Interleukin-1B and Interleukin-1 Receptor Antagonist Gene Polymorphisms and Gastric Cancer: A Meta-analysis M. Constanza Camargo, 1 Robertino Mera, 1 Pelayo Correa, 1 Richard M. Peek, Jr., 1 Elizabeth T.H. Fontham, 3 Karen J. Goodman, 4 M. Blanca Piazuelo, 1 Liviu Sicinschi, 1 Jovanny Zabaleta, 2 and Barbara G. Schneider 1 1 Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee; 2 Tumor Immunology Laboratory, Stanley S. Scott Cancer Center and 3 School of Public Health, Louisiana State University Health Sciences Center, New Orleans, Louisiana; and 4 Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada Abstract Background: Polymorphisms of interleukin-1B (IL1B )andits receptor antagonist (IL1RN) genes have been inconsistently associated with gastric cancer risk. We examined these associations by performing meta-analyses. Materials and Methods: Twenty-five studies testing the association between IL1B and/or IL1RN gene polymor- phisms and gastric cancer were examined: 14 studies of IL1B-511 ,14studiesof IL1B-31 ,8studiesof IL1B+3954 ,and 23studiesof IL1RN. Overall and ethnicity-specific summary odds ratios and corresponding 95% confidence intervals for gastric cancer associated with these polymorphisms were estimated using fixed- and random-effects models. Hetero- geneity and publication bias were evaluated. Results: IL1B-511T and IL1RN*2 were associated with gastric cancer risk in Caucasians, but not in Asians. For IL1B-511T , the association in Caucasians was stronger when intestinal-subtype and noncardia gastric cancer cases were examined. A nonsignificant trend was observed between IL1B-31C and gastric cancer in Caucasians. No significant association of IL1B+3954T and gastric cancer risk was detected. Studies with better methodologic characteristics reported stronger effects. There was no evidence of publication bias. Conclusion: IL1B-511T is associated with gastric cancer susceptibility in Caucasians. The meta-analyses suggest that the conflicting results among studies may be explained by variation in allele frequencies among the ethnic groups and variation in tumor types, as well as by the methodologic quality of the studies. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1674–87) Introduction In 2002, 1.9 million cancer cases worldwide, representing 17.8% of all cancers, were estimated to be associated with infectious agents, with 5.5% of all cancers attributable to Helicobacter pylori (H. pylori ) infection (1). Considering that chronic inflammation promotes the development of many gastrointestinal malignancies (2), a number of polymorphisms in genes related to the inflammatory response have been investigated as factors predisposing to gastric cancer (3). The most extensively studied are those encoding interleukin-1h (IL-1h) and its receptor antagonist (IL1Ra; refs. 4-6). IL-1h is a proinflammatory cytokine induced by H. pylori infection and is a powerful inhibitor of gastric acid secretion. Its effects promote hypochlorhydria, favoring further coloni- zation of H. pylori and a more severe gastritis. Over decades, gastric atrophy and adenocarcinoma may develop (7). Three single nucleotide polymorphisms (SNP) of the IL1B gene have been most frequently evaluated for association with gastric cancer: C-T base transitions at positions 511 and +3954 and a T-C base transition at position 31 (8-10). The SNPs at 31 and 511 are in near-complete linkage disequilibrium (4). IL-1 receptor antagonist is an anti-inflammatory protein that modulates the effects of IL-1h (11). The IL1RN gene contains an 86 bp variable number of tandem repeats (VNTR) polymor- phism in intron 2. Five different alleles have been described, with two to six repeats (12). The presence of IL1B-511T, IL1B-31C, IL1B+3954T , or IL- 1RN*2 alleles has been associated with gastric cancer risk in some reports (4, 13-15), but not in others (16, 17). Therefore, we did meta-analyses to find sources of variation in the reports. Materials and Methods Search Strategy and Study Selection. We searched for observational studies published from January 2000 (when the first association between IL1B gene polymorphisms and gastric cancer was published; ref. 4) to September 2005 using PubMed software to search Medline (U.S. National Library of Medicine, Bethesda, MD). Searching was done by two independent reviewers (M.C.C. and B.G.S.). Combinations of the keywords gastric cancer, IL-1, IL-1B, IL1RN, IL1B-511, IL1B-31, IL1B+3954 , association, polymorphisms, SNP, odds ratio (OR), gene, and allele were used. References cited in the selected articles were also considered. Two investigators (M.C.C. and M.B.P.) independently reviewed the articles and extracted the data; discrepancies were resolved through discussion. Studies testing the associ- ation between IL1B (31, 511 , and +3954 ) and/or IL1RN gene polymorphisms and gastric cancer were included if all the following conditions were met: (a ) the study assessed the association between gastric cancer and at least one of the polymorphisms; (b ) the study population included subjects with and without gastric cancer; (c ) the study reported ORs or data for their calculation; and (d ) the study was published in English or Spanish. Supplemental information regarding sample description for El-Omar et al. (4, 18) and Yang et al. (19) was taken from cited references (20-22), respectively. Additional information about 1674 Cancer Epidemiol Biomarkers Prev 2006;15(9). September 2006 Received 3/13/06; revised 5/31/06; accepted 7/17/06. Grant support: National Cancer Institute grant PO1CA028842 and Health Excellence Fund of the Board of Regents of the State of Louisiana grant HEF 2000-05-03. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requestsforreprints: M. Constanza Camargo, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, 2215 Garland Avenue, 1005 MRB IV, Nashville, TN 37232-0252. Phone: 615-3433951; Fax: 615-3436229. E-mail: maria.c.camargo@vanderbilt.edu Copyright D 2006 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-06-0189 on June 7, 2020. © 2006 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from