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Table of Contents   
REVIEW ARTICLE  
Year : 2010  |  Volume : 21  |  Issue : 4  |  Page : 568-574
Genetic polymorphisms in periodontal diseases: An overview


Department of Periodontics, Meenakshi Ammal Dental College and Hospital, Maduravoyal, Chennai, India

Click here for correspondence address and email

Date of Submission10-Aug-2008
Date of Decision27-Oct-2009
Date of Acceptance06-Feb-2010
Date of Web Publication24-Dec-2010
 

   Abstract 

Periodontitis is a multi-factorial disease; several risk and susceptibility factors are proposed in its natural history. Genetics is considered a susceptibility factor in relation to periodontitis. This article is a nonsystematic review of literature and focuses on the role of genetic polymorphisms in periodontal diseases.

Keywords: Genotype, genetic disease model, polymorphism

How to cite this article:
Vijayalakshmi R, Geetha A, Ramakrishnan T, Emmadi P. Genetic polymorphisms in periodontal diseases: An overview. Indian J Dent Res 2010;21:568-74

How to cite this URL:
Vijayalakshmi R, Geetha A, Ramakrishnan T, Emmadi P. Genetic polymorphisms in periodontal diseases: An overview. Indian J Dent Res [serial online] 2010 [cited 2019 Sep 18];21:568-74. Available from: http://www.ijdr.in/text.asp?2010/21/4/568/74226
Periodontics, like many other specialized areas of dentistry, is undergoing yet another change in the approach to diagnosis and treatment. The disease has not changed, but our understanding of the pathogenesis has improved. The current era of periodontics focuses on host risk factors.

Periodontics has evolved from a simplistic model to a more complex interplay between infection and host response. Emerging pathway models suggest that gene-environment interactions are etiologically important in disease pathogenesis. This article is an attempt to focus on genetic influence on periodontal disease, genetic polymorphism in particular and how this field will help improve patient treatment protocol. The article, which is a nonsystematic review of literature, will focus on the role of genetic polymorphisms in periodontal diseases.


   Genetics - An Insight Top


Genetics is the study of inheritance or heredity of living things. It is a wide ranging science that explores the transmission of biological properties from parent to offspring. The pioneer of genetics was Gregor Mendel (1822-1884).

Human genome contains approximately 30,000-40,000 genes. Approximately 5% of the genome actually codes for genes with some chromosomes containing a higher density of genes compared to other chromosomes. The function of remaining DNA is unclear. Genotype is the genetic makeup of an organism or cell distinct from its expressed features or phenotype.

Humans share 99.9% of their genetic information, which is why every human belongs to the same species. The final 0.1% differs from one person to the other. This seemingly small variation may very well be involved in disease susceptibility, drug and treatment response in periodontitis. [1]

Human genome refers to all the DNA genetic information in a cell's nucleus. Genes are composed of nucleotides and are organized in the chromosomes within the cell's nucleus. The sequence of nucleotides determines the expression of the gene. There may be multiple (poly) forms (morphism) of a gene, and the altered forms of a gene's structure are referred to as "genetic polymorphisms".

Researchers have estimated that every person has six billion nucleotides and 0.1% is polymorphic. Only a small fraction of these genetic variations are translated into alterations in aminoacid sequence that is phenotypically important.

Polymorphisms arise as a result of mutation. An alteration that changes only a single base pair is called point mutation. The most common form of point mutation is transition, comprising the substitutions of one nucleotide with another and the site harboring such changes is termed a "single nucleotide polymorphism". [2]

Recent studies have shown that single nucleotide polymorphisms occur once in every 100-300 bases. Other types of genetic polymorphisms result from insertions or deletions. [2]

The most common type of insertion/deletion polymorphism is the existence of variable numbers of repeated bases or nucleotide patterns in a genetic region. Repeated base patterns can consist of several hundreds of base pairs, known as a variable number of tandem repeats (VNTRs) or mini-satellites. [1] Also very common are micro-satellites, which consist of two, three or four nucleotide repeats, a variable number of times; micro-satellites are also referred to as simple tandem repeats (STR). The STRs may occur every 3-10kb genome width. [2]

