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REVIEW ARTICLE
Year : 2019  |  Volume : 22  |  Issue : 4  |  Page : 445-453

Do genetic polymorphisms affect susceptibility to periodontal disease? A literature review


Department of Periodontology, Faculty of Dentistry, Inonu University, Malatya, Turkey

Date of Acceptance10-Dec-2018
Date of Web Publication11-Apr-2019

Correspondence Address:
Dr. M O Uslu
Department of Periodontology, Faculty of Dentistry, Inonu University, Malatya
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_462_18

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   Abstract 


The pathogenesis of periodontal disease is not solely based on microbial dental plaque but is the result of the multifactorial and complex interaction between infection and host response. Many studies in the literature have demonstrated the differences between individuals in terms of host immune response and the presence of genetic components in numerous pathological conditions. Therefore, periodontitis may be defined as a complex genetic disorder with a phenotype formed by the genetic structure and environmental factors in the affected individual. So, determination of the genetic susceptibility profile associated with periodontitis might be very precious for developing novel diagnostic techniques and individual treatment strategies. To clarify the possible role of genetic polymorphisms in periodontal diseases, we searched PubMed for studies published on the subject since 1997 up to June 2018 and obtained data from original studies, meta analyzes, and systematic reviews. We included only case–control studies with large study populations.

Keywords: Aggressive periodontitis, chronic periodontitis, genetic polymorphisms, susceptibility


How to cite this article:
Toy V E, Uslu M O. Do genetic polymorphisms affect susceptibility to periodontal disease? A literature review. Niger J Clin Pract 2019;22:445-53

How to cite this URL:
Toy V E, Uslu M O. Do genetic polymorphisms affect susceptibility to periodontal disease? A literature review. Niger J Clin Pract [serial online] 2019 [cited 2019 Apr 22];22:445-53. Available from: http://www.njcponline.com/text.asp?2019/22/4/445/255929




   Introduction Top


Periodontitis is one of the most common diseases in adult populations globally and is a major public health problem because of its considerable cost to the medical care systems.[1] Although the existence of pathogenic bacteria is necessary for the onset and progression of periodontitis, the quantity and quality of these pathogens are not always consistent with disease severity.[2] Every individual may have a unique reaction that characterizes his/her susceptibility to periodontitis and this verifies the importance of host response in the disease course. Currently, periodontitis is defined as a “complex” or “ multifactorial” disease, which results from the interaction of a number of factors such as environmental and genetic factors involved in the etiology.

Complex diseases are characteristically polygenic, while each of various genes has a finite role so the disease genes in this diseases are regarded as susceptibility genes.[3] It is estimated that at least ≥20 susceptibility genes may be related to periodontitis, but the amount and kinds of susceptibility genes for similar situations may vary for alternative forms of the disease and ethnic background.[4]

The genetic origin of periodontal diseases is being investigated by genetic technologies developed in recent years. Candidate genes that may be associated with periodontal diseases have been identified and the contribution of these genes to the genetic basis of periodontal disease is being examined. If these genes can be detected, those who are prone to develop periodontal disease can be identified to take precautions or genetic therapies may be possible with the advancement of genetic technology.

Gene polymorphisms are variations at certain locations within the genome and affect >1% of the population. Genetic polymorphisms may modify the encoded proteins or their expressions, probably causing changes in innate and adaptive immunity.[5] Besides, they may also be preventive against certain diseases.[6] Single nucleotide polymorphisms (SNPs) associate variations of DNA sequence with phenotypic alterations and are generally investigated in studies of complex diseases. The largest part of genetic studies about periodontitis has concentrated on gene polymorphisms, which have roles in immunity or metabolism; such as cytokines, antigen recognition receptors, cell-surface receptors, and enzymes.[7] The reactions displayed by the host against infection is regulated by a large number of genes. Variations in genes that regulate the proficiency of the cellular and humoral immune system determine the individual risk level for the disease. Certain forms of changes in the genetic code may result in changes in the function or release of the encoded molecules. This may result in increased disease severity or increased susceptibility to disease.[8],[9]

