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Received: 19 January 2022    Accepted: 25 April 2022

DOI: 10.1111/iej.13756

REVIEW ARTICLE

Single nucleotide polymorphisms as a predisposing factor

for the development of apical periodontitis—­An umbrella
review

Aleksandar Jakovljevic1   | Jelena Jacimovic2   | Athina Christina Georgiou3,4   |

Nadja Nikolic5   | Anita Aminoshariae6   | Suzette V. van der Waal3,4   |
Venkateshbabu Nagendrababu7

1
Department of Pathophysiology, Abstract
School of Dental Medicine, University
Background: The interaction between heredity and different environmental factors
of Belgrade, Belgrade, Serbia
2
Central Library, School of Dental
in the modification of apical periodontitis (AP) susceptibility and prediction of its
Medicine, University of Belgrade, progression remain poorly elucidated.
Belgrade, Serbia Objectives: This umbrella review aimed to (i) analyse the available relevant sys-
3
Department of Preventive Dentistry,
tematic reviews in an attempt to determine the association between genotype and
Academic Centre for Dentistry
Amsterdam, University of Amsterdam allelic distribution of different single-­nucleotide polymorphisms (SNPs) and the de-
and Vrije Universiteit, Amsterdam, the velopment of AP, (ii) report deficiencies and gaps in knowledge in this area and (iii)
Netherlands
4
present recommendations to conduct future clinical studies and systematic reviews.
Department of Endodontics, Academic
Centre for Dentistry Amsterdam,
Methods: A literature search was conducted using Clarivate Analytics' Web of
University of Amsterdam and Science, Scopus, PubMed and Cochrane Database of Systematic Reviews, from in-
Vrije Universiteit, Amsterdam, the ception to October 2021, with no language restrictions, including a grey literature
Netherlands
5
search. Systematic reviews with/without meta-­analysis evaluating genotype and al-
Laboratory for Basic Science, School
of Dental Medicine, University of lelic distribution of different SNPs between adult patients with/ without AP were
Belgrade, Belgrade, Serbia included. All other type of studies were excluded. The methodological quality was
6
Department of Endodontics, School of assessed using the A MeaSurement Tool to Assess systematic Reviews (AMSTAR)-­2
Dental Medicine, Case Western Reserve
University, Cleveland, Ohio, USA
tool. Two independent reviewers were involved in study selection, data extrac-
7
Department of Preventive and tion and appraising the included reviews; disagreements were resolved by a third
Restorative Dentistry, College of Dental reviewer.
Medicine, University of Sharjah,
Results: The current study includes five systematic reviews. Three reviews per-
Sharjah, UAE
formed meta-­analysis. Three reviews were graded by AMSTAR 2 as ‘critically low’
Correspondence quality, whereas the other two were graded as ‘low’ and ‘moderate’ quality. Two
Aleksandar Jakovljevic, Department
reviews indicated that carriers of specific genotypes and alleles of tumour necrosis
of Pathophysiology, School of Dental
Medicine, University of Belgrade, factor-­alpha (TNF-­α) -­308 G > A and interleukin 1-­beta (IL-­1β) + 3954 C/T gene poly-
Belgrade, Serbia. morphisms are more susceptible to an acute and persistent form of AP. However,
Emails: dr.sasuli@hotmail.com;
a.jakovljevic@stomf.bg.ac.rs
high heterogeneity was observed.
Discussion: The statistical heterogeneity within included systematic reviews was
Funding: No funding
a consequence of clinical and methodological diversity amongst primary studies.
Although some of the included reviews suggested that carriers of specific genotype

© 2022 International Endodontic Journal. Published by John Wiley & Sons Ltd.

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700    wileyonlinelibrary.com/journal/iej
 Int Endod J. 2022;55:700–713.
JAKOVLJEVIC et al.    |
   701

and/or allele of TNF-­α −308 G > A and IL-­1β + 3954 C/T SNPs are more susceptible
to AP, their conclusions should be interpreted with caution.
Conclusions: No candidate genes could be identified as a definitive genetic risk
or protective factor for the development and progression of AP, and further high-­
quality genome-­wide association studies are warranted.

KEYWORDS
AMSTAR 2, apical periodontitis, endodontics, genetics, singlenucleotide polymorphisms, umbrella
review

