Clinical Oral Investigations (2021) 25:5613–5627

https://doi.org/10.1007/s00784-021-04074-5

REVIEW

Genetic variation involved in the risk to external apical root resorption

in orthodontic patients: a systematic review
Liz Helena Moraes Pinheiro1 · Ludmila Silva Guimarães1 · Leonardo Santos Antunes1,2 · Erika Calvano Küchler3 ·
Christian Kirschneck3 · Lívia Azeredo Alves Antunes1,2,4

Received: 25 January 2021 / Accepted: 8 July 2021 / Published online: 15 August 2021
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
Objective To perform a systematic review/meta-analysis to elucidate the scientific basis for the association between genetic
variations and risk of external apical root resorption (EARR) in orthodontic patients.
Materials and methods Four databases (PubMed, Web of Science, Scopus, LILACS) were electronically searched until
November 22, 2020, followed by manual and gray literature search. Case-control or cross-sectional studies that evaluated
genes involved in the susceptibility of orthodontic patients to EARR were eligible. Two reviewers applied the inclusion
and exclusion criteria, extracted qualitative data, as well as assessed methodological quality using instrument proposed for
genetic studies. For synthesis results, narrative and quantitative data (meta-analysis) were performed. The certainty of the
evidence was tested using the GRADE Working Group approach.
Results Of 201 articles in total, 16 studies were included in the review. Of these, 11 presented moderate and 5 of high
methodological quality. In the narrative analysis, from 16 studies, 15 studies (10 genes) showed a significant association
with EARR and 9 studies were included in the meta-analysis. Only the polymorphism rs208294 in P2RX7 (dominant model)
was associated with EARR (OR = 0.52, 95%CI = 0.29–0.95, p = 0.03) and presented a very low certainty of the evidence.
Conclusion Narrative analyses of individual studies demonstrated an association of many genes. The number of studies
for each genetic variation was very low, and methodological heterogeneity between the studies was observed. Quantitative
analyses (meta-analysis) could only show an involvement for P2RX7 (rs208294) in the risk of orthodontic patients to EARR
at a very low certainty of evidence. (CRD42018085411).
Clinical relevance The knowledge regarding the molecular aspects involved in the etiology of EARR will allow orthodontists
to use a personalized treatment and early diagnosis of risk patients. This systematic review demonstrates that more studies
are necessary to unravel the role of genetic variation for patients’ risk to EARR during orthodontic tooth movement.

Keywords Genetic polymorphism · Orthodontics · Root resorption · Systematic review

* Lívia Azeredo Alves Antunes

liviaazeredo@gmail.com
1
Postgraduate Program in Dentistry of Niterói,
Faculty of Dentistry, Federal Fluminense University,
Niterói, Rio de Janeiro, Brazil
2
Postgraduate Program in Dentistry, Department of Specific
Formation, School of Dentistry, Health Institute of Nova
Friburgo, Fluminense Federal University, Nova Friburgo, RJ,
Brazil
3
Department of Orthodontics, University Medical
Centre of Regensburg, Franz‑Josef‑Strauss‑Allee 11,
93053 Regensburg, Germany
4
Department of Specific Formation, School of Dentistry,
Fluminense Federal University, St. Doutor Silvio
Henrique Braune 22, Centro ‑ Nova Friburgo,
28625‑650 Rio de Janeiro, Brazil
Introduction
External apical root resorption (EARR) can be a negative
consequence or side effect of dental trauma or endodontic,
periodontal, or orthodontic treatment [1]. EARR is unpre-
dictable and can have serious impact on the dentition. In
some cases, the root decreases in its length until it reaches
the point of compromising the masticatory support per-
formed by the tooth and may even cause tooth loss [2–4].
Tooth movement during orthodontic treatment requires a
continuous application of forces, and consequently, there is a
response of the periodontal, bone, and dental tissue to these
forces. The basis of orthodontic treatment is closely related
to the clinical application of the concepts of biomechanics