Altough candidate gene association studies are widely performed methods in periodontal research, they may not identify all of the genetic risk. Many genes may be associated with the disease but may not be selected as candidate genes because of undefined functions and absence of information previously.[10]

Candidate SNPs investigated to define the genetic polymorphisms that have roles in susceptibility to periodontitis with respect to aggressive periodontitis (AP) and chronic periodontitis (CP) are:

The IL1 gene group

Interleukin-1 (IL1) is an effective proinflammatory mediator that is secreted in response to inflammatory stimuli and is involved in the regulation of healing, immunity, and inflammation.[11] Since IL1 has important roles in the initiation and progress of periodontal disease, it is investigated frequently in studies. There are three major members of the IL1 family: IL1α, IL1β, and IL1 receptor antagonist (RA). The genes encoding them are located at chromosome position 2q13-21.

Kornmann et al.[12] examined the relationship between IL1 genotype and periodontal disease for the first time and reported that genetic markers that promote IL1 production were powerful signs of disease susceptibility. Until now, a number of studies have been published that investigated the association of IL1 gene polymorphisms with AP and CP [Table 1].
Table 1: Gene polymorphisms of IL 1 gene group

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While Li et al.[13] have indicated a relation between the IL1A −889 polymorphism and AP in males only, Laine et al.[14] have reported in CP patients with the combined genotype (IL1B +3954, IL1A −889, and IL1RN) who were non-smokers and did not harbor A. Actinomycetemcomitans and P. gingivalis in Chinese population. These results propose that IL1 gene polymorphisms may also have a role although the other risk factors are not present. In the study performed by Loo et al.[15] on 1290 Chinese individuals, IL1A −889 CC genotype was significantly associated with CP. They reported that the gene polymorphisms might be useful to detect periodontitis susceptibility and severity. Besides, Puri et al.[16] demonstrated a positive association in Indian AP patients.

In a recently performed meta-analysis, 21 case–control studies were selected with 2,174 patients with CP and 1,756 controls from various ethnic groups.[17] This meta-analysis demonstrated that the −889 polymorphisms were significantly associated with a higher risk of development of CP in general; however, there was not a significant association in the Brazilian population. On the other hand, in an another meta-analysis on AP, no significant association was found.[18]

The studies investigating IL1B +3954 polymorphism have contradictory results [Table 1]. While Lopez et al.[19] have found that IL1B +3954 R allele was associated with CP, Laine et al.[14] have found a relationship only in a subgroup of CP patients. In the study performed by Brett et al.[20] on Caucasian AP patients, an association was found between the R/R genotype and AP. No associations were found in other study groups.[13],[21]

A meta-analysis was accomplished to assess the association between IL1B +3954 polymorphism and CP and significantly high risk was detected for Caucasians, but not for Asians when classified according to ethnicity.[22] On the other hand, a recent meta-analysis done by Ma et al.[23] showed that IL1B +3954 polymorphism has increased the risk of CP in Asians. The pooled results of another meta-analysis including 25 case–control studies involving 1,594 AP patients and 2,483 healthy controls showed that IL1B +3954 polymorphism was not correlated with AP susceptibility, regardless of ethnicity.[24]

IL1B −511 polymorphism has not been found to be related with CP in the studies performed [Table 1],[13],[20],[25] but in one Asian study associated with AP only in male smokers with N/R genotype.[13] In the meta-analysis performed by Zeng et al.,[26] IL1B −511 polymorphism was not associated with the risk of developing CP.

IL1 RA is an effective inhibitor of IL-α and β and has anti-inflammatory effects. Berdeli et al.[27] found IL1RN VNTR (+2018) gene polymorphism to be associated with AP and CP in Turkish Caucasians. The combined genotype (IL1B +3954, IL1A −889, and IL1RN) has been reported to be related with periodontitis susceptibility in a subgroup of CP patients.[14] However, according to a recent case–control study, IL1RN VNTR (+2018) gene polymorphism might be related with reduced susceptibility to generalized AP and CP in European populations.[28] It was also reported that a decrease in the amount of periodontopathogens would have contributed to this effect.

