Genetics in dentistry 3
Odontogenesis
• Complex series of events including cell interactions,
differentiation, elaboration of a unique extracellular matrix
and mineralization are required to produce dentin
• Tooth formation is highly regulated at the molecular level
• terminal differentiation of specific cell types
• epithelial-mesenchymal interactions
• secretion of specific extracellular matrices
• controlled processing of those matrices
• regulation of ion deposition
• mineralization of the dental tissues
2
Tooth Formation depends on:
• Genetic Factors
• Hundreds to several thousand genes likely involved (polygenic)
• Environmental Factors
• Nutrition
• Physical phenomenon
• Infection
3
Stages Required for Tooth
Formation
• Initiation
• Histodifferentiation
• Morphodifferentiation
• Apposition
• – Secretory Phase
• – Transition Phase
• – Maturation Phase
• Stages are not discrete
for any given tooth.
• Teeth develop over years
beginning with the
coronal portion of the
crown.
• Can be mineralizing at
the cusp tips while
cervically cells are
differentiating.
4
Odontogenesis
• Oral ectoderm
• Mesoderm
• Cells of neural crest
5
mesenchym
(ektomesenchyme
or mesoectoderm)
• Enamel evolve form ectoderm
• Other tissues from mesenchym
6
Tooth development
7
Molecular Determinants of
Tooth Formation
• Over 10,000 genes involved in making a tooth
• Most genes involved in odontogenesis are expressed in non-dental tissues
• Some genes are relatively specific for development of the dental tissues (e.g.
amelogenin gene)
8
Types of dentin
• Primary dentin
• rapidly produced dentin formed up to completion of root formation and
beginning of tooth function
• Secondary dentin
• normal physiological dentin production that proceeds slowly throughout the
life of the tooth
• Tertiary dentin
• dentin produced in response to external stimulus (e.g. caries, restoration
etc.)
• Normal Circumpulpal Dentin
9
Dentinogenesis
• begins with differentiation of odontoblasts in
teeth protuberances from peripheral parts of
the dental papilla
• slightly precedes amelogenesis
10
Odontoblasts
• Differentiated from mesenchymal cells
condensing adjacent to the inner enamel
epithelium
• Are tall columnar cells during active
formation of primary dentin
• Height decreases and less organelles are
present as cells become less active
11
Dentin ECM components
• Type I collagen – most abundant
• Type III & type V – predentin, not normally in
mature dentin
• Dentin sialophosphoprotein
• Dentin phosphophoryn
• Dentin sialoprotein
Dentin Matrix Protein 1
• Proteoglycans – numerous species
• Gla proteins – e.g. osteocalcin
12
SIBLING-family genes
SPARCL1: SPARC-like protein 1, DSPP: dentin sialophosphoprotein, DMP1: dentin matrix protein 1, BSP; bone sialoprotein,
MEPE: matrix extracellular phosphoglycoprotein, OPN: osteopontin. AMBN: ameloblastin, ENAM: enamelin
Predentin
• Unmineralized dentin matrix
• Always present in normal healthy teeth
• Usually 15 – 20 μm thick and is bounded by odontoblasts on pulp side
and dentin on outside
• Predentin exists in a closed compartment with components being
determined and regulated by the odontoblasts
14
Mechanisms of mineralization in Dentin
• Matrix Vesicles – initiates mineralization in
mantle dentin
• Collagen/phosphoprotein complex – required to
maintain and continue normal dentin
mineralization
15
Ameloblasts
 migration to future pulp
 bud stage - odontoblasts and ameloblasts
connected
 Secretion of proteins according to tightly
regulated gene expression and programmed
timing
 produce extracellular organic matrix of enamel
- a skeleton, which itself regulates the
initiation, growth and shape of inorganic
hydroxyapatite crystals, which produce mature
enamel
 thickness of the enamel depends on the
length of secretory phase of ameloblasts
16
17
Environmental Influences of
Amelogenesis
• Nutrition
• Major and minor components
• Calcium, phosphorus, protein, fluoride etc…
• Hypoxia
• Hyperthermia
• Infection
• Congenital rubella, syphillus, CMV, etc…
• Physical Determinants
• Space
• Trauma
• Interactions
18
Enamel maturation
 secretory phase - enamel „maturation“
 culminate in deposition of ions on the
sides of the enamel crystallites and
replacement of extrusion matrix
protein debris and fluid from the
structure.
