ORIGINAL PAPERs
Jan Kowalski
Polymorphysm of Interleukin-1 in Patients
with Advanced Generalized Periodontitis
– Evaluation of Clinical Data
Polimorfizm IL-1 u pacjentów
z zaawansowanym uogólnionym zapaleniem przyzębia
– ocena wskaźników klinicznych
Department of Periodontology and Oral Diseases, Medical University of Warsaw, Warsaw, Poland
Abstract
Background. The rapid advance in genetics has revealed the complexity of the possible correlation between the genotype and the severity of periodontitis. Nevertheless, there are several polymorphysms of certain genes that – based on the literature – could play a major role in the incidence and advancement of the inflammatory state of the periodontium. IL-1 genes, encoding interleukin-1, seem to be most discussed.
Objectives. The aim of this work was to evaluate the influence of IL-1 gene polymorphysms on the incidence of periodontitis, as well as the assessment of its contribution to the clinical state of periodontal tissues.
Material and Methods. The study group consisted of 40 generally healthy individuals (17 with generalized aggres-sive periodontitis, 23 with advanced generalzed chronic periodontitis). During the clinical examination the follow-ing parameters were evaluated: pocket depth, clinical attachment loss, plaque index, bleedfollow-ing index. Percentage of pockets deeper than 4 mms was also evaluated. A smear from the buccal mucosa was also collected with a cot-ton swab and sent for evaluation of IL-1 polymorphism. For the purpose of comparison, a control group was assembled from 20 generally healthy individuals with a healthy periodontium. They underwent clinical and genetic examination.
Results. In the study group, 15 out of 40 persons were revealed as having the positive genotype, understood as carrying the 2nd allele of IL-1A and IL-1B gene. In the control group, 10 out of 20 individuals were diagnosed with
a positive genotype. Logistic regression analysis has not shown a significant influence of positive genotype to the incidence of periodontitis. Comparison of clinical parameters in study group has not revealed any differences between persons carrying various alleles of IL-1 genes.
Conclusions. The IL-1 gene does not seem to play the role in the pathogenesis of periodontitis in the Polish popu-lation (Dent. Med. Probl. 2014, 51, 3, 345–350).
Key words: periodontitis, polymorphism, IL-1.
Streszczenie
Wprowadzenie. Wpływ czynnika dziedziczenia na zapoczątkowanie i rozwój zapalenia przyzębia od dłuższego czasu był tematem dyskusji naukowych. szybki postęp w genetyce wykazuje, że natura ewentualnego związku między genotypem a stopniem zaawansowania zapalenia przyzębia jest złożona. Zidentyfikowano jednak kilka polimorfizmów konkretnych genów, które – sądząc z doniesień naukowych – mogą pełnić znaczącą rolę w inicjacji i progresji procesu zapalnego przyzębia. Najwięcej uwagi poświęcono genom IL-1 kodującym interleukinę 1.
Cel pracy. Ocena wpływu polimorfizmów genowych IL-1 na występowanie zapalenia przyzębia oraz związku geno-typu IL-1 ze stanem klinicznym tkanek przyzębia.
Materiał i metody. Grupę badaną utworzono z 40 ogólnie zdrowych osób (17 z rozpoznaniem uogólnionego agre-sywnego zapalenia przyzębia, 23 z zaawansowanym uogólnionym przewlekłym zapaleniem przyzębia). W czasie badania klinicznego oceniano następujące wskaźniki stanu przyzębia: głębokość kieszonki, kliniczną utratę przy-czepu łącznotkankowego, wskaźnik płytki, wskaźnik krwawienia. szacowano również odsetek kieszonek o głębo-kości większej niż 4 mm. Za pomocą sterylnego wacika pobierano wymaz z błony śluzowej policzka i wysyłano do zbadania polimorfizmu IL-1. Do celów porównawczych utworzono grupę kontrolną z 20 ogólnie zdrowych osób, ze zdrowym przyzębiem. Poddano ją również badaniu klinicznemu i genetycznemu.
Dent. Med. Probl. 2014, 51, 3, 345–350
The hereditary factor in the pathogenesis of periodontitis has been the topic of scientific re-search since the 1970s [1]. A major breakthrough has coincided with the development of Human Genome Project [2]. In 1997 Kornman et al. [3] published the results of their study on adults with chronic periodontitis. Calculations have shown that non-smoking adults, carrying less frequent allele (allele 2) of gene encoding both interleukin-1 beta (IL-1B) and interleukin-1 alpha (IL-1A), had an almost 19-fold greater risk of developing clinical attachment loss. The explanation of this phenom-enon in genetically positive individuals would be connected to the overproduction of IL-1 by mac-rophages in response to bacterial infection of peri-odontal tissues. The manuscript was the impulse for developing and manufacturing the first com-mercially available genotype test in periodontolo-gy. since then numerous reports have been pub-lished on this topic. Initially, many reports con-firmed the data provided by Kornman et al. [4, 5]. Gore and coworkers [4] had noticed an increased frequency of positive genotype (predisposing to the disease) in the group of patients with an vanced chronic periodontitis than in the less ad-vanced forms of this disease. They also observed an insignificant increase of IL-1B production in individuals who were genetically susceptible [4]. Engebretson et al. [5] reported increased IL-1B lev-els in the gingival crevicular fluid of patients with a positive genotype, especially visible at shallow pockets. socransky and coworkers [6] noticed the correlation between the positive IL-1 genotype and the increased numbers of “red” and “orange” com-plexes bacteria (connected with the advanced form of chronic periodontitis). There was not a unani-mous confirmation for the usefulness of IL-1 gene test in periodontology. Ehmke and coworkers [7] failed to observe any influence of IL-1A and IL-1B genotype on the outcome of non-surgical peri-odontal therapy. Armitage et al. [8] has observed a significantly lower percentage of positive geno-type carriers in the Chinese population, bringing into question the importance of the genotype ex-amination. Papapanou and coworkers [9] designed a case-control study to evaluate the role of IL-1 genes in diagnosing periodontitis. IL-1 genotype was correlated with clinical parameters,
periodon-tal pathogens’ numbers and specific antibodies’ ti-ters. The study failed to show the potential of IL-1 genotype to distinguish healthy and diseased in-dividuals. There was, however, the correlation be-tween the positive IL-1 genotype and the degree of clinical attachment loss [9].
Until present, there is no agreement in the sci-entific society regarding the role of IL-1 genes in the pathogenesis of periodontitis. There are re-ports confirming [10–14] or denying [15–17] the usefulness of IL-1 genotype test. There was a di-rect discussion between prof. Kornman and his critics [18, 19], mainly focusing on the meaning of the word “susceptibility” used in the commercial test’s name. Recently published systematic reviews and meta-analytic studies tend to confirm the role of IL-1 genotype in the prediction of the severity of periodontal disease [20–23]. There may be a geo-graphic or racial factor involved. There seems to be an involvement of IL-1 gene in the course of the disease in Chileans [24] and Chinese [25], but studies conducted on Thai [26], Iranian [27], Turk-ish [28], Greek [29] and PolTurk-ish [30] populations failed to show such a relationship.
The aim of this work was to evaluate the po-tential involvement of IL-1 genotype in the inci-dence of the periodontitis, and to study the con-nection between the positive IL-1 allele and the clinical state of the patients with the advanced periodontitis.
Material and Methods
40 generally healthy individuals (20 males and 20 females aged 23–62 yrs) were enrolled in-to the study. The mean age was 38.6 years, medi-an 37 years. The criteria of inclusion into the study group were as follows:
– diagnosing generalized aggressive periodon-titis, interpreted as fulfilling generally known pri-mary features of aggressive periodontitis [31], with an inflammatory process affecting more than 2 teeth (not counting central incisors and first mo-lars), or;
– diagnosing advanced generalized chronic periodontitis, interpreted as a disease process re-sulting in clinical attachment loss (CAL) exceeding
Wyniki. 15 z 40 osób z grupy badanej zidentyfikowano jako posiadających pozytywny genotyp, definiowany przez nosicielstwo drugiego allelu zarówno IL-1A, jak i IL-1B. W grupie kontrolnej u 10 z 20 osób rozpoznano pozytywny genotyp. Analiza regresji logistycznej nie wykazała znaczącego wpływu pozytywnego genotypu na występowanie zapalenia przyzębia. Porównanie wskaźników klinicznych w grupie badanej również nie wykazało znaczących róż-nic między osobami z różnymi allelami genów IL-1.
Wnioski. Gen IL-1 nie wydaje się wpływać na patogenezę zapalenia przyzębia w populacji polskiej (Dent. Med. Probl. 2014, 51, 3, 345–350).
4 mms at least at one site, and CAL observed at least at 30% of measured sites;
– pocket depth (PD) exceeding 6 mms at least at one site in each of at least 4 quadrants (min 4 sites with PD > 6 mm in whole dentition).
The exclusion criteria were: – smoking habit;
– systemic disease or medication potentially affecting immunological response or microbiota;
– periodontal treatment undertaken recently (12 months period);
– antibacterial toothpaste or mouthwash used recently (3 months period).
Basing on the anamnesis and clinical exam-ination, study group comprised of 17 individu-als with generalized aggressive periodontitis and 23 individuals with advanced generalized chron-ic periodontitis.
The control group, consisting of 20 generally healthy individuals, with healthy periodontal tis-sues, was also assembled. The excluding criteria for this group were the same as for the study group.
In both groups, a clinical examination was performed, and the periodontal status of each in-dividual was evaluated, using the following pa-rameters:
– pocket depth [mm] (PD), described as the distance between the margin of the gingiva and the base of the periodontal pocket, measured at 6 sites per tooth, at 4 teeth with most advanced dis-ease process;
– clinical attachment loss (CAL), described as the distance between cemento-enamel junction and the base of periodontal pocket, measured at 6 sites per tooth, at 4 teeth with most advanced dis-ease process;
– plaque index (PI), described as the propor-tion of surfaces covered with dental deposits to all the surfaces evaluated, measured at 4 surfaces (vestibular, oral, mesial, distal) of each tooth;
– bleeding index (BI), described as the pro-portion of sites bleeding on probing in relation to all the sites measured (6 sites per tooth);
– percentage of pockets with PD exceeding 4 mms (PD4).
The individuals from the study and con-trol groups were subjected to the analysis of IL-1 polymorphisms. For that purpose a commercial-ly available test (Genotype PsT®, Hain Lifescience,
Germany) was used. A sample smear of buccal mu-cosa was collected in each person with the help of a sterile cotton swab (after drying the field of sam-pling with 10 s). The collected sample was placed in a sterile plastic tube and sent to the Hain Life-science laboratory in Nehren, Germany. The sam-ple was subjected to the standard procedure of the test’s producer. DNA was extracted and subject-ed to the polymerase chain reaction, using ready reagents of the manufacturer, including specific primers and polymerase enzyme. The reaction was taking place in the termocycler (GTQ-Cycler 96, 37 cycles). The amplified material was hybridized and tested for polymorphisms of IL-1 alpha (–889, rs1800587) and IL-1 beta (+3953, rs1143634). Indi-viduals were described as genetically positive, if at both loci the TT genotype was identified.
For each group and each clinical parameter mean value, median and standard deviation were calculated. For the purpose of comparing those variables Mann-Whitney test was utilized, with the standard assumption of significance threshold for p index being lower than 0.05 (index value was calculated). The same test was also used for de-tecting possible the significance between individ-uals with positive and negative IL-1 genotype. The possible coincidence between the positive geno-type and an the increased risk of developing peri-odontal disease was checked with logistic regres-sion analysis.
Results
The mean clinical values of both the study and control groups are presented in Table 1. All the pa-rameters measured were significantly higher in the patients with diagnosed periodontal disease. Generally, patients suffering from the inflamma-tion of periodontal tissues had very bad oral hy-giene (average 2/3 of dentition covered with
bacte-Table 1. Comparison of clinical examination in study and control groups
Tabela 1. Porównanie badania klinicznego w grupie badanej i kontrolnej
PD (mm) CAL (mm) PI (%) BI (%) PD4 (%)
study group (n = 40)
(mean ± sD) 4.62 ± 1.72 5.87 ± 2.54 65.6 ± 26.6 43.8 ± 30.2 22.2 ± 20.6
Control (n = 20)
(mean ± sD) 1.04 ± 0.12 0.38 ± 0.23 8.3 ± 7.1 0.2 ± 0.5 0
rial biofilm), resulting in extensive inflammation (over 40% of pockets bleeding on probing), and at least several teeth requiring specialized periodon-tal treatment (mean pocket depth above 4.5 mms, over 20% of sites with PD above 4 mms).
The comparison of the clinical parameters of patients from study group with positive or negative genotype are shown in Table 2. statistical analysis shows no difference in the parameters studied be-tween both subgroups of patients with periodon-tal disease.
Table 3 presents the results of the logistic re-gression analysis. The hypothesis that the positive genotype increases the risk of periodontal disease incidence found no support in the statistical data. In the control group, the distribution of the IL-1 polymorphism was equal. The value of p index was 0.356 (above 0.05 threshold), and the odds ra-tio of developing periodontal disease was 0.60.
Discussion
The development of the commercially avail-able test straight after the article of Kornman and coworkers [3] was the impulse for numerous in-vestigations of IL-1 gene cluster. The present study failed to reveal any trend in the clinical parame-ters favoring or neglecting the hypothesis of the influence of the IL-1 genotype on the clinical pa-rameters of the periodontal status. There may be at least two reasons contributing to these findings.
The first one is that worldwide research shows a great diversity of the significance of IL-1 poly-morphisms on the incidence and progress of peri-odontitis. On one hand, incidence of positive IL-1 genotype in the Thai population seems to be very low. Anusaksathien and coworkers [26] observed genotype predisposing to the greater secretion of interleuk1 in 1.6% of studied group (123 in-dividuals participated in that study). On the op-posite, extremum Papapanou et al. [9] examined 205 swedish individuals both with healthy and diseased periodontium and claimed the incidence of the positive genotype at over 40% (45.2% in peri-odontal patients). However, unlike the Kornman’s study [3], positive genotype was defined by Papa-panou and coworkers [9] if the rare allele was pres-ent at least at one locus, not at both of them, which may have biased the result towards the higher in-cidence of polymorphysm predisposing to the dis-ease. saleh and coworkers [31] examined south African population in periodontitis patients and healthy controls and observed the incidence of pos-itive genotype at 14.3% and 20%, respectively. The study of Laine and coworkers [10] revealed the fre-quency of predisposing allele in Dutch periodontal patients population at 42.1%. Most of the studies’ results oscillates around 20–40%. Amongst them is another study on the Polish population, con-ducted by Droździk et al. [30]. They observed the positive genotype in 34.4% of patients with diag-nosed chronic periodontitis and in 25% of aggres-sive periodontitis patients [30]. The odds ratio was at 0.78, close to the result observed in the present study.
Even considering and matching the group to neutralize the geographic factor, one must al-so take the racial bias into consideration. This is especially visible in the racially diversified areas, like Dekan Peninsula. studies performed in In-dia show very inconsistent results, even when per-formed in a similar region. Articles of Kaarthikey-an et al. [32] Kaarthikey-and ArchKaarthikey-ana et al. [33] have brought the conflicting conclusions, even though they were both performed on the population of south India. Both studies were conducted on numerical-ly very similar groups (61 vs. 60 respectivenumerical-ly). The
Table 2. Clinical parameters of periodontitis in the study group divided according to the IL-1 polymorphism
Tabela 2. Wskaźniki kliniczne zapalenia przyzębia w grupie badanej podzielonej według polimorfizmu IL-1
IL-1 genotype (n) PD (mm) CAL (mm) PI (%) BI (%) PD4 (%)
Positive (n = 15)
(Mean ± sD) 5.36 ± 1.95 6.55 ± 2.64 69.4 ± 22.4 44.7 ± 28.0 25.4 ± 25.8
Negative (n = 25)
(Mean ± sD) 4.15 ± 1.4 5.45 ± 2.43 63.3 ± 29.2 43.2 ± 32.2 20.3 ± 16.9
statistical significance p = 0.505 p = 0.258 p = 0.658 p = 0.786 p = 0.638
Table 3. Results of the logistic regression analysis
Tabela 3. Wyniki analizy regresji logistycznej Positive
genotype Negative genotype
Periodontitis 15 25
Periodontal health 10 10
Total 25 35
Risk 0.60 0.71
Confidence interval 0.20–1.78
study conducted by Kaarthikeyan et al. [32], pub-lished in 2009, claims no association of a single nucleotide polymorphism (IL-1B at +3954) with the incidence of periodontitis. Archana et al. [33] claimed that the composite genotype of IL-1A and IL-1B (IL-1A at +4845, not like –889 in the pres-ent study) could indicate the susceptibility of the advanced form of periodontal disease.
The present study failed to show any signifi-cant differences in the periodontal status between the patients with various genotypes of IL-1 clus-ter. similar results were reported in several studies called earlier. Rogers et al. [15] observed the same loci at the Caucasian individuals with chronic peri-odontitis, subjected to dental implant procedure. The composite genotype failed to show an asso-ciation with periodontal disease (single polymor-phism of IL-1B correlated), there was also no cor-relation of the genotype with the future failure of implantation procedure [15]. Christgau et al. [16] designed a 12-month-long observation of 47 adults treated with GTR. Genotype of IL-1 did not have any effect on the resolution of the surgical proce-dure; it also did not correlate with any of the clin-ical or radiographic parameters measured [16]. scapoli et al. [17] investigated over 200 Caucasians in a case-control manner to evaluate the influence of IL-1 gene on the course of an aggressive peri-odontitis. The obtained results did not show such an association [17].
such a small study group does not give permis-sion to draw decisive conclupermis-sions, but in the litera-ture the long lasting discussion between the advo-cates and antagonists of the importance of IL-1 gene seems to show more evidence that a single polymor-phisms cannot play a major role in the pathogenesis of periodontitis. Hetorogeneity of the course of the disease and dependence on the large number of en-vironmental factors does not support the thesis of the great importance of single mutations. One can certainly assume that more than 10, 20 or even more genes are important for the development of peri-odontitis. Therefore, in recent years, more attention has been put on the genome-wide studies, compar-ing the whole DNA of the diseased and healthy indi-viduals, and in this manner identifying single nucle-otide polymorphisms potentially responsible for the periodontitis. A great example of such a study may be the paper published last year by Divaris et al. [34], conducted on the population exceeding 4500. The authors failed to detect straight genome-wide asso-ciation signals for chronic periodontitis; however, six gene sites (NIN, NPY, WNT5A, NCR2, EMR1 and 10p15) seemed to show an association potential [34]. Genome-wide studies may be on the brink of a new era of genetic examinations, allowing a thorough examination of the whole DNA and revealing the candidate genes that are predisposed to periodon-titis more efficiently than hypothesis-based evalua-tions of single polymorphisms.
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Address for correspondence:
Jan Kowalski
Department of Periodontology and Oral Diseases Medical University of Warsaw
Miodowa 18 00-246 Warsaw Poland
E-mail: [email protected] Conflict of interest: None declared
Received: 10.06.2014 Revised: 28.06.2014 Accepted: 29.06.2014
Praca wpłynęła do Redakcji: 10.06.2014 r. Po recenzji: 28.06.2014 r.