Coexistence of IL1B +3954 and IL1A −889 has been defined as IL1 composite genotype.[12] Recently, Hamdy et al.[29] reported that this genotype in patients with inflamed periodontal or peri-implant tissues played a role as a risk factor causing greater tissue destruction and may affect outcomes of peri-implantitis treatment.

Fiebig et al.[21] examined various SNPs of the IL1 gene group, containing IL1RN, VNTR, IL1B −511, IL1A −889, and IL1B + 3954 on AP patients and healthy individuals with Caucasian origin and none of them was associated with AP. Nikolopoulos et al.[30] conducted a meta-analysis and reported an association of IL1B +3954 and IL1A −889 polymorphisms with CP but not with AP in Caucasians. In another systematic review and meta-analysis, Karimbux et al.[31] concluded that IL1A and IL1B polymorphisms would significantly contribute to CP in whites.

The TNFA gene

Tumor necrosis factor (TNF) is a proinflammatory cytokine regulating many immunological reactions. It is generated by lymphocytes, macrophages, and monocytes and augments the stage of inflammation. The TNFA gene maps to chromosome position 6p21.3. The SNPs that have been sought related to TNFA gene are mostly at positions −1031, −863, −857, −308, and −238.

A number of studies have been conducted considering the relationship between TNFA gene polymorphisms and CP and AP in different ethnic populations and no associations were found [Table 2].[20],[25],[32] Song et al.[33] performed a meta-analysis involving both AP and CP studies and indicated that TNFA −308 A allele was associated with CP but not with AP. However, a recent meta-analysis suggested that TNFA G-308A polymorphism might have been associated with AP susceptibility, especially in Caucasians and Asians, but not in Brazilians and Chileans.[34]
Table 2: Gene polymorphisms of TNF A, FcγR, and vit D

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The IL4 gene

Interleukin-4 (IL4) is a cytokine involved in inflammation by supporting B lymphocyte-mediated immunity and downregulating macrophage functions.

In studies, no correlation was found between IL4 gene polymorphisms and susceptibility to CP in different etnicities [Table 3].[25],[35],[36],[37] However, Holla et al.[35] found a haplotype of IL4 polymorphisms (−590/−33/−70 bp) to be associated with CP. Besides, Chen et al.[37] suggested that IL4 −1099 polymorphism and the two haplotypes at −33 and −1099 might be associated with CP in Chinese.
Table 3: Gene polymorphisms of IL 10, IL 4, and IL 6

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Three polymorphisms (IL4 −590, −33, and 70 bp) were examined in a meta-analysis and in most studies no significant association between these genetic variants and the risk of developing periodontitis was found.[38] In another meta-analysis, while all the studied IL4 polymorphisms were not significantly associated with periodontitis, the IL4 −33 was associated with reduced AgP susceptibility.[39]

The IL6 gene

Interleukin 6 (IL6) is a significant mediator involved in the inflammatory response, with both proinflammatory and anti-inflammatory effects. IL6 −174 and −572 polymorphisms were found to affect IL6 expression.

While Brett et al.[20] found a correlation between the IL6 −174 polymorphism and susceptibility to CP, Nibali et al.[40] found for a haplotype of combination of −174, −1363, and −1480 polymorphisms. Moreover, Holla et al.[41] suggested that −572 polymorphism might be protective for CP. In other studies, no association was found [Table 3].

Shao et al.[42] conducted a meta-analysis and reported that IL6 −174 polymorphism could not influence the risk of CP but raised the risk of AP. Also, −572 polymorphisms were seen to be related with the pathogenesis of periodontitis, including CP or AP. In the meta-analysis performed by Song et al.,[33] seven more studies were included and it has been reported that the IL6 −174 polymorphism had no association with the disease when analyzed for each ethnic group, except Brazilian population and CP. When stratified by ethnicity and disease type, an association between IL6 −572 polymorphism and CP and periodontitis in Europeans was demonstrated.

