Dr.Anupriya Sharma et al. / IJRID Volume 2 Issue 6 Nov.

-Dec 2012
Available online at www.ordoneardentistrylibrary.org

ISSN 2249-488X

Review- Article

INTERNATIONAL JOURNAL OF RESEARCH IN DENTISTRY

GENETICS AND PERIODONTITIS- A REVIEW

Dr.Anupriya Sharma1*, Dr. Gurpreet Kaur2, Dr. Ashish Sharma3
1. Dept. of Dentistry, Dr. R. P. Govt. Medical College, Kangra at Tanda (H.P)
2. Department of Periodontic, National Dental College, Derabassi
3. Dr .R .P. Govt. Medical College, Kangra at Tanda (H.P)
Received: 14 Sep 2012; Revised: 12 Oct. 2012; Accepted: 16 Nov. 2012; Available online: 5 Jan. 2013

ABSTRACT
Periodontitis is assumed to be associated with multiple modifying genes, i.e. polygenic. It is estimated that
for periodontitis between 10-50 genes may be involved. However, it is important to remember that the number and
type of modifying disease genes for the same disease may not be equal for different ethnic populations and may
also be influenced by environmental factors. Recent studies from multiple groups have pointed to genetics as an
important determinant of the severity and progression of periodontitis. A number of aspects of the inflammatory
and immune response that are suspected to play a role in the development of periodontitis have a clearly defined
genetic basis.
KEYWORDS: Genetics, Gene polymorphism, Periodontitis.

INTRODUCTION
Periodontitis is a multifactorial disease for which several risk and susceptibility factors are proposed in
the natural history of periodontitis .1A risk factor for periodontitis is a factor (environmental, behavioral or
biologic) confirmed by temporal sequence usually in longitudinal studies .The presence of a risk factor directly
increases the probability of disease occurring and the absence of a risk factor reduces this possibility.

Risk

factors are the part of a causal chain, or expose the host to the causal chain. Risk factors are by definition
modifiable. Susceptibility factors are, in contrast, nonmodifiable determinants or background factors, like age,
gender and genotype (genetic make up).Putative susceptibility factors, are determinants, only confirmed in cross
sectional or case control studies.
In a classical longitudinal study of natural history of periodontitis, Loe et al3 found that among
individuals with poor oral hygiene and no access to dental care, some develop disease at rapid rate whereas
others experienced little or no disease. This variation must have been attributable to either unrecognized
components of the environment or differences among individuals in their susceptibility to disease. Because host

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susceptibility may be described in terms of genetic variation, a relatively recent focus in periodontology has
been to quantify the genetic risk and identify specific gene variants that determine disease susceptibility.
HUMAN GENES AND POLYMORPHISM
Each normal human being has 23 pairs of chromosomes (the diploid human genome), 22 pairs of
autosomal chromosomes and one pair of sex chromosomes (XX for females and XY for males). From each pair,
one chromosome is inherited from father and one from mother. Each chromosome contains a single, very long
duplex of deoxyribonucleic acid (DNA). DNA consists of chemically linked sequences of nucleotides; these are
the building blocks of DNA and always contain a nitrogenous base. Four nitrogenous bases exist: adenine
(A), guanine (G), cytosine(C) and thymine (T).The bases are linked to a sugar (2-deoxyribose), where a
phosphate group is also added. The haploid human genome (i.e. one copy of 22 autosomal chromosomes and
one sex chromosome) consists of 3.3x 109