I N T RO DU CT ION microbial factors and heredity, suggesting that individual

Apical periodontitis (AP) represents a chronic inflamma-
tory reaction within tooth-­supporting tissues of teeth with
an infected root canal system. It is most often the result
of an irreversible infection by different microorganisms
within the root canal system that leads to pulp tissue ne-
crosis and progression of inflammatory reaction in the
periapical region of the affected teeth (Naïr,  2006). As a
result of the harmful effect of different microorganisms
and their virulence factors, the host's immune system is
activated leading to the recruitment of various cell types
and the production of cell-­specific mediators. Finally, it
results in the break-­down of tooth-­supporting tissues and
the formation of periapical lesions (Márton & Kiss, 2014).
Elimination of the infection with root canal treat-
ment will result in resolution of the AP inflammatory
response. It is, however, not always possible to sterilize
a once infected root canal space (Naïr,  2006; Ricucci &
Siqueira, 2010) and after root canal treatment; often, a re-
sidual lesion remains (Ricucci & Langeland, 1998).
Recent investigations revealed a considerable global
burden of AP (Jakovljevic, Nikolic, Jacimovic, et al., 2020;
Tibúrcio-­Machado et al.,  2021). Comparing with the re-
sults published until 2012 (Pak et al.,  2012), Jakovljevic,
Nikolic, Jacimovic, et al.  (2020) demonstrated an in-
creased AP prevalence in the general adult population
(6.3% vs. 5.4%) in both endodontically treated (41.3% vs.
35.9%) and untreated teeth (3.5% vs. 2.1%). Moreover, it is
important to note that several umbrella and systematic re-
views suggested the potential association between AP and
impairment of general health (Aminoshariae et al., 2017;
Georgiou et al.,  2019; Jakovljevic, Duncan, et al.,  2020;
Jakovljevic, Sljivancanin Jakovljevic, et al.,  2021;
Nagendrababu, Segura-­Egea, et al., 2020). Having this in
mind, it is still important to investigate aetiological factors
involved in the pathogenesis of AP to prevent its develop-
ment and suppress its potentially harmful effects on gen-
eral health.
In recent years, several research groups hypothesized
that AP arises because of a complex interplay between
genetic variations may contribute to different disease pre-
sentations and/or treatment outcomes (Fouad et al., 2020;
Küchler et al.,  2018). Variation in genetic constitution
between individuals modulates inflammatory and im-
munological responses in general, resulting in a range of
different responses to common environmental challenges
(Renz et al.,  2011). However, the mechanism of interac-
tion between heredity and different environmental factors
in the modification of AP susceptibility and prediction of
its progression remains poorly elucidated.
Previous investigations on animal knockout (KO) mod-
els investigated potential candidate genes that could act
as genetic markers for AP (AlShwaimi et al., 2013; Huang
et al., 2001; Rittling et al., 2010; Silva et al., 2011; da Silva
et al., 2012, 2014; Wan et al., 2014). Moreover, numerous
investigations on humans evaluated single-­ nucleotide
polymorphisms (SNPs) in several genes (e.g. in genes
for matrix metalloproteinases [MMPs] and their tissue
inhibitors, proinflammatory cytokines, bone resorption
regulators and heat shock proteins), as potential genetic
biomarkers for disease susceptibility modification (Amaya
et al.,  2013; Dill et al.,  2015; Evrosimovska et al.,  2015;
Menezes-­Silva et al.,  2012; Morsani et al.,  2011; de Sà
et al., 2007; Siqueira et al., 2009; Trombone et al., 2016).
SNPs, as the most common DNA sequence variations,
are the types of genetic factors that can contribute greatly
to the aetiology of complex diseases (Coetzee,  2019). So
far, the results of previous primary clinical studies are
rather inconclusive, and several systematic reviews and
meta-­analyses have tried to assess the association by qual-
itative and/or quantitative data synthesis (Aminoshariae
& Kulild,  2015; Jakovljevic, Nikolic, et al.,  2021; Salles
et al.,  2017, 2018; Torres et al.,  2020). Although some
systematic reviews suggested potential association be-
tween investigated genes and development of AP, the
results remain elusive and inconclusive (Aminoshariae
& Kulild,  2015; Jakovljevic, Nikolic, et al.,  2021; Salles
et al., 2017, 2018; Torres et al., 2020).
An umbrella review would help distinguish consistent
from contradictory findings and synthesize evidence from
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702       GENETIC PREDISPOSITION TO APICAL PERIODONTITIS
previous reviews on this topic. This method has recently
gained popularity in various sectors of dentistry, includ-
ing endodontology (Lin et al., 2021; Thang Le et al., 2021;
Vetromilla et al.,  2021; Jakovljevic, Duncan, et al.,  2020;
Nagendrababu, Duncan, et al.,  2020; Nagendrababu,
Segura-­
Egea, et al.,  2020). Thus, this umbrella review
aimed to (i) analyse the available relevant systematic re-
views in an attempt to determine the association between
genotype and allelic distribution of different SNPs and the
development of AP, (ii) report deficiencies and gaps in
knowledge in this area and (iii) present recommendations
and directions for future investigations.
MET H O DS
Protocol and registration
This umbrella review was developed, conducted and re-
ported following relevant methodological guidelines, such
as recommendations for umbrella reviews from Aromataris
et al. (2020) and Preferred Reporting Items for Systematic
Reviews and Meta-­Analyses (PRISMA) guidelines (Page
et al., 2021). The protocol of the current umbrella review
was established before the initiation and registered in the
International Prospective Register of Systematic Reviews
(PROSPERO) database (CRD42021261623).
Research question
Are SNPs in different genes of interest predisposing fac-
tors for AP development?
Eligibility criteria
Inclusion criteria were as follows:
Population: healthy population with no systemic
diseases.
Intervention/Exposure: patients with SNPs in different
genes of interest and AP.
Comparison(s): the differences in (i) AP cases and
healthy controls without AP; (ii) the post-­treatment AP
phenotype, that is persistent versus healed; and (iii) the
clinical forms of AP, acute versus chronic.
Outcome(s): genotype and allelic distribution of SNPs
in different genes of interest within three comparisons.
Study design(s): systematic reviews with or without
meta-­analysis evaluating genotype and allelic distribu-
tion of different SNPs between adult patients with and
without AP were included.
Case reports, clinical studies, laboratory studies, animal
studies, narrative and scoping reviews were excluded.
Information sources and search strategy
A comprehensive literature search was performed be-
tween 5 July and 8 October 2021. The following electronic
databases, Clarivate Analytics' Web of Science (including
Web of Science Core Collection—­WoS, Korean Journal
Database—­KJD, Russian Science Citation Index—­RSCI,
SciELO Citation Index—­SCIELO), Scopus, PubMed (in-
cluding MEDLINE) and Cochrane Database of Systematic
Reviews (CDSR) [Cochrane Library], were searched with-
out language, date, the status of publication or any other
restrictions. Search strategies were developed by the expe-
rienced medical librarian and information specialist (J.J.)
and the review team, based on preliminary searches and
identification of the most common free keywords and rel-
evant controlled vocabulary (Medical Subject Headings—­
MeSH, https://www.ncbi.nlm.nih.gov/mesh). Full search
strategies, including used index and free keywords,
Boolean operators (AND, OR), truncation (*, $) and prox-
imity (NEAR, W) operators, are presented according to
the searched database in Table  S1. Electronic literature
search strategies were peer-­reviewed by a second informa-
tion specialist using the Peer Review of Electronic Search
Strategies (PRESS) guideline (McGowan et al.,  2016),
and the feedback was incorporated before running the
final database search. Additionally, to identify ongoing
systematic reviews and meta-­ analyses, complementary
searches of the PROSPERO register (https://www.crd.
york.ac.uk/prosp​ero/) and Joana Briggs Institute (JBI)
Evidence Synthesis Reports (earlier titles: JBI Library
of Systematic Reviews and JBI Database of Systematic
Reviews and Implementation Reports) were completed.
Furthermore, to detect relevant unpublished manu-
scripts, conference papers, doctoral dissertations and
other grey literature, OpenGrey (http://www.openg​rey.
eu), Google Scholar (first 100 returns) and other avail-
able digital repositories (e.g. Networked Digital Library
of Theses and Dissertations (http://www.ndltd.org),
Open Access Theses and Dissertations (https://oatd.org),