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[3]. The applied force and duration of orthodontic treatment
have been pointed out as one main cause of EARR [2–5].
However, numerous other factors were associated with a
higher risk to EARR, such as age, sex, type of malocclu-
sion, root morphology, tooth loss and mechanics of retrac-
tion, consequences of orthodontic movements, and also the
genetic polymorphisms [2–4, 6, 7].
Genetic polymorphisms are variations in the DNA
sequence [6, 7]. Previous studies found an association
between genetic polymorphisms in different genes, such
as IL-1A, IL -1B, IL1RN, IL -6, SPP1, P2RX7, IRAK1,
OPG, RANK, and RANKL, and the susceptibility to
EARR after orthodontic treatment [1, 2, 4–14]. Previous
systematic reviews evaluating the association between genetic
polymorphisms and EARR were published between 2013
and 2018 [15–17]. However, due to the increasing scientific
evidences, new articles were published [14, 18, 19] and
new methods of systematic review synthesis emerged in the
literature [20]. Therefore, in this article we aimed to present a
contemporary systematic review with a well-designed and also
updated methodology to systematically identify and evaluate the
existing evidence in order to critically appraise the association
between genetic variations and EARR in orthodontic patients.
Systematic reviews are most helpful, if they are up-to-date
[21]. Therefore, this article aimed to present a contemporary
systematic review with well-designed and also updated
methodology to systematically identify and evaluate the existing
evidence in order to critically appraise the association between
genetic variations and EARR in orthodontic patients.
Materials and methods
Protocol and registration
This systematic review and meta-analysis were designed
according to the Cochrane Handbook for Systematic
Reviews recommendations [20]. A protocol was regis-
tered and can be assessed at the PROSPERO database
(CRD42018085411) (http://​www.​crd.​york.​ac.​uk/). This
systematic review was written according to the guidelines
of the Preferred Reporting Items for Systematic Reviews
(PRISMA 2020) [22]. A focused question was structured:
Is there an association between genetic variations and the
presence/severity of EARR in orthodontic patients?
Eligibility criteria
We included case–control or cross-sectional studies that
include a control group written in any language. The inclu-
sion criteria were as follows:
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Clinical Oral Investigations (2021) 25:5613–5627
Population (P): patients who received orthodontic
treatment
Exposition (E): the presence of a risk genotype/allele
in the studied genetic variants
Comparison (C): absence of the risk genotype/allele
Outcome (O): EARR​
Case reports, systematic reviews, book chapters, guide-
lines, studies evaluating parents and siblings, and animal and
in vitro studies were excluded.
Information sources and search strategy
A broad literature search was performed until November
22, 2020, in the following databases: MEDLINE (PubMed),
Web of Science, Scopus, and LILACS. MeSH (Medical Sub-
ject Headings) terms (https://​www.​ncbi.​nlm.​nih.​gov/​pub-
med), related terms, and free terms were used for MEDLINE
(PubMed) and Health Sciences Descriptors terms (http://​
decs.​bvs.​br) for LILACS. The Boolean operators “AND”
and “OR” were applied to combine the keywords (Supple-
mentary Table 1). The search was also conducted in gray
literature via OpenGrey (http://w
​ ww.o​ pengr​ ey.e​ u). A manual
search was done in the reference of the selected articles.
Selection process
All papers selected in the search strategy were saved in auto-
matic metadata and a reference manager software (Mendeley
Desktop, Londo, Mendely Ltd./Elsevier, version 1.19.4) to
remove the articles in duplicate. Two independent reviewers
(LHMP and LSG) performed the selection of the articles
and compared the results achieved. The articles that gener-
ated disagreement among the reviewers were discussed and
reviewed by a third author (LSA), reaching an agreement.
To evaluate the level of concordance between authors, 10%
of the publications were randomly selected and had their
rank compared determining a kappa statistic of 0.90. Stud-
ies with unclear abstract and title were read in its entirety to
minimize the possibility of disregarding important studies.
Subsequently, we accessed the full texts of potentially eli-
gible articles, and the inclusion and exclusion criteria were
reapplied as previously reported. A manual search of article
reference lists was done to complement the electronic search.
Data collection process and data items
Data extractions and qualitative analyses from the selected
studies were independently performed by two investigators
(LHMP and LSG). Doubts were solved in consensus meet-
ing with a third author (LSA). The data from the included
studies were compiled and organized according to sample
characterization of selected studies, type of orthodontic
Clinical Oral Investigations (2021) 25:5613–5627
treatment, and description of the investigated genetic
polymorphisms.
During the selection and extraction of data, contact with
the authors was established via email in case of missing or
unclear information, doubts, or lack of information. If the
authors contacted did not provide the requested data or did
not respond to the email within 40 days, the study would be
included only in the qualitative analysis.
Study risk of bias assessment
The selected studies selected were evaluated by two inde-
pendent investigators (LHMP and LAAA, kappa = 0.80).
We used a 10-point scoring sheet proposed by Clark and
Baudouin [23] with “1” meaning criterion present and “0”
criterion absent. After evaluation, a final quality score was
obtained by summing up each component, obtaining a rela-
tive percentage. Based on the score, the studies were clas-
sified into three categories: (i) high methodological quality
(low risk of bias), presenting 8 or more criteria; (ii) moder-
ate methodological quality (moderate risk of bias), present-
ing 5–7 criteria; (iii) low methodological quality (high risk
of bias), presenting 4 or less evaluated criteria.
During study risk of bias assessment if it presents miss-
ing results in a synthesis, a contact was also established as
previously reported.
Effect measures, synthesis methods and reporting
bias assessment
The extracted data were the frequency of each genotype and
allele. The models of analyses were established prior to the
overall analysis of the outcome according to (A) allele; (B)
dominant model; (C) recessive model. For the meta-analysis,
the odds ratio (OR) and 95% confidence interval (CI) were
estimated and used to evaluate the association between the
genetic variations and the presence/severity of EARR in
orthodontic patients.
The choice of effect models was made by analyzing the
clinical, methodological, and statistical heterogeneity of the
included studies. The heterogeneity was considered in this
study, the studies are carried out in different populations,
and a random effect was used. The calculation of the meta-
analysis and the creation of forest plots were performed with
RevMan 5.3. In forest plots, p < 0.05 was considered for the
general effect test.
In cases of covariables influencing the stability of the
main outcomes, sensibility analysis or meta-regression was
planned. In meta-regression, the number of covariates to be
included is limited to the number of studies considered in
the meta-analysis [24]. If the sum of included studies of an
outcome exceeded ten, funnel plots were also generated to
analyze publication test [25].
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Certainty assessment
Two reviewers (LHMP and LAAA) independently ana-
lyzed these evaluations. The quality of the evidence (cer-
tainty in the estimates of effect) was determined for the out-
come using the Grading of Recommendations Assessment,
Development and Evaluation (GRADE) approach. GRADE
defines the certainty of scientific evidence more clearly and
objectively and can be classified as high, moderate, low, or
very low. Observational studies start as low confidence and
can be rated down if the detected problem was related to risk
of bias, indirectness of the evidence, inconsistency, impreci-
sion, and publication bias. However, observational studies
can be upgrading for dose effect, large estimates of accuracy,
and residual plausible confounding [26].
Results
Study selection
The flowchart of the research strategy is presented in Fig. 1.
In MeSH (Medical Subject Headings) terms from 201
records identified via database, gray literature, and manual
search, 80 were removed as duplicates, and 121 records were
evaluated by title and abstract. No articles was included from
gray literature or hand search. After the exclusions, the full
text of 36 articles was screened, 20 excluded (reasons pre-
sented on Supplementary Table 2), and 16 studies included
in the qualitative evaluation [4–14, 18, 19, 27–29]. Nine
articles could be included in the quantitative analysis (meta-
analysis) [4, 6–10, 13, 18, 29].
Study characteristics
Data extraction and study characterization are described
in Tables 1 and 2. Studies included samples from different
populations/ethnicities: samples from the USA [10], from
Spain [6, 7, 28, 30], from the Czech Republic [4, 13], from
Portugal [5, 12], from Brazil [9, 14, 27], from China [11],
from Japan [26], from Germany [8], and from Iran [29]. The
sample size ranged from 54 patients [6, 27] to 462 patients
[19].
Table 1 reports orthodontic treatment characteristics.
All studies used fixed orthodontic appliances. Only two
articles [5, 12] used functional orthopedic devices and
fixed orthodontic appliances. Three articles did not report
data regarding the Angle classification of the skeletal
malocclusion [8, 10, 18]. All articles evaluated maxillary
teeth, with mandibular teeth additionally studied in only
one study [27]. Regarding the imaging exam diagnostic
methods, only one study used cone beam computed tomog-
raphy (CBCT) [11], whereas three studies used periapical
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Identification of studies via databases and registers Identification of studies via other methods