 almost all organic matrix proteins are
cleaved and removed and are replaced
by inorganic crystals.
 after secretory phase - no further
formation of crystals or prolongation
crystals already formed
 apoptosis of ameloblasts
19Dentin-enamel junction
Bulk of enamel
matrix:
Amelogenin
Lesser
components
Ameloblastin
Enamelin
Enamelin
Degradation:
MMP20, KLK4
DSPP
Proteiny a ECM
Nucleation of
hydroxyapatite by
acidic matrix proteins
immobilized on
insoluble collagen
matrix. Some acidic
matrix proteins, e.g.
dentin phosphoprotein,
have an affinity to
collagen. The surface
of the insoluble
collagen matrix
provides loci to reduce
interfacial energy for
nucleation. Calcium
ions are bound to the
acidic groups of the
acidic proteins, and
inorganic phosphates
are attracted by the
calcium ions. The ionic
complex thus formed
may constitute a
crystal nucleus.
Genetics
21
Genes and pathways
• more than 300 genes
• Signaling pathways:
• TGF beta (transforming growth factor),
• FGF (fibroblast growth factor),
• BMP (bone morfogenetic protein),
• SHH (Sonic hedgehog),
• Wnt,
• TNF (tumor necrosis factor),
• EDA (Ectodisplasin)
22
Genes and pathways
23
Gene regulation
 Modulators of signal pathways – e.g. Inhibitors of BMP and inhibitors of FGF.
 genes involved in the early stages of tooth development, have a different
function in the later stages of development.
 multifunctionality allows induction or regulation by different transcription
factors or regulators (AMBN, BGLAP, IBSP a COLLA2; BGLAP, COLLA2;
complex Vitamin D3/-VDR-RXR: CALB1, CST6, FOXO1)
24
Genes and development of enamel and
dentin
 amelogenin, enamelin, ameloblastin, a
MMP20 (matrix metaloproteinase 20) –
early secretory phase
 kalikrein 4 (KLK4), amelotin a odam
(apin) – iniciation of maturation
 KLK4 a MMP20 – layers of enamel
protein degradation
 FAM83H - reabsorption and secretion of
enamel proteins
 homeobox genes DLX (Distal less);
 DLX1 and DLX2 are specific for the
development of molars
25
Abnormalities of Tooth
26
Teeth abnormalities
27
Genetic:
Inherited disorders,
Age, Sex
Environment:
Nutrition, Disease
Socio-economic status
Teeth
formation
cells
Secretion and Maturation
Timing
Duration
Intensity
DENTAL DEFECTS
Diseases of hard dental tissues
• acquired • congenital
28
• Abrasion
• Erosion
• Resorption
• Discoloration of teeth
• genetic anomalies:
- teeth
- enamel
- dentin
Congenital abnormalities
• scaling of teeth
• changes in the shape of the teeth
• changes in the number of teeth
• abnomal structure of teeth
• disorders in eruption
29
Dentes praelacteales
• Natal teeth (dentes natales) - erupted at birth
• Neonatal teeth (dentes neonatales) - erupted at 1. - 30. day after
birth.
• From dentes praelacteales should be distinguished prematurely
erupted deciduous teeth - dentitio praecox.
