Archives of Oral Biology 84 (2017) 45–49

Contents lists available at ScienceDirect

Archives of Oral Biology

journal homepage: www.elsevier.com/locate/archoralbio

Research Paper

The absence of an association between Interleukin 1β gene polymorphisms MARK

and recurrent aphthous stomatitis (RAS)
⁎
Zuzanna Ślebiodaa, , Anna Kowalskab, Marta Rozmiarekb, Ewa Krawieckaa, Elżbieta Szponara,
Barbara Dorocka-Bobkowskaa
a
Department of Oral Mucosa Diseases, University of Medical Sciences, Poznań, Poland
b
Department of Nucleic Acids Function, Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland

A R T I C L E I N F O A B S T R A C T

Keywords: Objectives: Recurrent aphthous stomatitis (RAS) is a chronic, ulcerative disease with a probable polygenic mode
Recurrent aphthous stomatitis of inheritance and complex etiology with a strong immunological background. The aim of the present study was
Interleukin-β to determine the possible association between two single nucleotide polymorphisms (SNPs) of the IL-1β gene: IL-
Oral mucosa diseases 1β − 511 T > C (rs16944) and IL-1β + 3954C > T (rs1143634) and RAS susceptibility in a moderately large
group of patients.
Design: One hundred and four patients with minor, major and herpetiform RAS and 75 healthy volunteers were
genotyped at IL-1β − 511 T > C (rs16944) and IL-1β + 3954C > T (rs1143634) using the PCR-RFLP ap-
proach. The results were statistically analysed with chi-square test and test of difference between two rates of
structure, with p < 0.05 assumed to be a statistically significance level (Statistica 10, StatSoft®, Kraków,
Poland).
Results: There were no statistically significant differences in the genotype distribution for the IL-1β C[+3954]T
polymorphism between the RAS and control groups. The frequency of IL-1β*T[-511]/*T[–511] homozygotes
among the patients was significantly higher when compared to our study control (p < 0.0347). The results after
stratification into carriers and non-carriers of C and T alleles did not clearly indicate which SNP may be con-
sidered a risk factor for RAS.
Conclusions: The genetic association between the studied SNPs of the IL-1β gene and RAS remains controversial
and requires further investigation.

1. Introduction
Recurrent aphthous stomatitis (RAS; RAU-recurrent aphthous ul-
cers; canker sores) is a chronic, inflammatory disease characterized by a
repeated onset of single or multiple painful erosions and ulcers in
various regions of the oral mucosa (Belenguer-Guallar, Jiménez-
Soriano, & Claramunt-Lozano, 2014; Cui, Bruce, & Rogers, 2016). The
lesions are shallow, clearly defined, oval-shaped, surrounded by char-
acteristic erythematous halo and likely to occur on non-keratinized,
non-attached oral mucosa (Ship, Chavez, Doerr, Henson, & Sarmadi,
2000; Tarakji, Gazal, Al-Maweri, Azzeghaiby, & AlAizari, 2015). Ac-
cording to Stanley’s classification, involving the basic clinical features
of lesions, e.g.: their size and depth, the number of lesions per one flare-
up, their location and duration, three main types of aphthae can be
distinguished: major (MaRAS), minor (MiRAS) and herpetiform
(HeRAS) (Stanley, 1972). Approximately 80% of RAS patients present
with the minor type (Bazrafshani, Hajeer, Ollier & Thornhill, 2002;
Ślebioda et al., 2017). The condition is self-limiting in im-
munocompetent patients. Recurrent oral aphthae may also appear as a
component of several systemic syndromes like Behçet’s disease (BD),
Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome
(PFAPA) or Sweet’s syndrome (Akman et al., 2008; Alayli et al., 2007;
Contrucci & Martin, 2015; Kolly et al., 2013).
Based on epidemiologic studies, the condition is relatively common
and affects between 10% and 20% of the general population with the
second decade of life considered as a peak period of the RAS occur-
rence. It is more prevalent among females, non-smokers, white races
and people within a high socio-economic group (Belenguer-Guallar
et al., 2014; Cui et al., 2016; Tarakji et al., 2015).
The etiology of RAS has not been fully recognized to date. Current
evidence supports some variant of disturbed immune response in ge-
netically predisposed subjects, precipitated by local or environmental

