Mol Biol Rep (2017) 44:443–453

DOI 10.1007/s11033-017-4128-x

REVIEW ARTICLE

Polymorphisms in interleukins 17A and 17F genes

and periodontitis: results from a meta-analysis
Felipe Rodolfo Pereira da Silva1 · Larissa dos Santos Pessoa1 ·
Any Carolina Cardoso Guimarães Vasconcelos1,2 · Weberson de Aquino Lima3 ·
Even Herlany Pereira Alves1 · Daniel Fernando Pereira Vasconcelos1,4

Received: 12 November 2016 / Accepted: 19 September 2017 / Published online: 13 October 2017
© Springer Science+Business Media B.V. 2017

Abstract Polymorphisms in inflammatory genes such as and Begg’s tests in any allelic evaluation. This meta-analysis
interleukins 17A and 17F are associated with the risk of showed a non-significant association between the polymor-
development of periodontitis, although the results remain phisms rs2275913 and rs763780 in interleukins 17A and
contradictory. Hence, the aim of this study was perform a 17F genes and chronic and aggressive periodontitis in the
meta-analysis focusing on two polymorphisms (rs2275913 allelic evaluation.
and rs763780) in interleukins 17A and 17F genes, respec-
tively, in both chronic (CP) and aggressive periodontitis Keywords Cytokines · Chronic periodontitis · Aggressive
(AgP). A review in literature was performed in several periodontitis · Genetic · Genomics · Risk factors
databases for studies published before 25, September 2016.
The meta-analysis was obtained through the review man-
ager statistical software (version 5.2) with odds ratio (OR) Introduction
calculation and funnel plot (P < 0.05) for heterogeneity, as
well as the comprehensive meta-analysis software (version Periodontitis is a highly prevalent immune disorder that
3.3.070) for the assessment of publication bias. Seven arti- affects the supporting tissues around the teeth carrying out
cles with 1540 participants composed the results in which partial or complete loss of dental element due to intense
the mutant allele in the rs2275913 polymorphism did not inflammatory response [1]. The disease receives several
present significant association with the risk of CP or AgP classifications in dental clinics, out of which chronic peri-
(OR 1.56, 95% CI 0.77, 3.15, P = 0.21; OR 1.12, 95% CI odontitis (CP), usually with slower progression, and aggres-
0.05, 23.44, P = 0.94, respectively) nor was the mutant allele sive periodontitis (AgP), with swift progression, stand out
in rs763780 associated with the risk of CP (OR 1.19, 95% CI as the main classifications [2].
0.80, 1.76, P = 0.39) or AgP (OR 1.07, 95% CI 0.63, 1.84, Although periodontitis is caused by bacteria present in
P = 0.79). No bias of publication was observed by Egger’s periodontal sites, being responsible for the initiation of
immune host response, genetic factors are involved in the
pathogenesis and progression of periodontitis allowing tar-
* Daniel Fernando Pereira Vasconcelos get patients to prevent with an early diagnosis [3]. Among
vasconcelos@ufpi.edu.br the several genetic factors associated with periodontitis,
1 there are mainly genes associated with immunoregulatory
Laboratory of Histological Analysis and Preparation
(LAPHIS), Federal University of Piaui, Parnaiba, PI, Brazil molecules, and also among the types of bacterial coloniza-
2 tion in periodontal sites [4, 5].
Medicine School, Education Institute of Parnaiba Valley
(IESVAP), Parnaiba, PI, Brazil Genetic variations have been intensively studied with
3 reports on several recent data in literature about any pos-
Federal University of Rio Grande do Norte, Currais Novos,
RN, Brazil sible association of cytokines such as: IL-1 [6, 7], IL-6 [8]
4 and IL-18 [9] gene polymorphisms and periodontitis. All of
Universidade Federal do Piauí – UFPI, Campus Ministro
Reis Veloso, Colegiado de Biomedicina, Av. São Sebastião, these evaluations were carried out through meta-analysis,
2819, Reis Veloso, Parnaiba, PI 64204‑035, Brazil which is considered as a tool for combining studies with