DART-­Europe E-­theses Portal—­DEEP (https://www.
dart-­europe.org/basic​-­search.php), Opening access to
UK theses—­EThOS (https://ethos.bl.uk)) were explored.
Finally, to ensure the inclusion of significant studies that
may not have been identified through database and grey
literature searches, cited and citing references of included
reviews and relevant narrative reviews were also con-
sidered using citation indexes (WoS, Scopus and Google
Scholar). Performed searches were rerun during the
final drafting of the manuscript up to 26 October 2021,
JAKOVLJEVIC et al.
indicating no new relevant systematic reviews had been
published after the conclusion of the literature search.
Electronic databases' search results were exported auto-
matically from used sources and imported into the Rayyan
environment (Ouzzani et al., 2016) for duplicates removal
(using Rayyan's duplicate identification strategy and then
manually) and further analysis.
Selection process
Titles and abstracts of retrieved documents, followed by
the full text of any article considered to meet the inclusion
criteria, were assessed independently and in duplicate by
two reviewers (A.J. and J.J.). If the abstract was unclear,
the full paper was accessed to determine eligibility for
inclusion. Disagreements over the eligibility of certain
studies were resolved by discussion with a third reviewer
(V.N.).
Data collection and data items
Specialized data collection forms (Microsoft Excel™,
Microsoft Corporation, USA) were used for data extrac-
tion, performed independently by two reviewers (A.A.
and A.J.). From each study included in the final review,
the following information was recorded: name and coun-
try of the first author, year published, name of the journal,
search period, language, name and number of databases
used to search, number of studies included, quality assess-
ment tool used, outcomes assessed, meta-­analysis data
(pooled odds ratio (OR), risk ratio (RR), I2, etc.), limita-
tions and conclusions. Disagreements were resolved by
discussing with a third reviewer (V.N.).
Quality assessment of included
systematic reviews
Qualitative evaluation of selected reviews' methodology
was independently performed by two reviewers (A.C.G.,
N.N.) using the A MeaSurement Tool to Assess systematic
Reviews (AMSTAR)-­2, which is a critical appraisal tool
for systematic reviews that include randomized or non-­
randomized studies of healthcare interventions (Shea
et al., 2017). The two reviewers provided a decision of yes,
partial yes or no on 16 items of the AMSTAR 2 checklist
(https://amstar.ca/Amstar_Check​list.php) that evalu-
ate the appropriateness of the important components
of the method used. Any disagreements were discussed
with a third reviewer (V.N.) until optimal agreement
was achieved (100%). Based on the AMSTAR 2 suggested
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   703
decision rules, each included review was given an overall
confidence rating of ‘critically low’ (more than one critical
flaw with or without non-­critical weaknesses), ‘low’ (one
critical flaw with or without non-­critical weaknesses),
‘moderate’ (more than one non-­ critical weakness) or
‘high’ (no or one non-­critical weakness) (Shea et al., 2017).
Data synthesis method
Based on a modified narrative synthesis approach (Popay
et al., 2005), the conceptual framework for the data synthe-
sis of included systematic reviews with or without meta-­
analyses was developed and conducted. Summary tables
describe reviews and meta-­analyses characteristics and
findings. Applied meta-­analysis model, total samples, the
number of events in treatment and control groups, effect
size estimates and their 95% CI, heterogeneity estimates,
publication bias and quality of evidence were reported for
each meta-­analysis performed within included systematic
reviews. Conclusions of all available meta-­analyses were
evaluated based on the direction, magnitude and statisti-
cal significance of the effect estimates.
RESULTS
Literature search process
The searches resulted in 459 papers being initially identi-
fied, and after the removal of duplicates, 354 papers were
screened at the title and abstract stage (Figure  1). After
reviewing the title and abstracts, 349 were removed, and
the full texts for five systematic reviews with or without
meta-­ analyses were retrieved and finally assessed for
eligibility. After the full-­text evaluation, all five identi-
fied systematic reviews that addressed the research ques-
tion (Aminoshariae & Kulild,  2015; Jakovljevic, Nikolic,
et al.,  2021; Salles et al.,  2017, 2018; Torres et al.,  2020)
were included in the current umbrella review. The com-
plementary searches of the PROSPERO register and JBI
Evidence Synthesis Reports did not reveal any ongoing/
finalized systematic reviews.
Characteristics of included reviews
Table 1 shows the characteristics of the included systematic
reviews. Five systematic reviews met the inclusion criteria.
Four of them were published in the Journal of Endodontics,
whilst one was published in the Brazilian Dental journal.
The reviews were published between 2015 and 2021. Three
reviews used PubMed, Scopus, Web of Science or Virtual
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704       GENETIC PREDISPOSITION TO APICAL PERIODONTITIS
F I G U R E 1   PRISMA flow diagram for the umbrella review which included searches of databases, registers and other sources. *The total
number of records identified from each database or register searched is given in Table S1. **Exclusion of records was performed by a human
Health Library (Salles et al., 2017, 2018; Torres et al., 2020)
as databases to identify relevant studies, and they originate
from the same scientific group. One study (Jakovljevic,
Nikolic, et al.,  2021) used a very broad collection of data-
bases, namely Clarivate Analytics Web of Science, Scopus,
PubMed, Cochrane Central Register of Controlled Trials
and China National Knowledge Infrastructure databases,
and one study (Aminoshariae & Kulild,  2015) searched
MEDLINE, Embase, Cochrane and PubMed. The search
period within the reviews ranged from inception to 2020.
The number of studies included in each systematic re-
view ranged from 2 to 9. Three reviews (Aminoshariae
& Kulild,  2015; Salles et al.,  2017, 2018) used a 10-­point
modified proposed specific quality assessment scale for
genetic association studies for the quality assessment of
the included studies. The remaining two studies used the
STrengthening the REporting of Genetic Association stud-
ies (STREGA) checklist (Jakovljevic, Nikolic, et al.,  2021;
Torres et al., 2020) whilst one of them combined it with the
Grading of Recommendations, Assessment, Development
and Evaluations (GRADE) recommendations and a modi-
fied, specific quality assessment scales for genetic associa-
tions (Jakovljevic, Nikolic, et al., 2021).
Summary of meta-­analysis
Three of the five included systematic reviews performed
a meta-­analysis (Jakovljevic, Nikolic, et al.,  2021; Salles
et al.,  2017, 2018). In two of the included reviews (Salles
et al., 2017, 2018), the meta-­analysis was conducted using
the Cochran–­ Mantel–­Haenszel and fixed-­ effects model
to estimate effect size such as pooled RR and 95% confi-
dence intervals (CI), whilst the third used a random-­effects
model (Jakovljevic, Nikolic, et al.,  2021). The heteroge-
neity was assessed using I2 statistics. In the review of
Salles et al.  (2017), the meta-­analysis was performed for
the genotypes and allele distributions of tumour necro-
sis factor-­alpha (TNF-­ α) -­308 G > A gene polymorphism
between acute and chronic AP cases. An association was
observed (OR = 0.49, CI = [0.25–­0.96], p = .04) for geno-
type distribution. For the allele distribution, no significant
association was observed (OR  =  0.59, CI  =  [0.32–­1.08],
p  =  .08). The heterogeneity between the studies was low
(I2 = 0%). In the study of Jakovljevic, Nikolic, et al. (2021),
the meta-­analysis of Salles et al. (2017) was updated by the
addition of a study done by the same author (Jakovljevic,
Nikolic, Carkic, et al., 2020) and additional data that were
required after personal communication with the corre-
sponding authors of Dill et al. (2015). No association was
observed (OR = 0.69, CI = [0.37–­1.31], p = .26) for geno-
type distribution or for the allele distribution (OR = 0.81;
CI = [0.45–­1.44], p = .46). The heterogeneity was moderate
(I2 = 36% and I2 = 41%, respectively). Jakovljevic, Nikolic,
et al. (2021) also conducted meta-­analyses on genotype and
allele distribution between AP cases and controls and re-
ported no significant differences between the groups. The
authors found inconsistency with the results with a high
T A B L E 1   Main characteristics of the included systematic reviews