nucleotides, also written as

3.3x109 base pairs (bp).In a

chromosome, DNA is arranged in double helix model: two polypeptide chains in a duplex are associated
together by hydrogen bonding between the nitrogenous bases. These reactions are described as base pairing and
they are complementary: G pairs only with C and A pairs only with T. Therefore, if one chain of DNA is
sequenced, the complementary chain can be deduced.
DNA contains the genetic code and a given specific sequence of nucleotides that encodes for the
sequence of amino acids that constitutes the corresponding protein. The genetic code is read in a group of three
nucleotides; each trinucleotide sequence (triplet) is called a codon.
A gene consists of two parts:
1) A Coding region
2) A Promoter region
Within the coding region, intermittent areas of non coding DNA exist. These regions are called introns.
The true coding areas within the coding region are called exons. From the recent results of human genome
product, it is estimated that about 30,000-40,000 human genes exist. 4
ALLELES
Specific location on a chromosome is referred to as loci, and the variations in the nucleotide sequence at
a locus are termed alleles. For example, hemoglobin is complex molecule consisting of two -type and two type chains. Two or more alleles for a given locus may exist in nature throughout evolution, but may develop
any time. A polymorphic locus is one whose alleles are such that the most common, normal variant (N-allele)
among them occurs with <99% frequency in the population. Thus, if the locus is, for example, bi-allelic, the
rarer allele (designated R-allele) must occur with frequency >1% in the population.
GENE POLYMORPHISM
When different alleles of a given gene co-exist in the human population, it is called genetic
polymorphism. It arises as a result of mutation. These mutations occur as a result of normal cellular operation or
2

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random interactions with the environment. An alteration that changes only a single base-pair is called a point
mutation. The most common class of point mutation is the transition, comprising the substitution of one
nucleotide with another. The variation at the site harboring such changes has recently been termed asingle
nucleotide polymorphism.
SINGLE NUCLEOTIDE POLYMORPHISM, SNPS 5
It occurs as a single base pair sites in a human genome every 100-1,000 base pairs differing from
person to person as a result of deletions, insertions, or substitutions. The frequency of SNPs across the human
genome is estimated at every 0.3-1 kilo bases (kb). 5 The most common type of insertion/deletion polymorphism
is the existence of variable numbers of repeated bases or a nucleotide patterns in a genetic region. Repeated
base pattern can consist of several hundreds of base pairs, known as variable number of tandem repeats
(VNTRs or mini-satellites).Also very common are micro-satellites which consist of two, three or four
nucleotides repeats a variable number of times. Micro-satellites are also referred to as simple tenden repeats
(STRs) .
CGT GGT GAC CCC TT
A-antigen Sequence

Substitutions
CGT CGT CAC CGC TA
B-Antigen Sequence

Deletion of G
CGT GGT - ACC CCTT
O Antigen Sequence

GENETIC STUDY DESIGNS

Genetic marker refers to any gene or nucleotide sequence that can be mapped to a specific location or region
on a chromosome. From a genetic epidemiological viewpoint, any marker that is sufficiently polymorphic, or
variable, in the population can be used to map or locate disease alleles. The various genetic study designs are:
1. Segregation analysis 2.Twin studies 3.Linkage and association studies.
SEGREGATION ANALYSIS:
It refers to the study of the way in which a disorder transmitted in families so as to establish the
underlying mode of inheritance. The pattern of transmission through generation depends on whether the disease
alleles are contained in autosomes or sex chromosomes. They are dominant or recessive. They are fully or
partially penetrant. Penetrance refers to the probability that a particular phenotype will result from genotype.
Partial penetrant means that only a fraction of individual who inherits the disease alleles will be affected. The
statistical power of this design depends on the number and composition of families and the heterogeneity of the
disease. Heterogeneity means that there are different causes of disease among families. Segregation analysis has
low power of resolving heterogeneity.