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divergent results or to solve the problem of small sample
sizes in genetic studies [10]. Another example of genetic
variation in cytokine associated with periodontitis is the
polymorphisms in the interleukin-17 (IL-17) gene family.
This group of cytokine comprehends a family of six dif-
ferent molecules (IL7-A, IL-7B, IL-17C, IL-17D, IL-17E
and IL-17F) in which IL-17A (also known as IL-17) and
IL-17F are the better understood inflammatory mediators
[11]. ­CD4+ T helper cells produce both interleukins, playing
a central role in the pathogenesis of inflammation and auto-
immune diseases and others [12]. The IL-17 is an initiator
of inflammation contributing with the releasing of several
pro-inflammatory mediators in fibroblasts, macrophages,
endothelial and epithelial cells [13]. An in vitro experimen-
tal assay with cell cultures of fibroblasts and periodontal
ligament cells from healthy patients demonstrated that IL-17
enhances the inflammatory response induced by a chaperone
obtained from the periodontopathogen Tannerella forsythia
[14].
These authors showed that chaperone promotes bone
resorption and synergizes with IL-17. In addition, IL-17 was
related to a high cell expression in patients with type-1 leu-
kocyte adhesion deficiency periodontits and inflammatory
bone loss in mice [15]. High levels of IL-17 were found in
the saliva from patients with periodontitis [16] and in gingi-
val crevicular fluid from smoking and non-smoking patients
with CP submitted to initial periodontal treatment [17].
The up-regulation of IL-17 and, consequently, the aber-
rant production of this cytokine contribute to inflammatory
conditions [18], being suggested as a possible candidate
to target during periodontal inflammation [19]. However,
other studies bring divergent findings in which lower levels
of IL-17 were found the in saliva from CP patients com-
pared to controls [20, 21]. The current meta-analysis [22]
suggests that the high levels of IL-17A and IL-17F were
associated with rheumatoid arthritis indicating the role of
these cytokines in inflammatory disease. In addition, this
meta-analysis found a significant association between the
rs763783 polymorphism in IL-17F and the disease.
Studies evaluating genetic variation within IL-17 gene
family are necessary once that such interleukins are a pos-
sible key mediator in periodontal inflammation. In lit-
erature, there are studies focusing on two polymorphisms
(rs2275913—G197A, and rs763780—T7488C), occurring
in IL-17A and IL-17F, respectively, and patients with CP
[23–29], AgP [24–26] and localized aggressive (LAgP)
forms [29]. Nevertheless, so far there is not any meta-anal-
ysis approaching these polymorphisms in patients with the
disease.
This polymorphism was also associated with the severity
of rheumatoid arthritis in a previous case-control study [30],
as well as the rs2275913 polymorphism in IL-17A and the
rs3748067 polymorphism in IL-17F gene carrying out a high
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Mol Biol Rep (2017) 44:443–453
risk of gastric cancer in Chinese patients with Helicobacter
pylori infection [31]. The exact role of these polymorphisms
in inflammatory diseases or periodontitis remains unclear.
Nevertheless, these associations indicate a possible influ-
ence of these genetic variations in the molecular expression
of IL-17.
Likewise, the results about polymorphisms in IL-17A
and IL-17F genes and the risk of periodontitis are contra-
dictory, calling for a better evaluation. Therefore, because
of the lack of this information, the present study aimed to
perform a meta-analysis to evaluate the association between
the rs2275913 polymorphism in IL-17A and rs763780 poly-
morphism in IL-17F with periodontitis.
Materials and methods
This meta-analysis followed the recommended PRISMA
(Preferred Reporting Items for Systematic Reviews and
Meta-Analyses) statement [32].
Eligibility criteria
Articles were included in the current meta-analysis if the
studies met all the following criteria: (1) evaluation of IL-
17A and Il-17F gene polymorphisms with periodontitis; (2)
studies were case/control design; (3) case patients received