Records identified from: Records removed before

Identification

Databases (n = 201)* screening**:

Registers (n = 0) Duplicate records removed Records identified from:
(n = 80) Citation searching (n = 0)
* MEDLINE (PubMed) (n=58), Web of
**No automation tools were used for
exclusion and no records were removed for
Gray literature (n = 0)
Science (n=49), Scopus (n=92) and Lilacs other reasons.
(n=2)

Records excluded**
Records screened (n = 85)
(n = 121) n Main reason
12 In vitro studies
11 Animal studies
23 Literature reviews
3 Systematic review
Reports sought for retrieval 36 Outside of proposed theme
(n = 0)
Screening

Reports assessed for eligibility

(n = 36) Reports excluded:
(n = 20)
(reason on supplemental
table 2)

Studies included in review

Included

(n = 16)
Reports of included studies
(n = 0)

Fig. 1  PRISMA 2020 flow diagram for new systematic reviews that included searches of databases, registers, and other sources

exams [9, 14, 28] and the remaining studies lateral cepha-
lometric and/or panoramic radiographs.
The methods used to measure root resorption were
according to Harris et al. [30]; Linge and Linge’s method
[31, 32], as well as Linge and Linge’s method modified
by Brezniak [33], in the remaining studies [8, 14, 27, 28],
except for Guo et al. [11], who did not report the methods
used to assess EARR.
Risk of bias in studies
In Table 2, data related to the evaluation of study quality
were compiled. Five studies showed high methodologi-
cal quality (low risk of bias), and eleven showed moder-
ate methodological quality (moderate risk of bias). The
major problem detected was the absence of blinding and
the use of Bonferroni’s correction to avoid error type I
(false positive).
Present assessments of risk of bias due to missing
results were not presented for each synthesis assessed.
Results of syntheses: results of individual
studies (narrative syntheses)
Table 3 presents the qualitative description of the genes
and genetic polymorphisms of the included studies. Thir-
teen candidate genes (62 genetic polymorphisms in these
genes) were evaluated. Iber-Diaz et al. [19] investigated
14,714 genetic polymorphisms at chromosomes 2, 4, 8,
12, 18, X, and Y. IL1B (rs1143634) and IL1A (rs1800587)
were the genes most frequently evaluated [6–9, 18]. Except
for Tomoyasu et al. [27], the other studies showed a sig-
nificant association between EARR and genetic polymor-
phisms (rs12455775, rs3102724, rs2875845, rs1032128,
rs3102728, rs1143634, rs1800587, rs419598, rs9005,
rs1800796, rs1718119, rs208294, rs9138, rs11730582,
rs1059703, and rs731236) in 10 candidate genes (RANKL,
OPG, IL1B, IL1A, IL1RN, IL6, P2RX7, SSP1, IRAK1,
and VDR). Genetic polymorphisms located at chromo-
somes X and Y were also associated, particularly STAG2
rs1511846350 and RP1-30E17.2 rs55839915 using GWAS