30
Changes in the number of teeth
• Anodoncia - total absence of teeth
• Hypodontia - reduced number of teeth, usually 3. molar
• Oligodencia - multiple teeth missing
• Hyperdoncia - excess teeth, erupted or retained,
especially in the upper jaw
• Mesiodens - in the gap between the maxillary central
incisors
Gardner's syndrome – non-erupted excess teeth, colon
polyposis, osteoma in the bones including the jaw,
epidermoid cysts in the skin
31
Mesiodens
Fuze
Hypodoncie
Changes in the number of teeth
 autosomal dominant (AD) or
autosomal recessive (AR)
 MSX-1 gene exons mutations –
control of the development of
all epidermal organs
 PAX9 mutations -MSX1 is not
activated
 tooth development stopped at the
stage of bud
• MSX-1
• PAX-9
32
Changes in the number of teeth
 RUNX2 – TF for osteoblast
differentiation – connected with
supernumerary teeth in the
permanent dentition
 AXIN2 - severe oligodontia.
Leads to agenesis of most
permanent molars, premolars,
lower incisors and upper lateral
incisors
 Dlx (distal-less homeobox) failure
of tooth development
and loss of upper molars
• RUNX-2
• AXIN-2
• DLX
33
Genes and abnormal position of teeth
 Abnormalities of tooth
positions are often found
together with tooth agenesis.
 mutations in genes associated
with agenesis of teeth,
especially MSX1 and Pax9 could
also be the cause of an
abnormal position of teeth.
• MSX-1
• PAX-9
34
Changes in tooth size
• mikrodoncia • makrodoncia
35
• generalized - all teeth
are smaller (pituitary
dwarfism, Down
syndrome)
• single tooth (mostly
superfluous)
• relative generalized
(teeth normal or slightly
smaller, larger jaw)
• generalized - all teeth
larger (pituitary
gigantism, acromegaly)
• single tooth
relative generalized
(teeth normal or slightly
larger, lower jaw)
Changes in tooth shape
 accessory cusps-molars, incisors
 accessory roots
 peg shaped teeth conical- shaped crown
 separate double- tooth crown and common root with the root
canal (gemination, adhesions)
 taurodontia - abnormally large pulp cavity
 dens in dente - created by invagination of ectoderm into
mesoderm of dental crown pulp before calcification of hard
dental tissue - incorporated smaller tooth into the pulp of normal
tooth
36
Eruption abnormalities
• premature or delayed eruption
• retention of teeth-especially 3rd molar
• teeth improperly developed or built atypically
37
Abnormalities of teeth structure
Amelogenesis Imperfecta
• Group of hereditary conditions caused by mutations in genes important
in enamel formation.
• Phenotypes are highly variable depending on the mutation involved.
• Prevalence varies from 1:700 to 1:15,000 depending on population.
38
Abnormalities of teeth structure
Amelogenesis imperfecta (AI)
39
• hereditary disturbance of enamel
• affected - temporary and permanent dentition
• hypoplastic - thin enamel of normal hardness
- teeth not touching, the surface uneven, often
pigmentation
• hypomaturation - soft enamel, normally strong,
easily peeling off,
brown-yellow-white speckled
• hypocalciphication - initially normal thickness,
gradually decreasing, exposes the dentin
soft, cheesy consistency
Hypoplazie skloviny
Hypomineralizace skloviny
AI and genes
 inheritance AI
 X-linked,
 autosomal recessive (AR) or
autosomal dominant (AD).
Genes:
 autosomal dominant AMLEX
(amelogenin),
AMBN (ameloblastin enamel
matrix protein),
ENAM (enamelin) a
AMTN (amelotin),
FAM83H,
DLX3
 autosomal recessive
 MMP20
KLK4
• AMELX make up 90% of the
organic matter of enamel and is
cleaved by the enzyme MMP20
and KLK4 degraded by the
enzyme.
• ENAM makes up 5% of the organic
matter of enamel;
AMBN is essential for ameloblasts
activity and
• AMTN is involved in the
maturation of enamel.