diagnosis of chronic, aggressive periodontitis or localized
aggressive periodontitis and control patients had healthy
periodontal evaluation; (4) genotype frequency documented;
(5) diagnosis of the disease confirmed through clinical mani-
festations or radiographic findings as previously described
[33] and; (6) participants enrolled in allelic and genotypic
analysis did not present pregnancy or previous systemic dis-
orders such as diabetes or auto-immune disease.
Search strategy
A comprehensive search in literature was performed by
two investigators for studies that approached the associa-
tion between the rs2275913 and rs763780 polymorphisms
in IL-17A and IL-17F genes with periodontal disease in
humans. China DATABASE, Google Scholar, PubMed and
Web of Science were the medical and scientific databases
used in the literature retrieval. The following combined
keywords or Medical Subject Headings (MeSH) were
used: [(interleukin or cytokine or interleukin-17A or IL-
17A or interleukin-17F or IL-17F) and (genetic variation
or rs2275913 polymorphism or −197A/G polymorphism
or rs763780 polymorphism or −7488 T/C polymorphism
or His161Arg polymorphism) and (periodontitis or peri-
odontal disease or chronic periodontitis or aggressive
periodontitis)]. There was no language restriction in the
Mol Biol Rep (2017) 44:443–453
search strategy that approached studies published before
Aug 25, 2016. The abstracts of the studies found, as well
as their references, were screened by investigators to iden-
tify potential additional studies.
Data collection process
Two investigators independently reviewed all studies and
extracted the data using a standardized form. Data were
collected on the first author, year of publication, ethnic-
ity, country, study design, sample size, polymorphism or
polymorphisms evaluated, whether the allelic and geno-
typic frequencies were according to Hardy–Weinberg
equilibrium (HWE) and subject type. In order to assess
the quality of the studies included, the guidelines for sys-
tematic reviews of periodontal genetic association stud-
ies proposed by Nibali [34] were used, studies with <10
scores were excluded.
Statistical analysis
The statistical analysis of the data was performed with the
Review Manager software version 5.2 (RevMan, Nordic
Cochrane Centre, The Cochrane Collaboration, 2012) and
publication bias with the comprehensive meta-analysis sta-
tistical software version 3.3.070 (2014), available as a trial.
The chi-squared Q-based statistical test (­ I2) was used to
assess the presence of heterogeneity with evaluation of the
funnel plot for heterogeneity. When the value of I­ 2 was not
statistically significant (­ I2 < 50%, P > 0.05), the fixed-effect
model was used to estimate the pooled odds ratio (OR).
On the other hand, when heterogeneity was significant
­(I2 > 50%, P < 0.05), the random-effects model was used for
the OR calculation. In both methods, the P value < 0.05 was
considered statistically significant. Six genetic models were
evaluated considering “M” as a mutant allele and “m” allele
as a wild-type allele: (I) M allele versus m allele, (II) m
allele versus M allele, (III) MM genotype versus mm gen-
otype, (IV) mm genotype versus MM genotype, (V) MM
genotype versus mm + Mm genotype and (VI) Mm geno-
type versus MM + mm genotypes. Begg’s test and Egger’s
linear regression test (with P < 0.05) were used to evaluate
potential publication bias of reported associations, and the
Funnel plot asymmetry was also considered. In addition, a
sensitivity analysis was also performed to test the robust-
ness of the results pooled by omitting one included study
at a time to detect individual effects on the overall analyses.
All the data in the studies were dichotomous data expressed
as OR with 95% of confidence intervals (CI) to assess the
445
association between polymorphisms in IL-17A and IL-17F
genes and periodontitis.
Results
Systematic search in literature and characteristic
of studies included
At the end of the systematic search in literature, seven arti-
cles [23–29] were identified as shown in Fig. 1. 885 case
patients (697 patients diagnosed with chronic periodontitis
and 188 patients diagnosed with aggressive periodontitis)