⁎
Corresponding author at: Department of Oral Mucosa Diseases,University of Medical Sciences, ul. Bukowska 70, 60–812, Poznań, Poland.
E-mail address: zuzia_slebioda@o2.pl (Z. Ślebioda).

http://dx.doi.org/10.1016/j.archoralbio.2017.09.013
Received 9 February 2017; Received in revised form 6 September 2017; Accepted 17 September 2017
0003-9969/ © 2017 Elsevier Ltd. All rights reserved.
Z. Ślebioda et al.
factors, including stress and anxiety, mineral and vitamin in-
sufficiencies, hematologic disorders, food allergies and trauma (Buño,
Huff, Weston, Cook, & Brice, 1998; Eversole, 1997; Yakar, Serin, Coşar,
Arslan Taş, & Ataç, 2015). The role of genetic factors in the etiopatho-
genesis of RAS was first suggested by Miller and Ship in middle 60-s of
the 20-th century. They propounded the autosomal recessive or multi-
gene mode of inheritance with a modifying influence from the en-
vironment (Miller, Garfunkel, Ram & Ship, 1977; Ship, 1965). This was
confirmed in further studies of relatives and twins with RAS, where a
positive family history of the disease was reported in 24% to 46% of
cases (Bazrafshani, Hajeer, Ollier & Thornhill, 2002). The genetic risk
factors which determine the individual susceptibility to the disease
include various DNA polymorphisms distributed in the human genome,
especially those related to changes in the metabolism of cytokines
(Bazrafshani et al., 2002; Bazrafshani, Hajeer, Ollier, & Thornhill, 2003;
Guimarães et al., 2006, 2007; Najafi et al., 2014, 2015).
At the beginning of aphtha formation a massive lymphocytic in-
filtration in the epithelium occurs, leading to the development of oe-
dema. It is followed by the keratinocyte vacuolization and localized
vasculitis, which clinically presents as characteristic erythematous halo
surrounding the lesion. The area than ulcerates and is infiltrated by
neutrophils, lymphocytes and plasma cells. Subsequently the healing
and regeneration of the epithelium is observed (Jurge, Kuffer,
Scully, & Porter, 2006). The direct mechanism of this process remains
not fully understood. Both humoral and cellular types of immune re-
sponse in patients with RAS may become disrupted. The enhanced
production of pro-inflammatory Th1-type cytokines (IL-2, IL-12, TNF-α,
IFN-ɣ) with a reduced production of anti-inflammatory Th2-type cy-
tokines (IL-4, IL-5, IL-10, IL-13) and TGF-β were reported in several
studies of RAS patients, which may suggest the role of autoimmunisa-
tion in the pathogenesis of this entity (Buño et al., 1998; Eversole,
1997; Lewkowicz et al., 2003). Improperly initiated cascade of cyto-
kines, which activates certain immune processes, occurs in response to
some kind of not yet defined trigger factor, which may include viral and
bacterial antigens or stress. Initiation of the inflammatory process can
be induced by the effect of TNF-α on endothelial cell adhesion and its
chemotactic effect on neutrophils. Elevated TNF-α levels were found
directly in the lesional mucosa in RAS, while the expression of class I
and class II major histocompatibility complex (MHC) antigens was en-
hanced in basal epithelial cells in both pre-ulcerative and ulcerative
stages of RAS (Buño et al., 1998; Jurge et al., 2006). TNF-α is known for
stimulating the expression of MHC class I. Meanwhile, the expression of
MHC in the phase of healing was undetected, suggesting the role of
MHC in targeting local tissue for attack by cytotoxic T cells
(CD8 + cells) during the ulcerative process (Jurge et al., 2006). De-
creased levels of anti-inflammatory IL-10 reported in RAS may disturb
