Immunomodulatory Factors Gene Polymorphisms in Chronic Periodontitis

An Overview

Zahra Heidari; Bita Moudi; Hamidreza Mahmoudzadeh-Sagheb


BMC Oral Health. 2019;19(29) 

In This Article

Candidate SNPS Involved in CP

IL-1 Gene Cluster

Interleukin-1 (IL-1) is a pro-inflammatory cytokine, which encoded by IL-1 gene cluster at position 2q13–21. This cytokine produced by monocytes, macrophages and dendritic cells which induce a complex network of proinflammatory cytokines and plays an important role in the regulation of immune and inflammatory responses to infections. IL-1 induces the migration of immune cells to the sites of infection through the expression of adhesion factors on endothelial cells.[20,21]

IL-1 is composed of two different molecules with similar function, IL-1α and IL-1β. IL-1α regulates the intracellular events, whereas IL-1β act as an extracellular protein. It has been reported that the levels of IL-1α, IL-1β and also IL-1/IL-receptor antagonist (RA, anti inflammatory cytokine) have been increased in patients with periodontal diseases.[22,23] The data showed that the IL-1 cluster gene SNPs were associated with higher risk for periodontitis.[24–26] Karimbux et al.,[27] Mao et al.,[28] Yin et al.,[29] Zeng et al.[30] in their meta-analysis studies have revealed that IL-1α and IL-1β genetic variations are significant contributors to CP in different geographical populations. On the other hand, these studies showed that the selected polymorphisms of the IL-1 genes were associated with susceptibility to aggressive periodontitis but not to chronic periodontitis in the some populations.[31] At the first time, Kornman et al. reported a relationship between IL-1α − 889 and IL-1β + 3953 SNPs and disease severity in patients with periodontitis.[32] This study continued by other scientists to examine the relationship between the SNPs in interleukin-1 gene and periodontitis. Some polymorphisms of the IL-1 gene have been studied in association with both aggressive and chronic periodontitis: IL-1α − 889, + 4845; IL-1β − 511, − 31, + 3954 and IL1RN VNTR (variable number of tandem repeats), + 2018.

IL-1α-889C/T polymorphism is located in the IL-1α promoter. IL-1α − 889 and IL-1β + 3954 were strongly associated with the periodontitis.[32] This report caused that Kinane et al. evaluated the epidemiological properties of IL-1 gene polymorphisms in people with periodontitis.[33] Furthermore, it has been shown that IL-1α − 889 and IL-1β + 3954 risk alleles could increase and the IL1RN VNTR risk allele decrease the IL-1α and IL-1β levels in the gingival crevicular fluid of periodontal patients.[34–37] It means that these SNPs can increase or decrease the gene transcription and protein production levels, which causes changes in the inflammatory responses.

The case-control studies in Caucasians and non-Caucasians have been shown that IL-1 rare variant (R allele), were different among various populations. In this regard, the carriage rate of the IL-1α − 889R-allele varies from 43 to 90% and 35 to 79% in patients and controls, respectively. In addition, Asian populations have a lower carriage rate of the IL-1α − 889R-allele (8–23%) than other populations.[38,39] These findings demonstrate that the ethnicity may affect the carriage rate of SNPs among different population. Therefore, possible positive associations between an SNP and disease within one population may not necessarily be extrapolated to other populations. Only some studies have reported a relationship between the carriage rates of the IL-1α − 889R-allele and CP as a single genetic risk factor.[40–43]