and 655 control patients were enrolled in this quantita-
tive synthesis (meta-analysis). The articles were published
between 2012 and 2016 and evaluated the polymorphisms
in two forms of periodontitis: the chronic periodontitis
and/or aggressive periodontitis. Four articles [24–26, 29]
evaluated both forms of the disease and three only chronic
periodontitis [23, 27, 28]. Three articles [23, 25, 27] were
composed of an analysis carried out in mixed population,
more specifically in Brazilians, and three articles [25, 27,
28] allocated the participants in smokers and non-smokers
groups; none of the studies stratified the patients by gen-
der. Seven studies are in agreement with HWE, and in
contrast, three studies are out of HWE; Table 1 shows
the main characteristics of the studies and the quality
assessment score to every included study [34]. All arti-
cles underwent the minimal quality assessment score (10);
however, none of them reached the maximal score (20) in
this binary scale. Three articles [23, 25, 27] analyzed both
polymorphisms in IL-17A and IL-17F genes totaling two
different studies in each. Therefore, seven articles with ten
studies composed the meta-analysis.
Meta‑analysis of rs2275913 polymorphism
in the IL‑17A gene and periodontitis
Five articles [23, 25, 27–29] focused on the evaluation of
rs2275913 polymorphism in the IL-17A gene and peri-
odontitis. The results evidenced a non-significant asso-
ciation between the mutant allele with the risk of CP or
AgP/LAgP as shown in Fig. 2a, b (OR 1.56, 95% CI 0.77,
3.15, P = 0.21; OR 1.12, 95% CI 0.05, 23.44, P = 0.94,
respectively). For both results, the random-effects statis-
tical model was used for the OR calculation due to the
high heterogeneity (­ I2 = 88%, P < 0.00001 and ­I2 = 96%,
P < 0.00001, respectively). In the mixed population, there
was a non-significant association between the rs2275913
polymorphism in IL-17A gene and CP in mutant allelic
evaluation (P = 0.60). Table 2 shows the calculations
obtained from the meta-analysis for this aforementioned
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Fig. 1  Flow diagram for identification and selection of studies included in this current meta-analysis
polymorphism and periodontitis in all allelic and geno-
typic evaluation, as well as in stratified analysis by popula-
tion and smoking status.
Meta‑analysis of rs763780 polymorphism in the IL‑17F
gene and periodontitis
Evaluating the influence of rs763780 polymorphism in the
IL-17F gene and the disease, five articles [23–27] were
included in the meta-analysis. Table 1 shows the stratified
analysis of this polymorphism by chronic periodontitis and
aggressive periodontitis in the included studies. There was a
non-significant association between the rs763780 polymor-
phism in the IL-17F gene and CP (Fig. 2c) (OR 1.19, 95%
CI 0.80, 1.76, P = 0.39), or AgP (Fig. 2d) (OR 1.07, 95% CI
0.63, 1.84, P = 0.79); the fixed-effect statistical model was
used for the OR calculation because of the decreased value
of heterogeneity and non-statistical significance ­(I2 = 13%,
P = 0.33 and ­I2 = 0%, P = 0.94). Table 3 shows all allelic and
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Mol Biol Rep (2017) 44:443–453
genotypic calculations for rs763780 polymorphism in the
IL-17F gene and periodontitis with stratified evaluation by
form of disease, population and smokers.
Publication bias and sensitive analysis
In order to evaluate the individual effect of studies, a sen-
sitivity analysis was performed by omitting each study to
assess its impact on pooled ORs. No single publication
changed the pooled ORs qualitatively, which suggested that
results from this meta-analysis were accurate. No publica-
tion bias was found in the meta-analysis by Begg’s test and
Egger’s linear regression test for the allelic evaluation in
rs2275913 polymorphism and CP (P = 0.462 and P = 0.332,
respectively) and in rs763780 polymorphism and CP
(P = 0.806 and P = 0.786, respectively) or AgP (P = 1.000
and P = 0.910, respectively). Indeed, there was no asymme-
try in the funnel plot validating the tests performed (Fig. 3).
The evaluation of publication bias for rs2275913 and AgP/
Mol Biol Rep (2017) 44:443–453 447