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TWIN STUDIES:
The twin model is the most powerful method by which to study genetic aspects of periodontal diseases.
The relative influence of genetic and environmental factors on the complex disease can be estimated using the
twin studies. In the classical twin study, reared together monozygotic or dizygotic twins are compared to
estimate the effects of shared genes. Monozygotic twins (MZ) are genetically identical, whereas dizygotic (DZ)
or fraternal twins share on average 50% of their genes by descent. Twin data is used to estimate heritability,
which is the proportion of phenotypic variation.
LINKAGE AND ASSOCIATION STUDIES:
Linkage and association studies are used to map disease alleles to specific regions on chromosomes.
These studies exploit a unique feature of the way in which alleles segregate during meiosis. During
gemetogenesis, diploid cells containing 2N copies of each allele divide to become haploid (containing only one
copy of each parental allele). The probability that two alleles at different loci will recombine (termed as
recombination and crossover event) is generally proportional to the distance between them. Two alleles selected
at random from genome will recombine, and the chance that any two maternal or paternal alleles will be
transmitted together to an offspring is 50%. Alleles at nearby loci, however, tend to segregate together, i.e. they
are linked.
ROLE OF GENETICS IN PERIODONTITIS
The search for periodontitis susceptibility alleles is complicated because of the various reasons. Multiple
causes may exist for the same disease. This is referred to as etiological heterogenecity .Different genetic
mechanisms may lead to the same clinical endpoint. This is called genetic heterogenecity.
AGGRESSIVE PERIODONTITIS:
Early and aggressive periodontitis is a consistent feature in several inherited or genetic disorders, which
demonstrates the variety of ways in which gene mutations can affect risk for AP disease. Both segregation and
linkage analysis studies have been conducted to prove genetic cause of aggressive periodontitis. In most such
studies, the localized and generalized forms of AP disease have been considered variants of same disorder. This
is supported by the observation that both forms frequently occur in the same family. Linkage dominant form of
AP disease was found to cosegregate with dentinogenesis imperfect.6 Association studies have shown that two
human leukocyte antigens consistently associated with AP are HLA-A9 and B15.The risk for disease in patients
with these HLA-A9 and HLA-B15 is 1.5-3.5 times greater than in those lacking these antigens.7
CHRONIC PERIODONTITIS:
Both twin studies and association studies were done to confirm the role of genetics in chronic
periodontitis. Heritable influence could be found in the clinical attachment and the radiographic alveolar crestal
height. The concordance rate for disease was greater in the monozygous twins (23%) than in the dizygous
twins(8%).8This supported the role of genetics as a causation factor in chronic periodontitis.
4

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CYTOKINE GENE POLYMORPHISM
INTERLEUKIN AND TUMOR GROWTH FACTOR POLYMORPHISM
IL-1 and TNF- play important role in pathogenesis of periodontitis. IL-1 and TNF- levels are
increased in gingival crevicular fluid in periodontitis and these cytokines are found in higher levels in the
inflamed periodontal tissues compared to healthy gingival tissues. Genetically determined inter individual
differences have been observed for the IL-1 and TNF- production by peripheral blood mononuclear cells or
oral leukocytes isolated from individuals with and without periodontal disease.
Polymorphism in interleukin-1 (IL-1) cluster of gene (IL-1 genotype) may alter a persons inflammatory
response to periodontal pathogens and significantly increase the risk for severe diseases .9 The first study that
reported polymorphisms for the IL-1 genes in relation to periodontitis was presented by Kornman et al.1997.9
The combined presence of R-allele of the IL-1 gene at nucleotide position -889(IL-1-889T) and the R-allele of
the IL-1 gene at nucleotide position + 3953(IL-1+3953T )was associated with the severity of periodontitis in
non smoking Caucasian patients. The combined carriage rate of R-alleles IL-1-889T and IL-1+3953T is
designated as IL-1 composite genotype. 9
RECEPTOR GENE POLYMORPHISMS
FcR GENE POLYMORPHISMS: Leukocytes from both myloid and lymphoid lineages express receptors
(FcR) for constant (Fc) region of immunoglobulin G molecules
immune cells in the periodontal tissues

