Genetic aspects of dental disorders - The University of Adelaide

18 Pages·2001·0.14 MB·English

by  Ron Robinson

Australian Dental Journal 1998;43:(4):000-000
Genetic aspects of dental disorders
Grant C. Townsend*
Michael J. Aldred†
P. Mark Bartold‡
evidence of a genetic basis to each of these
Abstract
problems, for example, ‘My mother had chalky teeth
This paper reviews past and present applications of
quantitative and molecular genetics to dental too’ or ‘He’s inherited his father’s teeth and his
disorders. Examples are given relating to cranio- mother’s jaws’ or ‘Bad gums run in my family’, it is
facial development (including malocclusion), oral true to say that well-planned and executed scientific
supporting tissues (including periodontal diseases)
studies aimed at clarifying the genetic basis of these
and dental hard tissues (including defects of
conditions are few and far between. This is partly
enamel and dentine as well as dental caries).
Future developments and applications to clinical because their aetiologies are multifactorial, making
dentistry are discussed. Early investigations it difficult to design well-controlled studies.
confirmed genetic bases to dental caries, perio- Furthermore, most researchers of dental caries and
dontal diseases and malocclusion, but research
periodontal diseases have concentrated on environ-
findings have had little impact on clinical practice.
mental aetiological fa c t o rs, for example, dental
The complex multifactorial aetiologies of these
conditions, together with methodological problems, plaque, dietary fac t o r s, and oral hyg iene, presumably
have limited progress until recently. Present studies because these have been thought to be most
are clarifying previously unrecognized genetic and important.
phenotypic heterogeneities and attempting to
A multifactorial aetiology for all three conditions
unravel the complex interactions between genes
and environment by applying new statistical model- has generally been assumed, with both genetic and
ling approaches to twin and family data. Linkage environmental contributions to observed variability.
studies using highly polymorphic DNA markers are The paucity of evidence of any clear-cut single gene
providing a means of locating candidate genes,
effects has meant that genetic research in these areas
including quantitative trait loci (QTL). In future, as
has had little impact up to now on clinical dental
knowledge increases; it should be possible to
implement preventive strategies for those practice.
genetically-predisposed individuals who are As Neale and Cardon1 have pointed out, several
identified to be at risk.
questions need to be answered before a complete
Key words: H e r e d i t y, caries, periodontal diseases, understanding can be gained about how genetic
malocclusion, gene mapping, enamel defects, dentine
fa c t o rs influence a feature or disorder. These
defects.
include:
.
(Received for publication July 1997. Accepted August
1997.) How important are genetic effects on human
differences?
.
What kinds of action and interaction occur
Introduction
between gene products in the pathways between
The three most common problems in dentistry
genotype and phenotype?
today remain dental caries, periodontal diseases and .
Are the genetic effects on a trait consistent
malocclusion. While there has always been anecdotal
across sexes?
.
Are there some genes that have particularly
This paper is based on presentations made at a Symposium titled
Genetics of Common Dental Disorders held at the 36th Annual ou.tstanding effects when compared with others?
Scientific Meeting of the Intern ational Association for Dental Whereabouts on the human gene map are these
Research Australian and New Zealand Division in Sydney from 29
September to 1 October 1996. genes located?
*Department of Dentistry, The University of Adelaide.
Modern methods of quantitative genetic analysis
†School of Dental Science, The University of Melbourne.
‡Department of Dentistry, The University of Queensland. allow the first three questions to be addressed and
000 Australian Dental Journal 1998;43:4.
2
Table 1. Abbreviations used in the text the sum of the effects of all the genes influencing the
feature under study, a dominance component (Vd)
AD Autosomal dominant
AR Autosomal recessive resulting from the interaction of alleles at a single
CIPD Chronic inflammatory periodontal disease
gene locus, and an epistatic component (Vi) due to
cDNA Complementary DNA
CpG Coding part of gene the interaction of genes at different loci: that is,
DI Dentinogenesis imperfecta Vg=Va+Vd+Vi. The environmental variance can be
DNA Deoxyribonucleic acid
DNP1 Dentine matrix protein 1 p a rtitioned into a common env i r o n m e n t a l
DPP Dentine phosphoprotein component (Vec) shared by family members and a
DZ Dizygous
specific environmental component (Vew).