Genotype polymorphisms have also been associated with disease diagnosis, severity and presence of subgingival bacteria. Stefan Reichert et al. [3] investigated the relationship between Interferon -8 and Interleukin - 12 polymorphisms and certain periodontopathic bacteria or bleeding index. But none of these polymorphisms were significantly related to the presence of aggressive periodontitis or chronic periodontitis.

Nibali [4] found the association between IL - six genotypes and  Actinobacillus actinomycetemcomitans Scientific Name Search itans and  Porphyromonas gingivalis Scientific Name Search  smaller population of subjects with aggressive and chronic periodontitis. Nibali et al. showed that this association is not limited to cases of aggressive periodontitis because it was found in subjects with severe periodontitis. This study supported the hypothesis that complex interaction between the microbiota and the host genome are the basis of susceptibility to periodontitis.


   Genetic Disease Models Top


The search for genes important in genetic susceptibility to disease can be broadly divided into:

  • Major disease gene, which is responsible for disease expression, according to Mendel's law when a given aberrant allelic form is present. [5] To date, only one major disease gene has been revealed in relation to periodontitis; gene on chromosome 11 responsible for a severe form of prepubertal periodontitis (PLS). [6]
  • Modifying disease gene is identified to be involved in complex multifactorial diseases. [5] Most forms of periodontitis are likely to be associated with multiple modifying genes. It is estimated that for periodontitis, between 10 and 20 genes may be involved.

   Genetics in Relation to Periodontal Diseases Top


Periodontitis is a multi-factorial disease for which several risk and susceptibility factors are proposed in the natural history of periodontitis. [7] Genetics is considered a susceptibility factor in relation to periodontitis. Among the various study designs, population studies are used to find the frequencies of polymorphisms of candidate genes, by comparing between cases and controls.


   Polymorphism in Relation to Periodontal Diseases Top


1. Cytokine gene polymorphisms

  1. IL-1 gene polymorphism
  2. TNF-α gene polymorphism
  3. IL-10 gene polymorphism


2. Receptor and other gene polymorphisms

  1. FCgR gene polymorphisms
    • FcgRIIa-131 H/R polymorphism
    • FcgRIIIa-158 F/V polymorphism
    • FcgRIIIb polymorphism
  2. Cytokine and chemokine receptor gene polymorphisms
  3. Immune receptor gene polymorphism
  • FMLP receptor gene polymorphism


3. Metabolism - related gene polymorphism

  1. Vitamin D receptor gene polymorphism
  2. Calcitonin receptor gene polymorphism


4. Antigen - recognition related gene polymorphism

  • HLA gene polymorphism


5. Polymorphisms in the innate immunity receptors

  1. TLR2 and TLR4 gene polymorphisms
  2. CD 14 gene polymorphism
  3. CARD 15 gene polymorphism


6. Miscellaneous gene polymorphisms


   1. Cytokine Gene Polymorphisms Top


a. IL-1 gene polymorphismth

IL-1 gene cluster is located on chromosome 2. The first study that reported polymorphism for IL-1 gene in relation to periodontitis was presented by Kornman et al, [8] in Caucasians. He concluded that IL-1 composite genotype could be considered a putative severity factor for periodontitis in Caucasians.

Sensitivity and specificity of IL-1 "Genotype positive" model was depicted by Kornman et al, 1997 [8]

Diehl et al.1999 [9],[10],[11] showed the association of IL-1 gene cluster and aggressive periodontitis, but in direction different from the previous ones. He confirmed that IL-1 gene cluster acts as putative susceptibility factor for periodontitis.

