Current trends of genetics in apical periodontitis research

Küchler, Erika Calvano; Mazzi-Chaves, Jardel Francisco; Antunes, Leonardo Santos; Kirschneck, Christian; Baratto-Filho, Flares; Sousa-Neto, Manoel Damião

doi:10.1590/1807-3107bor-2018.vol32.0072

Erika Calvano Küchler

Universidade de São Paulo, School of Dentistry of Ribeirão Preto, Department of Pediatric Dentistry, Ribeirão Preto, SP, Brazil

Jardel Francisco Mazzi-Chaves

Universidade de São Paulo, School of Dentistry of Ribeirão Preto, Department of Restorative Dentistry, Ribeirão Preto, SP, Brazil

Leonardo Santos Antunes

Universidade Federal Fluminense, School of Dentistry of Nova Friburgo, Nova Friburgo, RJ, Brazil

Christian Kirschneck

University Medical Centre of Regensburg, Department of Orthodontics, Regensburg, Germany

Flares Baratto-Filho Corresponding Author: Flares Baratto-Filho, E-mail: fbaratto1@gmail.com

Universidade Positivo, School of Health and Biological Sciences, Curitiba, PR, Brazil

Manoel Damião Sousa-Neto

Universidade de São Paulo, School of Dentistry of Ribeirão Preto, Department of Restorative Dentistry, Ribeirão Preto, SP, Brazil

Corresponding Author: Flares Baratto-Filho, E-mail: fbaratto1@gmail.com

Declaration of Interests: The authors certify that they have no commercial or associative interest that represents a conflict of interest in connection with the manuscript.

Search 1: Studies with animal models
PubMed	#1 (Periapical Periodontitis [MeSH Terms]) OR Periapical Periodontitis [Title/Abstract]) OR Periapical Abscess [MeSH Terms]) OR Periapical Abscess [Title/Abstract]) OR Apical Periodontitis [Title/Abstract]
	#2 (knockout[Title/Abstract])
	#1 and #2
WOS	#1 TOPIC: (“Periapical Periodontitis”) OR TOPIC: (“Periapical Abscess”) OR TOPIC: (“Apical Periodontitis”) Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years
	#2 TOPIC: (knockout) Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years
	#1 and #2
Scopus	#1 (TITLE-ABS-KEY (“Periapical Periodontitis”) OR TITLE-ABS-KEY (“Periapical Abscess”) OR TITLE-ABS-KEY (“Apical Periodontitis”))
	#2 TITLE-ABS-KEY (knockout)
	#1 and #2
Search 2: Genetic polymorphism studies in humans
PubMed	#1 (Periapical Periodontitis [MeSH Terms]) OR Periapical Periodontitis [Title/Abstract]) OR Periapical Abscess [MeSH Terms]) OR Periapical Abscess [Title/Abstract]) OR Apical Periodontitis [Title/Abstract]
	#2 (Polymorphism, Genetic [MeSH Terms]) OR Polymorphism, Genetic [Title/Abstract]) OR Polymorphism, Single Nucleotide [MeSH Terms]) OR Polymorphism, Single Nucleotide [Title/Abstract]
	#1 and #2
WOS	#1 TOPIC: (“Periapical Periodontitis”) OR TOPIC: (“Periapical Abscess”) OR TOPIC: (“Apical Periodontitis”) Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years
	#2 TOPIC: (“Genetic Polymorphism”) OR TOPIC: (“Single Nucleotide Polymorphism”) Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, ESCI Timespan=All years
	#1 and #2
Scopus	#1 (TITLE-ABS-KEY (“Periapical Periodontitis”) OR TITLE-ABS-KEY (“Periapical Abscess”) OR TITLE-ABS-KEY (“Apical Periodontitis”)
	#2 (TITLE-ABS-KEY (“Genetic Polymorphism”) OR TITLE-ABS-KEY (“Single Nucleotide Polymorphism”)
	#1 and #2