The IL10 gene

Interleukin-10 is an antiinflammatory cytokine involved in controlling inflammation and preventing extreme tissue damage. Several promoter polymorphisms related to IL10 production have been investigated.

While no association was found in most of the studies [Table 3], Claudino et al.[43] found the −592 polymorphism to be associated with CP. Jaradat et al.[44] reported that −1087 and −592 polymorphisms might have predisposed to CP but not to AP. In another study, the −1087 polymorphism was reported to be related with an increased risk of CP too.[45] Moreover, they also reported that the existence of Vascular Endothelial Growth Factor, IL10, and TNFA together in the same subjects seemed to have a synergistic effect and increased the risk of disease.

However, Zhong et al.[46] conducted a metaanalysis and showed that there was not any relation between IL10 −1082 polymorphism and periodontitis but suggested that −592 and −819 polymorphisms were related to CP, especially among Caucasians.

The FcγR genes

Leukocyte receptors for the constant (Fc) part of IgG (FcγR) bind humoral and cellular immune systems and are accepted crucial in host defense. The FcγR genes encode three main receptors; CD16 (FcγRIII), CD32 (FcγRII), and CD64 (FcγRI), and these are also subdivided into subclasses as FcγRIa and b, FcγRIIa, b and c, and FcγRIIIa and b.

There was no association between FcγRIIa polymorphisms and AP or CP [Table 2],[47],[48],[49],[50] but Yamamota et al.[50] reported that the homozygous N/N genotype was associated with CP in smokers. Nibali et al.[47] investigated the FcγRIIb polymorphism with regard to AP and did not find any association. Regarding the FcγRIIIa polymorphisms, no associations have been found with AP or CP susceptibility [Table 2]. However, Kobayashi et al.[48] showed a relation for the composite genotype of the FcγRIIIa N allele and the FcγRIIIb +141 R allele with AP in Japanese. In the study performed by Nibali et al.,[47] the FcγRIIIb +141 N/N genotype was related to AP in Caucasians.

According to a meta-analysis performed by Song et al.,[51] the FcγRIIa and FcγRIIIa polymorphisms may contribute susceptibility to periodontitis in Caucasians, and the FcγRIIIb polymorphism may be associated with susceptibility to AP. Briefly, there is not strong proof for an association between FcγR polymorphisms and CP, and somewhat between FcγRIIIb 141 polymorphism and AP.

The VDR gene

Since vitamin D receptor (VDR) coordinates bone metabolism and immunological reactions and alveolar bone resorption is the main feature of periodontal disease, genetic polymorphisms of VDR are considered to have a role in susceptibility to periodontitis.

Several studies have investigated VDR polymorphisms of Apa I, Bsm I, Fok I, and Taq I in relation to AP and CP and the Taq I is the most studied one [Table 2]. In the study performed by Nibali et al.[52] Taq I N/N genotype was associated with both AP and CP but only in smokers. Park et al.[53] found an association between AP and both the FokI N/N genotype and the haplotype of Bsm I R /Fok I N /Taq I N. Studies related to Taq I SNP mostly have found associations with CP,[20],[52],[54] but Gunes et al.[55] have found an association for a haplotype of Apa I, Bsm I, and Taq I polymorphisms.

Recently, Mashhadiabbas et al.[56] conducted a meta-analysis and concluded that Bsm I, Taq I, Fok I, and Apa I polymorphisms in VDR gene might have not been associated with CP in overall population, although subgroup analysis stratified by ethnicity suggested a significant association between Bsm I polymorphism and CP risk in Caucasians.

Pattern recognition receptor genes

Toll-like receptors (TLRs) are molecules important in innate immunity; being involved in the recognition of bacterial components and in initiating local inflammatory response. CD14 is used as a coreceptor by both TLR2 and TLR4.

