IL1 receptor antagonist (IL1RA) and IL1beta (IL1β), members of the pro-inflammatory cytokine interleukin-1 (IL1) family, play a potential role against infection and in the pathogenesis of cancers. The variable number of tandem repeats (VNTR) polymorphism in the second intron of the IL1 receptor antagonist gene (IL1-RN) and a polymorphism in exon 5 of IL1B (IL1B+3954C>T, rs1143634) have been suggested in predisposition to cancer risk. However, studies have shown inconsistent results. To validate any association, a meta-analysis was performed with 14,854 cases and 19,337 controls from 71 published case–control studies for IL1-RN VNTR and 33 eligible studies contained 7,847 cases and 8917 controls for IL1B +3954. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated from comparisons to assess the strength of the association. There was significant association between the IL1-RN VNTR polymorphism and the risk of cancer for any overall comparison. Furthermore, cancer type stratification analysis revealed that there were significantly increased risks of gastric cancer, bladder cancer and other cancer groups. Infection status analysis indicated that the H. pylori or HBV/HCV infection and IL1-RN VNTR genotypes were independent factors for developing gastric or hepatocellular cancers. In addition, a borderline significant association was observed between IL1B+3954 polymorphism and the increased cancer risk. Although some modest bias could not be eliminated, this meta-analysis suggested that the IL1-RN VNTR polymorphisms may contribute to genetic susceptibility to gastric cancer. More studies are needed to further evaluate the role of the IL1B+3954 polymorphism in the etiology of cancer.
References
[1]
Smith DE, Renshaw BR, Ketchem RR, Kubin M, Garka KE, et al. (2000) Four new members expand the interleukin-1 superfamily. J Biol Chem 275: 1169–1175.
[2]
Patterson D, Jones C, Hart I, Bleskan J, Berger R, et al. (1993) The human interleukin-1 receptor antagonist (IL1RN) gene is located in the chromosome 2q14 region. Genomics 15: 173–176.
[3]
Engels EA, Wu X, Gu J, Dong Q, Liu J, et al. (2007) Systematic evaluation of genetic variants in the inflammation pathway and risk of lung cancer. Cancer Res 67: 6520–6527.
[4]
He B, Zhang Y, Pan Y, Xu Y, Gu L, et al. (2011) Interleukin 1 beta (IL1B) promoter polymorphism and cancer risk: evidence from 47 published studies. Mutagenesis 26: 637–642.
[5]
Pociot F, Molvig J, Wogensen L, Worsaae H, Nerup J (1992) A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest 22: 396–402.
[6]
Liu X, Wang Z, Yu J, Lei G, Wang S (2010) Three polymorphisms in interleukin-1beta gene and risk for breast cancer: a meta-analysis. Breast Cancer Res Treat 124: 821–825.
[7]
Kiyohara C, Horiuchi T, Takayama K, Nakanishi Y (2010) IL1B rs1143634 polymorphism, cigarette smoking, alcohol use, and lung cancer risk in a Japanese population. J Thorac Oncol 5: 299–304.
[8]
Tarlow JK, Blakemore AI, Lennard A, Solari R, Hughes HN, et al. (1993) Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet 91: 403–404.
[9]
El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, et al. (2000) Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404: 398–402.
[10]
Santtila S, Savinainen K, Hurme M (1998) Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro. Scand J Immunol 47: 195–198.
[11]
Figueiredo C, Machado JC, Pharoah P, Seruca R, Sousa S, et al. (2002) Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst 94: 1680–1687.
[12]
Handoll HH (2006) Systematic reviews on rehabilitation interventions. Arch Phys Med Rehabil 87: 875.
[13]
Midgette AS, Wong JB, Beshansky JR, Porath A, Fleming C, et al. (1994) Cost-effectiveness of streptokinase for acute myocardial infarction: A combined meta-analysis and decision analysis of the effects of infarct location and of likelihood of infarction. Med Decis Making 14: 108–117.
[14]
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629–634.