• Mutations in individual genes
leads to differences in phenotypic
expression of the disease.
40
Amelogenin
• There are now 15 different mutations in the amelogenin gene
(AMELX).
• The phenotypes vary from hypomaturation to hypoplastic defects
depending on the type of mutation
41
Amelogenin
• X – linked AI
• Amelogenin gene mutation with C deletion
at nucleotides g4114delC.
• Frameshift introduces premature stop
codon (L167fsX173).
• Truncates amelogenin protein deleting 18 c
terminal amino acids.
42
Non-Amelogenin Enamel Proteins
• The enamel extracellular
matrix is a complex mix
of multiple proteins,
some of which are
derived from
amelobalsts (enamelin,
ameloblastin) and others
that are not (albumin).
• Enamelin
• Ameloblastin
• Amelotin
• Amelin
• Tuft protein
• Keratin
• Albumin
43
Enamelin
• Low abundance glycoprotein immunolocalized to the secretory face
of the ameloblast Tome’s process.
• Parent protein is a 186 kD glycoprotein
• Cleaved into multiple smaller polypeptides
• May interact with amelogenin
44
Enamelin
AD hypoplastic AI
• Exon 4
• introducing stop codon
• Predicted protein is 52 amino
acids vs 1142 in wildtype
45
Single base deletion causes
enamelin protein to be 270 AA
vs wildtype 1142 AA in length.
MMP20 - Enamelysin
• Autosomal recesive AI
• matrix metalloproteinases – 483 amino acids (54kD).
• Expressed by ameloblasts and odontoblasts.
• Degrades amelogenin
46
Amelogenesis imperfecta
• Hypoplasia and hypomineralization
• Autosomal dominant hypoplastic hypomaturation AI with
taurodontism
47
Abnormalities of teeth structure
 Dentinogenesis imperfecta
48
• inadequate calcification of
dentin, which almost fills the
medullary cavity
• Teeth are gray, ocher-yellow,
reduced mechanical
resistance, abrasion occurs
rapidly
Dentinogenesis imperfecta
• Autosomal dominant clinically heterogenic disorders
Classification:
• Type I - Associated with osteogenesis imperfecta
• COL1A1 and COL1A2 mutations
• Type II – Autosomal dominant condition
• DSPP mutations
• (Type III – Autosomal dominant variant with large pulp chambers)
• Allelic to type II (DSPP mutations)
• dentin dysplasia I (DD I),
 dentin dysplasia II (DD II).
49
Osteogenesis Imperfecta
• Genetically and clinically heterogeneous group of
hereditary disorders characterized by
• Increased bone fragility
• Blue sclera of eye
• Hearing loss
• Joint laxity
• Dentinogenesis imperfecta (some families)
50
Dentinogenesis imperfecta
DGI I
 Molecular defects associated with OI
include mutations in the alpha-chains of
collagen type 1 and are phenotypically
characterized by increased bone fragility.
Collagen type 1 is the product of genes
COL1A1 and COL1A2.
 less than 10% of cases the disease is
caused by a recessive inheritance of the
disorder in the genes for CRTAP, PPIB and
LEPRE1
 ranging from the complete absence of
marrow and roots developed normally up
to the dentine
DGI II
• Approximately 10% of the dentin organic
material is formed by proteins other
than collagen, especially proteins
characteristic:
dentin phosphoprotein (DPP),
dentine sialoprotein (DSP) and
dentine glycoprotein (DGP).
Those are coded by chimeric protein
DSPP (dentin sialofosfoprotein)
In DGI II the temporary and permanent
dentition is affected. Primary dentition
impairment is far more serious than
impairment of secondary dentition
• DSPP Mutation in Dentinogenesis
ImperfectaShields Type II
• Non-sense mutation (Bln45stop) in exon 3 of
DSPP gene
51
Dentin dysplasia
DD-I
 Teeth are clinically of normal
shape, form and consistency.