the epithelization and prolong healing of the ulcers (Cui et al., 2016).
The Interleukin-1 family, consists of 11 individual members, in-
cluding IL-1α, IL-1β and IL-1 receptor antagonist (IL-1Ra). These pro-
teins are encoded by a gene cluster located on a chromosome 2
(2q14;2q21), which was cloned and mapped in 1985 (Schett,
46
Archives of Oral Biology 84 (2017) 45–49
Fig. 1. The structure of IL-1β gene and the localization of the studied
polymorphisms (own elaboration based on Drews-Piasecka 2011).
Dayer, & Manger, 2016; Vargas-Alarcón et al., 2015). Two separate
genes encoding IL-1α and IL-1β originate from a common ProIL-1 gene
and were probably formed via duplication. The IL-1 family cytokines
regulate immune and inflammatory responses to infections (Drews-
Piasecka, 2011; Eisenberg et al., 1991). Interleukin-1 is produced by
tissue macrophages, monocytes, fibroblasts, and dendritic cells, but is
also expressed by B lymphocytes, NK cells and epithelial cells. It acts as
a primary activator of the expression of endothelial cell adhesion mo-
lecules (ECAMs) which facilitate the migration of leucocytes into tis-
sues. Three polymorphisms related to a transition between C and T at
positions: −511 (T → C), −31 (T → C), and +3954 (C → T) have been
described and associated with a risk of several systemic disorders
(Łącka et al., 2014; Chen et al., 2015). Pociot, Mølvig, Wogensen,
Worsaae, and Nerup (1992) found the −511 (T → C), and +3954
(C → T) polymorphisms to be associated with the enhanced production
of IL-1β while the increased production of cytokines increased the risk
of RAS and Behçet's disease (Karakus, Yigit, Rustemoglu,
Kalkan, & Bozkurt, 2014; Lee et al., 2006; Liang et al., 2013; Pociot
et al., 1992).
Fig. 1 depicts the structure of IL-1β gene and the localization of the
polymorphisms studied in this paper.
The aim of the present study was to investigate the potential asso-
ciation between IL-1β c. − 511 T > C (rs16944) and IL-1β c.
+ 3954C > T (rs1143634) genetic polymorphisms and RAS in a co-
hort of patients.
2. Material and methods
2.1. Subjects and sample collection
The study group consisted of 104 unrelated Polish patients (39
males and 65 females) with RAS with a mean age of
35.08 ± 16.9 years and recruited from the Department of Oral Mucosa
Diseases at Poznań University of Medical Sciences in Poland. The
control group comprised of 75 generally healthy subjects (20 males and
55 females) with a mean age of 34.2 ± 16.4 years without a history of
RAS. Both study and control groups had the same geographic origin and
comparable socio-economic status. The study protocol included a de-
tailed medical history followed by a full extra- and intra-oral ex-
amination performed by a qualified dental team. Blood samples were
collected for DNA isolation and IL-1β genotyping of all participants.
The diagnosis of RAS was established based on clinical criteria de-
scribed by Ship, Chavez, Doerr, Henson, and Sarmadi (2000). The in-
clusion criteria for the study group were the presence of aphthae during
the examination and at least a 1-year history of RAS with a regular
mode of recurrences, defined as a minimum of two episodes per year.
Patients with MiRAS, MaRAS and HeRAS were enrolled in the study.
Patients on immunosuppressive and immunomodulating drugs or suf-
fering from any other oral mucosa disease characterized by the pre-
sence of erosions and ulcers were excluded from the study.
The study was approved by the Poznan University of Medical
Z. Ślebioda et al. Archives of Oral Biology 84 (2017) 45–49