There are conflicting results about IL-1β + 3954 SNP. Recently, Wu et al.[44] identified significant associations between moderate to severe adult CP and IL-1β polymorphisms in four different ethnicities: Caucasians, African Americans populations, Hispanics and Asians. A meta-analysis by Ma et al.,[45] showed that IL-1β + 3954 polymorphism probably increased the risk of CP in Asians, and might be in association with a strongly increased risk of CP in Indians, but not in Chinese populations. In Asian population the carriage rate of the IL-1β + 3954R-allele is lower (≤10%) than the Caucasian populations (13–74%).[38,39,46] Lopez et al., Moreira et al. and Wagner et al. have shown an association between the IL-1β + 3954R-allele and CP.[43,47,48] Laine et al. reported an association in a sub-group of patients.[42] Galbraith et al. and Gore et al. found a relationship between IL-1β + 3954R-allele and periodontitis and disease severity.[49,50] However, Rogers et al. reported an association between the normal variant (N-allele) of the IL-1β + 3954 and CP, but not for IL-1β + 3954R-allele.[51] In another study, Struch et al. have not found any significant differences for carriage rates of the IL-1β + 3954R-allele between CP patients and controls in a Caucasian population.[52] Although some results did not support that the IL-1β SNP could be identified as a risk factor for CP, but the synergistic interactions of the some genotypes of IL-1β SNPs with environmental factors might play an important role in the pathogenesis of periodontal disease.[53,54]

Amirisetty et al.[55] and Masamattiet al.[56] suggested a strong association of the IL-1β − 511 and + 3954 variants with chronic periodontitis in Indian population. Although, some studies reported carriage rates for IL-1β-511R-allele, but, nowadays, IL-1β-511 polymorphisms haven't been reported to be associated with CP. The finding showed that the carriage rate of the IL-1β-511R-allele was higher among Asians (67%) compared to Caucasians (43–59%).[46,50,57,58]

There were conflicting results about IL1RN gene encoding the IL-1Rα. There are few studies investigating IL1RN gene polymorphisms in periodontitis. The results of some meta-analysis suggested that IL-1RN VNTR polymorphism might contribute to an increased risk to CP.[59] In a Turkish population, the frequency of IL1RN + 2018R-allele in patients with CP was higher than controls.[60] Results have been shown that the presence of the IL1RN, IL-1α − 889 and IL-1β + 3954R-alleles simultaneously had an association with CP susceptibility[42] and severity[32] in nonsmoking Caucasian patients. In Asian populations, the prevalence of the composite genotype was very low (3%) but in Caucasian populations, it was significantly higher (10 to 46%).[38,39,61] In some case-control studies in Caucasians[47,62] and non-Caucasians,[63] the IL-1 composite genotype have reported as a risk factor for CP susceptibility. Meisel et al. showed that the IL-1 composite genotype was associated with periodontal disease only in Caucasian smokers.[64] Moreover, subjects with the IL-1 composite genotype have increased counts of periodontal pathogens.[65] Nevertheless, the findings revealed a higher frequency of IL-1 composite genotype in non-smoking patients who had not periodontal pathogens.[42] It means that IL-1 gene SNPs can change the susceptibility to the disease in the absence of other risk factors.

Taken together, the IL-1 gene cluster SNPs cannot be considered as risk factors for CP for all populations. However, IL-1 composite genotype may be a genetic risk factor for Caucasian population.


During an acute and/or chronic infection, immune cells, such as T cells produces IL-6 which causes inflammation in tissues.[66,67]

IL-6 can control the immune responses via the inhibition of type 1 cytokines and activation of type 2 cytokines. In addition, IL-6 involved in regulation of metabolic and neural processes. IL-6 can bind to its membrane glycoprotein GP130 receptor. Subsequently, IL-6-GP130 complex, leading to GP130 homodimer formation and signal induction.[66]

The IL-6 is encoded by the IL-6 gene localized on chromosome 7p21. Some studies demonstrated that polymorphisms of this gene can affect the concentration of IL-6 in serum.[68,69] Polymorphisms in the promoter region of the IL-6 gene affect transcription and expression of IL-6 in individuals. There are three SNPs in the IL-6 promoter region (− 597G/A, -572C/G and -174G/C), that have been reported in chronic inflammations. These SNPs control the up-regulation of IL-6 levels and affect the serum levels of circulating interleukin-6. The IL-6-174 could influence IL-6 expression levels. The subjects with IL-6-174C-allele have lower plasma levels of IL-6 compared to the individuals with G-allele.[70] Therefore, IL-6-174C-allele may prevent proper immune response against periodontal pathogens in the host.

