Review Article

Genetic polymorphisms in periodontal diseases: An overview

R Vijayalakshmi, A Geetha, T Ramakrishnan, Pamela Emmadi

Department of Periodontics,
Meenakshi Ammal Dental
ABSTRACT
College and Hospital Periodontitis is a multi-factorial disease; several risk and susceptibility factors are proposed in
Maduravoyal, Chennai, India
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.
Received : 10-08-08
Review completed : 27-10-09
Accepted : 06-02-10 Key words: Genotype, genetic disease model, polymorphism

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
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].
Address for correspondence:
Dr. R. Vijayalakshmi
E-mail: srvijayalakshmi@rediffmail.com
Access this article online
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PubMed ID:
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DOI:
10.4103/0970-9290.74226
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

Indian J Dent Res, 21(4), 2010 568

Genetic polymorphisms in periodontal diseases Vijayalakshmi, et al.
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 found the association between IL – six genotypes and
[4]
Actinobacillus actinomycetemcomitans and Porphyromonas
gingivalis in a 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
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
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
569
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
1. Cytokine gene polymorphisms
a. IL-1 gene polymorphism
b. TNF-α gene polymorphism
c. IL-10 gene polymorphism
2. Receptor and other gene polymorphisms
a. FCγR gene polymorphisms
• FcγRIIa-131 H/R polymorphism
• FcγRIIIa-158 F/V polymorphism
• FcγRIIIb polymorphism
b. Cytokine and chemokine receptor gene
polymorphisms
c. Immune receptor gene polymorphism
• FMLP receptor gene polymorphism
3. Metabolism – related gene polymorphism
a. Vitamin D receptor gene polymorphism
b. Calcitonin receptor gene polymorphism
4. Antigen – recognition related gene
polymorphism
• HLA gene polymorphism
5. Polymorphisms in the innate immunity
receptors
a. TLR2 and TLR4 gene polymorphisms
b. CD 14 gene polymorphism
c. CARD 15 gene polymorphism
6. Miscellaneous gene polymorphisms
1. CYTOKINE GENE POLYMORPHISMS
a. IL-1 gene polymorphism
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[9-11] 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%
Indian J Dent Res, 21(4), 2010
Genetic polymorphisms in periodontal diseases Vijayalakshmi, et al.
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.[19-21]
2. RECEPTOR AND OTHER GENE
POLYMORPHISMS
a. FCγR 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 FcγR is crucial for periodontal health.
Leukocytes exhibit receptors [R] for the constant region [Fc]
Indian J Dent Res, 21(4), 2010
of immunoglobulin molecule. In case of IgG, these receptors
are termed FcγR. FcγR belongs to the Ig superfamily. It links
the humoral part of host defense with cellular aspects. The
genes for FcγR are found on long arm of chromosome 1 and
encode 3 main classes.
Class Subclass
FcγRI FcγRIa and b
FcγRII FcγRIIa,b,c
FcγRIII FcγRIIIa 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
FcγRIIa-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 FcγRIIa-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. FcγRIIIa-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. FcγRIIIb polymorphism
In neutrophils, FcγRIIIb exists in two allelic forms, NA1
and NA2 as a result of nucleotide substitutions resulting
in changes in four aminoacids. FcγRIIIb-NA1 displays
more efficient interaction with IgG1 and IgG3 opsonized
bacteria compared with FcγRIIIb-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 FcγR
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
570
Genetic polymorphisms in periodontal diseases Vijayalakshmi, et al.
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
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 poly­
morphisms 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
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]
571
5. POLYMORPHISMS IN THE INNATE IMMUNITY
RECEPTORS
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-κB, which in turn led to decreased expression of
pro-inflammatory cytokines.[42] However, no association
was found with periodontitis.
6. MISCELLANEOUS GENE POLYMORPHISMS
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
Indian J Dent Res, 21(4), 2010
Genetic polymorphisms in periodontal diseases Vijayalakshmi, et al.
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) β, 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
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
Indian J Dent Res, 21(4), 2010
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
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
572
Genetic polymorphisms in periodontal diseases Vijayalakshmi, et al.
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
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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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.
Source of Support: Nil, Conflict of Interest: None declared.
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