Review Article| Volume 47, ISSUE 7, P1061-1069, July 2021

Download started.


Tumor Necrosis Factor Alpha −308 G/A Single-Nucleotide Polymorphism and Apical Periodontitis: An Updated Systematic Review and Meta-analysis

Published:March 25, 2021DOI:



      This study aimed to perform a more precise estimation of the association between tumor necrosis factor alpha (TNF-α) −308 G/A single-nucleotide polymorphism (SNP) and the risk of development of apical periodontitis (AP) and its phenotypes based on all available published studies.


      The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and is registered in PROSPERO (CRD42020176190). The literature search was conducted via Clarivate Analytics Web of Science, Scopus, PubMed, Cochrane Central Register of Controlled Trials, and China National Knowledge Infrastructure databases from inception to December 2020 with no language restrictions. Two reviewers were involved independently in the study selection, data extraction, and appraising the studies that were included. The quality of the included studies was evaluated using the Strengthening the Reporting of Genetic Association and the Grading of Recommendations Assessment, Development and Evaluation system. The frequencies of the genotypes and alleles of the TNF-α (G>A 308, rs1800629) gene with 95% odds ratio were used.


      Four studies met the inclusion criteria with moderate risk of bias. This study revealed no significant association between TNF-α −308 G/A SNP and AP and the risk of AP development. Moreover, there was no significant association between genotype or allele frequency distribution and clinical manifestations (acute vs chronic) of AP. The certainty of evidence per the Grading of Recommendations Assessment, Development and Evaluation system was very low.


      Because of very low certainty of evidence, whether there is an association between TNF-α −308 G/A SNP and AP warrants further well-designed multicentric studies to adjudicate a better understanding of the role of genetic factors in the etiopathogenesis of AP.

      Key Words:

