genetic factors associated with periodontal diseases

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CONTENTS Introduction

An insight to genetics

Genetic basis of disease

Methods of genetic analysis

Evidence for the role of genetic variants in

Periodontitis

Genetic and Inherited Disorders associated with

Aggressive Periodontitis

Genetic polymorphism

Gene Therapy

Gene therapy in Periodontics

A futuristic approach to the application of genetic


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INTRODUCTION

Microbial plaque induces

gingivitis which may

progress to chronic

destructive inflammatory

condition termed

periodontitis in susceptible

individuals.


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Pathogenesis of periodontal disease


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Putative pathogens are essential to develop

periodontitis, however, their mere presence is

insufficient to initiate periodontitis. (Haffajee and Socransky, 1994)

The primary etiology for periodontitis is bacteria,

however the extent and severity of periodontal

lesions can be influenced by environmentalfactors, acquired factors, and genetic

predisposition.(Kornman et al., 1997 and Salvi et al., 1997)

While microbial and other environmental factorsare believed to initiate and modulate periodontal

disease progression, there now exists strong

supporting evidence that genes play a role in the

predisposition to and progression of periodontaldiseases. Sofaer, 1990; Hart, 1994; Michalowicz, 1994; Hassel and Harris, 1995;


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PERIODONTITIS IS A MULTIFACTORIAL

DISEASE


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EOP: early-onset periodontitis; LAD: leukocyte adhesion deficiency; PMNs:

polymorphonuclear lymphocytes; PGHS prostaglandin endoperoxide synthase (also

referred to as cyclooxygenase)Periodontology 2000. Vol. 14. 1997,202-215


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Genetic factors influence inflammatory andimmune responses in general. Individuals mayrespond differently to common environmentalchallenges due to their genetic profile.Specifically different forms of genes(allelicvariants), can produce variations in tissuestructure (innate immunity), and inflammatorymediators (non-specific inflammation). Allelic

variants at multiple gene loci probably influenceperiodontitis susceptibility.(Kinane 2003).


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AN INSIGHT TO

GENETICS


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Basic Terminologies Genome refers to all the genes carried by an

individual or cell. The human genome consists ofmore than 3 billion pairs of bases contained in 22pairs of chromosomes, termed autosomes, and a pairof sex chromosomes.

Chromosome a nuclear structure carrying geneticinformation arranged in a linear sequence.

Gene a functional and physical unit of inheritance

that occupies a specific position (locus) withinchromosome. In other words, it is a sequence ofnucleotides located at a particular position on aparticular chromosome carrying a set of instructionsusually directing the synthesis of proteins.


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Allele one of several possible

alternative forms of a given gene at a

particular locus of a chromosome

differing in DNA sequence.

Different alleles are responsible for

variation in inherited characteristics such

as hair color or blood type.

In an individual, the dominant form of an

allele is expressed.

Homozygous the

presence of identical

alleles of one or more

specific genes (e.g.A/A).

Heterozygous the

presence of differing

alleles of one or more

specific genes (e.g.

A/B).


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Genotype the genetic makeup of an organism orcell distinct from its expressed features or phenotype.

Phenotype the observable characteristics displayedby an organism as influenced by environmentalfactors and independent of the genotype of theorganism. (Phenotype = genotype x environment)

Gene expression the process involving use of the

information in a gene via transcription and translationleading to production of a protein affecting thephenotype of the organism determined by that gene.

Autosomal dominant the dominant effect of onegene located on an autosome regardless of thepresence of the other normal copy.

Autosomal recessive A gene on an autosome thatis required in two copies to be active in an individual.

An individual who carries two such copies of the same

abnormal gene will be subjected to effects from thatgene.


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Genetic Variance

That portion of the phenotypic variance of a traitin a population which can be attributed to

genetic difference amongst individual.

Variance : Mutation or Polymorphism Mutation : a permanent transmissible change in the

genetic material that occur during DNA replication ormeiosis. (1% of population)


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Single Nucleotide Polymorphism

Polymorphism causedby the change in asingle nucleotidebelieved to be the mostcommon genetic

variation betweenindividual humans.