Number of
Country included
Name of of the Meta-­ studies Study design
the journal first analysis qualitative/ of included Instrument of Biological
Author, year published Databases searched author Search period Language performed quantitative studies quality assessment marker Conclusion Limitations
JAKOVLJEVIC et al.

Aminoshariae Journal of MEDLINE, Embase, USA Up to 2/2015 English No 9/0 Case–­control Modified proposed IL-­1β, IL-­1α, ‘Polymorphism and biologic -­The discussion does
and Kulid Endodontics Cochrane and specific quality IL-­6, RANK, modifiers by which some not elaborate on
(2015) PubMed assessment RANKL, individuals, if challenged the different gene
scale for genetic CD14, TLR4, by bacterial accumulation, polymorphisms
association IL-­8/CXCL8, may have a more vigorous examined or the
studies IL-­10, immunoinflammatory response risk of bias of the
FCγRIIIA, leading to AP’ included studies.
MMP2, -­The conclusion is not
MMP3, focused on genetic
TNF-­α susceptibility

Jakovljevic, Journal of Clarivate Analytics Web Serbia Up to 12/2020 English Yes 4/4 Case–­control STREGA, a TNF-­α ‘Because of very low certainty -­The meta-­analysis was
Nikolic, Endodontics of Science, Scopus, modified, of evidence, whether there conducted between
et al. (2021) PubMed, Cochrane specific quality is an association between 2 and 3 studies.
Central Register of assessment TNF-­α −308 G/A SNP -­The potential risk of bias
Controlled Trials scales for and AP warrants further of included studies is
and China National genetic well-­designed multicentric not discussed
Knowledge associations and studies to adjudicate a better
Infrastructure GRADE understanding of the role
databases of genetic factors in the
etiopathogenesis of AP’

Salles Brazilian Dental PubMed, Scopus, Web Brazil Up to English Yes 2/2 Case–­control 10-­point modified TNF-­α ‘The role of TNF-­α 308 G/A SNP -­The meta-­analyses were
et al. (2017) Journal of Science, Virtual 15/03/2016 proposed phenotypes is debatable. The conducted between
Health Library specific quality meta-­analysis demonstrated that 2 studies.
assessment the genotype distribution was -­The potential risk of bias
scale for genetic different amongst AP phenotypes; of included studies is
association however, there was no statistical not discussed
studies difference for allele distribution
amongst the groups. Further
studies are needed to confirm
and understand the underlying
mechanisms of the identified
association’

Salles Journal of PubMed, Scopus, Web Brazil Up to English Yes 6/4 Case–­control 10-­point modified IL-­1β, IL-­1α, IL-­6, ‘Polymorphisms in IL-­1β, IL-­6 and -­The meta-­analyses were
et al. (2018) Endodontics of Science, Virtual 15/03/2016 studies, proposed IL-­8, IL-­10, IL-­8 were associated with AP. conducted between
Health Library cross-­ specific quality IL-­12β Polymorphisms in IL-­1α, IL-­10 2 studies.
sectional assessment or IL-­12 β were not associated -­The potential risk of bias
studies, scale for genetic with AP regardless with the of included studies is
or cohort association methodology used. The meta-­ not discussed
studies studies analysis suggested that the
genotype and allele distribution
of IL-­1 β (+3954 C/T) gene
polymorphism was different in
persistent and healed AP. More
research in this area is warranted
  

to confirm these results.

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(Continues)
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706       GENETIC PREDISPOSITION TO APICAL PERIODONTITIS

heterogeneity (>70%) observed for both analyses. Finally,

factor kappa-­B; RANKL, receptor activator of nuclear factor kappa-­B ligand; SNP, single-­nucleotide polymorphism; STREGA, STrengthening the REporting of Genetic Association studies; STREGA: Strengthening and
-­Search was done up to
9/2017 whilst this

Recommendations, Assessment, Development and Evaluations; IL, interleukin; MMP, matrix metalloproteinase; NP, not performed, NM, not mentioned AP, apical periodontitis; RANK, receptor activator of nuclear
was published in
Salles et al. (2018) conducted a meta-­analysis on the geno-

Abbreviations: A, adenosine; AP, apical periodontitis; C, cytosine; CVD, cardiovascular disease; G, guanine; GRADE, Grading of Recommendations Assessment, Development and Evaluation; GRADE, Grading of
type distribution and the allele distribution of interleukin-­1

