10 whereas that of TNF--238 A allele is associated with a decreased risk of GC. 11 The IL-1 gene family includes IL-, IL-1 and the IL-1 receptor antagonist (IL-1Ra). The IL-1 gene has polymorphisms at positions -511, and -31, and there is a variable number of tandem repeats (VNTRs) in IL-1RN. 12 A recent break- through in the investigation of H. pylori-associated diseases is the discovery that polymorphisms of IL-1 and IL-1RN are strongly linked to the occurrence of hypochlorhydria and GC for Cauca- sians. 12,13 This implies that genetic host factors, such as cytokine polymorphisms, may render an individual susceptible to GC through modulation of gastric inflammation in a permissive cyto- kine environment. However, ethnicity might greatly affect the genotype status, 14,15 and a recent study from Japan revealed no difference in IL-1 genotypes between GC and controls. 14 There- fore, the importance of cytokine polymorphisms needs to be rep- licated in other ethnically diverse populations. An array of cytokines, which can be either a T-helper cell type 1 (Th1) response promoting cell-mediated immunity or a T-helper cell type 2 (Th2) response promoting humoral immunity, may determine the fate of inflammation. 9 In contrast to proinflamma- tory cytokines such as TNF- and IL-1, which are considered Th1 cytokines, relatively little is known about the role of antiinflam- matory cytokine genotypes in the pathogenesis of GC. In the Helicobacter felis murine model of infection, gastric inflammation is more severe in IL-10 knockout animals. 16 Likewise, a more severe gastric inflammation was observed in IL-4 gene-deficient mice infected with H. pylori. 17 Therefore, the balance between Th1 Grant sponsor: the Department of Health, Executive Yuan, Taipei; Grant numbers: DOH-86-TD-023 and DOH-86-HR-525; Grant sponsor: the Na- tional Science Council, Executive Yuan, Taipei; Grant number: NSC-90- 2314-B002-144-M58. *Correspondence to: Department of Internal Medicine, No. 7, Chung- Shan S. Rd., Taipei, Taiwan. Fax: +2-886-23947899. E-mail: jawtown@ha.mc.ntu.edu.tw 22 August 2002; 14 November 2002; 4 December 2002 DOI 10.1002/ijc.10987 Int. J. Cancer: 104, 617– 623 (2003) © 2003 Wiley-Liss, Inc. Publication of the International Union Against Cancer