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Endodontics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Sasaki H.
        • Stashenko P.
        • Franklin R.T.
        • et al.
        Interrelationship of the pulp and apical periodontitis. Hargreaves KM, Goodis HE, Tay F. (editors).
        in: Seltzer and Bender's Dental Pulp. Quintessence Publishing, Chicago2012: 277-299
        • Braz-Silva P.H.
        • Bergamini M.L.
        • Mardegan A.P.
        • et al.
        Inflammatory profile of chronic apical periodontitis: a literature review.
        Acta Odontol Scand. 2019; 77: 173-180
        • Fouad A.F.
        • Franklin R.T.
        • Seltzer S.
        • et al.
        Molecular mediators of pulpal inflammation. Hargreaves KM, Goodis HE, Tay F. (editors).
        in: Seltzer and Bender's Dental Pulp. Quintessence Publishing, Chicago2012: 241-275
        • Eigler A.
        • Sinha B.
        • Hartmann G.
        • Endres S.
        Taming TNF: strategies to restrain this proinflammatory cytokine.
        Immunol Today. 1997; 18: 487-492
        • Boyce B.F.
        • Li P.
        • Yao Z.
        • et al.
        TNF-alpha and pathologic bone resorption.
        Keio J Med. 2005; 54: 127-131
        • Safavi K.E.
        • Rossomando E.F.
        Tumor necrosis factor identified in periapical tissue exudates of teeth with apical periodontitis.
        J Endod. 1991; 17: 12-14
        • Sariban E.
        • Imamura K.
        • Luebbers R.
        • Kufe D.
        Transcriptional and posttranscriptional regulation of tumor necrosis factor gene expression in human monocytes.
        J Clin Invest. 1988; 81: 1506-1510
        • Wilson A.G.
        • di Giovine F.S.
        • Blakemore A.I.
        • Duff G.W.
        Single base polymorphism in the human tumour necrosis factor alpha (TNF alpha) gene detectable by NcoI restriction of PCR product.
        Hum Mol Genet. 1992; 1: 353
        • Carroll M.C.
        • Katzman P.
        • Alicot E.M.
        • et al.
        Linkage map of the human major histocompatibility complex including the tumor necrosis factor genes.
        Proc Natl Acad Sci U S A. 1987; 84: 8535-8539
        • Louis E.
        • Franchimont D.
        • Piron A.
        • et al.
        Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans.
        Clin Exp Immunol. 1998; 113: 401-406
        • Chen F.-C.
        • Zhang F.
        • Zhang Z.-J.
        • et al.
        Tumor necrosis factor-α gene polymorphisms and risk of oral cancer: evidence from a meta-analysis.
        Asian Pac J Cancer Prev. 2013; 14: 7243-7249
        • Zhou Y.
        • Vieira A.R.
        Association between TNFα - 308 G/A polymorphism and oral lichen planus (OLP): a meta-analysis.
        J Appl Oral Sci. 2018; 26: e20170184
        • Ding C.
        • Ji X.
        • Chen X.
        • et al.
        TNF-α gene promoter polymorphisms contribute to periodontitis susceptibility: evidence from 46 studies.
        J Clin Periodontol. 2014; 41: 748-759
        • Mo Y.-Y.
        • Zeng X.-T.
        • Weng H.
        • et al.
        Association between tumor necrosis factor-alpha G-308A polymorphism and dental peri-implant disease risk: a meta-analysis.
        Medicine (Baltimore). 2016; 95: e4425
        • Fouad A.F.
        • Khan A.A.
        • Silva R.M.
        • Kang M.K.
        Genetic and epigenetic characterization of pulpal and periapical inflammation.
        Front Physiol. 2020; 11: 21
        • Salles A.G.
        • Antunes L.A.
        • Carvalho P.A.
        • et al.
        Association between apical periodontitis and TNF-α – 308 G>A gene polymorphism: a systematic review and meta-analysis.
        Braz Dent J. 2017; 28: 535-542
        • Dill A.
        • Letra A.
        • Chaves de Souza L.
        • et al.
        Analysis of multiple cytokine polymorphisms in individuals with untreated deep carious lesions reveals IL1B (rs1143643) as a susceptibility factor for periapical lesion development.
        J Endod. 2015; 41: 197-200
        • Jakovljevic A.
        • Nikolic N.
        • Carkic J.
        • et al.
        Association of polymorphisms in TNF-α, IL-1β, GSTM and GSTT genes with apical periodontitis: is there a link with herpesviral infection?.
        Int Endod J. 2020; 53: 895-904
        • Moher D.
        • Shamseer L.
        • Clarke M.
        • et al.
        Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
        Syst Rev. 2015; 4: 1
        • Shamseer L.
        • Moher D.
        • Clarke M.
        • et al.
        Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation.
        BMJ. 2015; 349: g7647
      1. Higgins J.P. Thomas J. Chandler J. Cochrane Handbook for Systematic Reviews of Interventions. John Wiley & Sons, Chichester, UK2019
        • Nibali L.
        Suggested guidelines for systematic reviews of periodontal genetic association studies.
        J Clin Periodontol. 2013; 40: 753-756
        • Clark M.F.
        • Baudouin S.V.
        A systematic review of the quality of genetic association studies in human sepsis.
        Intensive Care Med. 2006; 32: 1706-1712
        • Aminoshariae A.
        • Kulild J.C.
        Association of functional gene polymorphism with apical periodontitis.
        J Endod. 2015; 41: 999-1007
        • Little J.
        • Higgins J.P.
        • Ioannidis J.P.
        • et al.
        Strengthening the reporting of genetic association studies (STREGA): an extension of the strengthening the reporting of observational studies in epidemiology (STROBE) statement.
        J Clin Epidemiol. 2009; 62: 597-608.e4
        • von Elm E.
        • Altman D.G.
        • Egger M.
        • et al.
        The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
        J Clin Epidemiol. 2008; 61: 344-349
        • Guyatt G.H.
        • Oxman A.D.
        • Vist G.E.
        • et al.
        GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
        BMJ. 2008; 336: 924-926
        • de Sá A.R.
        • Moreira P.R.
        • Xavier G.M.
        • et al.
        Association of CD14, IL1B, IL6, IL10 and TNFA functional gene polymorphisms with symptomatic dental abscesses.
        Int Endod J. 2007; 40: 563-572
        • Amaya M.P.
        • Criado L.
        • Blanco B.
        • et al.
        Polymorphisms of pro-inflammatory cytokine genes and the risk for acute suppurative or chronic nonsuppurative apical periodontitis in a Colombian population.
        Int Endod J. 2013; 46: 71-78
        • Kawashima N.
        • Suzuki N.
        • Yang G.
        • et al.
        Kinetics of RANKL, RANK and OPG expressions in experimentally induced rat periapical lesions.
        Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007; 103: 707-711
        • Siqueira J.F.
        • Rôças I.N.
        • Provenzano J.C.
        • et al.
        Relationship between Fcgamma receptor and interleukin-1 gene polymorphisms and post-treatment apical periodontitis.
        J Endod. 2009; 35: 1186-1192
        • Salazar-Pelaéz L.M.
        • Grisales R.O.
        • Yepes O.E.
        • et al.
        Genetic polymorphisms of interleukin-1 and the risk of chronic periapical periodontitis in a population in Antioquia, Colombia.
        Arch Oral Res. 2012; 8: 19-30
        • Salles A.G.
        • Antunes L.A.
        • Küchler E.C.
        • Antunes L.S.
        Association between apical periodontitis and interleukin gene polymorphisms: a systematic review and meta-analysis.
        J Endod. 2018; 44: 355-362
        • Ilic B.
        • Nikolic N.
        • Andric M.
        • et al.
        TNF-α (-308G>A) and TNF-R1 (36A>G) single nucleotide polymorphisms are strong risk factors for odontogenic keratocystic tumor development.
        J Oral Pathol Med. 2017; 46: 292-296
        • Li Y.
        • Yang J.
        • Wu X.
        • Sun W.
        TNF-α polymorphisms might influence predisposition to periodontitis: a meta-analysis.
        Microb Pathog. 2020; 143: 104113
        • Nikolopoulos G.K.
        • Dimou N.L.
        • Hamodrakas S.J.
        • Bagos P.G.
        Cytokine gene polymorphisms in periodontal disease: a meta-analysis of 53 studies including 4178 cases and 4590 controls.
        J Clin Periodontol. 2008; 35: 754-767
        • Wei X.-M.
        • Chen Y.-J.
        • Wu L.
        • et al.
        Tumor necrosis factor-α G-308A (rs1800629) polymorphism and aggressive periodontitis susceptibility: a meta-analysis of 16 case-control studies.
        Sci Rep. 2016; 6: 19099