Current trends of genetics in apical periodontitis research

Abstract:

Genetics is an emerging topic in endodontic research focusing on the host response regarding the pathogenesis of apical periodontitis (AP). A number of genetic epidemiological studies carried out by many investigators worldwide have shown evidence of an association between certain candidate genes and AP. Some studies have been conducted on knockout mice with a deficiency in certain proteins, leading to more or less severe AP, and thus suggesting a pivotal role of these genes in AP pathogenesis. Other research has evaluated the association between genetic polymorphisms in humans with different AP aspects; these studies pointed out that genetic polymorphisms in some candidate genes are involved in inter-individual variations in their response to AP. Therefore, the objective of this report was to provide an updated overview of the genes involved in AP pathogenesis, with a focus on the most relevant candidate genes.

Keywords:
Periapical Periodontitis; Polymorphisms; Genetic; Genes; Pathology; Endodontics

Introduction

Apical periodontitis (AP) is generally a sequel of a root canal system infection.¹ Although the infection of the root canal system by pathogens is the main factor involved in its pathogenesis, AP is considered a multifactorial condition, in which other aspects also need to be taken into consideration. Host risk factors such as age, gender and systemic conditions have been evaluated by innumerous researchers for many years.^2,3,4,5,6 However, the influence of the host's genetic background on AP pathogenesis is an emerging topic in endodontic research.

In fact, studies using knockout mice (KO) as an animal model,^{7,8,9,10,11,12,13,14,15} and studies with human samples,^{16,17,18,19,20,21,22,23,24,25,26,27,28,29} evaluating the complexity of endodontic biology, have revealed that many genes are involved in AP pathogenesis. These studies point to candidate genes that could act as genetic markers for inter-individual host response variations in AP establishment and formation.

So far, these studies have suggested the hypothesis that AP pathogenesis is a result of a complex interplay between microbial factors and genes. Therefore, the objective of this report was to provide an updated overview of the genes involved in AP pathogenesis, with a focus on the most relevant candidate genes.

Literature search strategy

This report systematically reviewed the current trends of genetics in AP pathogenesis research. Studies using KO and wild-type mice as the control, with experimentally induced AP, were included to enable identification of the candidate genes based on animal models. In contrast, only studies evaluating the association between genes (genetic polymorphisms) and AP phenotypes were considered in the task of identification the genes and genetic polymorphisms involved in AP pathogenesis in humans.

A systematic screening of the literature up to March 17, 2018, was undertaken using three electronic databases (PubMed, Scopus and Web of Science), including a hand search of corresponding reference lists and citation searching of key papers without language or date restrictions. Grey literature was also consulted through OpenGrey (http://www.opengrey.eu). Researchers were contacted to identify additional studies. The MeSH (Medical Subject Headings) terms (www.nlm.nih.gov/mesh/meshhome.html), related terms, and free terms used in the search were “Apical Periodontitis,” “Periapical Periodontitis,” “Periapical Abscess,” “Polymorphism,” “Genetic,” “Polymorphism, Single Nucleotide,” and “Knockout.” The Boolean research strategy used is reported in Table 1.

Table 1
Search strategy

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

Two authors (E.C.K. and L.A.A.) independently assessed selected titles and abstracts to validate the inclusion criteria. Studies appearing in more than one database were considered only once. In these cases, in which the abstract and the title were not clear, the study was read fully to minimize the possibility of overlooking important studies. The full text of all potentially relevant studies was reviewed. Any disagreement was discussed and solved by consensus between the authors. Data from the included studies were extracted and organized into tables. Figure 1 presents a flowchart of the review process. Twelve studies with KO mice and 14 studies conducted on humans were identified.

Figure 1
Flowchart of the review process.

Candidate genes involved in AP pathogenesis and phenotype, based on knockout animal studies

In endodontics, animal models—mainly of KO mice—have been a valuable tool to understand the role of genes in the progression of AP. A KO mouse is a genetically modified mouse (Mus musculus), in which researchers have inactivated, or “knocked out,” an existing gene. KO mice are a valuable tool for geneticists to understand the role of a gene in embryonic development, normal physiological homeostasis and pathological processes. Since humans and mice share about 99% of the same genes, this animal model is a good analogue for many human biological processes,³⁰ including AP pathogenesis. For geneticists, the targeted deletion of a gene in a mouse provides an important method to determine the biological role of a specific gene, and is useful in studying the in vivo gene function. It is also the best way to delineate the biological role of a protein.³¹ Our review included 12 articles that used KO mice as a model to study the role of a specific gene in AP formation and progression, as well as pathogenesis. In these studies, an experimentally AP was induced in molars for different periods, and compared with AP formation and progression in wild-type mice. These studies are presented in Table 2, together with the description of candidate genes.

Table 2
List of candidate genes, in alphabetic order, based on the animal knockout (KO) model studies.