Limitations
beta (IL-­1β) (+3954 C/T) gene between acute and chronic

2020
AP groups. Both comparisons were found not significant,
whilst heterogeneity was low (I2 = 0%). In the meta-­analysis
of genotype and allele distribution of IL-­1β (+3954 C/T)

were associated with a higher

MMP1, MMP2, MMP3 and MMP8

risk of periapical lesions’

gene polymorphism between persistent AP and healed per-

Reporting of Genetic Association statement; T, thymine; TIMP, tissue inhibitor of metalloproteinases; TLR, toll-­like receptor; TNF, tumour necrosis factor; USA, United States of America.
iradicular tissues group, a significant effect was observed
(p = .009 for genotype distribution and p = .005 for allele
distribution) with very high heterogeneity (I2 > 90%).
Conclusion

Methodological quality
MMP1, 2, 3, 8, 9,
13 and 14
Biological

The overall confidence of the systematic reviews included

marker

TIMP2

in this umbrella review is shown in Figure 2. Amongst in-

cluded reviews, three were categorized as ‘critically low’
quality assessment

(Jakovljevic, Nikolic, et al., 2021; Salles et al., 2017, 2018),

Instrument of

one was ‘low’ (Aminoshariae & Kulild,  2015), and one

STREGA

was ‘moderate’ (Torres et al., 2020). None of the five re-

views addressed Item 3 (Did the review authors explain
Study design

Case–­controls

their selection of the study designs for inclusion in the

of included

review?). A meta-­analysis was not performed in two re-

studies

views (Aminoshariae & Kulild, 2015; Torres et al., 2020);

therefore, Items 11(‘If meta-­analysis was performed did
quantitative
qualitative/
Number of
included

the review authors use appropriate methods for statisti-

studies

cal combination of results?’), 12 (‘If meta-­analysis was

3/0

performed, did the review authors assess the potential

performed

impact of RoB in individual studies on the results of the

analysis
Meta-­

meta-­analysis or other evidence synthesis?’) and 15 (‘If

No

they performed quantitative synthesis did the review au-

Language

thors carry out an adequate investigation of publication

English

bias (small study bias) and discuss its likely impact on the
results of the review?’) in the AMSTAR-­2 checklist were
30/09/2017
Search period

not applicable and were scored ‘0’.

In addition, we observed that the same primary studies
Up to

were repeatedly included in different systematic reviews

Country

(Table 2). Systematic reviews conducted by Aminoshariae &

author
of the

Brazil
first

Kulid  (2015) and Salles et al.  (2018) overlapped in five pri-

mary studies (Amaya et al., 2013; Dill et al., 2015; Morsani
of Science, Virtual
PubMed, Scopus, Web
Databases searched

Health Library

et al.,  2011; de Sà et al.,  2007; Siqueira et al.,  2009), whilst

Jakovljevic, Nikolic, et al.  (2021) overlapped in two pri-
mary studies (Amaya et al.,  2013; de Sà et al.,  2007) with
Aminoshariae & Kulid (2015) and Salles et al. (2018) (Table 2).
T A B L E 1  (Continued)

Endodontics
the journal
published

DISC USSION
Journal of
Name of

Need for an umbrella review

et al. (2020)
Author, year

Previous systematic reviews have reported multiple as-

Torres

sociations between gene polymorphisms and endodontic

JAKOVLJEVIC et al.    |
   707

Aminoshariae et al.
AMSTAR 2 Jakovljevic et al. 2021 Salles et al. 2017 Salles et al. 2018 Torres et al. 2020
2015

Item 1
Item 2
Item 3
Item 4
Item 5
Item 6
Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Item 13
Item 14
Item 15
Item 16

Overall
Low Critically low Critically low Critically low Moderate
confidence

Yes Partial Yes No No meta-analysis conducted

F I G U R E 2   Critical appraisal of the included systematic reviews. AMSTAR 2 –­Assessing the Methodological Quality of Systematic
Reviews 2; PICO –­Population, Intervention, Comparison, Outcome; * –­AMSTAR 2 critical domain; 1. Did the research questions and
inclusion criteria for the review include the components of PICO?; 2. Did the report of the review contain an explicit statement that
the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the
protocol?*; 3. Did the review authors explain their selection of the study designs for inclusion in the review?; 4. Did the review authors use
a comprehensive literature search strategy?*; 5. Did the review authors perform study selection in duplicate?; 6. Did the review authors
perform data extraction in duplicate?; 7. Did the review authors provide a list of excluded studies and justify the exclusions?*; 8. Did the
review authors describe the included studies in adequate detail?; 9. Did the review authors use a satisfactory technique for assessing the
risk of bias (RoB) in individual studies that were included in the review?*; 10. Did the review authors report on the sources of funding
for the studies included in the review?; 11. If meta-­analysis was performed did the review authors use appropriate methods for statistical
combination of results?*; 12. If meta-­analysis was performed, did the review authors assess the potential impact of RoB in individual studies
on the results of the meta-­analysis or other evidence synthesis?; 13. Did the review authors account for RoB in individual studies when
interpreting/ discussing the results of the review?*; 14. Did the review authors provide a satisfactory explanation for, and discussion of,
any heterogeneity observed in the results of the review?; 15. If they performed quantitative synthesis did the review authors carry out an
adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?*; 16. Did the review
authors report any potential sources of conflict of interest, including any funding they received for conducting the review?.