11

10

.Indeed, FcR are found on wide variety of

. FcRs are likely to play a role in the pathogenesis of periodontitis as

a bridge between the cellular and humoral branches of the immune system

The leukocyte FcR genes are

found on chromosome 1 and encode three main receptor classes: FcRI (CD64), FcR II(CD32) and FcR III
(CD16).
These classes are further divided into subclasses: FcRI a and b, FcR II a, b, and c and
FcR III a and b.
FcR IIIb is the most abundantly expressed IgG receptor on neutrophils. The G to A transition
polymorphism in the FcR IIa gene at nucleotide position +392 results in the substitution of histidine (H) for
argininin (R) at amino acid position 131 of the receptor molecule. Subjects homozygous for the FcR IIa

H131

allele (N-allele) bind IgG2 immune complexes efficiently, while individuals homozygous for the FcR IIa R131
allele(R-allele) are deficient for this interaction.It has been found that the N-allele carriage rate (FcR II H131) is
higher in AP subjects than in controls.12
METABOLISM RELATED POLYMORPHISMS
VITAMIN D RECEPTOR GENE POLYMORPHISM: Vitamin D and its receptors play a role in
phagocytosis by monocytes and affect monocytes differentiation. VDR exerts an effect on potent
osteoclastogenic cytokines, including IL-1, IL-6 and TNF-. In macrophage mRNA synthesis in vitro, VDR
mediates these effects via a variety of mechanisms including transcription regulation, mRNA stability, post
5

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translational modifications, and ligand induced stabilization of the gene products. The VDR gene exhibits
several polymorphisms, located in both the coding and the non -coding portions of the gene.
MATRIX METALLOPROTEINASE GENE POLYMORPHISM: The degradation of collagen fibres and
other extracellular matrix components in periodontitis results from activity of matrix metalloproteinases
(MMPs). MMPs comprise a structurally and functionally related family of proteolytic enzymes that play an
essential role in tissue remodelling and repair associated with development and inflammation. MMP-9(also
known as gelatinase B and 92-kDa type IV collagenase) is one of the MMPs that is active against denatured
collagens (gelatin) and type IV, V, and XI collagens in addition to the proteoglycans and elastin. The coding
region is situated on chromosome 20q11.2-13.1, and several variations have been detected in MMP-9 gene. The
SNP at position -1562 is due to a C to T substitution. This substitution results in loss of nuclear binding protein
to this region of the MMP-9 gene promoter and an increase in transcriptional activity in macrophages. Thus
individuals with T-allele have increased plasma levels of MMP-9.

ANTIGEN RECOGNITION RELATED POLYMORPHISM

HLA GENE POLYMORPHISM: Human leukocyte antigen (HLA) is involved in genetically predetermined
humoral immune response via recognition of foreign antigens. In humans the classical major histocompatibility
complex(MHC) class I molecules (HLA-A,B and C) are expressed on cells that immunosurvey host cells
including B cells, T cells ,macrophages and accessory cells for the presence of foreign peptides. The MHC
genes are the most polymorphic gene present in the genome of every species analyzed. It was suggested patients
with the HLA-DRB1* 1501-DQB1* 0602 genotype may have an accelerated T cell response to P. gingivalis
and an increased susceptibility to EOP in Japanese patients.13
N-FORMYL-L-METHIONYL-L-PHENYLALANINE RECEPTOR POLYMORPHISMS:
The

N-Formyl-L-methionyl-L-phenylalanine (fMLP)is a structural analogue of bacterial products

involved in neutrophil chemotaxis.The fMLP receptors are also involved in the activation and subsequent
response to certain chemotactic stimuli. The fMLP receptor genes are localized in chromosome 19. The fMLP
receptor gene was examined, and it was found that two single nucleotide base alterations (329T/C and 378C/G)
were associated with aggressive periodontitis.14
PST GENTIC SUSCEPTIBILITY TEST
The PST genetic test is for the first time a reliable way of assessing an individuals genetic risk for
periodontal disease, the most common cause of tooth loss. The PST (periodontal susceptibility test) genetic test
identifies patients who have specific variations in the IL-A and IL-B genes. Research indicates that patients who
have this genetic profile may have a 3 to 7 fold increased risk for periodontal disease and a 3 fold increased risk
for tooth loss.