Ethnicity also has a role to play in IL-1 gene polymorphism. Among White Europeans and Hispanics, prevalence of IL-1 positive individuals was found to be 30% and 26% respectively. IL-1 gene polymorphisms cannot be regarded as susceptibility/severity factor for periodontitis, but for non-smoking Caucasians. [12]

Anne Havemose - Poulsen et al. [13] demonstrate that in localized aggressive periodontitis patients, allele 2 of IL - 1 RN VNTR was associated with significantly higher levels of IL - 1 α, 6, 10 and TNF - α, whereas allele 2 of IL - 1β +3954 was associated with significantly lower levels of the same cytokine.

Moreira PR Costa et al. [14] evaluated the association of IL - 1A (-889) gene polymorphism in Brazilian individuals with different clinical forms and severity of periodontitis and demonstrated a significant association between the two.

b. TNF- α gene polymorphism

TNF-α gene lies on chromosome 6 within MHC gene cluster. Gene polymorphisms are G to A transition.

From the studies by Craandijk, 2002 [15] Shapira, 2001 [16] Schulz Machulla 2008 [17] , there is no indication that any of the related gene variations are related to susceptibility/severity of periodontitis. In 2008, Lydie et al. found that IL -4- polymorphism was at the promoter sequence - 590 C/T, -33C/T and intron 3 variable number tandem repeat of IL - 4 gene acted in a cooperative fashion and resulted in high production of IL - 4. [18]

In 2008, Stefan Reichert et al. [3] studied the expression of IL - 12 R β2 molecule in a crucial regulatory factor in the T - helper type differentiation of T cells. They found that single nucleotide polymorphism of the 5'flanking region of IL - 12RB2 leads to a very weak cellular immune response. They reported that the frequencies of variant alleles of IL - 12 RB2 were significantly higher in aggressive periodontitis patients as compared with healthy controls or chronic periodontitis patients.

c. IL-10 gene polymorphisms

IL-10 gene is located on chromosome 1, in a cluster with closely related IL-genes IL-19, 20, 24. IL-10 has an inhibitory effect on IL-1α, IL-1β, TNF-α, IL-6, IL-8 and IL-12. Functional disturbances in IL-10 due to genetic polymorphisms could be detrimental to host tissue and linked to periodontal disease susceptibility. [19],[20],[21]


   2. Receptor and Other Gene Polymorphisms Top


a. FCgR gene polymorphisms

The inflammatory cascade induced by IgG containing immune complexes is initiated by the IgG Fc receptors on phagocytes. Efficient clearance of IgG opzonised pathogens by phagocyte FcgR is crucial for periodontal health. Leukocytes exhibit receptors [R] for the constant region [Fc] of immunoglobulin molecule. In case of IgG, these receptors are termed FcgR. FcgR belongs to the Ig superfamily. It links the humoral part of host defense with cellular aspects. The genes for FcgR are found on long arm of chromosome 1 and encode 3 main classes.

Class - Subclass

FcgRI - FcgRIa and b

FcgRII - FcgRIIa,b,c

FcgRIII - FcgRIIIa and b

Polymorphisms in the genes encoding the low affinity receptors may result in variations in antibody binding and phagocytosis and hence susceptibility to periodontitis.

1. FcRIIa-131 H/R polymorphism

[Histidine H for arginine R] at position 131 results from a single G to A nucleotide substitution. Patients with FcgRIIa-R/R genotype could be more susceptible for periodontitis due to decreased capacity to phagocyte IgG2 opsonized Actinobacillus actinomycetemcomitans. [22] But this hypothesis may have to be rejected since Loos et al. [12] found that FcgRIIa-H/H genotype is higher in aggressive periodontitis subjects than in controls. A recent study by Nicu et al. [23] also proved that H/H genotype is associated with more periodontal destruction than H/R or R/R genotype.

