IL1 Receptor Antagonist Gene IL1-RN Variable Number of Tandem Repeats Polymorphism and Cancer Risk: A Literature Review and Meta-Analysis

Ying Zhang,Huiping Peng,Jianzhi Zhang,Quanlin Feng,Changming Liu,Masaru Katoh

doi:10.1371/journal.pone.0046017

Abstract

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.

Highlights

Interleukins (ILs) are pro-inflammatory cytokines produced by monocytes, macrophages and epithelial cells
To analyze the variable number of tandem repeats (VNTR) in the second intron of IL1 receptor antagonist gene (IL1-RN), polymerase chain reaction (PCR) was performed in most studies, direct sequencing was used by two studies [17,18], and the denaturing high performance liquid chromatography (DHPLC) was applied in one study [19]
20 studies investigated the interactions between the polymorphism and helicobacter pylori (H. pylori), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection status

Summary

Introduction

Interleukins (ILs) are pro-inflammatory cytokines produced by monocytes, macrophages and epithelial cells. The interleukin-1 (IL1) family consists of the cytokines IL1alpha (IL1a), IL1beta (IL1b) and a specific receptor antagonist (IL1RA) [1]. Several IL1B gene single nucleotide polymorphisms have been described to be associated with cancers to date [3]. In the second intron of the IL1-RN gene, there exists a variable number of tandem repeats (VNTR) with an 86 base pair nucleotide sequence as its repeating element. This region contains three potential protein binding sites: an interferon a silencer A, an interferon b silencer B and an acute phase response element, and may be of functional relevance [8]. The genotypes were classified as LL, 2L, and 22 [10]

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Results

Conclusion