Gene official full name	Nomenclature	References	Gene/protein Function^* * http://www.genecards.org/cgi-bin/carddisp.pl. Only the genes resulting in less or more severe AP are presented here.
Cannabinoid Receptor 2	CB2	Nikolaeva et al. (2015)³³33. Nikolaeva EP, Cox TC, Flake NM. Osseous characteristics of mice lacking cannabinoid receptor 2 after pulp exposure. J Endod. 2015 Jun;41(6):853-7. https://doi.org/10.1016/j.joen.2015.01.030 https://doi.org/10.1016/j.joen.2015.01.0...	The cannabinoid receptors are members of family 1 of the G-protein-coupled receptors and are located in immune cells.
Nitric Oxide Synthase	iNOS	Silva et al. (2011)⁹9. Silva MJ, Sousa LM, Lara VP, Cardoso FP, Carmo Júnior GM, Totola AH, et al. The role of iNOS and PHOX in periapical bone resorption. J Dent Res. 2011 Apr;90(4):495-500. https://doi.org/10.1177/0022034510391792 https://doi.org/10.1177/0022034510391792...	The protein encoded by this gene belongs to the family of nitric oxide synthases, which synthesize nitric oxide. Nitric oxide is a reactive free radical that acts as a biologic mediator in several processes, including antimicrobial activities.
Interleukin 6	IL6	Huang et al. (2001)⁷7. Huang GT, Do M, Wingard M, Park JS, Chugal N. Effect of interleukin-6 deficiency on the formation of periapical lesions after pulp exposure in mice. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001 Jul;92(1):83-8. https://doi.org/10.1067/moe.2001.115025 https://doi.org/10.1067/moe.2001.115025...	This gene encodes a cytokine that functions in inflammation and in the maturation of B cells.
Interleukin 22	IL22	Oliveira et al. (2015)¹⁴14. Oliveira KM, Silva RA, De Rossi A, Fukada SY, Feres M, Nelson-Filho P et al. Absence of interleukin 22 affects the oral microbiota and the progression of induced periapical lesions in murine teeth. Int Endod J. 2015 Jan;48(1):46-59. https://doi.org/10.1111/iej.12274 https://doi.org/10.1111/iej.12274...	This gene encodes a cytokine that contributes to the inflammatory response. is a α-helical cytokine that binds to a heterodimeric cell surface receptor composed of IL-10R2 and IL-22R1 subunits.
Interleukin 17 Receptor A	IL17RA	AlShwaimi et al. (2013)¹¹11. AlShwaimi E, Berggreen E, Furusho H, Rossall JC, Dobeck J, Yoganathan S et al. IL-17 receptor A signaling is protective in infection-stimulated periapical bone destruction. J Immunol. 2013 Aug;191(4):1785-91. https://doi.org/10.4049/jimmunol.1202194 https://doi.org/10.4049/jimmunol.1202194...	is a proinflammatory cytokine secreted by activated T-lymphocytes. It is a potent inducer of the maturation of CD34-positive hematopoietic precursors into neutrophils.
Matrix Metalloproteinase 9	MMP9	Wan et al. (2014)¹³13. Wan C, Yuan G, Yang J, Sun Q, Zhang L, Zhang J et al. MMP9 deficiency increased the size of experimentally induced apical periodontitis. J Endod. 2014 May;40(5):658-64. https://doi.org/10.1016/j.joen.2014.01.003 https://doi.org/10.1016/j.joen.2014.01.0...	is a protein-coding gene that plays an essential role in local proteolysis of the extracellular matrix, in leukocyte migration and in bone osteoclastic resorption.
