genetic factors associated with periodontal diseases
TRANSCRIPT
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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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