 X-rays - sharp conical roots
with apical constriction.
 Pre-eruptive pulp
obliteration, which leads to
the remains of the pulp in a
crescent shape parallel to the
cement-enamel junction in
the permanent dentition and
to the total obliteration of
the pulp in deciduous
dentition
DD-II
 resemble symptoms in DGI-II,
 permanent dentition is either
unaffected or shows mild
radiographic deviations.
 X-ray - no temporary tooth pulp,
in permanent teeth - funneledshaped
marrow space with
growths emerging as
pathologically calcified pieces of
marrow.
 Dental roots in both dentitions
are normal.
52
Ectodermal Dysplasia
• Clinically and genetically diverse group of conditions affecting development of
tissues derived from ectoderm incl. teeth.
• Two affected tissues (e.g. hair, fingernails, teeth, skin).
• Two main types:
• Hypodidrotic (lack of sweat gland, hair, hypodontia)
• Hidrotic – normal perspiration levels (variable hair, teeth, nail abnormalities)
53
Ectodermal Dysplasia Molecular Defects
• First ED gene defect was reported in 1996
• • Molecular defects have now been identified
• in 10 to 20 ectodermal dsyplasias
• Hypohidrotic X linked ED
• Reiger Syndrome
• Tricho Dento Osseous Syndrome
• Autosomal Dominant/Recessive ED
• Clouston ED
• Incontinentia Pigmenti
54
Ectodermal Dysplasia Molecular Defects
• X-linked hypohidrotic ED
• transmembrane protein (ectodysplasin-A)
• Gene defect - can not run normally signals required for interaction
ectoderm-mesoderm
• Autosomal dominant and recessive hypohidrotic ED
• tumor necrosis factor receptor (Downless DL)
• mutation in gene for GJB6
• Rieger Syndrome
• homeobox gene (RIEG, PITX2)
• Tricho-dento-osseous syndrome
• homeobox gene (DLX3)
55
Other genes and dysplasia
Witkop syndrome (Tooth-and-nail
syndrome; TNS)
• rare autosomal dominant
ectodermal dysplasia
• manifests as defects hypodontia
and nail beds with normal sweat
glands and normal patterns of
hair.
• type of non sense mutation in the
gene for MSX1.
Mutations in the p63 gene
• are involved in the pathogenesis
of several syndromes that include
ectrodactylia, syndactyly,
ectodermal dysplasia and cleft.
• Expression of the p63 gene is
important for the development of
ectodermal organs including
teeth
56
Syndromes asociated with orophacial defects
• Van der Woude syndrome is an autosomal dominant disorder that is characterized by a cleft lip or
palate and the obvious defects of the lower lip - gene IRF6 (interferon regulatory factor).
• Crouzon syndrome is an autosomal dominant disorder that is characterized by the premature
closure of cranial sutures, maxillary hypoplasia and maxillary pseudo-cleft - with mutations in the
FGFR2 and FGFR3
• Apert syndrome is an autosomal dominant genetic disorder that causes abnormal development of
the skull - with mutations in the FGFR2 gene
• Treacher Collins syndrome is a disorder characterized by structures derived from the first and
second branchiálního arc: hypoplastic zygoma and mandible, micrognathia, Coloboma, ear defects,
the Lateran facial cleft, cleft palate. - Mutations in the gene for TCOF1
• Down's Syndrome - an underdeveloped facial bones, characterized by delayed development and
eruption of teeth (eruptions tarda), missing teeth, incorrect position - chromosomal aberrations
• Pierre-Robin syndrome is an autosomal recessive disorder with heterogeneous etiology. It is already
known X-linked form of disorder. It is a syndrome characterized by a cleft palate, hypoplastic
mandible and tongue hypertrophy
• Marfan syndrome is a rare autosomal dominant genetic disorder of connective tissue. Characteristic
maxillarní / mandibular retrognacie, micrognathia, narrow arched palate with stěsnanými teeth, and
symptoms similar to symptoms in dentinogenesis imperfecta - mutations in the gene for fibrillin-1