2. FcgRIIIa-158 F/V polymorphism

[Phenylalanine, F for valine,V] at position 158, results from G to T substitution at nucleotide 559 in the DNA sequence. The V/V variant is capable of efficient binding of IgG 1, 3, 4 relative to F/F variant in both monocytes and natural killer cells. This substitution was also associated with recurrence of adult periodontitis compared to individuals without recurrence. [24]

3. FcgRIIIb polymorphism

In neutrophils, FcgRIIIb exists in two allelic forms, NA1 and NA2 as a result of nucleotide substitutions resulting in changes in four aminoacids. FcgRIIIb-NA1 displays more efficient interaction with IgG1 and IgG3 opsonized bacteria compared with FcgRIIIb-NA2 and was found to be associated with increased resistance to periodontitis in an elderly Japanese population. [25]

To summarize, the possibility that genes encoding for FcgR are associated with susceptibility and severity of several forms of periodontitis in different ethnic groups seems promising. Further research is needed in the area.

b. Cytokine and chemokine receptor gene polymorphisms

Receptors are important constituents of the whole cytokine system. Through these membrane bound or circulating proteins, cell responses to various cytokines are elicited or blocked. The soluble form of TNF -receptor 2, which is shed from the cell surface significantly reduced the loss of connective tissue and alveolar bone in experimental periodontitis. [26]

c. Immune receptor gene polymorphism

Fmlp Receptor polymorphism depressed chemotactic response to n-formyl-1-methionyl-1-leucyl-1-phenylalanine peptides has been confirmed in studies done by VanDyke et al. and Serhan CN. [27]


   3. Metabolism - Related Gene Polymorphism Top


a. Vitamin D receptor gene polymorphism

The 3' portion of the VDR gene includes a cluster of linked polymor­phisms: Bsml, Apal and Taql sites. [28] The first two sites are in the region of the gene from intron 8 to the 3' untranslated region. A silent mutation within codon 352 of the ninth exon alters a Taql site. The presence of the restriction endonuclease site has been denoted by b, a, t; the absence of the restriction endonuclease site has been denoted by B, A, T. VDR gene polymorphisms are normally deter­mined by polymerase chain reaction (PCR) and restriction enzyme diges­tion. The VDR gene polymorphisms are commonly present. If these poly­morphisms influence the level or func­tion of the VDR, they may be pathogenic. [29]

Li et al. [30] found in his study that F O K I polymorphism of vitamin D receptor gene might be associated with generalized aggressive periodontitis in Chinese patients. The carriage of F allele increases the risk of developing generalized aggressive peridontitis. Nibali et al. [31] found that Vitamin D receptor Taq - 1 TT polymorphism was moderately associated with both the presence and the progression of periodontitis in smokers, while no association was detected in non-smoking individuals.

b. Calcitonin receptor polymorphism

Nosaka et al. [32] have found that patients with this polymorphism were 20 times more likely to suffer buccal marginal bone loss than patients who were calcitonin receptor genotype negative.


   4. Antigen - Recognition Related Gene Polymorphism Top


HLA gene polymorphism

HLA genetics

Human leukocyte antigen (HLA) is involved in genetically predetermined humoral response via recognition of foreign antigens. The MHC genes are the most polymorphic genes present in the genome of every species analyzed. The various alleles associated with disease in Periodontics are:

HLA-DRB1.1501-DQB1.0602 genotype, HLA-DR4 and its subtypes [33],[34]


   5. Polymorphisms in the Innate Immunity Receptors Top


a. TLR2 and TLR4 gene polymorphisms

The TLR2 gene polymorphism has been reported to decrease the ability of TLR2 to mediate a response to bacterial cell wall components. The TLR4 gene polymorphism has been reported to attenuate the efficacy of lipopolysaccharide (LPS) signaling and decrease the capacity to elicit inflammation. [35]