Sciences Ethics Committee (approval code: 878/11) and complied with

the guidelines of the Declaration of Helsinki. All participants were in-
formed in detail about the nature of the study before consent was ob-
tained for the examination and genetic screening.

2.2. DNA isolation

DNA extraction from 200 μl peripheral blood samples was per-

formed with QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany) in
accordance with the manufacturer’s instructions and under standar-
dized conditions to prevent variation in DNA quality.
IL-1β c. + 3954 and c. − 511 polymorphisms were assessed by the
PCR-RFLP approach described earlier by Kanemoto, Kawasaki,
Miyamoto, Obayashi, and Nishimura (2000). Genotyping was carried
out by a two-step procedure, including amplification and digestion.
Amplification was performed with a total volume of 30 μl of reaction
mixture, consisting of H20 (2 μl), PCR Master Mix (Taq DNA poly-
merase, MgCl2, dNTPs) (15 μl), Primer 1 and 2 (2 μl each) and matrix
genomic DNA (9 μl) and included 38 cycles. The quality of amplicons
was tested by electrophoretic separation in 2% agarose gel containing
ethidium bromide and 1 × TBE (Tris/Borate/EDTA) buffer. A DNA size
marker (pUC19 DNA/MspIHpaII) was used to evaluate the length of
PCR products (249 bp for +3954 SNP and 304 bp for −511 SNP). The
results of the electrophoretic separation were visualized using UVP
BioDoc-it transiluminator. Digestion of the products with restrictive Fig. 2. Two genotypes of IL-1β C[+3954]T. The products of DNA digestion with TaqI
enzymes (TaqI for +3954 and Eco88I (AvaI) for −511; Thermo Sci- enzyme separated in 3% agarose gel. Lane 1: heterozygote 1/2; Lane 2: homozygote 1/1;
entific) was carried out with the reaction mixture with a total volume of Lane 3: DNA size marker pUC19.