(FBN1). FBN1
57
Caries
 Multifactorial disease with endogenous and exogenous factors
 predisposing factors:
 inheritance- relation to caries or caries resistance
 diet rich in carbohydrates
 fluorine content in drinking water-resistant dental caries have higher fluorine
content in hard tissues
 personal hygiene-enhanced plaque formation by a lack of hygiene
 tooth- shaped teeth with fissures – more caries
58
Caries (caries dentium)
• dekalcification of hard dental tissues
• bacteria-Lactobacillus acidophilus and Streptococcus that break down
sugars, food debris, forming organic acids causing decalcificationproteolytic
enzymes break down organic ingredients
• plaque-thin coating of bacteria, mucus and desquamated epithelial cells
• other effects-type food composition of saliva, pH
• Decalcification of enamel-whitish chalk stain, softening, a cavity filled with
food residue and bacteria-spreading further decay process affects dentin,
spreads thrue the dentin tubules until marrow - occurs pulpitis
• Mutations in the genes that cause structural failure of enamel formation
(AMLEX, Enam, KAL4 and MMP20) lead to the formation of the enamel
more susceptible to tooth decay.
59
Periodontal disease
Multifactorial disorder
Environmental factors
Conception of periodontal disease
Page & Kornman
Microbial
infection
Immune
reaction
Metabolism
of ECM –
Alveolar
bone and
connective
tissues
Clinical signs
of disease and
its progression
Genetic risk factors
Ab
PMNs
LPS+
Ag Ck
PG
MMP
Syndromic Forms of Periodontitis
• Severe periodontitis presents as part of the clinical manisfestations of
several monogenetic syndromes.
• Significance of these conditions is that they clearly demonstrate that
a genetic mutation at a single locus can impart susceptibility to
periodontitis.
Papillon LeFevre Syndrome
• Clinically characterized by:
• Palmoplantar hyperkeratosis
• Severe early onset
periodontitis that results in
premature loss of the
primary and secondary
dentition (distinguishes PLS
from other plamoplantar
keratoderma)
• Prevalence 1/ 4million
• No gender or racial
predilection
CTSC gene encodes for Cathepsin C
protease
• CTSC gene lies on chromosone 11q14-q21; seven exons encoding
for lysosomal protease cathepsin C.
• It is expressed at high levels in a variety of immune cells including
polymorphonuclear leucocytes, macrophages, and in epithelial
regions commonly affected by PLS, including the palms, soles,
knees, and oral keratinized gingiva (RT-PCR) (Hart et al., 1999).
• Cathepsin C is a protease enzyme that processes and activates a
number of granule serine proteases critical to immune and
inflammatory responses of myeloid and lymphoid white blood
cells
Mutations in CTSC gene
• Mutations in Cathepsin C (CTSC) gene are implicated for PLS
• For example:
• One exon 1 nonsense mutation (856CT): introduces a
premature stop codon at amino acid 286.
• Three exon 2 mutations:
• single nucleotide deletion (2692delA) of codon 349: introduces a frameshift
and premature termination codon,
• 2 bp deletion (2673-2674delCT): introduces a stop codon at amino acid 343,
and
• GA substitution in codon 429 (2931GA): introduces a premature
termination codon.
• Truncated or altered conformation of the protein may not be transported to
the organelle and may not be able to activate protein kinases
• In other words, Cathepsin C activity in these patients is nearly absent
Polymorphism Studies on Periodontitis
• Host response is predominantly influenced by genetic make-up.
• Several features of host’s innate immune response may contribute to
susceptibility to AgP and include epithelial, connective tissue,
fibroblast, and PMN defects.
• Aspects of the host inflammatory response namely cytokines are
crucial variants influencing host respone in periodontitis.