Table 1  Characteristics of studies included in the quantitative synthesis (meta-analysis)

First author and reference Year Ethnicity Country Study design Simple size

Corrêa [23] 2012 Mixed Brazil C/Cc 30/30 (CP)

Jain [24] 2013 Asian India C/Cc 63/101 (CP)
61/101 (AgP)
Saraiva [25] 2013 Mixed Brazil C/Cc 85/72 (CP)
45/72 (AgP)
Erdemir [26] 2015 Caucasian Turkey C/Cc 90/90 (CP)
57/90 (AgP)
Zacarias [27] 2015 Mixed Brazil C/Cc 140/173 (CP)
Borilova Linhartova [28] 2016 Caucasian Czech Republic C/Cc 244/154 (CP)
Chaudhari [29] 2016 Asian Indian C/Cc 35/35 (CP)
35/35 (LAgP)
First author and reference Polymorphism HWE Age Subject type Score

Corrêa [23] rs2275913 No 40.5 ± 8.1/45.5 ± 8.7 CP-healthy 14

rs763780 Yes
Jain [24] rs763780 Yes 37.56/data no show CP-healthy 13
25.29/data no show AgP-healthy
Saraiva [25] rs2275913 Yes 49/31 CP-healthya 14
rs763780 Yes 34/31 AgP-healthya
Erdemir [26] rs763780 Yes 47.3 ± 2.3/34.7 ± 1.2 CP-healthy 12
39.6 ± 1.8/34.7 ± 1.2 AgP-healthy
Zacarias [27] rs2275913 Yes 47.0 ± 9.2/45.6 ± 9.2 CP-healthya 14
rs763780 No
Borilova Linhartova [28] rs2275913 Yes 52.5 ± 9.8/48.5 ± 10.7 CP-healthya 13
Chaudhari [29] rs2275913 No 21.2 ± 4.6/data no show CP-healthy 13
37.2 ± 4.2/data no show LAgP-healthy

Mixed—Brazilian and others ethnicities

C case, Cc control, CP chronic periodontitis, AgP aggressive periodontitis, LAgP localized aggressive periodontitis, HWE Hardy–Weinberg
equilibrium
a
Studies with smokers and non-smokers patients

LAgP was not possible due to the few number of studies
included in this analysis (n = 2).
Discussion
Genetic variations in cytokines are responsible for changes
in the gene expression patterns of these inflammatory media-
tors [35]. For instance, a meta-analysis focusing on IL-10
showed important information about polymorphisms within
this cytokine gene and periodontitis susceptibility [36]. A
few of studies have focused on evaluating rs2275913 poly-
morphism and rs763780 polymorphism, in IL-17A and IL-
17F genes, respectively, in patients with periodontal disease.
Hence, due to an inconsistency in results and somewhat
limited studies available, we performed this meta-analysis.
Despite the limited number of included studies, the use of
suggested guidelines for evaluation of these studies demon-
strated the acceptable quality of studies in this meta-analysis
(Table 1).
Due to the limited number of studies in Caucasian and
Asian ethnicities for each polymorphism (n = 1), a strati-
fied analysis based on these populations could not be per-
formed, as well as a stratified analysis considering the AgP
and LAgP forms in IL-17A gene variation. Therefore, the
studies composed of these both forms of periodontitis,
taken the aggressive aspect of the disease, were aggregated
in the meta-analysis.
The minor allele frequency (MAF) of rs2275913 poly-
morphism (the wild type allele) was described with the
value of 0.38, 0.38 and 0.216 in Caucasian, South Asian
and American ethnicities, respectively. Indeed, the fre-
quency of A allele in rs2275913 was significantly lower
(P < 0.05) than in G allele in a previous study on Cauca-
sian patients with RA from Norway [37] and periodontitis
[27]. On the other hand, in the rs763780 polymorphism,
the MAF (the mutant allele) was described with the value
of 0.058, 0.091 and 0.061 in Caucasian, South Asian and
American ethnicities, respectively. Saraiva et al. [25]
brought similar findings about the allele frequency of this