disease (Aminoshariae & Kulid, 2015; Salles et al., 2017,
2018; Torres et al., 2020). However, observed associations
have been the subject of much discussion due to the fact
that they were based on case–­control studies and an unas-
certained causal relationship (Fouad et al., 2020; Küchler
et al.,  2018). The question as to what factors contribute
to the onset and progression of the inflammation and to
what extent deserve further investigation. Heredity may
be a significant contributing factor in the face of micro-
biological challenges, mainly because inflammation is a
dynamic and complex process with many components,
including the host's immune response based on genetic
susceptibility. The disease, microbiome, environment, nu-
trition, health, epigenetics, oral hygiene and smoking play
an important part in the host's response to an invasion
(Shaddox et al., 2021). To date, genome-­wide association
studies (GWASs) for endodontics have yet to be under-
taken. This gap in the literature makes it hard to ascertain
the evidence from case–­control studies with late-­onset
disease phenotypes. Hence, this umbrella review was
performed to critically review the previous systematic re-
views, report deficiencies and gaps in knowledge in this
area, and present recommendations and directions for fu-
ture investigations.
Heredity as the risk (or protective) factor
for development and progression of AP:
Revealing the current facts
Heredity affects the occurrence of numerous diseases
(Altshuler et al.,  2008; Igo et al.,  2019), and therefore,
 |
708       GENETIC PREDISPOSITION TO APICAL PERIODONTITIS

identifying and characterizing the associated risk (or pro-
tection) are important for improving the understanding of
the aetiopathogenesis of AP and potentially for developing
interventions based on revealed genetic findings. Although
SNPs can affect gene activity or protein production
(Coetzee, 2019) and consequently contribute to structural
and/or functional changes in the apical periodontium, no
single gene variant has yet clearly arisen as definitely in-
fluencing the development and progression of AP (Fouad
et al., 2020; Küchler et al., 2018). The studies included in
this umbrella review attempted to evaluate the association
of various SNPs with (i) the development of AP; (ii) the
post-­treatment AP phenotype, that is persistent AP versus
healed periradicular tissues after endodontic treatment or
(iii) AP phenotype, acute AP versus chronic AP.
Salles et al.  (2017) evaluated the association between
AP phenotypes and TNF-­α −308 G > A polymorphism, and
based on the pooled data from only two primary studies
(Amaya et al., 2013; de Sà et al., 2007), found a significant
difference between patients with acute and chronic AP for
genotype distribution (p = .04), but not for the allele dis-
tribution. However, when performing an updated review,
Jakovljevic, Nikolic, et al. (2021) added the data from two
other primary studies (Dill et al., 2015; Jakovljevic, Nikolic,
Carkic, et al., 2020), that were not included in the seminal
systematic review (Salles et al.,  2017). In the quantitative
synthesis, the authors reported no statistically significant
difference between acute and chronic AP groups, with
a substantial increase in heterogeneity between the re-
sults. The authors have also assessed the possible asso-
ciation of this SNP with the development of AP between
affected and controls. Similarly, the authors did not report
any significant association with substantial heterogeneity
between study results. The observed discrepancy in the
association results between the included meta-­ analyses
(Salles et al.,  2017; Jakovljevic, Nikolic, et al.,  2021) for
the TNF-­ α −308  G > A polymorphism, presentation of
different AP phenotypes and development of AP arose as
the consequence of including additional primary studies
(Dill et al., 2015; Jakovljevic, Nikolic, Carkic, et al., 2020)
in pooled analysis. An increased number of participants
with different ethnicity and genetic backgrounds led to
changes in the final results of the updated meta-­analysis
(Jakovljevic, Nikolic, et al., 2021). In addition, the influence
of different genetic backgrounds on susceptibility to a dif-
ferent form of periodontal disease has been postulated in
previous investigations (Chen et al., 2012). Taken together,
these results emphasize the need for further studies of ge-
netic polymorphisms and the replication of already studied
SNPs within new cohorts to confirm or refute the observed
findings, including in different populations and ethnicities.
In another systematic review, Salles et al. (2018) ana-
lysed SNPs in several interleukin genes and showed that
polymorphisms in IL-­1β, IL-­6 and IL-­8 were associated
with various AP phenotypes, which is a finding also re-
ported in the previously published review by Aminoshariae
& Kulid (2015). Although with high heterogeneity, a meta-­
analysis (Salles et al., 2018) of only two included primary
studies (Morsani et al.,  2011; Siqueira et al.,  2009) sug-
gested that the genotype and allele distribution of IL-­1β
(+3954 C/T) gene polymorphism was different between
persistent and healed AP in post-­treatment AP (p = .009,
p  =  .005, respectively). In this specific case, the pooled
analysis was conducted on a population of North and

T A B L E 2   Number of overlapping primary studies amongst the included systematic reviews