Immunological Polymorphisms
• MHC or HLA genes determine our response to particular antigens.
• Japanese study of AgP pts found a significant association for pts with
atypical BamH1 restriction site in the HLA.DQB gene (Takashiba et al.
1994).
• Hodge & Kinane (1999) found no assoc. in caucasian AgP pts and this
restriction site.
IL-1 Gene Polymorphisms
• In 1997 Kornman et al found an association between polymorphisms
in genes enconding for IL-1a(-889) and IL-1B(+3953) and an increased
severity of periodontitis.
• The specific genotype of the polymorphic IL-1 cluster (called PSTperiodontitis
susceptibility trait) was associated with severity of PD in
only non-smokers, and distinguished individuals with severe
periodontitis from those with mild disease.
Genetic control of IL-1: Genes and Locus of SNPs associated with controlling IL-
1 biological activity
Genes Polymorphism
Locus
Current Locus
assessed with test
Controlled product
IL-1A Allele 2 -889 Allele 2 IL-1A +4845 IL-1 alpha
IL-1B Allele 2 +3953 Allele 2 IL-1B +3954 IL-1 beta
IL-1RN Protein receptor antagonist
(impedes IL-1 alpha and beta)
Genetic Susceptibility Test for 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 +3954 locus.
*IL-1A +4845 is being used because it is easier to identify than IL-1A -889 and 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 transcription should begin at +1 instead of zero.
Interleukin 1
• A proinflammatory multifunctional cytokine.
• Enables ingress of inflammatory cells into sites of infection
• Promotes bone resoroption
• Stimulates eicosanoid (PGE2) release by monocytes and fibroblasts
• Stimulates release of MMP’s that degrades proteins of the ECM.
• Forms IL-1α and IL-1B
IL-1 as modulator for Periodontitis
• Kornman et al. (1997)
• Genotype-positive non-smokers  18.9 times more likely to have severe periodontitis (when
compared with genotype-negative non smokers)
• No significant association between periodontal status and genotype detected when smokers
were included in the statistical analysis.
• 86% of the severe periodontitis patients were accounted for by either smoking or IL-1
genotype
• Presence of allele 2 at IL-1A -889 or IL-1B +3953 did not significantly increase the risk of
periodontitis among smokers and non-smokers.
+IL-1 genotype and IL-1 protein
• The specific periodontitis-associated IL-1 genotype consists of a variant in the IL-B gene that is
associated with high levels of IL-1 production.(Poiciot et al 1992)
• Patients positive for composite IL-1A (+4845) and IL-1B (+3954) periodontitis-associated genotype
has higher level of IL-1B in GCF, but not in gingival tissue before and after treatment (Kornmann et
al 1999)
• Carriage of allele 2 in the (-889) locus resulted in an almost four fold increase of IL-1 protein levels
in chronic periodontitis patients (Shirodaria et al., 2000)
• Attachment loss
Kornman et al. (1997)
• Reported 18.9 times greater risk (OR=18.9) of finding severe periodonitis among nonsmokers
genotype-positive.
McDevitt et al. (2000)
• Among non-smokers or former smokers, genotype positive individuals had 3.75 greater
odds of having moderate to advanced periodontitis than genotype-negative.
• Genotype and tooth loss
McGuire and Nunn (1999)
• Genotype-positive individuals had a 2.7 greater chance than genotype-negative patients
of losing a tooth.
• Combined effect of being genotype-positive and heavy smoker increased the odds of
tooth loss to 7.7 compared with genotype-negative non-smokers.
• PST can be helpful in treatment planning.
Prevalence of genotype positive individuals in different
ethnic groups
• Frequency of many genetic alleles varies between ethnic groups, therefore, it is necessary to establish allele frequencies in populations
before genetic test can be evaluated and used.