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Fig. 2  a Forest plot of comparison of mutant allele versus wild type
allele in rs2275913 polymorphism and chronic periodontitis and b
aggressive periodontitis. c Forest plot of comparison with mutant
polymorphism in IL-17F and Brazilian patients with peri-
odontitis. More genetic population studies are required for
a better analysis of these polymorphisms into the diverse
ethnical groups.
The rs2275913 polymorphism in the IL-17A gene was
indicated as a protective factor against chronic periodontitis
in the Brazilian population [25]. Nevertheless, a recent study
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Mol Biol Rep (2017) 44:443–453
allele versus wild type allele in rs763780 polymorphism and chronic
periodontitis, and d aggressive periodontitis
also evaluated this polymorphism and brought contradictory
results that the A allele was associated with chronic peri-
odontitis in this population [27]. Corroborating this finding,
the meta-analysis showed that the AA genotype for polymor-
phism in the IL-17A gene was associated with an elevated
risk of chronic periodontitis (OR 1.73, 95% CI 1.13, 2.65,
P = 0.01).
Mol Biol Rep (2017) 44:443–453 449

Table 2  Meta-analysis of association between rs2275913 polymorphism in IL-17A gene and periodontitis (allelic and genotypic comparisons;
and stratified analysis)
Variable Comparison (n) Case/control M versus m m versus M
rs2275913 OR (95% CI) P OR (95% CI) P

Overall (CP) 5 411/396 1.56 (0.77, 3.15) 0.21 0.64 (0.32, 1.29) 0.21
Overall (AgP/LAgP) 2 60/85 1.12 (0.05, 23.44) 0.94 0.89 (0.04, 18.69) 0.94
Mixed (CP) 3 132/207 1.31 (0.47, 3.61) 0.60 0.76 (0.28, 2.11) 0.60
Smokers (CP) 3 179/102 0.93 (0.45, 1.90) 0.84 1.08 (0.53, 2.22) 0.84
Variable Comparison (n) Case/control mm versus MM MM versus Mm/mm
rs2275913 OR (95% CI) P OR (95% CI) P

Overall (CP) 5 411/396 0.58 (0.38, 0.89) 0.01 1.60 (1.06, 2.39) 0.02
Overall (AgP/LAgP) 2 60/85 0.40 (0.17, 0.95) 0.04 1.74 (0.75, 4.03) 0.20
Mixed (CP) 3 132/207 0.55 (0.28, 1.08) 0.80 1.60 (0.84, 3.04) 0.15
Smokers (CP) 3 179/102 1.10 (0.22, 5.42) 0.91 0.95 (0.42, 2.17) 0.90
Variable Comparison (n) Case/control MM versus mm Mm versus mm/MM
rs2275913 OR (95% CI) P OR (95% CI) P

Overall (CP) 5 411/396 1.73 (1.13, 2.65) 0.01 0.86 (0.65, 1.15) 0.32
Overall (AgP/LAgP) 2 60/85 2.53 (1.05, 6.05) 0.04 1.07 (0.51, 2.24) 0.85
Mixed (CP) 3 132/207 1.82 (0.93, 3.55) 0.80 0.85 (0.55, 1.32) 0.47
Smokers (CP) 3 179/102 0.91 (0.18, 4.52) 0.91 0.83 (0.50, 1.36) 0.45

CP chronic periodontitis, AgP aggressive periodontitis, LAgP localized aggressive periodontitis, M mutant allele, m wild type allele, OR odds
ratio, CI confidence intervals, NO not obtained by failure in the statistical analysis program
Bold values—random-effects statistical model used

