It is widely accepted that cytokines and oral pathogens play central roles in the inflammatory process associated with the etiology of periodontitis (Taylor et al., 2004
; Wu et al., 2007
; He and Shi, 2009
). As a pleiotropic cytokine, IL-6 is induced in response to several inflammatory stimuli (Terry et al., 2000
). IL-6 also regulates the expression of cytokines such as IL-1, IL-10, and tumor necrosis factor-α (Opal and DePalo, 2000
; Woods et al., 2000
). IL-6 is present in endothelial cells, fibroblasts, and macrophages in periodontitis patients, but is absent from these cells in healthy individuals (Takahashi et al., 1994
). Clinical studies indicate that IL-6 plays a crucial role in the inflammatory response to Gram-negative bacteria (Dalrymple et al., 1996
) by affecting the composition of the subgingival microbiota and increasing the susceptibility to colonization with periodontopathogenic bacteria (Cooke and Hill, 2001
; Ishihara et al., 1997
; Coats et al., 2009
). IL-6 is also a potent stimulator of osteoclast differentiation and bone resorption (Gemmell et al., 1997
; Hughes et al., 2006
), which are typical of periodontitis. The intensity of IL-6 expression is positively correlated with attachment loss (Moreira et al., 2007
) and IL-6 is associated with continuous tissue destruction in periodontitis (McCauley and Nohutcu, 2002
). Furthermore, levels of IL-6 are elevated in periodontitis patients (Loos, 2005
; Loos et al., 2000
) and decreased after successful periodontal therapy (D′Aiuto et al., 2004a
). Thus, the available evidence indicates that IL-6 is involved in the pathogenesis of periodontitis.
Because of the notion that genetic factors may predispose to periodontitis, several studies had been conducted to determine whether IL-6 gene polymorphisms predispose to periodontitis. However, the results of studies on the associations between these polymorphisms and clinical forms of periodontitis are contradictory. By and large, our meta-analysis showed that carriers of the −174 G allele had an increased risk of developing periodontitis. And specifically, the IL-6 −174 G allele could not modify the risk of CP, but increased the risk of AP. Furthermore, compared with −572 C allele carriers (genotypes GC and CC), individuals carrying the GG genotype had a significantly higher risk of CP. These findings suggest that common polymorphisms in the IL-6 promoter region modify the risk of periodontitis.
A recent study also reviewed the association between the IL-6 −174 G/C polymorphism and periodontitis (Nikolopoulos et al., 2008
). It is difficult to compare their results directly with ours for three reasons. First, the previous review focused on the pathogenesis of CP, whereas we paid more attention to whether common IL-6 polymorphisms increase the risk of aggressive or chronic types of periodontitis. Second, our review is the more comprehensive one of the two, as we identified 6 studies on the association between IL-6 polymorphisms and periodontitis compared with four studies in the other report. Finally, our study is the first to summarize the association between the IL-6 −572 C/G polymorphism and periodontitis.
After the initial meta-analysis of the −174 G/C polymorphism and CP, a case-control study (Nibali et al., 2009
) involving 271 CP patients and 144 controls was published and was included in a subsequent analysis. There was no significant association between this polymorphism and CP, which is in accordance with the results of the previous analysis (Nikolopoulos et al., 2008
). Notably, in the study Caucasian Brazilians genotype GG was statistically associated with susceptibility to severe form of CP (Trevilatto et al., 2003
). The result reminds us that the association of IL-6 −174 G/C polymorphism with severe form of CP should be paid more attention to in subsequent investigations. Moreover and interestingly, one association study performed by Nibali et al.(2008b
), which involved 224 AP patients and 231 controls, revealed that the −174 G allele is statistically significantly associated with an increased risk of AP. Although the sample size was not large enough, the results nevertheless indicated that the IL-6 −174 G allele is associated with susceptibility to AP. Compared with the −174 C allele, the −174 G allele significantly increased the expression of IL-6 (Fishman et al., 1998
), which explains the positive relationship between the −174 G/C polymorphism and AP. Furthermore, Nibali et al.(2008c
) revealed that the IL-6 −174 GG genotype is associated with an increased OR of concomitant detection of Aggregatibacter actinomycetemcomitans
and Porphyromonas gingivalis
. These results imply that the IL-6 −174 G/C polymorphism cause periodontitis by altering immune competence.
The IL-6 −572 C/G polymorphism has also been studied in the context of susceptibility to periodontitis (Holla et al., 2004
; Komatsu et al., 2005
; Nibali et al., 2009
). When we pooled data from previous studies, there was no remarkable difference in allelic frequency distribution between CP cases and controls. However, compared with C allele carriers (genotypes GC and CC), the GG genotype significantly increased the risk of CP, suggesting that the −572 G allele is associated with the pathogenesis of CP under the recessive genetic model. A meta-analysis of the association between the −572 C/G polymorphism and AP was not conducted because only one relevant study was detected (Nibali et al., 2008b
). According to genotyping data (Nibali et al., 2008b
), the −572 G allele significantly increased the risk of developing AP compared with the −572 C allele (OR: 1.79, 95% CI: 1.18~2.72, P
=0.006). Therefore, on the basis of the aforementioned evidence, we concluded that the −572 C/G polymorphism is associated with the pathogenesis of periodontitis, as it predisposes to either CP or AP. However, as one study has shown that the −572 G polymorphism reduces the transcriptional activity of the IL-6 promoter (Gu et al., 2008
), the mechanism of this polymorphism predisposed to periodontitis seems too complicated. Herein, functional investigations on the association of IL-6 −572 C/G polymorphism with periodontitis are warranted. Besides the well-discussed IL-6 −174 G/C and −572 C/G polymorphisms, the −6331 T/C polymorphism in the promoter region of the gene could also alter the transcriptional activity of IL-6 (Smith et al., 2008
). Actually, the IL-6 −6331 T/C polymorphism is in complete linkage disequilibrium with the −6106 A/T polymorphism. Nibali et al.(2009
) recently reported that −6106 TT increased the risk of localized AP in Caucasian population. Therefore, we could conclude that IL-6 −6331 T/C polymorphism is involved in the pathogenesis of periodontitis among Caucasians. However, the association of IL-6 −6331 T/C polymorphism with risk of periodontitis requires to be confirmed in other ethnics.
The power of mapping and characterization analyses of disease-causing genes is significantly increased when association studies are based on haplotypes instead of genotypes (Akey et al., 2001
). Holla et al.(2004
) and Nibali et al.(2009
) hypothesized that IL-6 haplotypes confer susceptibility to periodontitis. As a result, some haplotypes of IL-6 gene were discovered to be associated with the risk of developing periodontitis. However, it is difficult to determine the role of a particular haplotype in disease susceptibility using meta-analysis.
In conclusion, our meta-analysis indicates that the IL-6 −174 G allele could not modify the risk of CP, but increased the risk of AP. And −572 C/G polymorphism is associated with the pathogenesis of periodontitis, as it predisposes to either CP or AP. The association of IL-6 −174 G/C polymorphism with severe form of CP should be paid more attention to in future investigations.