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 Table 1  Sample characteristics of the selected studies
Author/year Population (eth- Sample (N) and study Mean age (SD) Orthodontic tech- Methods used to Imaging exams Evaluated Tooth/ Angle malocclusion
nicity) design nique detect EARR​ teeth

Gülden et al., Germany (NR) N = 258 NR NR Linge and Linge’s Orthopantomo- Canines, premo- NR
2009 [8] EARR = 96 method (1983) grams scanned lars and molars
Control = 162 (mesial and
distal roots)
Lages et al., 2009 Brazilian (Cauca- N = 61 18.9 (5.2) Straight wire Linge and Linge’s Periapical Maxillary incisors Class I
[9] sian) EARR = 23 method (1991) (central and Class II
Control = 38 modified by lateral) Class III
Brezniak (2004)
Tomoyasu et al., Japanese (Japa- N = 54 NR NR According to Har- Lateral cephalo- Maxillary and Class I
2009 [27] nese) Case ris et al., 1997 metric mandibular cen- Class II
Clinical Oral Investigations (2021) 25:5613–5627

(EARR > 2.0 mm) = NR Panoramic radio- tral incisors Class III
Control graphs Mandibular first
(EARR < 2.0 mm) = NR molar mesial
root and distal
root
Fontana et al., Brazilian (Cauca- N = 377 14.9 (-) Edgewise or According to Periapical radio- Maxillary central Class II, division 1
2012 [28] sian) EARR = straight wire Linge and graphs incisors
Control = 38 techniques Linge’s method
(1991)
Iglesias-Linares Spain (Caucasian) N = 54 NR Straight wire According to Lateral cephalo- Maxillary incisors Class I
et al., 2012 [7] EARR = 25 Linge and metric (central and Class II
Control = 29 Linge’s method Panoramic radio- lateral) Class III
(1991) modi- graphs
fied by Brezniak
(2004)
Iglesias-Linares Spain (Caucasian) N = 73 23.78 (5.91) Straight wire According to Lateral cephalo- Maxillary premo- Class I
et al., 2012 [6] EARR = 30 Linge and metric lars (vital and Class II
Control = 43 Linge’s method Panoramic radio- root filled teeth. Class III
(1991) modi- graphs Split-mouth and
fied by Brezniak parallel group
(2004) design)
Linhartova et al., Czech Republic N = 106 15.2 (5.0) Straight wire or Linge and Linge’s Lateral cephalo- Maxillary incisors Class I
2013 [4] (NR) EARR = 32 segmental tech- method (1991) metric (central and Class II
Control = 74 nique modified by Panoramic radio- lateral) Class III
Brezniak (2004) graphs
Pereira et al., 2014 Portuguese (Cau- N = 195 (before and after 17.24 (6.8) Hyrax and straight Linge and Linge’s Lateral cephalo- Maxillary incisors Class I
[5] casian) treatment) wire method (1991) metric (central, lateral) Class II
modified by Panoramic radio- Maxillary canines Class III
Brezniak (2004) graphs

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 Table 1  (continued)
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Author/year Population (eth- Sample (N) and study Mean age (SD) Orthodontic tech- Methods used to Imaging exams Evaluated Tooth/ Angle malocclusion
nicity) design nique detect EARR​ teeth

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Iglesias-Linares Spain (Caucasian) N = 87 EARR: 24.7 Straight wire Linge and Linge’s Lateral cephalo- Maxillary incisors Class I
et al., 2014 [29] EARR = 37 (5.95) method (1991) metric (central, lateral) Class II
Control = 50 Control: 23.8 modified by Panoramic radio- Class III
(5.33) Brezniak graphs
(2004)
Sharab et al., 2015 USA (Caucasian) N = 134 EARR: 15.78 Edgewise Malmgren et al. Panoramic Maxillary incisors NR
[10] EARR = 67 (1.13) (1982) radiographs— (central, lateral)
Control = 67 Control: 15.79 occlusal
(1.14)
Guo et al., 2016 Han Chinese (NR) N = 174 (root resorption 14.07 (3.1) Straight wire NR Cone beam com- Maxillary incisors Class I
[11] volume) puted tomog- (left central) Class II
raphy Class III
Pereira et al., 2016 Portuguese (Cau- N = 195 (before and after 17.24 (6.8) Hyrax and straight Linge and Linge’s Lateral cephalo- Maxillary incisors Class I
[12] casian) treatment) wire method (1991) metric (central, lateral, Class II
modified by Panoramic radio- and canines) Class III
Brezniak (2004) graphs
Borilova Lin- Czech Republic N = 99 EARR: 14.6 (3.2) Fixed orthodon- Linge and Linge’s Lateral cephalo- Maxillary incisors Class I
hartova et al., (Caucasian) EARR = 30 Control: 15.2 tic appliance method (1991) metric (central, lateral) Class II
2017 [13] Control = 69 (5.3) therapy modified by Panoramic radio- Class III
Brezniak graphs
Castilhos et al., Brazilian (Cauca- N = 338 14.9 Edgewise and Linge and Linge’s Periapical radio- Central incisor Class II, division 1
2019 [14] sian) EARR = 178 Straight Wire method (1991) graphs teeth with the
Control = 160 longer root
Benhnaz et al., Iran (NR) N = 140 17.34 ± 5.29 Straight wire or Linge and Linge’s Lateral cephalo- Maxillary incisor NR
2020 [18] EARR = 58 17.5 ± 6.23 segmental tech- method (1991) metric
Control = 82 nique modified by Panoramic radio-
Brezniak graphs
Iber-Diaz et al., Spain (NR) N = 462 EARR: Fixed orthodon- Linge and Linge’s Lateral cephalo- Maxillary central Class I
2020 [19] EARR = 101 21.52 ± 11.65 tic appliance method (1991) metric and lateral inci- Class II
Control = 361 Control: therapy modified by Panoramic radio- sors Class III
22.83 ± 11.66 Brezniak graphs