EOP Early onset periodontitis
h2 Heritability estimate Heritability estimates, h2, that can range in value
HLA Human leukocyte antigen
from 0 to 1.0 (or 0-100 per cent) indicate how much
LOD Logarithm of odds
LJP Localized juvenile periodontics of the observed variation of a character can be
mRNA Messenger RNA
attributed to genetic effects. The ratio Vg/Vp is
MSTRA Minnesota study of twins reared apart
Mx Genetic modelling program referred to as broad-sense heritability whereas the
MZ Monozygous ratio Va/Vp is termed narrow-sense heritability. A
p Short arm of chromosome
list of abbreviations used in this paper is provided in
PCR Polymerase chain reaction
PMN Polymorphonuclear leukocyte Table 1.
PRP Proline-rich proteins
q Long arm of chromosome It is important to realize that heritability estimates
QTL Quantitative trait locus need to be interpreted with caution as they relate
RFLP Restriction fragment length polymorphism
only to the population under study at a particular
RNA Ribonucleic acid
SPP1 Osteopontin time, including the prevailing env i r o n m e n t a l
SSCP Single strand chain polymorphism influences. Furthermore, as Smith and Bailit3 have
Va Additive genetic variance
Vd Dominance variance noted, ‘contrary to popular opinion, the extent to
Ve Environmental variance which genes determine a trait has no relationship
Vec Common environmental variance
whatsoever with the success of environmental inter-
Vew Specific environmental variance
Vg Genetic variance vention’. Traditional quantitative genetic analyses in
Vi Epistasis variance
human populations deal with variation between
VNTR Variable number of tandem repeat
Vp Phenotypic variance individuals not with mean values. For this reason it
XAI X-linked amelogenesis imperfecta is inappropriate to say for example that ‘tooth size is
YAC Yeast artificial chromsome
(cid:1) Theta – recombination fraction strongly genetic’ – rather one should say that
‘variation in tooth size between individuals has a
strong genetic component’.
provide some insight into the fourth. Resolution of Genetic and environmental factors have often
the fifth question requires application of the been assumed to be independent for the purposes of
methods of molecular genetics. analysis, but in practice this is unlikely to be the
case. Three factors that should be considered are:
Analysis of multifactorial traits a s s o rt i ve mating whereby there is non-random
pa i r ing between mates for the trait under inves t i g a ti o n ;
Rigorous statistical analysis of multifac t o r ial traits
genotype-environmental correlation when different
began with R. A. Fisher’s seminal paper2in which he
genotypes are not distributed at random in all
sh o wed how the corre l a tions between relati v es of
possible environments; and genotype-environment
different degree could be explained using the
interaction in which environmental effects on
pr inciples of Mendelian inherit a n c e . Although the
phenotype differ according to genotype.
impact of quantitati v e genetics has been considerable
U n f o rt u n at e l y, most previous genetic studies of
in agriculture where selective breeding is possible,
dental disorders have been based on assumptions
until recently most studies in human populations
that have never been tested.
ha ve been confined to partitioning observed var ia ti o n
into genetic and environmental components based
on comparisons between relat i ves, for example, Twin studies
parents and offspring, siblings, half-sibs, twins. The classical twin approach for separating the
The variability between individuals in a trait’s effects of nature and nurture involves comparing
phenotype (Vp) can be considered to result from a identical (monozygous) twins and non-identical
combination of the genetic variance (Vg) and the (dizygous) twins. Differences between monozygous
environmental variance (Ve). Assuming that there is (MZ) twin pairs reflect environmental fa c t o rs ,
no interaction between these two sources of var ia ti o n , whereas differences between dizygous (DZ) twin
Vp=Vg+Ve, genetic variance can be partitioned pairs are due to both genetic and environmental
fu r ther into an additive component (Va) representing factors. Therefore, greater similarities between MZ
Australian Dental Journal 1998;43:4. 000
3
twin pairs compared with DZ twin pairs can be these methods to clarify the genetic basis of dental
interpreted as reflecting genetic influences on the disorders has been limited by the difficulties of
feature(s) being studied. obtaining data from large family pedigrees and also
The traditional twin analysis method based on in identifying appropria te polymorphic marker loci.9, 1 0
c o rr e l ations is limited, but the development of
s o p h i s t i c ated genetic modelling methods made Molecular approaches
possible with improved computing power has now With marked advances in molecular genetic
provided an opportunity to fit complex multivariate technology in recent years, gene mapping techniques
models to human data, test their goodness of fit, are now providing powerful approaches for locating
make estimates of genetic and env i r o n m e n t a l genes associated with various diseases and disorders.