The carriage rates of the IL-6-174C-allele were 37–67% and 44–54% in Brazilian[71–73] and Caucasian populations,[58,74,75] respectively. In addition, IL-6 -174, − 190 and − 597 SNPs were not polymorphic in a Japanese population.[76] Heidari et al.[77] Brett et al.,[58] Babel et al.,[74] Tervonen et al.[75] and Trevilatto et al.[72] have revealed the association between IL-6-174G/C and susceptibility to CP. Nevertheless, Nibali et al. found an association for IL-6-174 in combination With IL-6 -1480 and − 1363 SNPs, but not for IL-6 -174 alone.[78]

With regard to the other IL-6 gene SNPs, it has been revealed that the IL-6-572 SNP may be a protective factor for CP.[79] In addition, the results have been suggested that the IL-6-1363 G/T and IL-6R + 48,892 A/C polymorphisms may contribute to genetic susceptibility to CP in Chinese population.[80] However, in a meta-analysis, Nikolopoulos et al.[81] did not show any association between IL-6-174 and CP, but, it seems that IL6–174 SNP may be change the susceptibility to CP.


Interleukin-10 (IL-10) is an anti-inflammatory cytokine which has vital role in pathogenesis of periodontal diseases.[82,83] This cytokine is expressed by various cells specially leukocytes. In addition, T helper 1 (Th1), Th2, CD8 T cells and B cells, from the adaptive immune system can express IL-10. Macrophages, mast cells, natural killer cells in the innate immune system also produce IL-10 cytokine.[84] Interleukin-10 can control viral infections and related tissue damages via stimulating the secretion of immune factors, controlling the phagocytosis and antigen presentation. In addition, IL-10 can play a role in the regulation of proinflammatory cytokines such as IL-1 and TNF-α. On the other hand, IL-10 improves the innate and adaptive immunity.[85,86]

The gene encoded IL-10 is located on chromosome 1q31-q32. This gene is in a cluster with closely related to the IL-19, IL-20, and IL-24. Polymorphisms in the promoter region of the IL-10 gene can affect the expression of IL-10 cytokine which leads to changes in inflammatory processes.[87–89] There are some conflicting results regarding the association between IL-10 polymorphisms and CP.[90–92] Some studies to analyze the SNPs in the promoter region of the IL-10 gene and its relation with periodontal disease have revealed that these polymorphisms might be associated with susceptibility to CP.[93–97] However, in some studies, analysis of allelic and genotypic frequencies of IL-10 SNPs revealed no causal relationship between the presence of polymorphisms and development of CP.[98,99]

The IL-10 -1082, − 819, and − 592 polymorphisms are in linkage disequilibrium and produce two important haplotypes. The studies revealed that IL-10 -1082, − 819 and − 592 polymorphisms were related to the CP in Swedish, Turkish and Brazilian patients.[90,92] Moreover, in vitro studies have reported that GCC/GCC genotype is associated with increased expression of IL-10 cytokine compare to the other genotypes.[100,101]

The in vitro and in vivo studies have been shown that, IL-10-592R-allele was related to the lower levels of IL-10 and may change the expression of IL-10 in response to inflammatory disease.[100–102] IL-10 can prevent the periodontal tissue destruction through inhibiting the receptor activator of nuclear factor-κB (RANK) and matrix metalloproteinases (MMPs).[103,104] Therefore, subjects with IL-10-592R-allele have a higher risk for susceptibility to inflammatory diseases.

With regard to the other IL-10 SNPs, the results have been shown that IL-10-1082 polymorphism were not associated with CP susceptibility, especially, in Caucasians, and the carriage rates of the IL-10-1082R-allele were 44–81%.[91,105] However, there was an association between IL-10-1082 N-allele and CP in Swedish Caucasians.[90]

The IL-10-819 SNP has been associated with CP in Brazilians but not in other populations.[91,92,105]

Scarel et al., Sumer et al. and Claudino et al. have found a higher R-allele carriage rate for IL-10-592 SNP in CP patients.[91,92,102] The carriage rate of the IL-10-592R-allele were 68–75% and 41% - 51 in CP patient and controls, respectively.