NR not reported, EARR​external apical root resorption

Clinical Oral Investigations (2021) 25:5613–5627
 Table 2  Assessment of risk of bias of included studies
Criteria evaluated Control Hardy–Wein- Case group Primer* Repro- Blinding Power Statistics Corrected Independent Score Meth-
group berg equilib- ducibility calcula- statistics replication odological
rium tion quality

Gülden et al., 2009 [8] 1 1 1 1 0 0 1 1 0 1 7 M

Lages et al., 2009 [9] 1 0 1 1 1 0 1 1 0 1 7 M
Tomoyasu et al., 2009 [27] 1 1 1 1 0 0 1 1 0 1 7 M
Fontana et al., 2012 [28] 0 1 1 1 1 0 1 1 0 0 6 M
Iglesias-Linares et al., 2012 [6] 1 0 1 1 1 0 1 1 0 1 7 M
Clinical Oral Investigations (2021) 25:5613–5627

Iglesias-Linares et al., 2012 [7] 1 0 1 1 1 0 1 1 0 1 7 M

Linhartova et al., 2013 [4] 1 1 1 1 1 1 1 1 0 1 9 H
Iglesias-Linares et al., 2014 [29] 1 1 1 1 1 0 1 1 0 1 8 H
Pereira et al., 2014 [5] 0 1 1 1 1 0 1 1 0 1 7 M
Sharab et al., 2015 [10] 1 1 1 1 1 0 1 1 1 1 9 H
Guo et al., 2016 [11] 0 0 1 1 1 0 1 1 1 1* 7 M
Pereira et al., 2016 [12] 0 1 1 1 1 0 1 1 0 1* 7 M
Borilova Linhartova et al., 2017 [13] 1 1 1 1 1 0 1 1 0 1* 8 H
Castilhos et al.2019 [14] 1 1 1 1 1 0 1 1 0 1 8 H
Benhanz et al., 2020 [18] 1 1 1 1 0 0 1 1 0 1 7 M
Iber –Diaz et al., 2020 [19] 1 0 1 1 1 0 0 1 0 0 5 M

M moderate quality (moderate risk of bias), H high quality (low risk of bias)
*
Criteria for quality assessment of the selected articles, adapted from Clark and Baudouin (2006) and Lips et al. (2017); “1” means present and “0” absent
Control group, if there is a control group without EARR​
Hardy–Weinberg equilibrium, acceptable studies if their groups were in Hardy–Weinberg equilibrium
Case group, defined with sufficient details to allow its replication (inclusion and exclusion criteria)
Primer, primer sequence published in the paper or report to use commercial TaqMan
Reproducibility, provide a reference to allow replication such as genotyping method or EARR evaluation
Blinding, adequate studies performed the genotyping while blind to the clinical status of the patient
Power calculation, the data were sufficiently available to detect a significant difference in genomic frequency between case and control groups at the 0.05 level, and it was calculated for allelic
and genomic associations
Statistics, present their major findings with described tests of significance including p values
Corrected statistics, if a study examined two or more SNPs, the presence of Bonferroni’s correction was acceptable to avoid error type I (false positive)
Independent replication, studies that either performed as a confirmatory study or were specifically designed to confirm earlier polymorphism studies in different populations.* Studies that
included genes not evaluated previously and genes to confirm earlier polymorphism studies were considered as “1”

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Table 3  Description of the selected studies—genetic polymorphisms evaluated and associated

Authors/year Genes and genetic polymorphisms evaluated Genetic polymorphism in association with EARR​

Gülden et al., 2009 [8] IL1A (rs1800587) IL1A (rs1800587)