Aminoshariae and Salles Salles Torres Jakovljevic, Nikolic,

Kulid (2015) et al. (2017) et al. (2018) et al. (2020) et al. (2021)
Number of studies included 9 2 6 3a 4
in the review
Aminoshariae and 2 5 1 2b
Kulid (2015)
Salles et al. (2017) 2 2 0 2
Salles et al. (2018) 5 2 0 2c
Torres et al. (2020) 1 0 0 0
b c
Jakovljevic, Nikolic, 2 2 2 0
et al. (2021)
a
Only three primary studies related to single-­nucleotide polymorphism of matrix metalloproteinase genes were included, other included studies (n = 12) were
related to gene expression analysis.
b
Aminoshariae and Kulid (2015) did not include unpublished data related to TNF-­α (−308 G > A) single-­nucleotide polymorphism which were included in
Jakovljevic, Nikolic, et al. (2021) obtained per personal request to the authors (Dill et al., 2015).
c
Salles et al. (2018) did not include unpublish data related to TNF-­α (−308 G > A) single-­nucleotide polymorphism which were included in Jakovljevic, Nikolic,
et al. (2021), obtained per personal request to the authors (Dill et al., 2015).
Gray shades -­not comparable data between same studies.
JAKOVLJEVIC et al.
South Americans, and participants in both primary stud-
ies were reported to be of mixed ethnic backgrounds.
Finally, in another systematic review, Torres
et al. (2020) performed a qualitative synthesis from only
three included primary studies (Evrosimovska et al., 2015;
Menezes-­Silva et al., 2012; Trombone et al., 2016) and re-
ported that SNP in Mmp1, Mmp3 and Mmp8 genes could
be associated with an increased risk of AP development.
Although MMPs, along with other mediators of inflam-
mation, play an important role in the pathogenesis of AP,
this qualitative synthesis represents only a base for further
primary studies and systematic reviews, and more data
are needed to corroborate an increased risk of AP devel-
opment in carriers with SPNs in different MMPs genes.
Based on the analysis of the results of included system-
atic reviews, it is obvious that the role of SNPs in the de-
velopment and progression of AP is still unclear and given
conclusions should be interpreted with caution.
Although well-­conducted primary studies on humans
are sparse, there are several animal studies with promis-
ing findings (AlShwaimi et al., 2013; Huang et al., 2001;
Rittling et al., 2010; Silva et al., 2011; da Silva et al., 2012,
2014; Wan et al.,  2014). Previous genetically modified
mouse models with inactivated, or KO gene of interest,
revealed that KO mice for IL 6 (Huang et al.,  2001), os-
teopontin (Rittling et al.,  2010), inducible nitric oxide
synthase (Silva et al., 2011), toll-­like receptor 2 (da Silva
et al.,  2012), IL-­17 receptor A (AlShwaimi et al.,  2013),
myeloid differentiation factor 88 (da Silva et al., 2014) and
MMP 9 (Wan et al., 2014) exhibited more severe periapical
bone resorption compared with wild-­type mice. Although
this animal model is a good analogue for many human
diseases, including AP (Küchler et al., 2018), the observed
results could not be simply translated on humans without
further investigations and their confirmation.
On the contrary, based on previous candidate gene and
genome-­wide association studies in Periodontology, Nibali
et al. (2017) identified that SNPs in the vitamin D receptor
(VDR), the Fc-­cRIIA and the IL-­10 genes are associated
with periodontitis with ‘strong’ level of evidence. Having
in mind that AP and periodontitis both share similar im-
munological challenges in response to microbial invasion
these findings also might be valuable for directing future
investigations in Endodontology.
It has to be stressed that the mono-­causality concept of
aetiopathogenesis of AP is definitely obsolete, and it is now
clearly considered as a multifactorial disease, suggesting that
its complex nature involves overlapping inherent and envi-
ronmental risk factors (Fouad & Khan, 2019). Unfortunately,
current knowledge reveals that any candidate genes could
not be identified as a definitive genetic risk or protective fac-
tor for the development and progression of AP based on pre-
vious studies on humans and further GWASs are warranted.
   |
   709
Quality of the individual
systematic reviews
The AMSTAR 2 tool was created for a simpler and more
user-­friendly guideline used to rate the overall confidence
(e.g. ‘high’, ‘moderate’, ‘low’ and ‘critically low’) in the re-
sults of a systematic review (Shea et al., 2017). It is criti-
cal to note that AMSTAR 2 was not intended to generate
any scoring; however, it certainly provides an overall rat-
ing (e.g. ‘high’, ‘moderate’, ‘low’ and ‘critically low’) based
on seven critical and nine non-­critical domains (Shea
et al.,  2017). Amongst five included reviews, no system-
atic review was available without flaws in ‘the critical
domain’. Three systematic reviews (Jakovljevic, Nikolic,
et al., 2021; Salles et al., 2017, 2018) were rated as ‘critically
low quality’. According to previous descriptive analyses
of overviews of reviews published in different Medicine
fields, it seems that authors do not universally undertake
the risk of bias and/or quality assessments of SRs before
concluding their results (Li et al., 2012). Interestingly, in-
cluded reviews without meta-­analysis were ascertained as
‘low’ (Aminoshariae & Kulid, 2015) and ‘moderate’ qual-
ity (Torres et al., 2020). Overall, none of the evaluated re-
views addressed: ‘Item 3: Did the review authors explain
their selection of the study designs for inclusion in the
review?’ The selection of study types for inclusion in sys-
tematic reviews should not be arbitrary (Shea et al., 2017).
Therefore, authors must justify the inclusion of various
study designs (randomized controlled trials (RCTs) or
non-­randomized studies (NRSs), or both) in their review.
Although, RCTs due to quality of investigation and pro-
vided level of evidence are preferred, restriction of a re-
view to only NRSs is justified when RCTs cannot provide
the necessary outcome data, or in the case where reviews
of RCTs have been completed and the review of NRSs will
complement what is already known (Shea et al., 2017).
Strengths of the review
To the best knowledge of the authors, this umbrella review
is the first to systematically compile and appraise the cur-
rently existing evidence on the association between heredi-
tary factors (i.e. SNPs) and the development of AP using
AMSTAR 2. The following aspects can be considered as
strengths of the current review: (i) an a priori protocol of
the umbrella review was registered in the PROSPERO da-
tabase before starting the review process, (ii) current review
followed strict eligibility criteria, (iii) literature search was
performed in four databases with no language restriction,
(iv) literature searched in grey literature and (v) literature
search process, data extraction and appraisal of reviews
were carried out by two experienced independent authors.
 |
710       GENETIC PREDISPOSITION TO APICAL PERIODONTITIS
Limitations of the review
Several limitations should be acknowledged: (i) amongst
the included reviews, only three performed a meta-­
analysis. The reporting and validation of the quantitative
effect estimates, and discernment of publication bias have
been affected by the under-­utilization of meta-­analytical
pooling. However, the presence of high methodological
or statistical heterogeneity amongst the selected studies
and the sparse study numbers can preclude the use of
meta-­analysis in systematic reviews. Furthermore, (ii) the
presence of methodological flaws in the selected system-
atic reviews and (iii) the primary studies in the included
systematic reviews exhibiting significant heterogeneity
of association amongst the studies. The genetic polymor-
phisms that have mostly been studied in endodontics are
single-­nucleotide polymorphisms. However, different
methodologies, methods for assessment and study designs
further complicate direct comparison. (iv) The quality
of the individual studies was not assessed in the current
review as this was expected to be done by the authors of
these SRs and meta-­analyses.
Reporting deficiencies and gaps in
knowledge/methodology
During the process of reviewing primary clinical studies
and systematic reviews related to the association between
heredity and development and progression of AP, several in-