Gene official full name	Nomenclature	References	Gene/protein Function*
Cannabinoid Receptor 2	CB2	Nikolaeva et al. (2015)33	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)9	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)7	This gene encodes a cytokine that functions in inflammation and in the maturation of B cells.
Interleukin 22	IL22	Oliveira et al. (2015)14	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)11	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)13	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)12	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)8	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);10 Oliveira et al. (2015);14 Rider et al. (2016);15 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)15

Note:
• ^*
  http://www.genecards.org/cgi-bin/carddisp.pl. Only the genes resulting in less or more severe AP are presented here.

After AP induction, KO mice for IL6,⁷OPN,⁸iNOS,⁹TLR22,¹⁰IL17RA;¹¹MyD88¹² and MMP9¹³ developed more severe AP than wild-type mice; on the other hand, KO mice for IL22³² and for CB2³³ developed less severe AP. Animals deficient in PHOX, which mediates the generation of reactive oxygen species, did not present alterations in the AP phenotype.⁹

These findings suggest that IL6, IL17AR, OPN, iNOS, MMP9, TLR2 and MyD88 are candidate genes, which might increase the risk for more severe AP phenotypes. On the other hand, IL22 and CB2 may be involved as candidate genes in protection from AP.

Studies evaluating genetic polymorphisms

In the past decade, a growing number of studies have demonstrated that genetic polymorphisms play an important role in AP pathogenesis and phenotype.^{16,17,18,19,20,21,22,23,24,25,26,27,28,29} The genetic polymorphisms studied in endodontics have so far focused on single nucleotide polymorphisms, also known as SNP. These genetic polymorphisms are the most common form of DNA sequence variation, and account for more than 90% of all variations present in the human genome.³⁴ Genetic polymorphisms could serve as useful genetic markers for identifying genes associated with the pathogenesis of complex alterations, such as AP.

Genetic association studies have been conducted to evaluate the association between genetic polymorphisms and different AP phenotypes, and thus determine whether genetic polymorphisms are associated with AP. If there is in fact an association, then the specific allele, genotype or haplotype of a polymorphism is found more often than what is expected by chance in the affected group. Different study designs were used, such as a comparison of 1) acute AP and chronic AP; 2) persistent AP and a periapical healed periodontium; and 3) deep caries lesion with AP and deep caries lesion without AP.

Table 3 presents a list of these studies, together with the genes and polymorphisms evaluated, including the respective study design used. In fact, these studies have provided new etiologic perspectives for AP pathogenesis, with a greater focus on host response.

Table 3
List of articles and genetic polymorphisms evaluated by the authors.

Authors/year	Study design	Genes/Polymorphisms	Results
Sá et al. (2007)16	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)17	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)18	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)19	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)20	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)21	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).
		IL1B (+3954, rs1143634)
Amaya et al. (2013)22	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)23	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)25	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)24	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)26	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)27	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)28	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)29	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)

• Note: PAP means persistent apical periodontitis.

Final considerations and conclusions

The present review clearly highlights that genetic factors may contribute to inter-individual variation in AP pathogenesis and severity of host response (phenotype). It is important to emphasize that candidate genes were identified based on the observations and results obtained from the KO animal studies. If a deficiency of genes was involved in more or less severe AP, these genes became candidates to be studied in humans. However, it is also important to underscore that studies with animal models are not the only way to select candidate genes to be evaluated in human samples. The functions of the gene or the gene family in question are also important clues. Genes are considered candidate genes for AP pathogenesis, if genetic polymorphisms can be identified and associated with the condition. There may be one or many candidate genes in each gene family. In addition, a genome-wide association study approach, which uses a high density of genetic markers spread over the entire human genome and a large sample size, could identify potentially new genetic polymorphisms.

Another important aspect observed from this review was the lack of validation studies. Only few researchers have evaluated whether genetic polymorphisms in genes involved in AP pathogenesis in animal models are also involved in AP phenotypes in humans. Furthermore, this review identified the absence of proper replication of genetic association studies in different populations. Although replications are considered a key part of genetic epidemiological research, only few research groups aimed to replicate previous studies with results compiled in two meta-analyses,^35,36 which report an association between the genetic polymorphism − 308 G>A in TNF-α with acute AP and the polymorphism +3954 C>T in IL1B with persistent AP.

In summary, in the present review, we have systematically collected and screened various studies exploring the role of genes and genetic polymorphisms in AP pathogenesis, thus presenting an updated overview of the field and offering useful information for carrying out future research focusing on the role of various genetic factors. Based on the available data, further identification of candidate genes and their role in AP pathogenesis and phenotype was deemed warranted and necessary.

Moreover, patients with AP may have one or more genetic polymorphisms in several different genes, requiring the translation of new genetic findings into meaningful dental practice or public health applications.

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• ²²
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• ²⁵
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Publication Dates

• Publication in this collection
  18 Oct 2018
• Date of issue
  2018

History

• Received
  04 May 2018
• Reviewed
  29 May 2018
• Accepted
  06 June 2018