Lages et al., 2009 [9]
Tomoyasu et al., 2009 [27]
Fontana et al., 2012 [28]
Iglesias-Linares et al., 2012 [7] IL1A (rs1800587)
Iglesias-Linares et al., 2012 [6] IL1 A (rs1800587)
Linhartova et al., 2013 [4]
Iglesias-Linares et al., 2014 [29] OPN genes SSP1 (rs9138/ rs11730582)
Pereira et al., 2014 [5]
Sharab et al., 2015 [10]
Guo et al., 2016 [11]
Pereira et al., 2016 [12]
Borilova Linhartova et al.,
2017 [13]
Castilhos et al. 2019 [14]
Benhnaz et al., 2020 [18]
Iber-Diaz et al., 2020 [19]
IL1B (rs1143634)
IL1B (rs1143634) IL1B (rs1143634)
IL1B (rs1143634) -
*VDR (rs731236-TaqI) VDR (rs731236)
IL1B (rs1143634)
IL1B (rs1143634) IL1RN (rs419598)
IL1RN(rs419598)
IL1B (rs1143634)
IL1B (rs1143634)
IL1A(rs1800587) IL1RN (rs9005)
IL1B (rs1143634)
IL1RN (rs9005)
SPP1(rs9138 and rs11730582)
OPG or TNFRSF11B (rs3102735) P2RX7 (rs1718119)
RANK or TNFRSF11A (rs1805034)
IL1B (rs1143634)
P2RX7 (rs1718119)
P2RX7 (rs208294, rs1718119, and rs2230912) P2RX7 (rs208294)
*CASP1 (rs580253, rs554344, and rs530537)
IL1B (rs1143634)
IL1A (rs1800587)
IL1RA (IL1RNrs419598)
*IL6 (rs1800796) IL-6 (rs1800796)
IL1RN (rs419598)
IL1B (rs1143634) IRAK1 (rs1059703)
IL1RN (rs315952)
*IRAK1 (rs1059703)
*IL17A (rs2275913) P2RX7
P2RX7(rs208294/rs1718119) (rs208294 and rs1718119)
OPN genes SPP1(rs9138/rs11730582)
OPG or TNFRSF11B (rs2073618 and rs3102735)
RANKL or TNFSF11 (rs1038434, rs3742257, OPG or TNFRSF11B (rs3102724, rs2875845,
rs931273, and rs12585229) rs1032128, and rs3102728)
RANK or TNFRSF11A (rs7233197, rs4941125, RANKL (rs12455775)
rs4485469 and rs4941129, rs7237982, rs8086340,
rs4500848, rs17069845, rs12956925, rs9951012,
rs8083511, rs17720953, rs12455775, rs3826620,
rs7236060, rs6567272, rs4524034, rs12970081,
rs8099222, rs7239667, rs17069898, rs17069902,
rs8089829, rs17069904, and rs12959396,
rs4426449)
OPG or TNFRSF11B (rs11573938, rs3102724,
rs11573884, rs2875845, rs1032128, rs3134057,
rs1485289, rs3134060, rs3102728, rs11573856,
rs7010267, and rs11573901)
IL1A (rs1800587) IL1B (rs1143634)
IL1B (rs1143634)
14,714 genetic polymorphism at *chromosomes 2, 4, Genetic polymorphism located at chromosomes X and
8, 12, 18, X, and Y Y. Particularly, STAG2 (rs1511846350 and RP1-
30E17.2 (rs55839915)

EARR​, external apical root resorption; IL(-1A -1B, -RN, -6, 17), interleukin α(-β, -receptor antagonist); P2XR7, purinoreceptor P2X7; OPN,
osteopontin; SPP1, secreted phosphoprotein 1 or osteopontin; RANKL, receptor activator of nuclear factor kappa-Β; RANK or TNFRSF11A,
tumor necrosis factor receptor superfamily member 1­ 1A; OPG or TNFRSF11B, tumor necrosis factor receptor superfamily member 11B; IRAK1,
interleukin 1 receptor–associated kinase; CASP1, caspase-1/interleukin-converting enzyme
*
Genes/genetic polymorphism studied only once

