Association between TNFα - 308 G/A polymorphism and oral lichen planus (OLP): a meta-analysis

Abstract Objectives To determine whether Tumor Necrosis Factor alpha (TNFα) –308 G/A polymorphism is associated with oral lichen planus (OLP). Material and Methods A systematic electronic search of the literature was conducted to identify all published studies on the association between TNFα –308 G/A polymorphism and OLP. All case-control studies evaluating the TNFα –308 G/A polymorphisms in OLP were selected. A meta-analysis of the studies that fulfilled the inclusion criteria was performed. Odds ratios (OR) with 95% confidence intervals (CI) were also calculated. Results Seven studies comprising 450 OLP cases and 867 controls were included in the meta-analysis. In the pooled analysis, TNFα –308 G/A polymorphism was associated with OLP with random effects and OR of 2.33 (95%CI=1.07-5.11; p=0.03), assuming a dominant mode of inheritance (AA+GA vs. GG). In the subgroup analysis by ethnicity, TNFα –308 G/A was associated with a significantly increased odds ratio of OLP in mixed ethnicity (OR=5.22; 95%CI=1.93-14.15; p=0.001), but not in Asians (OR=1.57; 95%CI=0.54-4.54; p=0.41) or Caucasians (OR=1.45; 95%CI=0.19-11.22; p=0.72). For subgroup analysis based on HCV (hepatitis C virus) infection status, significant increased risk of OLP was found among patients with mixed HCV infection status (OR=3.77; 95%CI=1.07-13.2; p=0.038), but not in patients without HCV infection (OR=2.09; 95%CI=0.63-6.91; p=0.22) and patients with HCV infection (OR=0.48; 95%CI=0.13-1.69; p=0.25). Conclusion Our results suggest that –308 G/A polymorphism in TNFα is a potential genetic marker for OLP.

However, the etiopathogenesis of OLP is still unclear.
Cytokines play an important role in the pathogenesis of OLP, and a bulk of evidence suggests that OLP is a T-cell-mediated disease 12,16 . TNFα is a potent immunomodulator and proinflammatory cytokine that has been found to play roles in the pathogenesis of multiple inflammatory or autoimmune diseases 2 .
A higher level of TNFα has been found in serum from OLP patients compared to controls 15 . The subepithelial T cells of OLP contain TNFα mRNA and express TNFα cytokine 6,17 . TNFα production may be partially determined at the genetic level.
The TNFα gene is a member of the TNF superfamily located on chromosome 6q21, within the major histocompatibility complex (MHC) class III region 3 .
Several polymorphisms and mutations have been identified within TNFα, among which a genetic variation at position −308 of the TNFα gene that results in two allelic forms, including a guanine (G) that represents the common variant and an adenine (A) that defines the less common one. G/A polymorphism at position −308 of the TNFα gene promoter is reported to increase TNFα transcription and produce higher levels of this cytokine 11,18 . The possible association between TNFα −308 (rs1800629) G/A polymorphism and OLP has been studied by several investigators 1,2,5-7,10,19 .
However, the results have been inconclusive or even contradictory. Differences in ethnicity, lack of statistical power, and involvement of HCV infections are potential factors underlying the discrepant results of these studies. Meta-analysis is a widely used tool to overcome the problem of the small sample sizes and inadequate statistical power of genetic studies of complex traits 13 . Jin, et al. 9 (2012) conducted a metaanalysis on TNFα −308 G/A polymorphism and lichen planus and did not find significant association between them. The studies available at that time were limited.
Herein, we conducted a meta-analysis to assess the association between genetic variants of TNFα −308 G/A polymorphism and risk of OLP with the most updated literature on this association.

Material and methods
Study selection and data extraction A comprehensive literature search was conducted on Medline, PubMed, Embase, and Science Citation Index for all articles that were published by April 17, 2017 on the association between TNFα −308 G/A polymorphism and OLP risk. The search terms were used as follows: ("oral lichen planus" or "OLP") and ("tumor necrosis factor" or "TNF" or "tumor necrosis factor-α" or "TNF-α" or "TNF-α" or "tumor necrosis factor-a") and ("Polymorphism" or "mutation" or "variant"). Selection criteria of an eligible study were:

Subgroup analysis
The prevalence of OLP varies among different ethnic populations mainly due to variations in genetic background. Therefore, to determine whether the effects were due to ethnic differences, subgroup analysis by ethnicity was performed. As for ethnicity subgroup, our meta-analysis revealed that TNFα −308 G/A was associated with a significantly increased risk

Sensitivity analysis and publication bias
In addition, sensitivity analysis was performed by removing one data set at a time. Statistically excluding any individual study did not resolve the genetic heterogeneity. The pooled OR was recalculated in the absence of each study, and OR was not significantly changed ( Figure 7 and Table 2).
The shape of the funnel plots did not reveal any evidence of obvious asymmetry (Figure 8), suggesting that there was no obvious publication bias. Egger's test showed no significant publication bias in this metaanalysis (t=0.65, p=0.54 for AA+AG vs. GG).

Figure 4-Forest plot of oral lichen planus (OLP) risk associated with TNF-α-308 G/A stratified by hepatitis C virus (HCV) infection status.
For each study, the estimate of OR and its 95%CI is plotted with a box and a horizontal line     Despite those limitations listed aforementioned, our meta-analysis also has its advantages. First, it contains the latest data on the association between TNFα −308 G/A polymorphism and OLP risk. Also, to our knowledge, it is the first meta-analysis that investigated the association between TNFα −308 G/A polymorphism and oral lichen planus risk.
ZHOU Y, VIEIRA AR