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Gene Expression


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Environmental Exposures

Differences in physiologic functioning ofproteins due to polymorphisms can beenhanced by certain environmental factors(eg.

smoking, diabetes, microbes).

If the protein functions in the inflammatoryprocess then certain polymorphisms can

increase or decrease risk for diseasephenotype.


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Genetic Basis of Disease Genetic variance and environmental

exposures are the key determinants tophenotypic differences.

Simple Mendelian Diseases followpredictable & simple patterns of transmission.In most cases a single gene locus is the majordeterminant of disease.

Complex genetic disease are moreprevalent, do not follow simple pattern offamilial distribution, and are the result ofinteraction of multiple different gene loci as

well as environmental factors.


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Simple Mendelian Diseases


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Complex Genetic Diseases No correlation between presence of allele and

occurrence of disease.

Associated polymorphisms not directly linked.

Each polymorphism contributes to a small partof the disease process, sometimes requiring

multiple genes to develop disease phenotype.

Environmental factors are also critical toetiology.


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Familial Aggregation

Twin Studies

Segregation Analysis Linkage Studies

Association Studies/ Candidate gene approach

Genome wide analysis

Methods of Genetic Analysis


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Familial Aggregation

Many diseases run in families, and the

degree of clustering within the family can be

estimated by comparing the number of disease

cases in relatives of patients to the risk ofdisease in the general population .

Difficulties : in addition to having many genes

in common, family members also share manyaspects of a common environment (e.g., diet,

nutrition, smoking, infectious organisms and

shared socioeconomic factors).


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Twin Studies

Comparisons of traits, including diseases inmonozygotic, dizygotic, or usually both types

of twins aimed at determining whether variation

in the trait among members of a population is

caused by genetic variation in inherited DNAsequences, environmental exposures in the

subjects previous lives, or some combination

of both of these processes.

Twin studies often measure the concordance

rates of twins with a particular trait or disease

of interest .


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Disadvantage :

A genetic mutation may not have

complete penetrance.Environmental conditions may contribute

to the development of the disease (e.g.,

one twin may smoke and the other may

not).Furthermore, many diseases are polygenic

(i.e., caused by alterations in multiple

genes).


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Segregation Analysis

Statistical analyses of the patterns oftransmission of a disease in families in an

attempt to determine the relative likelihood

that the disease is caused by a single gene

with dominant or recessive inheritance, bymultiple genes, or entirely by variation in

exposure to risk factors.

The observed proportions of offspring who have

the trait or disease being evaluated (i.e., the

phenotype) are compared with the proportions

that are expected in the general population .


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Linkage analysis

A technique used to map a gene responsiblefor a trait to a specific location on a

chromosome. It is based on the fact that

genes that are located close to each other on

the chromosome tend to be inherited togetheras a unit. As such, these genes are said to be

linked.

Very expensive DNA markers are required.

Crossover between A and B much more likely thanbetween B and D


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A difficulty with linkage analyses is that manydiseases are not caused by a single gene of

major effect but rather by multiple genes of

minor effect.

In the latter situation, multiple genes each

contribute a small amount to the

phenotype/disease/ trait, and the linkage study

approach has little power for detection. In those casesassociation analysis methods may be used.


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Association Studies

A gene mapping approach that tests whetherone allele of a gene occurs more often in

patients with the disease than in subjects

without the disease.

Aim : to identify which genes are associated

with the disease.

Candidate genes are chosen on the basis oftheir known or presumed function (i.e., they

have some plausible role in the disease

process such as producing a protein that is

important in the disease pathogenesis).Conce tuall this makes sense but re uires


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Genome Wide Association Study

(GWAS)

A GWAS investigates genetic variation across theentire genome simultaneously, with the aim of identifyinggenetic associations related to a trait or disease ofinterest.