13
Clinical Oral Investigations (2021) 25:5613–5627
technique (genotyped using the high-throughput Axiom
platform with the GeneTitan).
Results of syntheses: meta‑analysis (quantitative
syntheses)
A meta-analysis was performed to combine comparable
results. Seven studies were not included, studies evaluating
before and after the treatment without a control group [5,
11, 12, 27] and studies without comparable results [14, 27,
30]. Meta-analysis was performed with 9 studies [4, 6–10,
13, 18, 29] evaluating the 7 polymorphisms in 5 genes as
follows: P2RX7 (rs208294 and rs1718119), SPP1 (rs9138
and rs11730582), IL1A (rs1800587), IL1B (rs1143634), and
ILIRN (419,598).
Figures 2, 3, and 4 present the forest plots for genotypes
and allelic distributions of these genes. Only one association
(OR = 0.52, 95%CI = 0.29–0.95, p = 0.03) was observed for
the distribution of the P2RX7 genotype rs208294 in a domi-
nant model, as shown in Fig. 3.
This study did not have enough covariables to perform
the meta‑regression or sensitivity analysis. Publication bias
cannot be assessed once there were no subgroup analyses.
Certainty of the evidence
For gene P2RX7 (rs208294) that presented statistical sig-
nificance (Fig. 3), the certainty of the evidence was very
low (Supplementary Table 3). For the other genes (P2RX7
rs1718119; SSP1 rs9138 and rs11730582; IL1A rs1800587;
IL1B rs1143634; and ILIRN 419,598), the certainty of the
evidence was also very low for analyses of polymorphisms
(Supplementary Tables 3 to 9). Major problems were few
events, small sample size, and considerable heterogeneity
across studies.
Discussion
Original and relevant findings
Advances in genetic studies have contributed to the search
for EARR-related genes in the context of orthodontic tooth
movement. As noted in previous studies [15–17], there
was no scientific evidence of possible genes involved in
the susceptibility to EARR in consequence of orthodontic
tooth movement. According to these authors, there is still
a gap in the literature on the association of genetic poly-
morphisms with EARR as consequence of orthodontic tooth
movement. In this systematic review and meta-analysis,
we found 16 articles. These papers found an association
in 10 different specific genes (RANKL, OPG, IL1B, IL1A,
IL1RN, IL6, P2RX7, SSP1, IRAK1, and VDR) as well as
5621
genetic polymorphisms located at chromosomes X and
Y, particularly STAG2 (rs1511846350) and RP1-30E17.2
(rs55839915). From these, 5 genes (7 genetic polymor-
phisms) were included in the meta-analysis, and only one
genetic polymorphism (rs208294 in P2RX7) was associated
with EARR. Thus, the findings of this systematic review and
meta-analysis are different from previous reports and sup-
port that P2RX7 gene (rs208294) is involved in susceptibil-
ity to EARR in orthodontic patients. However, this finding
was a preliminary result needing more studies to detect this
association.
Critical appraisal of the investigation itself:
limitations and positive aspects
The probability of risk of bias in the selection of studies is
low, as the search was performed either manually or using a
considerable number of databases for all bibliographic ref-
erences of the selected articles. We also checked the gray
literature to identify unpublished and ongoing studies and
included all languages as well. In addition, we used common
MeSH terms and keywords from articles published in the
area in order to minimize sources of inconsistency and the
possibility of not finding potentially eligible studies.
To evaluate individual studies, the present systematic
review and meta-analysis demonstrated a great scientific
basis of studies of moderate and high methodological qual-
ity, thus presenting a low risk of bias using the quality
assessment proposed by Clark and Baudouin [23] for genetic
studies. To evaluate the studies’ outcomes, we applied the
GRADE approach, providing certainty of the evidence of the
present systematic review and meta-analysis not applied in
previous studies [15–17]. The certainty of the evidence of
genetic polymorphism (rs208294 in P2RX7) associated with
EARR was very low. The number of studies for each genetic
variation was very low; 2 studies [10, 13] were considered
little evidence available for this association.
Publication bias could not be detected due to the small
number of papers included in the meta-analysis subgroup.
However, in a qualitative analysis of publication bias, we did
not detect one study that differs systematically from other
studies. Thus no upward bias in the summary effect from
studies with larger than average effects, which are more
likely to be published, is to be expected.
Critical comparison with relevant literature
In qualitative analyses of the studies’ findings, 10 genes
were involved in susceptibility to EARR as a consequence
of orthodontic tooth movement. Interleukins were the group
of genes that were most explored and associated with EARR
[4, 6–9, 11, 13, 18]; however in the meta-analyses, the inter-
leukins were not associated with EARR.
13
5622 Clinical Oral Investigations (2021) 25:5613–5627

a
P2RX7 (rs208294)

P2RX7 (rs1718119)

SPP1 (rs9138)

SPP1 (rs11730582)

IL1A (rs1800587)

IL1B (rs1143634)

IL1RN (rs419598)

Fig. 2  Gene frequency regarding allele

13
Clinical Oral Investigations (2021) 25:5613–5627 5623

b
P2RX7 (rs208294)

P2RX7 (rs1718119)

SPP1 (rs9138)

SPP1 (rs11730582)

IL1A (rs1800587)

IL1B (rs1143634)

IL1RN (rs419598)

Fig. 3  Gene frequency regarding dominant model

13
5624 Clinical Oral Investigations (2021) 25:5613–5627

c
P2RX7 (rs208294)

P2RX7 (rs1718119)

SPP1 (rs11730582)

SPP1 (rs9138)

IL1A (rs1800587)

IL1B (rs1143634)

IL1RN (rs419598)