30.8 μl, consisting of H2O (18 μl), 10 x buffer (2 μl), PCR product
(10 μl) and enzyme (0.8 μl), incubated at the appropriate temperature Table 2
overnight (See Table 1). The digested products were separated elec- The distribution of IL-1β C[+3954]T genotypes and alleles in RAS patients and control
group.
trophoretically with 2% (+3954) or 3% (−511) agarose gel with
ethidium bromide. The IL-1β genotype evaluation was based on the RAS Controls p OR
analysis of DNA fragments pattern directly in the gel. Allele and gen-
otype frequencies were estimated by direct counting. Genotype
Fig. 2 shows the products of DNA digestion with TaqI enzyme se- 1/1 62 (59.62) 44 (58.67) 0.9016
1/2 36 (34.62) 28 (37.33) 0.7131
parated in 3% agarose gel. 2/2 6 (5.70) 3 (4.00) 0.6062

Allele
2.3. Statistical analysis C (*1) 0.7692 0.7733 0.9274
T (*2) 0.2308 0.2267 0.9274
The results were statistically analysed using the test of difference
between two rates of structure and chi-square test to evaluate the Carriage of C allele
Carriers 98 (94.2) 72 (96) 0.5872
compliance of the genotype distribution with the results expected based
Non-carriers 6 (5.8) 3 (4) 0.5872
on Hardy-Weinberg equilibrium with p < 0.05 assumed to be a sig-
nificance level (Statistica 10, StatSoft®, Kraków, Poland). Carriage of T allele
Carriers 42 (40.38) 31 (41.33) 0.9038
Non-carriers 62 (59.62) 44 (58.67) 0.9038
3. Results

The distribution of the alleles and genotypes for IL-1β C[+3954]T
polymorphism in the RAS group and the control group is presented in
Table 2.
The distribution of alleles in the study and the control population
was comparable. There were no significant differences in IL-
1β*C[+3954] (*1) and IL-1β*T[+3954] (*2) allele frequencies be-
tween the groups (p = 0.9274). The number of *1 allele carriers was
similar in the study and the control groups. Also the proportion of *2
allele carriers and non-carriers was almost equal in both groups.
A frequency of homozygotes for the 1/1 genotype was also similar
in the two compared groups (59.6% vs 58.7%), as in case of homo-
zygotes for the 2/2 genotype (5.8% vs 4%). Heterozygotes of the 1/2
genotype were observed more often in the control group, although the
difference was statistically insignificant (34.6% vs 37.3%; p = 0.7131).
Table 3 shows the distribution of alleles and genotypes for IL-1β T[-
511]C polymorphism in the examined groups.

Table 1
Primer sequences, restriction enzymes and conditions used for IL-1β T[-511]C and IL-1β C[+3954]T polymorphisms.

Gene Primer sequence Restriction enzyme/Condition Genotype

IL-1β C[+3954]T F: 5′-GTTGTCATCATCAGACTTTGACC-3′ TaqI IL-1β [+3954]*C/*C (1/1)

R: 5′-TTCAGTTCATATGGACCAGA-3′ (65 °C/14–17 h) IL-1β [+3954]*C/*C (1/2)
IL-1β [+3954]*T/*T (2/2)
IL-1β T[–511]C F: 5′-TGGCATTGATCTGGTTCATC-3′ Eco88I (AvaI) IL-1β [–511]*T/*T (1/1)
R: 5′-GTTTAGGAATCTTCCCACTT-3′ IL-1β [–511]*T/*C (1/2)
(37 °C/15–20 h) IL-1β [–511]*C/*C (2/2)