The completion of the Human Genome Project in2003 and the development of microarray technologiescapable of assaying SNPs have made GWAS possible.

This method has the potential to identify the geneticcontributions to common diseases.

An important advantage of this approach is,because the entire genome is analyzed, the techniquepermits the genetics of a disease to be investigated in anonhypothesis-driven way. It is not necessary to


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A GWAS requires that well -characterizedcases and controls be identified.

A disadvantage of GWAS is that large clinical

sample sizes are required to reduce the

likelihood of differences between cases and

controls being observed simply by chance as a

result of the hundreds of thousands of

multiple statistical tests required to search

the entire human genome.


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Evidence for the Role of Genetic

Variants in Periodontitis

Familial Aggregation:

German studies of familial nature in the early 20th

century have shown aggregation of chronic formsof periodontitis in families. This strongly

suggested genetic predisposition. (Revd by Hassell &Harris ,1995)


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Twin study

Michalowicz et al. (1991) studied dizygoustwins reared together and apart andmonozygous twins reared together and apart.

Mean probing depth and attachment levelvaried less for monozygous twins thandizygous twins.

Twin groups had similar oral hygiene andsmoking history.

Concluded genetics plays a role in


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Segregation analysis

Segregation analysis in North American familiesperformed by Marazita et al. (1994).

Studied >100 families, segregating aggressive

forms of periodontitis, and found support forautosomal dominant transmission. Concludedautosomal dominant inheritance with ~70%penetrance occurred in Blacks and non-Blacks.

While others Beaty et al. (1987), Long et al.(1987),Saxen et al. (1980) have found support forautosomal recessive transmision of aggressiveperiodontitis.


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Linkage analysis

Boughman et al. (1986).Gene for Dentinogenesisimperfecta-III (DGI-III) had been previously localized

to chromosome 4. They performed linkage analysis

and showed close linkage of gene for Aggressive

periodontitis( AgP) to this DGI-III gene in the familiesof Southern Maryland.

Hart et al. (1993) evaluated support for linkage ofAgP near chromosome 4 in different population of

families (14 African American and 4 Caucasian).

Results showed that in these populations no linkage

existed .

Recently, Li and coworkers (2004) reported evidence

of a gene responsible for localized aggressive

periodontitis located on chromosome 1q25. To date, a


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Genetic and Inherited Disorders

associated with Aggressive

Periodontitis

Severe periodontitis presents as part of the

clinical manifestations of several monogenetic

syndromes.

Significance of these conditions is that they

clearly demonstrate that a genetic mutation ata single locus can impart susceptibility to

periodontitis.


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Genetic Polymorphism

In humans, studies of inherited variations in the immunesystem are

necessarily complex, and the observed phenotype is

usually the

result of multiple genetic and environmental influences.

It is likely that genetic polymorphisms exist for many of

these

immunological factors, eg.

- Immunoglobulin G2 production

- FcRII receptor heterogeneity

- Mediators of inflammation

-Prostaglandin E2 (PgE2)


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Immunoglobulin G2 production

Serum IgG2 levels in localized aggressiveperiodontitis(LAP) cases are higher than serum

levels of generalized aggressive

periodontitis(GAP) cases (Lu et al. 1994)

IgG2 in LAP associated with protection in LAP(Gunsolley et al.1987)

The IgG molecules contain :

- gamma heavy chains (Gm allotypes)

- kappa light chains (Km allotypes)

Currently the only allotype identified for IgG2 is


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The Gm allotype genes, or genes in linkageequilibrium with them, appear to influenceexpression of the IgG2 molecule.

This response appears to be race specific, andyoung Caucasians of the low-responderphenotype G2m(null) [G2m("), G2m(-n) and

G2m(-23)]are predisposed to specific bacterialinfections.

Choi et al. (1996) : The rapidly progressive

periodontitis patients who were positive for theG2m(23) allotype had elevated antibody toPorphyromonas gingivalis .