Our recent study showed that (unpublished data), the prevalences of AG and GG genotypes of IL-10-1082 in comparison with the AA genotype were significantly higher in CP patients than control groups. In addition, subjects with at least one IL-10-1082-G allele significantly had an increased risk for CP. The distribution of the IL-10-819 and IL-10-592 genotypes was not different between CP and control subjects. The combination of different genotypes showed that GCC haplotype was significantly different between case and control groups. Our results demonstrated that IL-10-1082 polymorphism was a putative risk factor for CP and associated with increased susceptibility to the disease.

In a Japanese population haplotype frequencies of the IL-10 -1082, − 819, and − 592 SNPs have been analyzed and no significant differences were found between groups in regard to the carriage rates of the haplotypes.[106] The remarkable point was that the IL-10-1082 N-allele was absent among the Japanese, but not in Caucasians.[90,106]

Finally, it seems that, IL-10-592 SNP has been associated with CP susceptibility and might be a genetic marker for CP susceptibility. Given that IL-10 can inhibit the matrix metalloproteinases and reduce the periodontal tissue destruction,[103,104] recommended to reveal the possible relationship between IL-10 polymorphisms (− 1082, − 819, − 592) and chronic periodontitis. These studies need to be replicated to enable conclusions to be drawn.


Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine involved in inflammations. TNF-α can control the production of chemokines or cyclooxygenase products, which consequently induce inflammation. It is produced by many cell types mainly macrophages. TNF-α controls the apoptotic cell death and inflammation and inhibit viral replication through the regulation of immune cells.[9,107,108] Insufficient TNF-α production causes various diseases such as cancer, psoriasis and inflammatory bowel diseases.[107,109,110] By destructing arachidonic acid, this cytokine causes an increment of prostaglandin E2 concentration, and then activation of osteoclasts. TNF-α stimulates osteoclasts differentiation and along with IL-1 may cause release of the matrix metalloproteinase (MMPs) and destruction of the extracellular matrix and bone resorption.[81,111,112] This mechanism probably is done on inflamed periodontal tissues during CP disease.

The human TNF-α gene is located on chromosome 6p21.3. This gene has an AU-rich element in the 3' UTR region that is a polymorphic site.[9,108,113]

It has been shown that the TNF-α gene SNPs were risk factors for periodontitis in both Caucasians and non-Caucasians populations. A number of important SNPs in the TNF-α gene have been studied: − 1031, − 863, − 857, − 376, − 308, and − 238 (in promoter region) and + 489 (in the first intron).

Yang et al.[114] reported that TNF-α-1031 SNP was a risk factor for CP. However, there was lack of association between TNF-α-857C/T and -238G/A gene polymorphisms and susceptibility to CP in Chinese population. Some findings from meta-analysis by Ding et al.,[115] supported that TNF-α-308G/A and -863C/A polymorphisms may contribute to the susceptibility to periodontitis. The results of some studies revealed an association between TNF-α-308 SNP and periodontitis.[116] The carriage rate of the TNF-α-308R-allele in Japanese population[46] was 2–3% and significantly was lower than other populations (18–44%).[49,58,75,111,117–121] Our study on an Iranian population did not show a significant difference in frequencies of TNF-α-308 genotypes and alleles between CP and control groups.[108] Stereological analysis of interdental gingiva in the same CP patients with different TNF-α-308 SNP also showed no significant differences in volume density of epithelium, connective tissue, collagenous and non-collagenous matrixes and blood vessels between CP patients.[9]

With regard to the other SNPs in TNF-α gene, the results have been revealed that the frequencies of TNF-α-238R-allele were different between various ethnic populations.[46,117,120] Soga et al.[46] reported positive associations between TNF-α − 1031, − 863, and − 857 SNPs and CP. But, these findings have not been replicated and needed for further studies to evaluate the real function of the TNF-α polymorphisms in CP susceptibility.


