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Interleukin-1 receptor antagonist polymorphism (rs2234663) and periodontitis susceptibility: A meta-analysis

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Abstract

Objective

The results of recent published studies focusing on interleukin-1 receptor antagonist (IL-1RN) gene variable number of tandem repeats (VNTR) polymorphism in periodontitis susceptibility are often conflicting. We performed a meta-analysis in order to investigate the potential association of IL-1RN VNTR polymorphism with susceptibility to either chronic (CP) or aggressive (AgP) periodontitis.

Design

Nineteen studies involving a total of 2011 cases and 1719 controls were searched without any language restriction. Odds ratios (ORs) along with their 95% confidence intervals (CIs) were calculated to compare the distribution of alleles and genotypes between cases and controls. Both fixed and random effects models were used to pool the data.

Results

The IL-1RN VNTR polymorphism was marginally associated with an elevated risk of CP in overall populations (22 versus LL (L means the long alleles): OR = 1.47, 95% CI 1.00–2.18, p = 0.05), and the association was consistently significant in severe CP subgroup (OR = 4.02, 95% CI 1.84–8.80, p < 0.0005). Further stratified analysis restricted to Hardy–Weinberg equilibrium studies showed evidence for an increased risk with CP in Asians (2 allele versus L allele: OR = 1.82, 95% CI 1.31–2.54, p < 0.0005), however, a decreased risk with AgP in Caucasians (L2 versus LL: OR = 0.50, 95% CI 0.32–0.78, p = 0.002).

Conclusions

This meta-analysis suggested that IL-1RN VNTR polymorphism might contribute to an increased risk on CP and a decreased risk on AgP. However, further well-designed studies with large sample size are needed to determine the robustness of these observations in different populations.

Introduction

Periodontitis is an infectious disease of the supporting tissues of teeth. The accumulation of bacteria in the gingival crevice might trigger an inflammatory process, which, if left untreated, destroys the periodontium and, eventually, results in tooth loss.1 Periodontitis emerges either in chronic or aggressive forms.2 Chronic periodontitis (CP) is rather common affecting up to 30% of adults, while 7–13% of the adult population will develop severe forms of destructive periodontal disease.3 Aggressive periodontitis (AgP), which has its onset primarily during early adult years, is characterized by the rapid, severe attachment loss and alveolar bone destruction.4 Although pathogenic microbes is regarded as the primary etiological factor of periodontitis, genetic factors as well as environmental factors affect the age of onset, severity, and lifetime risk of developing periodontitis.5

The role of interleukin-1 (IL-1) family in the pathogenesis of periodontitis has been extensively demonstrated. The IL-1 gene cluster on chromosome 2q13 contains three related genes within a 430 kb region, IL-1A, IL-1B, and IL-1RN, which encode the pro-inflammatory cytokines IL-1α and IL-1β, as well as the endogenous anti-inflammatory cytokine IL-1 receptor antagonist (IL-1ra), respectively.6 IL-1ra binds to IL-1β receptors without inducing signal transduction, thereby acting as an antagonist to IL-1β.7 The IL-1RN gene contains a variable number of tandem repeats (VNTR) of 86 bp polymorphism in intron2 (rs2234663), generating a short allele with two repeats (IL-1RN VNTR*2) and long alleles with three to six repeats (IL-1RN VNTR*L), respectively.8 The relationship of these alleles (especially carriage of allele 2) with periodontitis has not been as extensively reviewed as the “composite genotype (IL-1A −889 and IL-1B +3954)”,9, 10 although a number of reports suggest a complex allele-dependent regulating effect of this gene on IL-1 production.11, 12

To date, many association studies have shown conflicting results of the relationship between IL-1RN VNTR polymorphism and susceptibility to CP and AgP. Under the hypothesis that the IL-1RN VNTR polymorphism may have a causal association with periodontitis, we performed a meta-analysis on all eligible studies to estimate the overall periodontitis risk and to quantify the potential between-study heterogeneity.

Section snippets

Search strategy

We performed a systematic search of studies that addressing the association between IL-1RN VNTR polymorphism and periodontitis. The literature was searched in electronic bio-medical databases including the Medline, PubMed (US National Library of Medicine), Embase, Google Scholar and CNKI (the last search update was 9 January 2012). A combination of the terms “interleukin-1 receptor antagonist”, “IL-1RN”, “VNTR”, “periodontal disease”, “periodontitis”, “polymorphism” were entered both as Medical

Eligible studies

After a careful screening of the published literature (Fig. 1), a total of 19 eligible case–control studies involving 2011 cases and 1719 controls were identified in the meta-analysis. Basic characteristics of selected studies are summarized in Table 1. Among them, six studies written in Chinese were retrieved and translated into English,17, 18, 19, 20, 21 one of which conducted by Yang in 2007 was an unpublished doctoral dissertation. Eight studies reported data on severe CP cases.17, 18, 19,

Discussion

The current meta-analysis of 19 studies is the first quantitative evaluation of the potential association of IL-1RN gene polymorphism with susceptibility to either CP or AgP. In 2008, a meta-analysis by Nikolopoulos et al. found that IL-1A −889C/T and IL-1B +3954C/T polymorphisms were both associated with increased CP risk.35 Although it would be desirable to examine the risk of periodontitis associated with a limited number of haplotypes for these polymorphisms, unfortunately, such data are

Funding

This study was supported by grants from the National Natural Science Foundation of China (Grant No. 81170962), Projects of Science and Technology Department of Jiangsu Province (Grant Nos. BK2011763 and BK2008363) and Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (Grant No. PAPD 2011-2013).

Competing interests

The authors declare that they have no conflicts of interests.

Ethical approval

Not required.

Acknowledgements

The authors thank Dr. Meilin Wang (Department of Molecular and Genetic Toxicology, School of Public Health, Nanjing Medical University, Nanjing) for his valuable help during the statistical analysis.

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