parameters, and specify interactions between them. Functional cloning uses the protein sequence and
A p a rt from comparisons of monozygous and thereby the putative corresponding DNA sequence
dizygous twins, there are other twin models that to clone the relevant gene, or by extracting the
provide insights into the contributions of genetic and messenger RNA (mRNA) from the tissue to
environmental factors to observed variability. The produce a complementary DNA (cDNA). This
monozygous co-twin model involves comparisons of cDNA corresponds to the DNA sequence of the
monozygous twins where each member of a pair has coding regions (exons) of a gene.
been exposed to different environmental effects. For Positional cloning, also known as reverse genetics,
example, identical twins might be treated with is used to identify the location of the mutant gene on
different appliances to correct similar malocclusions a particular chromosome by virtue of its cosegrega-
and the outcomes compared.4 tion with polymorphic DNA markers. The first
generation of these markers were termed restriction
Studies of twins reared apart overcome the problem
fragment length polymorphisms (RFLPs). RFLPs
of twins displaying similarities because of their
arise as a result of minor alterations in the DNA
common environment. Since 1978, Bouchard and his
sequence on pairs of chromosomes. The DNA,
co l l e a g u e s 5 in the USA have been studying mono-
usually obtained from peripheral blood leucocytes,
zygous and dizygous twins who were separated at
is digested with a restriction enzyme which recognizes
bi r th and reunited in adulthood. The twins travel
particular DNA sequences and cuts at a certain
from all over the world to Minnesota where they
point in the sequence. The resulting DNA fragments
undergo an intensive week of psychological and
are then separated in an agarose gel where the
medical eval u a ti o n s .
distance they migra te depends upon their size, shorte r
Another approach involving twins, the monozygous
fragments migrating further than larger fragments
twin half-sib model, offers a powerful way of
over a given period of time. The DNA is then trans-
resolving shared genetic and environmental disease
ferred from the gel to a nylon membrane (Southern
risks in families, as well as clarifying maternal effects
blotting) where it can be probed by markers.
and the importance of assortative mating.6 Mono-
The markers are DNA fragments which have been
zygous twins are assumed to have identical genotypes,
mapped to parts of chromosomes. Because of the
so their offspring are genetically related as half-sibs
variation in cutting sites, in an ideal situation the
but are socially first cousins. A nested analysis of
probe will bind to two different sized fragments of
variance similar to that used in analysing data from
DNA. The probe is labelled using a radioisotope
half and full-sibling litters in animal studies can be
and appears as one or more bands on an autoradio-
applied to provide estimates of genetic and
graph. The different bands are referred to as alleles,
environmental effects.
and by following the segregation of these alleles with
the disease, the position of the gene is established.
Segregation and linkage analysis
The limitation of RFLPs is that individuals are
Segregation analysis is a statistical method for frequently homozygous at a given marker, that is,
determining the mode of inheritance of a particular they have two alleles of the same size.
phenotype from family data, particularly with the To establish linkage (the position of the diseased
aim of elucidating single gene effects or so-called gene in relation to the RFLPs) affected individuals
major genes. With increasing computer powe r , need to be heterozygous, that is, have two alleles of
models have been developed to detect the contrib ut i o n different sizes. Linkage analysis depends upon
of individual genetic loci that have large effects having a sufficient number of meioses, either in one
against a background of polygenic and environ- or more large pedigrees or multiple smaller pedigre e s .
mental effects.7,8 Once evidence of major genes has It is difficult to establish linkage without a number of
been detected, linkage analysis provides a means of three-generation (or more) pedigrees. Linkage also
de t e r mining where individual genes are located within relies upon the fact that, at meiosis, recombination
the genome. Until recently, however, application of events occur on the chromosomes. Thus, some
000 Australian Dental Journal 1998;43:4.
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individuals will inherit exact copies of their parents’ Craniofacial development, including
chromosomes while others will inherit chromosomes malocclusion
which represent rearrangements of the ori gi n a l
Dental occlusion reflects the interplay between a
chromosomes. These recombination events are the
number of factors including tooth size, arch size and
key to mapping of a gene.