These polymorphisms have been correlated with hypo-responsiveness to inhaled LPS, sepsis and infection caused by gram negative bacteria. [36] However, despite the perceived importance of these functional TLR polymorphisms, no relation with periodontitis has been observed. [37] James JA et al. [38] studied whether there is an association between the frequency of functional polymorphisms in the toll-like receptor 4 and cluster of differentiation 14 (CD 14) genes and periodontitis. The results concluded that TLR4 gene polymorphism is associated with a decreased risk of aggressive periodontitis but not chronic periodontitis.

b. CD 14 gene polymorphism

Increased serum levels of sCD14 have been known to be associated with periodontitis. [39] There are contradictory findings from the studies of Holla et al. [40] and Yamazaki et al. [41] which did not find any association between CD14 genome polymorphism and chronic periodontitis.

c. CARD 15 gene polymorphism

Polymorphism led to impaired activation of nuclear factor-kB, which in turn led to decreased expression of pro-inflammatory cytokines. [42] However, no association was found with periodontitis.


   6. Miscellaneous Gene Polymorphisms Top


a. Cathepsin C gene polymorphism

Cathepsin C is a proteinase and is expressed in the hyperkeratotic epithelial lesions such as palms, knees and oral keratinized gingiva. Hart et al. identified a gene on chromosome 11 containing the cathepsin C gene, responsible for prepubertal periodontitis as well as Papillon - Lefevre syndrome (PLS). All patients with pre-pubertal periodontitis were found to be homozygous for an A-G mutation at gene position +1040, resulting in a substitution of the amino acid tyrosine by a cysteine. This gene polymorphism was shown to be functional as there was a diminished activity of cathepsin C in PLS. Another study by Noack et al. [43] reported two novel gene mutations at positions 947 and 1268, which were associated with these two diseases.

b. MMP gene polymorphism

Ustun K Alptekin et al. [44] examined the association between MMP-1-1607 1G/2G polymorphism and chronic periodontitis susceptibility in a Turkish population. The results concluded that there was no significant association between this polymorphism and susceptibility to periodontitis.

c. Polymorphism in smokers

Cytochrome P450 (CYP) enzymes, CYP1a1 and CYP2E1, are important in the activation of xenobiotics, especially tobacco-derived substances such as polycyclic aromatic hydrocarbons [45] and nitrosamines.

On the other hand, glutathione S-transferase (GST) MI and N-acetyltransferase (NAT1 and NAT2) are involved in detoxification of these associated metabolites. Polymorphism of CYP1A1 and CYP2E1 are associated with enhanced catalytic activities of these enzymes. In addition, the null GSTM1 genotype and mutation in NAT gene result in the inability to efficiently detoxify xenobiotics. [46]

It has been reported that the slow acetylator genotype of NAT2 is associated with a higher risk of periodontitis, particularly in smokers. [47] Therefore, polymorphism of other xenobiotics metabolizing enzymes, CYPs and GSTs may also contribute to individual susceptibility to develop periodontitis.

Kocher et al. [48] and Meisel et al. [47] conducted studies in Caucasian population which demonstrated that the N-acetyl transferase slow phenotype was significantly associated with severity of bone loss. Meisel et al. [49] noted that the possible protective effects seen in non-smokers might be due to an allele of myeloperoxidase (MPO), which is not obvious in smokers.

d. Other polymorphisms

Other polymorphisms include ACE (Angiotensin converting enzyme), ER2 (Endothelein receptor 2), IL (Interleukin) 2, IL4, IL6, IFN-GR (Interferon gamma receptor) 1, MMP (Matrix mettaloproteinase)-1, MMP3, MMP9, MPO (Myeloperoxidase), RAGE (Receptor for advanced glycation end products), TGF (Transforming growth factor) b, TIMP (Tissue inhibitor of metalloproteinase) 2, Plasminogen activation, Mannose binding lectin, Osteoprotegrin and TNFR (Tumor necrosis factor receptor) 2 gene polymorphisms. Association between these polymorphisms and periodontal disease is yet to be proved.[50]