47
Z. Ślebioda et al. Archives of Oral Biology 84 (2017) 45–49

Table 3 group, which is consistent with the Guimarães et al. (2007) results.
The distribution of IL-1β T[–511]C genotypes and alleles in RAS patients and control Some differences in the genotypes distribution may be caused by dif-
group.
ferences in the qualification criteria used in the discussed studies.
RAS Controls p OR Bazrafshani et al. (2002) included only patients with MiRAS, while in
the other studies subjects with all types of RAS were recruited. The
Genotype genetic background of this condition may vary between the clinical RAS
1/1 54 (51.9) 27 (36) 0.0347 1.92
subtypes. Although Bazrafshani et al. (2002) demonstrated a slightly
1/2 41 (39.4) 40 (53.3) 0.0651
2/2 9 (8.7) 8 (10.7) 0.6509 higher frequency of IL-1β *T[+3954] allele in patients when compared
to controls, we did not confirm this observation in our study. IL-1β
Allele
T(*1) 0.7163 0.6267 0.0732
*T[+3954] allele appeared at similar frequencies in both the RAS and
C (*2) 0.2837 0.3733 0.0732 control groups.
Our study showed a higher frequency of IL-1β*T[-511]/*T[-511]
Carriage of T allele homozygotes among the patients when compared to the controls
Carriers 95 (91.3) 67 (89.3) 0.6499
(p < 0.0347). After stratification into carriers and non-carriers of *C
Non-carriers 09 (8.7) 08 (10.7) 0.6499
and *T alleles the results did not clearly indicate which SNP may be
Carriage of C allele
considered a risk factor for RAS. In Yakar, Serin, Coşar, Arslan Taş, and
Carriers 50 (48.1) 48 (64) 0.0350 0.5208
Non-carriers 54 (51.9) 27 (36) 0.0350 1.9200 Ataç (2015) study no statistically significant differences in the IL-1β T[-
511]C genotype distribution were reported, however IL-1β *C[-511]
allele was slightly more prevalent within the RAS group. The *C allele
Also in case of this tested SNP, the distribution of alleles in the study was previously considered to be associated with an increased produc-
and the control population was similar. The differences in IL-1β*T[- tion of IL-1β (Yakar et al., 2015). However, according to Bazrafshani
511] (*1) and IL-1β *C[-511] (*2) allele frequencies were considered et al. (2002), the differences in the IL-1β T[-511]C genotype distribu-
insignificant (p = 0.0732). The proportion of *1 allele carriers was si- tion among the RAS and control groups were significant. The IL-1β *C[-
milar in the study and the control groups, while the percentage of *2 511] allele was observed more often in patients than in healthy subjects
allele carriers was significantly higher in the control group compared to (p < 0.00002). Therefore, the IL-1β *C[-511] allele was related to a
the RAS patients (48.1% vs 64%; p = 0.0350). 2.5-fold risk of developing RAS when compared to the IL-1β *T[-511]
Homozygosity for the 1/1 genotype was observed significantly more allele, while the homozygous individuals with 2/2 genotype had an 4.5-
often in the RAS group compared to the controls (51.9% vs 36%; fold risk of RAS (OR = 4.5). Thus far such a strong correlation between
p = 0.0347). Heterozygosity was observed more frequently in the IL-1β *C[-511] allele and RAS susceptibility was demonstrated only by
control group than in RAS subjects, although the difference was not Bazrafshani et al. (2002). This genetic association was not confirmed
statistically significant (53.3% vs 39.4%; p = 0.0651). The frequency of neither by Yakar et al. (2015), nor in our study. Also Akman et al.
homozygotes for the 2/2 genotype was comparable in both groups, (2008) who studied the role of several IL-1β polymorphisms in Turkish
although they appeared insignificantly more often among the controls patients with Behçet's disease and RAS, did not confirm the previous
than in RAS group (10.7% vs 8.7%; p = 0.6509). findings of Bazrafshani et al. (2002). The IL-1β *C[-511] allele ap-
The distribution of IL-1β genotypes in the case group and in the peared slightly but statistically insignificantly more often in RAS sub-
controls were in accordance with the results expected from the Hardy- jects than in the controls (p = 0.09). No differences in the genotype
Weinberg equilibrium (p < 0.76 and p < 0.23, respectively). distribution were reported between the Behçet's disease group and
healthy people, which is in agreement with Coskun et al. (2005) and
Karasneh et al. (2003). In contrast the Alayli et al. (2007) study con-
4. Discussion cluded that the IL-1β C[-511]C genotype was related to a high risk of
BD.
In our study population we were not able to demonstrate a genetic Based on our observations the genetic association between the
association between the IL-1β C[+3954]T polymorphism and the risk studied SNPs of the IL-1β gene and RAS still remains controversial and
of RAS. The frequency of the 2/2 genotype among RAS patients was requires further examination. The clinical heterogeneity of RAS may
insignificantly higher than in controls (5.7 vs 4.0%, p = ns). However, suggest a polygenic mode of inheritance.
the allele distribution in this study was at variance with the results The identification of genes and their mutations involved in etio-
presented by other authors. pathogenesis of diseases seems to be a crucial goal of current human
Guimarães et al. (2007) observed a higher frequency of IL-1β genetics research. Defining the direct genetic etiologic factor in RAS
C[+3954]T heterozygotes among the RAS subjects compared with the creates an opportunity to develop individualized treatment methods for
controls. Moreover, the authors did not found a higher frequency of 2/2 high risk groups in the future.
genotype either among the patients or among the healthy controls.
Based on those findings it was assumed that the 1/2 genotype might be Funding
associated with RAS. According to Guimarães et al. (2007) the het-
erozygotic genotype was related to a 2.5-fold higher risk of RAS The study was supported by Grant No. 502-14-02209325-09854 of
(OR = 2.5). However, our results did support this thesis- the hetero- the Poznań University of Medical Sciences.
zygosity was observed in similar frequencies in both the study and
control groups (34.62 vs 37.33%, p = ns). Contrary to Guimarães et al.
(2007), the distribution of genotypes reported by Bazrafshani et al. Conflict of interest
(2002) did not indicate an association between the IL-1β C[+3954]T
polymorphism and RAS susceptibility in a Brazilian population. As in The authors declare no conflict of interest.
our paper, the authors observed an insignificantly higher frequency of
2/2 homozygotes in the RAS group. Bazrafshani et al. (2002) found a Ethical approval
higher frequency of heterozygotes than 1/1 homozygotes among the
RAS subjects, while the frequencies of these genotypes in the control The study was approved by the Poznan University of Medical
group were comparable. In our study there was a significantly higher Sciences Ethics Committee (approval code: 878/11) and complied with
frequency of 1/1 homozygotes compared to heterozygotes in RAS the guidelines of the Declaration of Helsinki.