[15]
Melo Barbosa HP, Martins LC, Dos Santos SE, Demachki S, Assumpcao MB, et al. (2009) Interleukin-1 and TNF-alpha polymorphisms and Helicobacter pylori in a Brazilian Amazon population. World J Gastroenterol 15: 1465–1471.
[16]
Rocha GA, Guerra JB, Rocha AM, Saraiva IE, da Silva DA, et al. (2005) IL1RN polymorphic gene and cagA-positive status independently increase the risk of noncardia gastric carcinoma. Int J Cancer 115: 678–683.
[17]
Hefler LA, Grimm C, Lantzsch T, Lampe D, Leodolter S, et al. (2005) Interleukin-1 and interleukin-6 gene polymorphisms and the risk of breast cancer in caucasian women. Clin Cancer Res 11: 5718–5721.
[18]
Chen A, Li CN, Hsu PI, Lai KH, Tseng HH, et al. (2004) Risks of interleukin-1 genetic polymorphisms and Helicobacter pylori infection in the development of gastric cancer. Aliment Pharmacol Ther 20: 203–211.
[19]
Lu W, Pan K, Zhang L, Lin D, Miao X, et al. (2005) 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. Carcinogenesis 26: 631–636.
[20]
He BS, Pan YQ, Xu YF, Zhu C, Qu LL, et al. (2011) Polymorphisms in interleukin-1B (IL-1B) and interleukin 1 receptor antagonist (IL-1RN) genes associate with gastric cancer risk in the Chinese population. Dig Dis Sci 56: 2017–2023.
[21]
Lee KM, Park SK, Hamajima N, Tajima K, Choi JY, et al. (2006) Genetic polymorphisms of interleukin-1 beta (IL-1B) and IL-1 receptor antagonist (IL-1RN) and breast cancer risk in Korean women. Breast Cancer Res Treat 96: 197–202.
[22]
Singh H, Sachan R, Goel H, Mittal B (2008) Genetic variants of interleukin-1RN and interleukin-1beta genes and risk of cervical cancer. BJOG 115: 633–638.
[23]
Ahirwar DK, Agrahari A, Mandhani A, Mittal RD (2009) Cytokine gene polymorphisms are associated with risk of urinary bladder cancer and recurrence after BCG immunotherapy. Biomarkers 14: 213–218.
[24]
Con SA, Takeuchi H, Con-Chin GR, Con-Chin VG, Yasuda N, et al. (2009) Role of bacterial and genetic factors in gastric cancer in Costa Rica. World J Gastroenterol 15: 211–218.
[25]
Palli D, Saieva C, Luzzi I, Masala G, Topa S, et al. (2005) Interleukin-1 gene polymorphisms and gastric cancer risk in a high-risk Italian population. Am J Gastroenterol 100: 1941–1948.
[26]
Sehouli J, Mustea A, Koensgen D, Chen FC, Lichtenegger W (2003) Interleukin-1 receptor antagonist gene polymorphism is associated with increased risk of epithelial ovarian cancer. Ann Oncol 14: 1501–1504.
[27]
Erzin Y, Koksal V, Altun S, Dobrucali A, Aslan M, et al. (2008) Role of host interleukin 1beta gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) polymorphisms in clinical outcomes in Helicobacter pylori-positive Turkish patients with dyspepsia. J Gastroenterol 43: 705–710.
[28]
Perri F, Piepoli A, Bonvicini C, Gentile A, Quitadamo M, et al. (2005) Cytokine gene polymorphisms in gastric cancer patients from two Italian areas at high and low cancer prevalence. Cytokine 30: 293–302.
[29]
Glas J, Torok HP, Schneider A, Brunnler G, Kopp R, et al. (2004) Allele 2 of the interleukin-1 receptor antagonist gene is associated with early gastric cancer. J Clin Oncol 22: 4746–4752.
[30]
Heneghan MA, Johnson PJ, Clare M, Ho S, Harrison PM, et al. (2003) Frequency and nature of cytokine gene polymorphisms in hepatocellular carcinoma in Hong Kong Chinese. Int J Gastrointest Cancer 34: 19–26.