   Evidence from Meta-Analysis Top


Clinical implications of recent studies of genetic polymorphisms

  • The association between particular genes and disease may only be apparent in certain populations
  • The association between groups of interacting genes and disease may be stronger than those between individual genes and disease
  • The association between disease and genes may be indirect, due to the effect of environmental risk factors [50]

   Issues to be Addressed for Meaningful Disease Association Studies Top


a. Ethnic heterogeneity

In designing a case-control study, subjects should be carefully matched by ethnic origin in addition to other potential confounding factors in order to avoid systematic differences in genetic composition between the two groups. [51] Also, in the presence of large biological and environmental variability, genetic effects can differ across different populations, or among generations within the population. [52] Variation in genotype frequencies across diverse populations may affect the number of individuals at increased risk for a disease. [53]

b. Clinical classification

Classifying periodontal disease has been a long standing dilemma largely influenced by paradigms that reflect the understanding of the nature of periodontal diseases during a given historical period. In addition, microbial plaque deposition, smoking and systemic diseases largely influence the phenotypic expression of the disease. Aggressive and chronic periodontitis probably share a common pathogenic pathway, so several common polymorphisms may exist and / or overlap between the two.

c. Functional polymorphisms and direct evidence

In the 2001 report of the international SNP Map Working Group, they approximated around 1.42 million single nucleotide polymorphisms in the human genome. [54] Structural gene defects can affect the qualitative response and regulatory polymorphisms can alter the response quantitatively. Majority of the studies only statistically demonstrated an association between polymorphisms and periodontitis. Kinane et al. [55] have outlined the requirements in providing a disease - polymorphism association:

  • The polymorphism must influence the gene product
  • Biases in the study population should be recognized and controlled for confounders such as smoking and socioeconomic class
  • The affected gene product should be part of disease etiopathology
Factors such as study design, methods of recruitment of case and controls, selection of candidate genes, functional significance of polymorphisms chosen for study and statistical analysis require close attention to ensure that only genuine associations are detected. [49] Also, sample size of the study subjects has to be taken into account. The results of small studies might differ significantly from the results of larger studies, but large studies with thousands of participants might not be carried out. [56]

Also, controls should be clearly defined for a case-control study in periodontitis. The overuse and misuse of the venerable P-value has been criticized. It has been suggested that the data presented should be evaluated using CI and RR values, as these portray the effect size with a description of its precision. This is in contrast to the P-value, which tests against the null hypothesis of no association and could provide false positive associations. [57]

Problems with genetic susceptibility tests

  • The data demonstrate either cross-sectional or retrospective associations, not prospective data of the disease.
  • The polymorphisms utilized in this test have been evaluated only in certain populations, not in all.
  • The tests have limited sensitivity and specificity.
  • The genes in question determine a relatively small, but significant, component of the overall risk of the disease.


Problems in research

  • Whatever be the cause of the disease, symptoms are the same.
  • In majority of the cases, periodontitis is influenced by environmental risk factors, rather than solely by genetic factors.
  • It is difficult to find out the recombination fraction.
  • Genetic studies in relation to periodontitis are hampered by population heterogeneity and differences in patient selection and diagnostic criteria.
  • Valid comparison between different studies is not possible because of the different definitions that have been used for cases of chronic and localized and generalized aggressive forms of periodontitis. [58]

   Conclusion Top


As such, the high susceptibility genes responsible for periodontitis have not yet been recognized and further research is needed in this regard.

 
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Correspondence Address:
R Vijayalakshmi
Department of Periodontics, Meenakshi Ammal Dental College and Hospital, Maduravoyal, Chennai
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-9290.74226

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    Abstract
    Genetics - An In...
    Genetic Disease ...
    Genetics in Rela...
    Polymorphism in ...
    1. Cytokine Gene...
    2. Receptor and ...
    3. Metabolism - ...
    4. Antigen - Rec...
    5. Polymorphisms...
    6. Miscellaneous...
    Evidence from Me...
    Issues to be Add...
    Conclusion
    References

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