48
Z. Ślebioda et al.
References
Akman, A., Ekinci, N. C., Kacaroglu, H., Yavuzer, U., Alpsoy, E., & Yegin, O. (2008).
Relationship between periodontal findings and specific polymorphisms of interleukin
−1α and −1β in Turkish patients with Behçet’s disease. Archives of Dermatological
Research, 300, 19–26.
Alayli, G., Aydin, F., Coban, A. Y., Sullu, Y., Canturk, F., Bek, Y., et al. (2007). T helper
type 1 cytokines polymorphisms: Association with susceptibility to Behcet’s disease.
Clinical Rheumatology, 26, 1299–1305.
Bazrafshani, M. R., Hajeer, A. H., Ollier, W. E. R., & Thornhill, M. H. (2002). IL-1B and IL-
6 gene polymorphisms encode significant risk for the development of recurrent
aphthous stomatitis (RAS). Genes and Immunity, 3, 302–305.
Bazrafshani, M. R., Hajeer, A. H., Ollier, W. E., & Thornhill, M. H. (2003). Polymorphisms
in the IL-10 and IL-12 gene cluster and risk of developing recurrent aphthous sto-
matitis. Oral Diseases, 9(6), 287–289.
Belenguer-Guallar, I., Jiménez-Soriano, Y., & Claramunt-Lozano, A. (2014). Treatment of
recurrent aphthous stomatitis. A literature review. Journal of Clinical and Experimental
Dentistry, 6(2), e168–74.
Buño, I. J., Huff, J. C., Weston, W. L., Cook, D. T., & Brice, S. L. (1998). Elevated levels of
interferon gamma, tumor necrosis factor alpha, interleukins 2, 4, and 5, but not in-
terleukin 10, are present in recurrent aphthous stomatits. Archives of Dermatology,
134, 827–831.
Chen, Y. J., Han, Y., Mao, M., Tan, Y. Q., Leng, W. D., & Zeng, X. T. (2015). Interleukin-
1βrs 1143634 polymorphism and aggressive periodontitis susceptibility: A meta-
analysis. International Journal of Clinical and Experimental Medicine, 8(2), 2308–2316.
Contrucci, R. B., & Martin, D. B. (2015). Sweet syndrome: A case report and review of the
literature. Ear, Nose, Throat Journal, 94(7), 282–284.
Coskun, M., Bacanli, A., Sallakci, N., Alpsoy, E., Yavuzer, U., & Yergin, O. (2005). Specific
interleukin-1 gene polymorphisms in Turkish patients with Behcet's disease.
Experimantal Dermatology, 14, 124–129.
Cui, R. Z., Bruce, A. J., & Rogers, R. S. (2016). Recurrent aphthous stomatitis. Clinical
Dermatology, 34(4), 475–481.
Drews-Piasecka, E. (2011). Znaczenie wybranych wariantów polimorficznych genów układu
cytokin w etiologii porodu przedwczesnego. Dissertation. Poznań University of Medical
Sciences.
Eisenberg, S. P., Brewer, M. T., Verderberg, E., Heimdal, P., Brandhuber, B. J., &
Thompson, R. C. (1991). Interleukin 1 receptor antagonist is a member of the in-
terleukin 1gene family: Evolution of a cytokine control mechanism. Proceedings of the
National Academy of Sciences of the United States of America, 88(12), 5232–5236.
Eversole, L. R. (1997). Immunopathogenesis of oral lichen planus and recurrent aphthous
stomatitis. Seminars in Cutaneous Medicine and Surgery, 16, 284–294.
Guimarães, A. L., de Sá, A. R., Victória, J. M., Correia-Silva, J. F., Pessoa, P. S., Diniz, M.
G., et al. (2006). Association of interleukin-1beta polymorphism with recurrent
aphthous stomatitis in Brazilian individuals. Oral Diseases, 12(6), 580–583.
Guimarães, A. L., Correia-Silva, J. F., de Sá, A. R., Victória, J. M., Diniz, M. G., Costa, F.
O., et al. (2007). Investigation of functional gene polymorphisms IL-1beta, IL-6 IL-10
and TNF-alpha in individuals with recurrent aphthous stomatitis. Archives of Oral
Biology, 52(3), 268–272.
Jurge, S., Kuffer, R., Scully, C., & Porter, S. R. (2006). Mucosal disease series: Number VI.
Recurrent aphthous stomatitis. Oral Diseases, 12, 1–21.
Kanemoto, K., Kawasaki, J., Miyamoto, T., Obayashi, H., & Nishimura, M. (2000).
Interleukin (IL)1beta, IL-1alpha, and IL-1 receptor antagonist gene polymorphisms in
patients with temporal lobe epilepsy. Annals of Neurology, 47(5), 571–574.
Karakus, N., Yigit, S., Rustemoglu, A., Kalkan, G., & Bozkurt, N. (2014). Effects of in-
terleukin (IL)-6 gene polymorphisms on recurrent aphthous stomatitis. Archives of
Dermatological Research, 306(2), 173–180.
49