consistencies in methodology and reporting were identified.
The most important inconsistencies that were observed in
previously published primary studies are lack of sample size
calculation, unmatched study groups, the inappropriate def-
inition of eligibility criteria and analysis of polymorphisms
of a single gene of interest. The existence of the inconsist-
encies mentioned above in future primary studies will have
a significant impact on the scientific contribution of these
investigations. Although it is important to investigate previ-
ously assessed SNPs in different populations, future GWASs
are essential in order to ascertain the evidence.
In addition, the most significant inconsistencies ob-
served amongst included systematic reviews were the lack
of a rationale for selecting study designs for inclusion, the
absence of a list of excluded studies with justification, the
failure to disclose sources of funding for included studies,
the absence of conducting publication bias and the failure
to analyse the risk of bias of included studies. The genetic
association studies are usually non-­randomized, observa-
tional studies and their inclusion in the systematic reviews
is justified when there are no randomized clinical studies
or their appraisal will sufficiently complement existing
knowledge. Also, a complete list of potentially relevant
studies with justification for the exclusion is necessary be-
cause unjustified exclusion may cause bias in the review
process (Shea et al., 2017). Reporting sources of funding is
another important item that authors of future systematic
reviews and meta-­analyses should follow because it will
be easier to analyse separately the results from commer-
cially funded and independently funded studies and avoid
potential conflicts of interest (Shea et al.,  2017). Finally,
evaluation and discussion of the risk of bias and publica-
tion bias are enormously important because both analyses
significantly influence the interpretation and discussion
of the results (Shea et al., 2017).
In this regard, to improve the quality of future primary
clinical studies and systematic reviews, the following rec-
ommendations on how to conduct and report them are
proposed.
Future recommendations for primary
clinical investigations
Future primary clinical studies should be conducted
and reported according to the STREGA checklist (Little
et al.,  2009), which represents an extension of the
STrengthening the Reporting of OBservational Studies in
Epidemiology (STROBE) Statement (von Elm et al., 2007)
and provides additions to 12 of the 22 items on the STROBE
checklist. The additions are related to population stratifi-
cation, genotyping errors, modelling haplotype variation,
Hardy–­Weinberg equilibrium, replication, selection of par-
ticipants, the rationale for the choice of genes and variants,
treatment effects in studying quantitative traits, statistical
methods, relatedness, reporting of descriptive and outcome
data, and the volume of data issues that are important to
consider in genetic association studies (Little et al., 2009).
In this regard, in future, investigators should consider
following the below-­given criteria whilst conducting pri-
mary clinical studies:
1. Authors should state clearly and define properly the
eligibility criteria of study.
2. Authors should succinctly describe the case selection
of study.
3. Authors have to match the patients in case and control
group, and the control group must be comparable with
having the same exposure as the experimental group.
4. Authors have to perform a sample size calculation
before starting the investigation, or they should suc-
cinctly describe and provide a power calculation cor-
recting for Type I error.
5. Authors should adjust for Hardy–­ Weinberg
Equilibrium (HWE), a principle stating that the ge-
netic variation of a population will remain constant
JAKOVLJEVIC et al.
from one generation to the next in the absence of
disruptive factors (Mayo, 2008). Testing for deviation
from HWE has a role in detecting errors of genotyp-
ing in large-­scale studies, such as identifying SNPs for
which the clustering algorithms used to call genotypes
have broken down (Royo, 2021).
6. Authors should adjust for confounding factors.
7. In case of longitudinal studies, authors should pro-
vide adequate follow-­up and any attrition should be
accounted for with reasons why.
8. Authors should describe and state clearly all investi-
gated outcomes.
9. Authors should ascertain a causal relationship using
Hill's criteria (Hill, 1965).
10. Authors should conduct GWASs in order to ascertain
the evidence.
Future recommendations for systematic
reviews and meta-­analyses
In the future, reviewers should consider following the
below-­given criteria whilst conducting and reporting sys-
tematic reviews and meta-­analyses:
1. Authors have to provide the rationale for their selection
of the study designs for inclusion in the systematic
review.
2. Authors have to provide a list of excluded studies, with
justification. Studies excluded without good justifica-
tion could introduce bias in the findings.
3. Authors must report the sources of funding for the stud-
ies included in the systematic review. It is observed that
commercially funded studies favour the product of inter-
est compared with independently sponsored studies. The
funding information can be used to categorize and com-
pare the results to identify any skewness in the results.
4. The effect of risk of bias of the included studies should
be taken into consideration in the results' discussion,
analysis, conclusions and recommendations formu-
lated in the review (Moher et al., 2009; Shea et al., 2017).
5. Authors have to perform an adequate investigation of
publication bias (small study bias) and discuss its likely
impact on the results of the systematic review.
CON C LUS I ON S
Overall, the Endodontic literature has a small number of
poorly conducted primary clinical studies related to the
role of genetic polymorphisms in the pathogenesis of AP.
To date, based on earlier studies on humans, no candi-
date genes could be identified as a definitive genetic risk
   |
   711
or protective factor for the development and progression
of AP, and further GWASs are warranted. Moreover, pri-
mary clinical studies are characterized with significant
methodological inconsistencies, including small or inad-
equate sample size, unmatched study groups, different
eligibility criteria, studies performed on different eth-
nic populations, etc. Consequently, the results of meta-­
analyses in previous systematic reviews are characterized
by very high heterogeneity and should be interpreted with
substantial caution. This investigation offered future rec-
ommendations for primary clinical studies, systematic re-
views and meta-­analyses that should be followed in order
to provide more reliable evidence of genetic risk factors
for the development and progression of AP.
CONFLICT OF INTEREST
The authors deny any conflicts of interest related to this
study.
AUTHOR CONTRIBUTION
AJ, JJ, ACG, NN, AA, SVW and VN conceptualized and de-
signed the study, contributed to material preparation, data
collection, analysis and final approval of the manuscript.
AJ, AA, VN prepared the first draft of the manuscript.
ETHICAL APPROVAL STATEMENT
The study did not require ethics approval.
DATA AVAILABILITY STATEMENT
The data that supports the findings of this study are avail-
able in the supplementary material of this article.
ORCID
Aleksandar Jakovljevic  https://orcid.
org/0000-0001-6512-4934
Jelena Jacimovic  https://orcid.org/0000-0002-6537-7269
Athina Christina Georgiou  https://orcid.
org/0000-0001-7198-5909
Nadja Nikolic  https://orcid.org/0000-0002-8513-9313
Anita Aminoshariae  https://orcid.
org/0000-0001-8399-9988
Suzette V. van der Waal  https://orcid.
org/0000-0002-6407-3714
Venkateshbabu Nagendrababu  https://orcid.
org/0000-0003-3783-3156
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How to cite this article: Jakovljevic, A., Jacimovic,
J., Georgiou, A.C., Nikolic, N., Aminoshariae, A. &
van der Waal, S.V. et al. (2022) Single nucleotide
polymorphisms as a predisposing factor for the
development of apical periodontitis—­An umbrella
review. International Endodontic Journal, 55,
700–713. Available from: https://doi.org/10.1111/
iej.13756