The possible role of IL-17A and IL-17F was explored
in results in which these interleukins were shown to be
responsible for neutrophil recruitment through the induc-
tion of several pro-inflammatory mediators such as matrix
metalloproteinase, tumor necrosis factor-α (TNF-α), IL-6
and IL-8 [38]. ­C D4 + T-cells express both molecules in
their cellular surface [39]. Moreover, IL-17A expression
was higher in periodontal lesions located adjacent to the
site of bone resorption than in the controls (P = 0.0077)
[40], with bone loss being orchestrated by IL-17 stimula-
tion [41]. The IL-17 production was stimulated by Por-
phyromonas gingivalis in cell culture dependent on IL-1B
signaling, indicating which periodontopathogens may acti-
vate inflammatory cells with enhancement of IL-17 secre-
tion in periodontitis [42]. Polymorphisms in these genes
may influence upon the progression of periodontitis.
In order to evaluate rs763780 polymorphism in IL-17F
gene and periodontitis, the results also showed a non-sig-
nificant association between this polymorphism and the
disease for any comparison calculated (Table 3). In order
to calculate the pooled OR in this analysis, the fixed-effect
statistical model was used because of a non-interference of
heterogeneity ­(I2 < 50%, ­Pheterogeneity > 0.05) in contrast to
the allelic evaluation in rs2275913 polymorphism and CP,
which was calculated through the random-effects model.
The fixed-effect model assumes that all studies shared the
same effect size and, by contrast, random-effects model
allows different effect sizes [43]. Actually, the use of ran-
dom-effects in the meta-analysis calculation might result
in more weight to studies containing small sample size,
which may not be totally trustworthy [44]. Therefore, the
use of fixed-effect makes the results accurate.
In the evaluation of the aggressive form of periodontitis,
neither the polymorphism in IL-17A nor the polymorphism
in IL-17F was significantly associated with the disease
(Tables 2, 3). A limited number of studies included in a
quantitative synthesis may bias the results. The high lev-
els of IL-17 in patients with aggressive periodontitis were
related in literature, as well as the decrease in the value of
levels of this IL after periodontal therapy by means of non-
surgical methods [45]. The value of the association between
AA genotype in rs2275913 polymorphism and the risk of
AgP was significantly high (OR 2.53, 95% CI 1.05, 6.05,
P = 0.04) corroborating a previous study that demonstrated
a significant association with the A allele in this polymor-
phism and this form of the disease [29].
A stratified analysis about ethnicity was performed and
the results in mixed population revealed a non-significant

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Table 3  Meta-analysis of association between rs763780 polymorphism in IL-17F gene and periodontitis (allelic and genotypic comparisons;
and stratified analysis)
Variable Comparison (n) Case/control M versus m m versus M
rs763780 OR (95% CI) P OR (95% CI) P

Overall (CP) 5 314/392 1.19 (0.80, 1.76) 0.39 0.84 (0.57, 1.25) 0.39
Overall (AgP) 3 182/236 1.07 (0.63, 1.84) 0.79 0.93 (0.54, 1.59) 0.79
Mixed (CP) 3 133/203 1.65 (0.95, 2.85) 0.08 0.61 (0.35, 1.05) 0.08
Smokers (CP) 2 115/58 0.89 (0.32, 2.50) 0.82 1.13 (0.40, 3.17) 0.82
Variable Comparison (n) Case/control mm versus MM MM versus Mm/mm
rs763780 OR (95% CI) P OR (95% CI) P

Overall (CP) 5 314/392 0.46 (0.17, 1.28) 0.14 0.66 (0.37, 1.16) 0.15
Overall (AgP) 3 182/236 1.92 (0.08, 48.06) 0.69 0.51 (0.02, 12.81) 0.68
Mixed (CP) 3 133/203 0.41 (0.14, 1.25) 0.12 0.65 (0.34, 1.26) 0.20
Smokers (CP) 2 115/58 No – 0.47 (0.05, 4.53) 0.52
Variable Comparison (n) Case/control MM versus mm Mm versus mm/MM
rs763780 OR (95% CI) P OR (95% CI) P

Overall (CP) 5 314/392 2.17 (0.78, 6.03) 0.14 1.28 (0.69, 2.39) 0.44
Overall (AgP) 3 182/236 0.52 (0.02, 13.01) 0.69 1.27 (0.42, 3.81) 0.67
Mixed (CP) 3 133/203 2.42 (0.80, 7.29) 0.12 1.19 (0.57, 2.48) 0.65
Smokers (CP) 2 115/58 No – 1.31 (0.44, 3.90) 0.62