A positive PST result does not mean that a person will necessarily develop periodontal disease,

the susceptibility to which is multifactorial and testing genotype- positive for IL-1 polymorphism (PST6

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positive) does not exclusively determine whether a person will develop a periodontal disease. It is important to
emphasize that the IL- 1 genetic test is a risk assessment tool and not a diagnostic test

.Risk for disease

severity increases with addition of each modifying factor.

ADVANTAGES OF KNOWING THE GENES INVOLVED IN PERIODONTITIS
Identifying genes can result in novel diagnostics for risk, early detection and individualized treatment
approaches. Identifying genes that contribute to the pathogenesis of periodontitis can have significant public
health, therapeutic and scientific repercussions. Environmental factors involved in the causation of periodontal
diseases can be modified or eliminated.
BIBLIOGRAPHY:
1.Page RC, Offenbacher, S, Schroeder H.E, Seymour, G.J. & Kornnman, KS. Advances in

the pathogenesis

of periodontitis: Summary of developments, clinical implications and future directions. Periodontology 2000 .
1997;14:216-248.
2.Norderyd O. (1998) Risk for periodontal disease in a Swedish adult population. Cross-sectional and
longitudinal studies over two decades. Swedish Dental Journal Supplement. 1998;132: 1-67.
3. Loe H, Anerud A, Boysen H, et al. Natural history of periodontal disease in man: Rapid moderate, and no
loss of attachment in Sri Lankan laborers 14 to 46 years of age. J Clin Periodontol.1986; 13:431.
4.Venter JC,Adams MD,Myers EW,et al. The sequence of the human genome.
Science. 2001;291:1304.
5. Schork NJ, Fallin

D & Lanchbur S. Single nucleotide polymorphisms and the future of genetic

epidemiology. Clinical Genetics .2000; 58: 250-264.

6.Boughman JA, Astemborski JA. & Suzuld JB. Phenotypic assessment of early onset periodontitis in
siblings. Journal of Clinical Periodontology. 1992;1:233-239.
7.Sofaerja. Genetic approaches in the study of periodontal diseases. J Clin Periodontol. 1990;17:401.
8. Corey LA, Nance WE, Hofstede P & Schenkein HA. Self-reported periodontal disease in a Virginia twin
population. Journal of Periodontology. 1993; 64:1205-1208.
9.Kornman KS, Crane A , Wang HY, Giovine FS, Newman MG, Pirk FW, Wilson Jr. TG, Higginbottom FL
& Duff G. The interleukin- I genotype as a severity factor in adult periodontal disease. Journal of Clinical
Periodontology.1997;24:72-77.
10.Van der Pol

WL

& Van de Winkel

JGJ.

IgG receptor polymorphisms: Risk factors for disease.

Immunogenetics .1998a; 48:222-232.

11.Yuan ZN, Schreurs O, Gjermo P, Helge land K & Schenck K. Topical distribution of Fc gammaRI, Fc
gammaRII and Fc gammaRIII in inflamed human gingiva. Journal of Clinical Periodontology .1999; 26:441
447.

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12.Loos BG, Leppers-Van de Straat, FGJ, Van de Winkel, JGJ & Van der Velden U. Fc receptor gene
polymorphisms in relation to periodontitis. Journal of Clinical Periodontology 2003; 30:595-602.
13.Takashiba S, Noji S, Nishimura F et al. Unique intronic variations of HLA-DQ beta gene in early onset
periodontitis. J Periodontol.1994; 65:379.
14.Gwinn MR, Sharma A, De Nardin E. Single nucleotide poly morphisms of the N-formyl peptide receptor in
localized juvenile periodontitis. J Periodontol .1999; 70:1194,

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