Myeloid Differentiation Primary Response 88	MyD88	Silva et al. (2014)¹²12. Silva RAB, Nelson-Filho P, Lucisano MP, De Rossi A, Queiroz AM, Silva LAB. MyD88 knockout mice develop initial enlarged periapical lesions with increased numbers of neutrophils. Int Endod J. 2014 Jul;47(7):675-86. https://doi.org/10.1111/iej.12204 https://doi.org/10.1111/iej.12204...	This gene encodes a cytosolic adapter protein, which has a central role in the innate and adaptive immune response. acts as an essential signal transducer in the interleukin-1 and signaling pathways.
Osteopontin	OPN	Rittling et al. (2010)⁸8. Rittling SR, Zetterberg C, Yagiz K, Skinner S, Suzuki N, Fujimura A, et al. Protective role of osteopontin in endodontic infection. Immunology. 2010 Jan;129(1):105-14. https://doi.org/10.1111/j.1365-2567.2009.03159.x https://doi.org/10.1111/j.1365-2567.2009...	Osteopontin is an extracellular structural protein and an organic component of bone. It is involved in the regulation of immune responses and enhancement of leucocyte migration
Toll Like Receptor 2	TLR2	Silva et al. (2012);¹⁰10. Silva RA, Ferreira PD, De Rossi A, Nelson-Filho P, Silva LA. Toll-like receptor 2 knockout mice showed increased periapical lesion size and osteoclast number. J Endod. 2012 Jun;38(6):803-13. https://doi.org/10.1016/j.joen.2012.03.017 https://doi.org/10.1016/j.joen.2012.03.0... Oliveira et al. (2015);¹⁴14. Oliveira KM, Silva RA, De Rossi A, Fukada SY, Feres M, Nelson-Filho P et al. Absence of interleukin 22 affects the oral microbiota and the progression of induced periapical lesions in murine teeth. Int Endod J. 2015 Jan;48(1):46-59. https://doi.org/10.1111/iej.12274 https://doi.org/10.1111/iej.12274... Rider et al. (2016);¹⁵15. Rider D, Furusho H, Xu S, Trachtenberg AJ, Kuo WP, Hirai K et al. Elevated CD14 (Cluster of Differentiation 14) and Toll-Like Receptor (TLR) 4 Signaling Deteriorate Periapical Inflammation in TLR2 Deficient Mice. Anat Rec (Hoboken). 2016 Sep;299(9):1281-92. https://doi.org/10.1002/ar.23383 https://doi.org/10.1002/ar.23383... Barreiros et al. (2018)	TLR2 and TLR4 are protein coding for genes that play a fundamental role in pathogen recognition and activation of innate immunity. They are single, membrane-spanning, non-catalytic receptors usually expressed on sentinel cells, such as macrophages and dendritic cells, which recognize structurally conserved molecules derived from microorganisms.
Toll Like Receptor 4	TLR4	Rider et al. (2016)¹⁵15. Rider D, Furusho H, Xu S, Trachtenberg AJ, Kuo WP, Hirai K et al. Elevated CD14 (Cluster of Differentiation 14) and Toll-Like Receptor (TLR) 4 Signaling Deteriorate Periapical Inflammation in TLR2 Deficient Mice. Anat Rec (Hoboken). 2016 Sep;299(9):1281-92. https://doi.org/10.1002/ar.23383 https://doi.org/10.1002/ar.23383...