13
 Clinical Oral Investigations (2021) 25:5613–5627
◂Fig. 4  Gene frequency regarding recessive model
Interleukins are expressed during orthodontic tooth
movement [34]. IL1A is processed and released in response
to cell injury, inducing apoptosis, mainly in inflammatory
processes [35]. IL1B is directly linked to the inflammatory
process; therefore, its connection with orthodontic move-
ment occurs due to a local tissue inflammation [36]. Other
interleukins are important in determining the intensity and
duration of the inflammatory response. The gene encoding
IL1RA (IL1RN), a member of the interleukin 1 cytokine fam-
ily, has been linked to a number of inflammatory and auto-
immune diseases, as well as increased resistance to infec-
tions [6]. IL1RA inhibits the activities of IL1A and IL1B and
modulates a variety of interleukin 1–related immune and
inflammatory responses [37]. IL6 is produced in response
to tissue infection and is thus important for host defense
via acute phase stimulation and immunological protection.
However, a continuous and deregulated IL6 synthesis may
have a pathological effect on chronic inflammation and auto-
immunity, with the chronic inflammation factor being more
related to orthodontic mobility [11]. Genetic polymorphisms
in interleukins are the most explored in EARR and ortho-
dontic tooth movement [4, 6–9, 11, 18]. Except for IL1A
(rs1800587) and IL1B (rs1143634), the other interleukins
(IL1RN-rs419598, rs9005; IL6-rs1800796) were evaluated
only in one population and not replicated in independent
populations. This also happened in the majority of the genes
evaluated. The replication of these genes in other/independ-
ent populations is necessary in order to critically appraise
their relation with EARR in orthodontic patients.
IL1B (rs1143634) was the polymorphism most related
to EARR with four articles [6, 7, 9, 18] reporting a statisti-
cal association. It is important to highlight that the results
from different populations are not consistent, as observed
in the present meta-analysis. The population-based differ-
ences might explain discrepancies between these studies.
Type II error due to small sample sizes was observed in
most of these studies. In a previous meta-analysis [15], no
association between genes and EARR was observed, and
the authors suggested additional multicenter and better-con-
trolled investigations to verify their results. Including two
more recent studies [10, 18] in our meta-analysis, the present
results still confirm the absence of scientific evidence and
also affirm that this outcome presents a very low certainty of
the evidence considering the GRADE approach.
A study shows that OPN (osteopontin) is involved in acti-
vation during the root resorption process [38]. Likewise,
the process of regulating odontoclasts can be modulated by
the combination of genes still unknown in associations to
orthodontic tooth movement, which can act as a protective
or a risk factor for EARR [29].
5625
The genetic polymorphism rs1059703 in IRAK1
was associated with EARR in the study performed by
Pereira et al. [12]. IRAK1 is involved in osteoporosis and
decreased bone mineral density [39, 40]. The role of VDR
and osteoporosis or low bone density is well-known. VDR
has also been involved in alveolar bone and tooth loss and
susceptibility to EARR [28].
Among the evaluated genes, P2RX7 should be high-
lighted, once our meta-analysis showed that this gene
could be a biomarker for susceptibility to EARR in ortho-
dontic patients. This gene belongs to the purinoceptor
family. During the compression of the periodontal liga-
ment occurring during orthodontic tooth movement, ATP
(adenosine triphosphate) is released from the surrounding
cells. During the process of extracellular ATP binding, the
purinergic receptor-7 channel (P2RX7) P2X on the surface
of macrophages and monocytes alters its conformation
by creating channels in the cell membrane that facilitate
the exchange of potassium (K), sodium (Na), and/or cal-
cium (Ca) ions from within the cell [10]. During this ion
exchange process, the potassium ions are lost from the
cell, while the other intracellular ions increase. This leads
to the activation of the inflammatory complex inside the
cell containing the enzyme caspase-1 (also known as inter-
leukin-converting enzyme encoded by the CASP1 gene),
influencing EARR.
Generalization, implications, perspectives,
and recommendations
The main objective of this systematic review was to
answer the question proposed and minimize the chance
of type I error, or systematic error, by eliminating studies
with a high risk of bias and reducing publication bias.
Among the 16 studies detected, 10 genes were involved
in susceptibility to EARR in orthodontic patients, five
genes (seven genetic polymorphisms) could be evaluated
in the meta-analysis, and a dominant model for one gene
(P2RX7—rs208294) demonstrated an association after
the combination of the studies. The meta-analyses were
realized with a little number of studies, so there is little
evidence available for each association. Thus, further stud-
ies on genetic polymorphisms in genes related to EARR
are important in order to identify patients with a higher
risk to develop this detrimental side effect in orthodontic
post-treatment, which is a challenge in clinical practice.
The knowledge regarding the molecular aspects
involved in the etiology of EARR will allow orthodon-
tists to use a personalized treatment and early diagnosis of
susceptible patients. The search for biomarkers identifying
patients most likely to develop severe phenotypes of EARR
ought to accelerate the successful future development of
13
5626
disease-modifying EARR drugs or improvements in the
orthodontic management of patients at a high risk of
EARR.
Conclusion
This systematic review provides new insights regarding the
role of some genetic polymorphisms and EARR in ortho-
dontic patients. Narrative analyses of individual articles
demonstrated an association of many genes. The number
of studies for each genetic variation was very low, and
methodological heterogeneity between the studies was
observed. Quantitative meta-analysis could only show an
involvement for P2RX7 (rs208294) in the risk of orthodon-
tic patients to EARR at a very low certainty of evidence.
However, this updated evidence demonstrates that more
studies are necessary to unravel the role of genetic poly-
morphisms for patients’ susceptibility to EARR during
orthodontic tooth movement.
Supplementary Information The online version contains supplemen-
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 00784-0​ 21-0​ 4074-5.
Author contribution All authors contributed to the study conception
and design. Data collection and analysis were performed by Liz Helena
Moraes Pinheiro, Lívia Azeredo Alves Antunes, Ludmila Silva Guima-
rães, and Leonardo Santos Antunes. The first draft of the manuscript
was written by Liz Helena Moraes Pinheiro and Lívia Azeredo Alves
Antunes. The final draft was written and revised by Lívia Azeredo
Alves Antunes (systematic review methods), Erika Calvano Küchler
(genetic polymorphisms), and Christian Kirschneck (orthodontics), and
all authors commented on previous versions of the manuscript. All
authors read and approved the final manuscript.
Funding This systematic review and meta-analysis study was financed
in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior—Brasil (CAPES)—Finance Code 001 and by the Alexander
von Humboldt Foundation (Küchler/Kirschneck accepted on July 4,
2019).
Declarations
Ethics approval Not applicable.
Informed consent Not applicable.
Conflict of interest The authors declare no competing interests.
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