The CD14 gene

The CD14 −260 promotor polymorphism has an impact on transcriptional activity and enhances the levels of soluble CD14 and the density. Moreover, increased levels of soluble CD14 have been shown to be associated with periodontitis.[57]

Regarding the association between CD14 −260 polymorphism and CP, whereas Laine et al.[58] and Yamazaki et al.[59] mentioned a relationship between early disease progression and polymorphism, the other studies did not find any relation about CP susceptibility [Table 4].[60],[61] Additionally, no association has been found for AP.[62]
Table 4: Gene polymorphisms of CD 14, TLR 4, and MMP 1

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In the meta-analysis performed by Han et al.,[63] no significant association was found in general, but further stratified analyses revealed links between CD14 −260 polymorphism and the severity of CP.

The TLR2 and TLR4 genes

Several studies have investigated TLR polymorphisms in relation to periodontitis [Table 4]. James et al.[62] indicated a relation between TLR4 +399 and +299 polymorphisms and AP, whereas Schröder et al.[64] found with CP. Fukusaki et al.[65] examined 13 SNPs of TLR4 and TLR2 genes and reported that TLR4 +3725 polymorphism was associated with CP in Japanese.

Ozturk et al.[66] concluded that TLR4 +299 polymorphism might be a risk factor for susceptibility to CP and TLR4 +399 polymorphism might be protective against AP as a result of their meta-analysis. On the other hand, the overall results of the meta-analyses performed by Song et al.[67] and Zheng et al.[68] all failed to reveal any association between TLR4 +299 or +399 polymorphisms and periodontitis. A recently performed meta-analysis, which included 18 studies, found an association between TLR4 C>G (rs7873784) allele and CP in Asians.[69] However, they did not detect any significant relevance between other TLR4 polymorphisms and periodontitis susceptibility in overall and subgroup analyses.

The MMP1 gene

Matrix metalloproteinases (MMPs) are proteolytic enzymes that are responsible for the breakdown of extracellular matrix and basement membranes during the beginning and development of a variety of diseases and have been confirmed to be related to the pathogenesis of periodontitis.

Among them, MMP-1 is a significant enzyme capable of breaking down collagen type I, II, and III which are the main components of the periodontal extracellular matrix. The −1607 insertion/deletion polymorphism of the MMP1 gene has been proven to affect the transcriptional activity of MMP1.

Itagaki et al.[70] have studied the relationship between −1607 polymorphism and AP and CP but found no association. However, two studies in Caucasian CP patients reported an association [Table 4]. Whereas Pirhan et al.[71] suggested that the −1607 polymorphism could be associated with susceptibility to severe CP in the Turkish population, Holla et al.[72] showed an association among nonsmokers. On the contrary, Holla et al.[72] reported that another SNP (−422) was associated with CP patients who smoke.

Li et al.[73] performed a meta-analysis containing 11 case–control studies and demonstrated that MMP1 −1607 polymorphism was associated with CP, especially the severity of the disease condition.


   Conclusion Top


Gene polymorphisms may cause phenotypic differences in inflammatory response, which is important in the individual's sensitivity to disease, in the progression of disease, or in the response to treatment. The identification of risk factors may also lead to more effective and costeffective preventive approaches. The incidence of genetic polymorphisms may differ according to ethnicity, so a potential association between a genetic polymorphism and disease for a population may not certainly be valid for others. That's why, the ethnic background of the studies is much more important. The discrepancies between the studies may be due to varied selection criteria of patients or their ethnicity. Moreover, there is need for much more comprehensive studies including thousands of individuals to identify the effects of polymorphisms accurately with regard to statistical power. Despite all these facts, the findings demonstrate a possible association between the FccRIIIb, IL1B, VDR, IL1RN, and TLR4 polymorphisms and AP; and between the TLR4, IL6, IL1B, MMP1, IL10, VDR, CD14, and IL1RN polymorphisms and CP susceptibility in specific populations. In the future, genome-wide association studies may discover novel loci susceptible to periodontitis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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