Authors/year	Study design	Genes/Polymorphisms	Results
Sá et al. (2007)¹⁶16. Sá AR, Moreira PR, Xavier GM, Sampaio I, Kalapothakis E, Dutra WO et al. Association of CD14, IL1B, IL6, IL10 and TNFA functional gene polymorphisms with symptomatic dental abscesses. Int Endod J. 2007;40(7):563-72. https://doi.org/10.1111/j.1365-2591.2007.01272.x https://doi.org/10.1111/j.1365-2591.2007...	45 cases of symptomatic dental abscesses and 53 cases of asymptomatic inflammatory AP without previous exacerbation	CD14 (-260 C/T, rs2569190)	Genotype and allele distribution for the genetic polymorphism in IL6 was associated with symptomatic dental abscesses.
		IL1B (+3954 C/T, rs1143634)
		IL6 (-174 G/C, rs1800795)
		IL10 (-1082 G/A, rs1800896)
		TNFA (-308 G/A, rs1800629)
Siqueira Junior et al. (2009)¹⁷17. Siqueira JF Jr, Rôças IN, Provenzano JC, Daibert FK, Silva MG, Lima KC. Relationship between Fcgamma receptor and interleukin-1 gene polymorphisms and post-treatment apical periodontitis. J Endod. 2009 Sep;35(9):1186-92. https://doi.org/10.1016/j.joen.2009.05.006 https://doi.org/10.1016/j.joen.2009.05.0...	18 cases with PAP and 44 cases with root-canal-treated teeth exhibiting healthy/healing periradicular tissues	FcgRIIA (R131 or H131, rs1801274)	There was a statistical association observed for the genetic polymorphism in the FcγRIIIb gene (p<0.001).
		FCgRIIIB (NA1 or NA2, rs1050501)
		IL1A (–889, rs1800587)
		IL1B (+3954, rs1143634)
Morsani et al. (2011)¹⁸18. Morsani JM, Aminoshariae A, Han YW, Montagnese TA, Mickel A. Genetic predisposition to persistent apical periodontitis. J Endod. 2011 Apr;37(4):455-9. https://doi.org/10.1016/j.joen.2011.01.009 https://doi.org/10.1016/j.joen.2011.01.0...	34 cases with signs/symptoms of AP and 61 controls showing healing periradicular tissues	IL1B (+3954, rs1143634)	There was an association between the genetic polymorphisms and AP (p<0.001).
Siqueira Junior et al. (2011)¹⁹19. Siqueira Junior JF, Rôças IN, Provenzano JC, Guilherme BP. Polymorphism of the FcγRIIIa gene and post-treatment apical periodontitis. J Endod. 2011 Oct;37(10):1345-8. https://doi.org/10.1016/j.joen.2011.06.025 https://doi.org/10.1016/j.joen.2011.06.0...	26 cases with PAP and 43 cases with root-canal-treated teeth exhibiting healthy/healing periradicular tissues	FcgRIIIA (V/F158, rs396991)	The genetic polymorphism in FcγRIIIa was not associated with AP.
Menezes-Silva et al. (2012)²⁰20. Menezes-Silva R, Khaliq S, Deeley K, Letra A, Vieira AR. Genetic susceptibility to periapical disease: conditional contribution of MMP2 and MMP3 genes to the development of periapical lesions and healing response. J Endod. 2012 May;38(5):604-7. https://doi.org/10.1016/j.joen.2012.02.009 https://doi.org/10.1016/j.joen.2012.02.0...	158 cases with deep carious lesions but no periapical lesions, and 110 cases with periapical lesions and deep carious lesions	MMP2 (rs243865, rs2285053, rs243847, rs2287074, rs9923304, rs11639960)	The genetic polymorphisms rs639752 (p=0.03) and rs679620 (p=0.004) in MMP3 were associated with AP. An altered transmission of MMP2 haplotypes (p=0.000004) was observed.
		MMP3 (rs639752, rs650108, rs679620, rs522616)
		MMP9 (rs3918253, rs17576, rs17577)
		MMP13 (rs2252070)
		MMP14 (rs1042704)
		TIMP2 (rs9894526)
Salazar-Pelaéz et al. (2012)²¹21. Salazar-Pelaéz LM, Fernández Grisales RO, Zulúaga Yepes OE, Vargas KO, Tobón Calle D. Il-1 gene polymorphisms and the risk of chronic periapical periodontitis in a population from Antioquia, Colombia. Arch Oral Biol. 2012;8(1):19-30.	27 cases with PAP and 27 cases with a healthy periapex	IL1A (-889, rs1800587)	There was no association of the polymorphisms evaluated with AP (p>0.05).
	27 cases with PAP and 27 cases with a healthy periapex	IL1B (+3954, rs1143634)
Amaya et al. (2013)²²22. Amaya MP, Criado L, Blanco B, Gómez M, Torres O, Flórez L 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 Jan;46(1):71-8. https://doi.org/10.1111/j.1365-2591.2012.02097.x https://doi.org/10.1111/j.1365-2591.2012...	63 cases with acute suppurative AP and 57 diagnosed with chronic nonsuppurative AP	IL1B (rs1143634)	An association was observed for the genetic polymorphism IL8/CXCL8-251 (rs4073) (p=0.04).
		IL8/CXCL8 (rs4073)
		IL12B (rs3212227)
		TNFA (rs1800629)