Transforming growth factor beta (TGF-β) is a multifunctional cytokine that controls proliferation, cellular differentiation, apoptosis, angiogenesis, and immune reactions. TGF-β is secreted by various inflammatory cells such as macrophages during tissue injury and regulates synthesis of connective tissue components and matrix proteins by fibroblasts and other cell types via chemotactic mechanisms.[11,122]

This cytokine exists in three isoforms: TGF-β1, TGF-β2 and TGF-β3 that have been expressed in high levels in most tissues. Various cells that secret TGF-β also has autocrine signaling properties because these cells express the TGF-β receptor family. TGF-β can induce differentiation of fibroblasts at the sites of inflammation in order to repair the lesions. In addition, it seems that induction of TGF-β secretion leads to increased eradication of inflammation through apoptotic mechanisms.[11,123]

TGF-β1 is a pleiotrophic growth factor that is involved in the regulation of numerous immunomodulatory processes.[124] It was suggested that TGF-β1 could be considered as a disease predictive biomarker.[125] Studies indicated that the expression level of TGF-β1 mRNA in the regulatory T cells present in the gingival tissue is correlated with periodontitis.[126,127] Khalaf et al.[128] reported that the expression level of TGF-β1could predict the progression of periodontitis. TGF-β1 can increase osteoprotegerin expression in bone marrow stromal cells. Therefore, it seems that TGF-β1 has a supportive role against the bone destruction process during CP.[127]

TGF-β1–29C/T, -509C/T, and -788C/T, are the main TGF-β1 SNPs. In our previous study,[10] we did not find a significant association between -509C/T and -788C/T variants of the TGF-β1 gene and risk of CP in an Iranian population. We proposed that TGF-β1–29 SNP, may contribute to the development of CP. Moreover, Holla et al.,[129] could not find an association between TGF-β1–29 and − 509 SNPs and CP in a Czech population. In line with our results, Kobayashi et al.[130] did not find any association between TGF-β1 polymorphisms and periodontitis in the Japanese population. Also, Atilla et al.[131] have found that TGF-β-788 variant was not associated with CP in a Turkish population. Nevertheless, the results of our quantitative studies showed that TGF-β1–509 and − 29 SNPs were strongly associated with quantitative parameters of connective tissue constituents of interdental gingiva in CP patients.[2,11,12] On the other hand, de Souza et al.[132] found that frequency distribution of TGF-β1–509 genotypes and alleles in the severe CP was significantly different from the control and moderate CP groups. Cui et al.[133] in a meta-analysis suggested that the TGF-β1–509 SNP was associated with the periodontitis risk in Asians but not in Caucasians. Atanasovska-Stojanovska et al.[134] concluded that polymorphisms of TGF-β1 gene were associated with an increased risk of CP in a Macedonian population. They found an association between the -29C/T SNP and susceptibility to CP.

In regard to the other TGF-β1 polymorphisms, Babael et al.[135] revealed that the TGFβ1-codon 25 variant was more common in control subjects than in CP patients. However, Erciyas et al.[68] did not show an association between TGFβ1-codon 10 and 25 SNPs and periodontitis.

In conclusion, the data suggest that TGF-β1 gene polymorphisms may contribute to a genetic risk factor for CP. However, further studies analyzing gene-gene and gene-environment interactions are required. Such studies lead to have a better understanding of the association between the TGF-β1 SNPs and CP risk.


Type II class of interferons such as interferon gamma (IFN-γ) play an important role in controlling the immune system. The IFN-γ gene is located on chromosome 12q24 and usually produced by natural killer (NK) cells, Th1 and cytotoxic T lymphocyte cells.[8] IFN-γ can activate the macrophages and increase the expression of Class II MHC molecules and then induce anti-viral and anti-tumor functions. It can inhibit the replication of viruses and inflammatory diseases will occur if the amount of protein change.[136] High levels of IFN-γ are expressed in diseased periodontal tissues and associated with severity of disease. It seems that IFN-γ is involved in the alveolar bone resorption in periodontitis.[137,138]