• Caucasions:
• 29% of northern european caucasions were genotype positive (Kornman et al., 1997)
• African Americans:
• 14.5% of non-diseased individuals and 8% of patients with localized form of aggressive periodontitis were
genotype-positive. (Walker et al., 2000)
• Chinese:
• 2.3% of sample of 132 mod-severe periodontitis cases were genotype-positive (Armitage et al., 2000)
• Hispanics:
• 26% of hispanic individuals with peridontitis were genotype-positive (Lopez et al., 2005)
Take home message: Dissimilarity in the prevalence of genotypes in different ethnic
groups precludes extrapolating data from one group to another.
80
 Porphyromonas gingivalis
 Bacteroides forsythus, newly Tanarella forsythensis
 Actinobacillus Actinomycemcomitans
 ……….
Microbial factors
• The bacteria themselves are not able to cause disease:
• A wide range of host susceptibility
• Differences in prevalence and extent between the teeth
BUT
Dental plaque biofilm infection
• Ecological point of view
• Ecological community evolved for survival as a whole
• Complex community of more than 400 bacterial species
• Dynamic equilibrium between bacteria and a
host defense
• Adopted survival strategies favoring growth in plaque
• “Selection” of “pathogenic” bacteria among microbial community
• Selection pressure coupled to environmental changes
• Disturbed equilibrium leading to pathology
• Opportunistic infectio
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Reaction of the organism to bacterial
infection
• Gate input - usually mucosal surfaces (violation of integrity)
• The fate of the host depends on:
- Immunity (largely genetically determined)
- Pathogenicity of bacteria (invasive ability, production of toxins, the ability to
resist the defense mechanisms of the host)
non-invasive - multiply the point of entry into the body
threatening in case of toxin production
(defense - only neutralizing Pt)
Invasive - penetrate into the organism (x extracellular intracellular)
(defense are Pt, complement, phagocytosis vs. macrophages)
- The size of the infectious dose
Identifying virulence factors
• Microbiological and biochemical studies
• In vitro isolation and characterization
• In vivo systems
• Genetic studies
• Study of genes involved in virulence
• Genetic transmission system
• Recombinant DNA technology
• Isogenic mutants
• Molecular form of Koch’s postulates (Falkow)
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Koch’s postulates
• A Molecular form of Koch’s postulates
• The phenotype should be associated with pathogenic species (strains)
• Specific inactivation of genes associated with virulence should lead to a
decrease in virulence
• Complementing inactivated genes with the wildtype genes should restore full
virulence
Falkow, 1988
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TLRs
• First described as a gene for type I transmembrane receptor
 important role in dorzoventral embryonic development of Drosophila
 absence of tolls has led to a serious brake-down of defense against fungi
and bacteria G+
Mammalian homologues - similar role??
TLRs receptors and ligands in
periodontal disease
Local problem?
Periodontitis• follows the loss of pulp vitality - the dead tooth
• Infection is usually odontogenic
• Trauma - one-time or repetitive microtrauma
• Acute periodontitis (apical)
• Hyperemia and serous exudation
• Suppuration, osteoclastic bone remodeling
• Strong pain at all stages, swelling in the later stages
• Relationship of polymorphisms in genes IL1B, IL1RN, FcγRIIIb, VDR and
TLR4 with an aggressive type of periodontitis.
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Periodontitis
Chronic periodontitis (periapical)
• Secondarily from acute periodontitis
Primarily chronic (more frequent)
• Forms:
Granulomatous
Granulomatous progressive - fistula (mucosal and cutaneous)
Diffusion - dismantled and alveolar bone
• granulation tissue
macrophages
Possibility of creating radicular cysts
• The type of chronic periodontitis is associated with polymorphisms in
genes for IL1B, IL1RN, IL6, IL10, VDR, CD14, TLR4 and MMP1.
• Meta-analysis of published data have associated variants
ofpolymorphisms IL1A-889, IL1B 3954, IL1B-511, TNFA-308 and IL6-
174 to aggressive and chronic periodontitis.
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