Archives of Oral Biology 84 (2017) 45–49
Karasneh, J., Hajeer, A. H., Barrett, J., Ollier, W. E. R., Thornhill, M., & Gul, A. (2003).
Association of specific interleukin 1 gene cluster polymorphisms with increased
susceptibility for Behcet's disease. Rheumatology, 42(7), 860–864.
Kolly, L., Busso, N., von Scheven-Gete, A., Bagnoud, N., Moix, I., Holzinger, D., et al.
(2013). Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome is
linked to dysregulated monocyte IL-1β production. Journal of Allergy and Clinical
Immunology, 131(6), 1635–1643.
Łącka, K., Paradowska-Gorycka, A., Maciejewski, A., Kramer, L., Herman, W. A., & Łącki,
J. K. (2014). Interleukin 1 beta (IL1beta) gene polymorphisms (SNP-511 and SNP
+ 3953) in Hashimotoąs thyroiditis among the Polish population. Experimental and
Clinical Endocrinology and Diabetes, 122, 544–547.
Lee, Y. J., Kang, S. W., Park, J. J., Bae, Y. D., Lee, E. Y., Lee, E. B., et al. (2006).
Interleukin-18 promoter polymorphisms in patients with Behçet's disease. Human
Immunology, 67(10), 812–818.
Lewkowicz, N., Lewkowicz, P., Kurnatowska, A., Banasik, M., Glowacka, E., Cedzyński,
M., et al. (2003). Innate immune system is implicated in recurrent aphthous ulcer
pathogenesis. Journal of Oral Pathology and Medicine, 32, 475–481.
Liang, Y., Xu, W. D., Zhang, M., Qiu, L. J., Ni, J., Wang, X. S., et al. (2013). Meta-analysis
of association between cytokine gene polymorphisms and Behcet's disease risk.
International Journal of Rheumatic Diseases, 16(6), 616–624.
Miller, M. F., Garfunkel, A. A., Ram, C., & Ship, I. I. (1977). Inheritance patterns in re-
current aphthous ulcers: Twin and pedigree data. Oral Surgery Oral Medicine and Oral
Pathology, 43, 886–891.
Najafi, S., Firooze Moqadam, I., Mohammadzadeh, M., Bidoki, A. Z., Yousefi, H., Farhadi,
E., et al. (2014). Interleukin-10 gene polymorphisms in recurrent aphthous stoma-
titis. Immunological Investigations, 43(4), 405–409.
Najafi, S., Yousefi, H., Mohammadzadeh, M., Bidoki, A. Z., Firouze Moqadam, I., Farhadi,
E., et al. (2015). Association study of interleukin-1 family and interleukin-6 gene
single nucleotide polymorphisms in recurrent aphthous stomatitis. International
Journal of Immunogenetics, 42(6), 428–431.
Pociot, F., Mølvig, J., Wogensen, L., Worsaae, H., & Nerup, J. (1992). A TaqI poly-
morphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta
secretion in vitro. European Journal of Clinical Investigation, 22(6), 396–402.
Schett, G., Dayer, J. M., & Manger, B. (2016). Interleukin-1 function and role in rheumatic
disease. Nature Reviews Rheumatology, 12(1), 14–24.
Ślebioda, Z., Krawiecka, E., Rozmiarek, M., Szponar, E., Kowalska, A., & Dorocka-
Bobkowska, B. (2017). Clinical phenotype of recurrent aphthous stomatitis and in-
terleukin-1β genotype in a Polish cohort of patients. Journal of Oral Pathology and
Medicine, 46(8), 657–662.
Ship, J. A., Chavez, E. M., Doerr, P. A., Henson, B. S., & Sarmadi, M. (2000). Recurrent
aphthous stomatitis. Quintessence International, 31(2), 95–112.
Ship, I. I. (1965). Inheritance of aphthous ulcers of the mouth. Journal of Dental Research,
44, 837–844.
Stanley, H. R. (1972). Aphthous lesions. Oral Surgery Oral Medicine and Oral Pathology, 33,
407–416.
Tarakji, B., Gazal, G., Al-Maweri, S. A., Azzeghaiby, S. N., & AlAizari, N. A. (2015).
Guideline for the diagnosis and treatment of recurrent aphthous stomatitis for dental
practitioners. Journal of International Oral Health, 7(5), 74–80.
Vargas-Alarcón, G., Cruz-López, M., Valladares, A., Álvarez-León, E., Juárez-Cedillo, T.,
Pérez-Méndez, O., et al. (2015). The interleukin-1-511 T > C (rs16944) gene poly-
morphism is associated with risk of developing silent myocardial ischemia in diabetic
patients. Immunology Letters, 168, 7–12.
Yakar, T., Serin, E., Coşar, A. M., Arslan Taş, D., & Ataç, F. B. (2015). The relationship of
recurrent aphthous stomatitis and Helicobacter pylori, cytokine gene polymorphism
and cobalamin. The Turkish Journal of Gastroenterology, 26(4), 304–308.