Rôças et al. (2014)²³23. Rôças IN, Siqueira JF Jr, Del Aguila CA, Provenzano JC, Guilherme BP, Gonçalves LS. Polymorphism of the CD14 and TLR4 genes and post-treatment apical periodontitis. J Endod. 2014 Feb;40(2):168-72. https://doi.org/10.1016/j.joen.2013.10.006 https://doi.org/10.1016/j.joen.2013.10.0...	41 cases with post-treatment PAP and 42 cases with root-canal-treated teeth exhibiting healthy/healing periradicular tissues	CD14 (-260 C/T, rs2569190)	There was no association of the polymorphisms evaluated with AP (p>0.05).
		TLR4 (+896A>G, rs4986790)
Dill et al. (2015)²⁵25. Dill A, Letra A, Souza LC, Yadlapati M, Biguetti CC, Garlet GP 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 Feb;41(2):197-200. https://doi.org/10.1016/j.joen.2014.10.016 https://doi.org/10.1016/j.joen.2014.10.0...	136 cases with deep carious lesions and periapical lesions and 180 cases with deep carious lesions but no periapical lesions	IL10 (rs5743626)	Genetic polymorphism in IL1B (rs1143643) showed allelic (p=0.02) and genotypic (p=0.004) association with AP.
		IL1B (rs1143643, rs1143634 and rs16062)
		TNF (rs1800629)
		IL6 (rs2069830)
		OPG (rs1131380)
		RANKL (rs12721445)
		RANK (rs35589394)
Evrosimovska et al. (2015)²⁴24. Evrosimovska B, Dimova C, Popovska L, Zabokova-Bilbilova E. Matrix matalloproteinase-8 gene polymorphism in chronic periapical lesions. Prilozi. 2015;36(2):217-224. https://doi.org/10.1515/prilozi-2015-0070 https://doi.org/10.1515/prilozi-2015-007...	120 cases with chronic AP and 120 cases without any signs of chronic or acute inflammatory process	MMP8 (-799 C/T)	MMP-8 polymorphism -799 C/T was a risk factor for expression of chronic AP (p<0.05).
Maheshwari et al. (2016)²⁶26. Maheshwari K, Silva RM, Guajardo-Morales L, Garlet GP, Vieira AR, Letra A. Heat Shock 70 Protein Genes and Genetic Susceptibility to Apical Periodontitis. J Endod. 2016 Oct;42(10):1467-71. https://doi.org/10.1016/j.joen.2016.07.010 https://doi.org/10.1016/j.joen.2016.07.0...	183 cases with deep carious lesions and AP, and 217 cases with deep carious lesions but without AP	HSPA4 (rs14355)	Genetic polymorphisms in HSPA1L and HSPA6 showed significant allelic association (p<0.05). We also observed altered transmission of HSPA1L haplotypes (p=0.03).
		HSPA6 (rs1042881)
		HSPA1L (rs2075800, rs2227956 and rs2227955)
		HSPA4L (rs1380154)
		HSPA9 (rs1042665, rs10117)
Trombone et al. (2016)²⁷27. Trombone AP, Cavalla F, Silveira EM, Andreo CB, Francisconi CF, Fonseca AC et al. MMP1-1607 polymorphism increases the risk for periapical lesion development through the upregulation MMP-1 expression in association with pro-inflammatory milieu elements. J Appl Oral Sci. 2016 Jul-Aug;24(4):366-75. https://doi.org/10.1590/1678-775720160112 https://doi.org/10.1590/1678-77572016011...	111 patients presenting periapical granulomas, and 214 controls	MMP1 (-1607 1G/2G, rs1799750)	The MMP1-1607 1G/2G and 1G/2G+2G/2G genotypes were significantly more prevalent in AP patients than in the controls.
Miri-Moghaddam et al. (2017)²⁸28. Miri-Moghaddam E, Farhad-Mollashahi N, Baghaee E, Bazi A, Garme Y. Role of Thr399Ile and Asp299Gly polymorphisms of toll-like receptor-4 gene in acute dental abscess. J Clin Exp Dent. 2017 Feb;9(2):e196-201.	50 cases with acute AP abscesses and 50 patients with asymptomatic AP	TLR4 (Thr399Ile / 1196 C>T, rs4986791 and Asp299Gly / +896 A>G, rs4986790)	The polymorphism Thr399Ile in TLR4 may play a role in the pathogenesis of acute apical abscesses.
Petean et al. (2018)²⁹29. Mazzi-Chaves JF, Petean IBF, Soares IMV, Salles AG, Antunes LAA, Segato RAB et al. Influence of genetic polymorphisms in genes of bone remodeling and angiogenesis process in the apical periodontitis. Braz Dent J. 2018 Mar-Apr;29(2):179-83. https://doi.org/10.1590/0103-6440201802260. https://doi.org/10.1590/0103-64402018022...	64 cases with signs/symptoms of PAP and 84 subjects with root-canal-treated teeth exhibiting healthy periradicular tissues.	RANK (rs3826620),	Genetic polymorphisms in RANK rs3826620 (p=0.02) and RANKL rs9594738 (p=0.03) were associated with PAP.
		RANKL (rs9594738)
		OPG (rs2073618)

[1] Corresponding Author: Flares Baratto-Filho, E-mail: fbaratto1@gmail.com

Brasil

Brasil

Current trends of genetics in apical periodontitis research

Abstract: