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Hanee Bae
5th Year, Group 13Association between Interleukin-1 Family Polymorphism and
the Susceptibility of Periodontitis
Systemic review of literature
Prof. Zygimantas Guobis MD, ph D
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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES MEDICAL ACADEMY
FACULTY OF ODONTOLOGY Clinic of Oral and Dental Diseases
Association between Interleukin-1 Family Polymorphism and
the Susceptibility of Periodontitis
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This thesis was done
by student ……… Supervisor………...
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……….... ………..
(name surname, year, group) (degree, name surname)
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(day/month) (day/month)
Kaunas, 2017
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TABLE OF CONTENTS
SUMMARY ... 오류! 책갈피가 정의되어 있지 않습니다. Background... 오류! 책갈피가 정의되어 있지 않습니다. Aim ... 오류! 책갈피가 정의되어 있지 않습니다. INTRODUCTION ... 7SELECTIONCRITERIAOFTHEARTICLES.SEARCHMETHODSANDSTRATEGY ... 7
Focused Question ... 7
Inclusion and Exclusion Criteria ... 8
Search Sterategy and Selection... 9
DATA ANALYSIS ... 10
Risk of bias ... 15
DISCUSSION ... 16
CONCLUSIONS ... 18
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Summary
Periodontitis is a chronic inflammatory disease that causes tooth loss through the breakdown of
supporting bone and connective tissues. It is initiated primarily by Gram-negative anaerobic and
microaerophilic microorganisms. The prevalence of severe generalized forms of chronic
periodontitis (CP) is reported to be from8% to 13%, and after treatment most disease progression
occurs in 20% to 25% of the population. Current evidence indicates that specific bacteria are
essential for disease initiation, but genetic and environmental host modifiers appear to influence
disease severity. For example, analysis of disease expression in twins suggests that up to 50% of the
variance in clinical phenotype is explained by genetics [21].
Cytokines, small proteins released by cells, are the most common signals in immune regulation. The
field of cytokine gene research has continuously evolved in the periodontology literature; allelic
variations in genes encoding cytokines have been shown to affect the susceptibility and progression
of periodontal disease [23].
Variations in IL-1 genes were first associated with CP in whites in 1997. Many studies
subsequently explored the role of IL-1 gene polymorphisms in periodontitis with mixed results.
Several factors may contribute to the observed variance [2].
To find out the significance between IL-1 family polymorphism and the susceptibility of
periodontitis, total of thirteen studies were analyzed in this review. The majority (ten out of thirteen)
studies have shown that there is strong association between IL-1 family polymorphism and the
susceptibility of periodontitis.
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Introduction
Periodontitis is an infectious, inflammatory disease that is defined as irreversible destruction of teeth supporting tissue, such as periodontal ligament and alveolar bone. Its common results are increased probing depth, increased recession, or both [1]. It is primarily induced by Gram-negative anaerobic microorganisms. However, clinicians and researchers long have been suspecting that the severity of the disease depends on not only the infectious agents itself, rather, largely determined by genetic susceptibility and environmental factors. Since human genome study has opened a new level of understanding the world of chronic immune-inflammatory diseases, there have been many experiments and studies to find out the association between periodontitis and the typical
inflammation related agent, cytokine. Among many forms of cytokines, the interleukin-1 (IL-1) cytokine family has key regulatory roles in innate and adaptive immunity and in pathogenesis of infectious, autoimmune, and auto inflammatory diseases, as well as mediating systemic
inflammatory responses comprising fever, hepatic acute-phase proteins, and leukocyte activation [2]. Polymorphisms in the IL-1 cluster have been the main locus of attention in recent studies because of the fundamental role of IL-1β in the pathogenesis of periodontal disease. Kornman et al., suggested that periodontitis associated genotype (PAG) had an approximately 7 times greater chance of having severe periodontitis than those who were PAG negative. PAG is a composite IL-1 genotype found by the combination of two rare alleles at separate single nucleotide polymorphisms (SNP) in this cluster at position (-889) in the IL-1A promoter and at (+ 3954) of the IL-1B gene [3]. Based on such information, a quantitative analysis of the association between IL-1 genes and periodontitis in well-defined patient populations would be a beneficial study topic. The primary objective of this review, therefore, is to assess the association of IL-1 gene variants with periodontitis and to determine the strength of the effect.
Selection Criteria of the Studies. Search Method and Strategy
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The focused question addressed in this study is: “Are specific IL-1 gene variations associated with the susceptibility of periodontitis?”
Inclusion and Exclusion Criteria
Inclusion criteria were: 1) evaluated association of IL-1 gene polymorphisms with periodontal disease; 2) published in English; 3) used a primary or secondary outcome of periodontitis
progression; 4) all individuals or separately analyzed subsets were adults >35 years old; and 5) all individuals were otherwise healthy.
Exclusion criteria were: 1) primary outcomes involved endpoints other than periodontitis severity or progression, such as peri-implant disease or postsurgical soft-tissue healing; 2) Studies were done with other family of interleukin-1, such as IL-4 or IL-6; and 3) the publication was published more than ten years ago.
Search Strategy
The following electronic databases were searched through March 2017: 1) PubMed Central; 2) Journal of Periodontology Online; 3) BioMed Central; 4) International Journal of Dentistry; 5) Wiley Online Library; and 6) Biotechnology and Biotechnological Equipment. Searches were done with topic words of “Periodontitis” and “Genetic polymorphism”. When the volume of the search result was too large, other topic word “IL-1” was applied to narrow the search.
Study Selection
Articles were initially screened based on the titles and abstracts. The accepted articles were read for study design, and some were eliminated based on inclusion and exclusion criteria listed above.
Data Collection Process
The reviewer (HB) read the final list of articles to extract the following: 1) genetic variants assayed; 2) population studied; 3) sample size; 4) smoking status; 5) other clinical parameters and outcomes; and 6) study design. Each article in the final set was evaluated for distribution of any of the
following polymorphisms: IL1A (-889); IL1A (+4845); IL1B (-511); and IL1B (+3954).
Search Results
Through primary database searching, total of 82 potential relevant records were identified. After database searching, there was also an addition of one more relevant record, which was available in hard copy [1]. During screening, total of 65 records were excluded according to exclusion criteria; the most common reason of exclusion was the publication date. Out of 18 full-text articles that were assessed for eligibility, 5 were excluded; some of them studied inappropriate outcomes, such as
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peri-implant disease or postsurgical soft-tissue healing. As a result, thirteen studies were included in qualitative synthesis (Fig 1).
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Inc
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Records identified through database searching
(n =83)
Additional records identified through other sources (n =1) Records screened (n = 84) Records excluded (n =65) · Not IL-1 27 · Non- English 6 · Non- adult 2 · Published more
than 10 years ago 30
Full-text articles assessed for eligibility
(n = 19 )
Articles excluded after full-text review
(n = 6) · Inappropriate
outcomes 3 · Published more
than 10 years ago 2
· Duplicate 1
Studies included in qualitative synthesis
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Figure 1. Literature Search Reviews
Data analysis
Ethnicity of the studied groups was not considered; all reviewed articles had various types of ethnicity groups examined. Studies races include Caucasians [4][9], Japanese [5], Chinese [6][8], Indian [14][15], multiple [10][12], Dravidian [13], and unknown [7]][11][16]. Six studies had total
sample sizes ＜200 [4][9][13][14][15][16] and other seven studies had total samples sizes ＞200
[5][6][7][8][10][11][12] (Table 1).
Table 1. Studies races and sample sizes of reviewed articles.
Author Studied Race
Number of Periodontitis patients examined Number of Healthy people examined (Control group) Total number of people examined Havemose-Poulsen et al. [4] Caucasian 45 25 70 Kobayashi et al. [5] Japanese 100 100 200
Loo et al. [6] Chinese 440 850 1290
Ianni et al. [7] Unknown 71 306 377
Yin et al. [8] Chinese 336 366 702
Barnea et al. [9] Caucasian 66 31 97 Zeng et al. [10] Multiple 2173 3900 6073 Lavu et al. [11] Unknown 200 200 400 Wu et al. [12] African- American 151 71 222
11 Caucasian 435 445 880 Hispanic 166 143 309 Asian 156 157 313 Shete et al. [13] Dravidian 97 101 198 Amirisetty et al. [14] Indian 29 31 60
Puri et al. [15] Indian 40 20 60
Ribeiro et al.
[16] Unknown 95 50 145
Objective periodontal values are one of the critical parts to be clearly determined before this literature review. Each reviewed studies had different clinical parameters to examine periodontitis patients. Havemose-Poulsen et al. [4] used probing depth (PD), clinical attachment loss (CAL), and radiograph as clinical parameters for periodontitis patients. Kobayashi et al. [5] also used PD and CAL, although they did not use radiograph as additional parameter. Loo et al. [6] used many clinical data, such as PD, CAL, sites % with BOP, sites % with gingival recession, and sites % with calculus. Ianni et al. [7] used simplified oral hygiene index (OHI-S) as their clinical parameter, and the mean value was 3.75 for selected group of periodontitis patients. Barnea et al. [9] used PD, CAL and BOP as their parameters. Wu et al. [12] also used PD and CAL, with no additional radiograph examination mentioned. Shete et al. [13] has stated that they used PD, CAL, OHI-S, plaque index and calculus index; however, they have not included any tables or data which shows the exact values of examined clinical parameters. Puri et al. [15] have stated that they used PD, CAL and additional radiograph as their clinical parameters. Lastly, Ribeiro et al. [16] have used PD and CAL, with no additional radiographs. For the mentioned studies above, the PD was ＞4mm, CAL was
＞5mm to be considered as periodontitis patients. Some studies did not have any clear periodontal values; they were only mentioned as „recruited periodontal patients‟ [8][10][11][14]. Examined clinical parameters for each reviewed studies are summarized in the table below (Table 2). PD and
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CAL were the most common clinical parameters to examine periodontitis patients. Although each study used different clinical parameters, all of them used multiple parameters to ensure more reliable study results (Table 2).
Table 2. Clinical Parameters used in Each Study
Author Types of Clinical Parameters Probin g Depth (PD) Clinica l Attach ment Loss (CAL) Radiogr aph BOP Sites % with gingiv al recessi on Sites % with Calcu lus OH I-S Calcu lus index Plaq ue inde x Not specific ally mention ed Havemo se-Poulsen et al. [4] + + + Kobayas hi et al. [5] + + Loo et al. [6] + + + + + Ianni et al. [7] + Yin et al. [8] + Barnea et al. [9] + + + Zeng et al. [10] + Lavu et al. [11] + Wu et al. [12] + + Shete et al. [13] + + + + + Amiriset ty et al. [14] + Puri et al. [15] + + +
13 Ribeiro
et al.
[16]
+ +
Although all of the reviewed articles studied about the correlation between IL-1 family and susceptibility to periodontitis, there were differences in which of the IL-1 family they studied; Two articles studied the significance of IL-1A (-889), four articles showed significance of IL-1B (-511) (+3954) and the rest of articles studied both IL-1A and IL-1B. Among these thirteen articles, only three of them [7][9][10] concluded that there are no significant association between gene
polymorphism of IL-1 family and susceptibility of periodontitis (p＞0.05). All other ten articles
showed significant associations (p＜0.05) (Table 3).
Table 3. Analyzed polymorphism and Significance of it with susceptibility of Periodontitis
Author
Targeted IL-1 Genetic Variants Analyzed Significa nt associati on between IL-1 polymor phism and suscepti bility of periodo ntitis IL-1A (-889) IL-1A (+4845) IL-IB (-511) IL-1B (+3954) Havemose-Poulsen et al. [4]
Yes Yes Yes Yes
Yes (p=0.008 for IL-1A and p=0.047 for IL-1B) Kobayashi
et al. [5] Yes Yes
Yes (p=0.03 for IL-1B and p=0.000 01 for IL-1A) Loo et al. [6] Yes Yes Yes (p=0.000 8 for
IL-14 1A and p=0.000 4 for IL-1B) Ianni et al. [7] Yes No (p=0.974 ) Yin et al. [8] Yes Yes Yes (p=0.008 for IL-1A and p=0.004 for IL-1B) Barnea et al. [9] Yes No (p=0.84) Zeng et al. [10] Yes No (p=0.47) Lavu et al. [11] Yes Yes (p=0.023 ) Wu et al. [12] Yes Yes Yes (p=0.004 ) Shete et al. [13] Yes Yes Yes (p=0.034 ) Amirisetty et al. [14] Yes Yes (p=0.04) Puri et al. [15] Yes Yes (p＜ 0.01) Ribeiro et al. [16] Yes Yes (p=0.026 )
Smoking, a well-characterized risk factor for periodontitis, has been studied for interaction with IL-1 genotype, with conflicting results. However, the genetic interaction with smoking was not
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Risk of bias
The risk of bias is shown in below (Table 4). Table 4. Risk of bias
Reference Selection Bias Performance bias Blinding of Outcome Assessment (Detection bias) Incomplete Outcome Data Reporting Bias Havemose-Poulsen et al. [4] + + + + + Kobayashi et al. [5] + + + + + Loo et al. [6] + - + + + Ianni et al. [7] ? + - + ? Yin et al. [8] + + + + + Barnea et al. [9] + ? - + + Zeng et al. [10] - + + + ? Lavu et al. [11] + ? + + + Wu et al. [12] + + - + + Shete et al. [13] + + + + + Amirisetty et al. [14] + + ? + + Puri et al. [15] + + + + + Ribeiro et al. [16] + - + + +
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Discussion
As periodontitis is a fairy common infectious inflammatory disease that affects the quality of life greatly, many studies have been attempted to analyze its possible genetic factor. And as a result, majority of studies have shown that the genetic variants of some cytokines increase susceptibility to this disease [8]. At present, the search for risk alleles for periodontitis must focus on candidate gene regions. Recently, genome-wide association studies using single nucleotide polymorphisms or microsatellite polymorphisms have become realistic due to the development of promising high-throughput and cost-effective single nucleotide polymorphism typing [17].
IL-1 represents a group of proinflammatory cytokines whose activity has been identified as a trigger of inflammatory disorders. Many studies have reported that IL-1 levels are characteristically increased in diseased periodontal tissues, and they are thought to be a critical determinant of periodontitis outcome [8].
Extracellular IL-1β is primarily produced and released by activated macrophages and fibroblasts [8]. The IL-1β rs1143634 single nucleotide polymorphism is associated with various inflammatory conditions, and some investigations have shown the T allele to be a risk factor in the development of severe periodontitis. However, other researchers have failed to confirm such an association and the relevance of IL-1β rs1143634 to periodontitis outcome remains controversial. Given the interest surrounding these polymorphisms, IL-1α rs17561 and IL-1β rs1143634 are likely to be the most important sequence variants determining periodontitis pathophysiologic conditions [8].
In this review, total number of 11,396 cases were analyzed; 4,600 periodontitis cases and 6,796 healthy cases. The analyses for the association of periodontitis with either the IL1A or IL1B gene variation individually or for the IL1A and IL1B genotype pattern were statistically significant in ten articles.
Despite of this possible correlation between IL-1 family polymorphism and the susceptibility of periodontitis, three studies that were reviewed in this review have concluded that they could not find the significant relationship between the two. This result might act as possible proof of the complex nature of the periodontitis.
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This analysis has number of limitations. First, although comprehensive search method was applied, the number of studies that are reviewed in this review is small. Second, possible affecting factors such as gender and race were not taken into account, which may lead to possible influence of the result. Given the fact that the clinical parameters examined for each study was different, there are chances that the severity of periodontics was differently recorded. Although this does not affect the result of the relationship between periodontitis and IL-1 family polymorphism, it is possible to say that these studies were not done under the exact same control. Another possible affecting factor that has not been taken into account in this review is smoking. As smoking is known as one of the most problem-causing factor for periodontitis, there are chances that diagnosed periodontitis patient did not have any genetic factor which leads to periodontitis, but rather, the periodontics was simply caused by smoking. Lastly, the exact loci of analyzed IL-1 family might have been different, as some articles only addressed the group of IL-1 family, rather than describing the exact loci of polymorphism [6][7][8][12].
In the presence of numerous bacteria, including periodontal pathogens, the immune response in conjunction with tissue destruction have been shown to play an important role in the chronic inflammatory process in periodontium. It has been suggested that cytokines are probably significant factors in the maintenance of tissue homeostasis and ensure the delicate balance between different factors internal and external to the host [18]. Moreover, attempts have been made to outline and describe how these parameters influence the disease course and treatment results. Current evidence points to the impact of genetic factors in the pathogenesis of periodontitis, e.g. some gene polymorphisms of IL-1B (+3954) and IL-1A (-889), appear to correlate with disease severity. [18]. However, as three of the analyzed studies suggest, despite major advances in awareness of genetic risk factors for periodontal disease, we are still away from determining the genetic basis of both aggressive and chronic periodontitis. To date, major gene mutations, which result in the periodontitis phenotype in otherwise systemically healthy individuals, have not been identified and no specific genetic risk factor for the disease has been identified. The studies fail to quantity the magnitude of contribution of a particular disease associated allele to disease risk. This failure to quarantine the sensitivity and specificity of test precludes determination of the clinical utility of the association [19]. Although most of the reviewed studies concluded positive relationship, it is difficult to say that the IL-1 family polymorphism is the definite sign of susceptibility of periodontitis, because the reviewed studies examined different types of IL-1 family, and also there are three studies which concluded no definite relationship between the IL-1 family polymorphism
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and the susceptibility of periodontitis.
Conclusion
From these thirteen reviewed studies, ten of them showed the significant association between IL-1 family polymorphism and the susceptibility of periodontitis, and three of them concluded that there are not significant relationship between IL-1 family polymorphism and susceptibility of periodontitis. This genetic polymorphism was single nucleotide polymorphism (SNP), and the allele for polymorphism was T allele.
In conclusion, approximately 77% of the reviewed articles (ten out of thirteen) said polymorphism of Interleukin 1- family has a strong association with the susceptibility of periodontitis, with the strongest relationship defined by the p-value of 0.00001 [5].
Future recommandations:
Future studies should apply more strict disease classification, larger study cohorts, adjust for relevant risk factors in periodontitis, and include analysis of multiple genes and polymorphisms. Novel statistical methods may allow a better assessment of multiple genes and polymorphisms within the same pathway and interactions with environmental factors. The possibility to include data from multiple genes and polymorphisms or haplotypes and environmental data, and to model their interactions, will give us a better assessment of periodontitis and its pathophysiology [20].
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