CP chronic periodontitis, AgP aggressive periodontitis, M mutant allele, m wild type allele, OR odds ratio, CI confidence intervals, NO not
obtained by failure in the statistical analysis program
Bold values—random-effects statistical model used

association between the polymorphisms assessed and the
risk of periodontitis for any comparison (P > 0.05). It is
important to note that Brazilians exclusively composed the
mixed population in this meta-analysis. Variations in Brazil-
ian population have been clearly described in literature with
a high degree of admixture from Amerindians, African and/
or European ancestors [46]. A very few studies included in
this analysis may represent a limitation to pooled OR calcu-
lation, although the results are accurate by the use of fixed-
effect model in response to decreased value of ­I2.
For a better understanding about the rs2275913 and
rs763780 polymorphisms in IL-17A and IL-17F genes,
respectively, and other factors in the included patients, an
analysis approaching smoking status evidenced a non-sig-
nificant association with CP (Tables 2, 3). These results are
according to a previous study that proved a negative correla-
tion between cigarettes smoked per day and IL-17A levels
in gingival sample tissues from smokers with CP (−0.13,
­PPearson < 0.05) [47].
The present meta-analysis is the first to approach these
polymorphisms in IL-17A and IL-17F with periodontitis.
Nevertheless, some important limitations should be noted.
First, the limited number of studies could be the reason of
the non-significant associations found in the pooled OR
calculations; more studies are required with an increase
in total number of patients (case and controls), which
brings robust results and also validate the data. Besides,
a non-significant P value does not always represent clini-
cal relevance [48], thus these values must be considered
with caution. Second, the small numbers evaluating the
aggressive form of periodontitis prevented the complete
analysis about publication bias for rs2275913 polymor-
phism. Third, periodontitis is a complex immune disease
with a combination of several factors such as: age, gender,
oral hygiene, use of alcohol drinks, ethnicity and genetic
variation. A complete stratified analysis considering other
factors that influence upon the development, progression
and damage of periodontitis was not possible due to the
limited data provided by the studies. The approach of these
factors could highlight the influence of polymorphisms in
IL-17A and IL-17F genes and the risk of periodontitis.
In conclusion, this meta-analysis with seven articles in
697 patients diagnosed with CP, 188 patients diagnosed
with AgP and 655 control patients totaling 1540 partici-
pants showed a non-significant association between the
rs2275913 polymorphism in the IL-17A gene and the
rs763780 polymorphism in the IL-17F gene with the risk
of CP (P = 0.21; P = 0.39, respectively), AgP (P = 0.94;

13
Mol Biol Rep (2017) 44:443–453 451

Fig. 3  a Funnel plot for publi-

cation bias in allelic evaluation
in rs2275913 polymorphism
and chronic periodontitis. b
Funnel plot for publication bias
in allelic evaluation in rs763780
polymorphism and chronic
periodontitis or c aggressive
periodontitis

13
452
P = 0.79, respectively), mixed population (P = 0.60;
P = 0.08, respectively) and smokers with chronic periodon-
titis (P = 0.84; P = 0.82) in allelic evaluation as well as in
other performed comparisons (P > 0.05).
Acknowledgements Federal University of Piaui supported this study
(UFPI—Edital PIBIC 2014/2015; Edital PIBIC 2015/2016), CNPq
(455104/2014-0) and CAPES by FRPS. We thank teacher Abílio
Borghi for the grammar review of the article.
Author contributions FRPS, ACCGV, WAL and DFPV contributed
in the conception, design, data collection, statistical analysis and draft-
ing of the manuscript. LSP, EHPA contributed in the data collection,
statistical analysis and review of the manuscript. All authors approved
the final version for submission.
Compliance with ethical standards
Conflict of interest The author declares there is no conflict of in-
terests.
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