IFN-γ has a heterodimeric receptor that consists of Interferon gamma receptor 1 (IFNGR1) and Interferon gamma receptor 2 (IFNGR 2). When IFN-γ binds to its receptor, the JAK-STAT signaling pathway is activated. Also, if IFN-γ is attached to the glycosaminoglycan heparan sulfate, it will be deactivated.[139]

Polymorphisms of IFN-γ and its receptor can cause chronic inflammatory diseases.[8,140–142] Recently, Heidari et al. have studied the association between the IFN-γ and IFN-γR1 gene polymorphisms and risk of CP in an Iranian population. They revealed that IFN-γ (+ 874 A/T) was significantly in positive association with chronic periodontitis.[8] In addition, our another investigation (unpublished data), showed that there was a significant relationship between the IFN-γ (+ 874 T/A) gene polymorphism and the risk of hepatitis B virus infection as another chronic inflammatory disease in Iranian population. We did not find any significant differences in IFN-γR1 (− 611A/G), IFN-γR1 (+ 189 T/G), IFN-γR1 (+95C/T) SNPs between case and control groups.

The + 874 T allele is linked to the 12 CA repeats and the A allele is connected with the non-12 CA repeats. This specific sequence provides a binding site for the transcription factor NFkB which induces IFN-γ gene expression.[143,144] Babel et al., Reichert et al. and Hooshmand et al. studied allele and genotype frequencies of IFN-γ polymorphisms in patients with periodontitis.[135,145,146] In addition, Reichert et al.[145] confirmed a significant relationship between IFN-γ + 874 variant and some periodontal pathogens such as aggregatibacter actinomycetemcomitans and prevotella intermedia. However, Holla et al.[147] did not find significant relationship between variants of the IFN-γ and susceptibility to CP or microbial composition. Loo et al.[148] study also did not find any significant differences in their selected genes (IL-1b, IL-6, IFN-γ and IL-10) between the CP patients and healthy subjects.

In regard to the IFN-γR1 SNPs, the effects of IFN-γR1–611 SNP are stronger than of IFN-γ R1–56.[149] Rosenzweig et al.[150] found that G-611 carrier constructs are stronger in promoter activity than constructs carrying -611A. IFN-γ R1 + 95C/T SNP seems to control the intron-exon splicing process.[151]

In conclusion, IFN-γ gene seems to be a good candidate for association with CP. However, larger studies are needed to confirm the relationships of IFN-γ genetic variations and pathogenesis of CP, because the studies have not yielded any strong indication that it might be an important factor in disease susceptibility.

Vitamin D

Vitamin D can control the survival and homeostasis of the cell. It is closely related to the immunomodulatory factors which leads to a reduction of the severity of the inflammation. The combination of vitamin D and its receptor (VDR) induces innate immunity systems through inhibiting the Th1 cell functions and activating the Th2 cell responses.[152,153]

Vitamin D and vitamin D receptor are important mediators of bone metabolism. Dysfunction of these compounds and their gene polymorphisms lead to bone resorption, which is one of the most common complications of the periodontal disease. Also, vitamin D and its receptor can regulate phagocytosis by monocytes.[154]

The gene encoding VDR is located on chromosome 12q12–q14. Several studies showed that the VDR gene variations were associated with chronic infectious diseases, especially hepatitis and tuberculosis.[155–158] However, till now the actual role of the VDR SNPs in CP susceptibility have not been clarified completely. It has been reported that the Fok1 polymorphism may change the expression of the protein, but not the Taq1, Bsm1, and Apa1 polymorphisms.[159] In this regard, it has been identified that VDR SNPs, such as Taq1, Bsm1, Fok1, and Apa1 were associated with CP.[58,160–167] The carriage rates of the VDR Taq1R-allele were 4–23% in Asian populations[163,164] which were significantly lower than other ethnic populations (42–78%). In some studies, the Taq1N-allele has been related to CP susceptibility. There was not an association between VDR Bsm1 SNP and CP.[160–162] Given that the VDR gene can affect both immune functions and bone metabolism, therefore, VDR SNPs, specially the VDR Taq1 may be risk factors for CP susceptibility. Further studies should be undertaken to confirm the current preliminary data.