In addition to host factors, environmental factors


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FcRII receptor heterogeneity


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Polymorphisms in Fc receptors expressed on thesurface of phagocytic cells have been shown tobe important determinants of susceptibility to

infections.

The immunoglobulin Fc receptor II genes havebeen mapped to chromosome 1.

FcyRII gene has two expressed alleles, whichdiffer significantly in their ability to bind humanIgG2.

The two alleles differ by the amino acid, atposition 131.

- arginine (R131)

- histidine (H131), recognizes IgG2,


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Wilson et al. (1996) : IgG2 was significantly more

effective in

mediating phagocytosis of A.

actinomycetemcomitans, when

used with human neutrophils that werehomozygous for the

H131 receptor as compared to neutrophils from

individuals

homozygous for the R131 receptor.

The genetic polymorphism that defines the FcyRII

receptor,

therefore a ears to be a romisin marker for


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Mediators of inflammation

PROSTAGLANDIN E2(PGE2)- Potent biological mediators

- Diverse physiological effects

- Has also been implicated in a variety of pathological

conditions including periodontitis.

Wang et al. (1996) : identified linkage of the chromosome

9q32-33

region with early-onset periodontitis.

This physical region includes the gene for prostaglandin

endoperoxide

synthase 1, and this observation encourages further

studies associating

genetic markers of prostaglandin E with clinical


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INTERLEUKIN 1 (IL-1)

Elevated tissue and gingival fluid levels of interleukin1(IL)

in particular have been repeatedly associated with

periodontitis.

A family of three IL-1 genes cluster on chromosome

2q13.

At times the overproduction of immuno-regulatory

mediators

may actually prove harmful to the host.


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Genetic control of IL-1: Genes and Locus of SNPs

associated with controlling IL-1 biological activity

Genetic Susceptibility Testfor periodontitis: tests for the

presence of at least one copy of allele 2 at the IL-1A +4845

loci and at least one copy of allele 2 at the IL-1B +3954locus.

*IL-1A +4845 is being used because it is easier to identify than IL-1A -889and it is essentially concordant with it.

** IL-1B +3953 has been now renumbered as IL-1B +3954 because the

current convention indicates that the numbering of the transcriptionshould begin at +1 instead of zero.

Genes Polymorphism

Locus

Current Locus accessed

with test

Controlled product

IL-1 Allele2 -889 Allele 2 IL-1 +4845* IL-1

IL-1 Allele 2 +3953 Allele 2IL-1 +3954** IL-1

IL-1RN Protein receptors

antagonist (impedesIL-1 & )


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In 1997, Kornman et al., found an associationbetween

polymorphisms in the genes encoding for

interleukin1(+889)

and interleukin-1(+ 3953) (termed the composite

genotype)

and an increased severity of periodontitis.

One of these genotypic polymorphisms IL-1 at

(+3953) is

associated with a fourfold increase in IL- l

production.


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Gene Therapy

Gene therapy uses purified preparations of agene or a fraction of a gene, to treat diseases.

There are four approaches:

1. A normal gene inserted to compensate fora nonfunctional gene.

2. An abnormal gene swapped for a normalgene.

3. An abnormal gene repaired throughselective reverse mutation.

4. Change the regulation of gene pairs.


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Gene therapy in Periodontics

1. Protein based approach: trials have beenconducted using Transforming growth factor-,Bone morphogenetic ptoteins-2,6,7,12, Vascularendothelial growth factor and Platelet derivedgrowth factor.

2.Cell based approach: skeletal muscle derivedcells can be used for delivery of BMP-2.

3.Gene- delivery approach:

-In vivo gene delivery: The genetic materialis transferred directly into the body of the patient.

- Ex vivo gene delivery: The genetic materialis first transferred into the cells grown in vitro and thento the patients body.

A f t i ti h t th li ti f


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A futuristic approach to the application of

genetic profiles in the management of

aggressive periodontitis.

Periodontology 2000, Vol. 30, 2002, 7990


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genetic factors associated with periodontal diseases

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