[31]
Zhang WH, Wang XL, Zhou J, An LZ, Xie XD (2005) Association of interleukin-1B (IL-1B) gene polymorphisms with risk of gastric cancer in Chinese population. Cytokine 30: 378–381.
[32]
Abazis-Stamboulieh D, Oikonomou P, Papadoulis N, Panayiotidis P, Vrakidou E, et al. (2007) Association of interleukin-1A, interleukin-1B and interleukin-1 receptor antagonist gene polymorphisms with multiple myeloma. Leuk Lymphoma 48: 2196–2203.
[33]
Sobti RC, Kordi Tamandani DM, Shekari M, Kaur P, Malekzadeh K, et al. (2008) Interleukin 1 beta gene polymorphism and risk of cervical cancer. Int J Gynaecol Obstet 101: 47–52.
Lim WY, Chen Y, Ali SM, Chuah KL, Eng P, et al. (2011) Polymorphisms in inflammatory pathway genes, host factors and lung cancer risk in Chinese female never-smokers. Carcinogenesis 32: 522–529.
[36]
Xue H, Lin B, Ni P, Xu H, Huang G (2010) Interleukin-1B and interleukin-1 RN polymorphisms and gastric carcinoma risk: a meta-analysis. J Gastroenterol Hepatol 25: 1604–1617.
[37]
Wang P, Xia HH, Zhang JY, Dai LP, Xu XQ, et al. (2007) Association of interleukin-1 gene polymorphisms with gastric cancer: a meta-analysis. Int J Cancer 120: 552–562.
[38]
Willett W (1989) The search for the causes of breast and colon cancer. Nature 338: 389–394.
[39]
Tirona MT, Sehgal R, Ballester O (2010) Prevention of breast cancer (part I): epidemiology, risk factors, and risk assessment tools. Cancer Invest 28: 743–750.
[40]
Press DJ, Pharoah P (2010) Risk factors for breast cancer: a reanalysis of two case-control studies from 1926 and 1931. Epidemiology 21: 566–572.
[41]
Speirs V, Kerin MJ, Newton CJ, Walton DS, Green AR, et al. (1999) Evidence for transcriptional activation of ERalpha by IL-1beta in breast cancer cells. Int J Oncol 15: 1251–1254.
[42]
Reichlin S, Chen G, Nicolson M (2000) Blood to brain transfer of leptin in normal and interleukin-1beta-treated male rats. Endocrinology 141: 1951–1954.
[43]
Hu X, Juneja SC, Maihle NJ, Cleary MP (2002) Leptin–a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst 94: 1704–1711.
[44]
Yin N, Wang D, Zhang H, Yi X, Sun X, et al. (2004) Molecular mechanisms involved in the growth stimulation of breast cancer cells by leptin. Cancer Res 64: 5870–5875.
[45]
Rose DP, Komninou D, Stephenson GD (2004) Obesity, adipocytokines, and insulin resistance in breast cancer. Obes Rev 5: 153–165.
[46]
Atherton JC (1997) The clinical relevance of strain types of Helicobacter pylori. Gut 40: 701–703.
[47]
Yu MW, Chen CJ (1994) Hepatitis B and C viruses in the development of hepatocellular carcinoma. Crit Rev Oncol Hematol 17: 71–91.
[48]
Ruzzo A, Graziano F, Pizzagalli F, Santini D, Battistelli V, et al. (2005) Interleukin 1B gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) polymorphisms in Helicobacter pylori-negative gastric cancer of intestinal and diffuse histotype. Ann Oncol 16: 887–892.
[49]
Powell EE, Edwards-Smith CJ, Hay JL, Clouston AD, Crawford DH, et al. (2000) Host genetic factors influence disease progression in chronic hepatitis C. Hepatology. 31: 828–833.
[50]
Leung N (2005) HBV and liver cancer. Med J Malaysia 60 Suppl B: 63–66.
[51]
Shirodaria S, Smith J, McKay IJ, Kennett CN, Hughes FJ (2000) Polymorphisms in the IL-1A gene are correlated with levels of interleukin-1alpha protein in gingival crevicular fluid of teeth with severe periodontal disease. J Dent Res 79: 1864–1869.