shape, the number and arrangement of teeth, size
More recently, a new generation of polymorphic
and relationships of the jaws, and also the influences
markers has been employed. These variable number
of the soft tissues including lips, cheeks and tongue.
of tandem repeat (VNTR) markers rely upon var ia ti o n s
The term ‘malocclusion’ is generally used to refer to
in the number of repeat sequences in non-coding
variations from normal occlusal development, and
regions of chromosomes. The VNTRs may be either
although in some instances it is possible to specify
dinucleotide repeats (repeats of two DNA bases,
the cause of a particular malocclusion, for example,
usually cytosine and adenine) or tri-, tetra-, or
genetic syndromes, embryo l o gical defects, or
penta-nucleotide repeats. VNTRs have an advantage
trauma, most malocclusions represent va ri at i o n s
over RFLPs in that the number of repeats is (in
from normal development for which there is no
theory) infinitely variable and these markers are
apparent cause.
more likely to be heterozygous. VNTRs obviate the
need for Southern blotting. They are identified Indeed, the term ‘occlusal variation’ seems a more
using the polymerase chain reaction (PCR) which a p p r o p ri ate term than ‘malocclusion’ as it
uses primer sequences flanking the variable segment emphasizes the continuous range of dental occlusal
to amplify the DNA using a thermal cycler. The relationships that are observed, with the more severe
resulting amplified DNA fragments are then cases being located at the extremes of the distrib ut i o n .
separated by electrophoresis in a polyacrylamide gel With so many factors involved in the development of
and revealed by autoradiography. Detection systems occlusion it is little wonder that most examples of
other than radioactive systems are now available and malocclusion display multifactorial inheritance, with
some of these processes can be automated. both genetic and environmental influences
Cosegregation of a disease with one or more DNA contributing to phenotypic variability.
markers can be confirmed by statistical analysis. The Most previous studies have found a relatively
measures of cosegr e g ation are the LOD score strong genetic contribution to variation in cranio-
(logarithm of the odds for linkage as opposed to no
facial morphology, but standard errors of heritability
linkage) with a value of three being regarded as
e s t i m ates have rarely been prov i d e d .1 1 I n d e e d ,
significant, this indicating a one-thousand-fold
Hunter12 has questioned the value of continuing to
likelihood of linkage. The other measure is the
p u rsue traditional family studies to estimat e
recombination fraction which is an indication of the
heritabilities for dento-facial variables, given the lack
distance from the marker to the gene. With a high
of any real clinical application to the findings. How-
LOD score and a low recombination fraction the
ever, as Proffit13 has pointed out, history indicates
researcher can be fairly certain that the gene
that prevailing views about the causes of malocclu-
responsible for the disease has been localized.
sion (that is, heredity versus environment) have
The next stage is to clone the gene which can be a
affected the type of treatment offered to patients to
long and frus t r a ting process. Numerous techniques
a surpr ising degree. Hopefully, a better underst a n d i n g
are available to accomplish this. If the disease has
of the relative effects of genetic and environmental
been localized to a small area of a chromosome, the
influences on different occlusal features should
cu r rent strategy would be to use the markers either
ul t i m a tely lead to improved preven t i v e and treatm e n t
side of the disease (flanking markers) to probe a yea s t
planning rationales in clinical dentistry.
ar tificial chromosome (YAC) library and this, in turn,
can be used to screen other libraries containing There have been several excellent reviews of
smaller fragments of DNA such as cosmid librarie s . genetic studies of craniofacial development and
Typical YACs are considerably larger than cosmids so morphology.11,14-18 In their comprehensive review of
this approach enables the relevant section of DNA to the problems and methods in studies of the genetics
be analysed on a smaller scale. Other techniques that of dental occlusion, Smith and Bailit3 listed five
can be used include identification of the coding parts main research objectives:
at the beginning of genes (CpG islands) and exon 1) Elucidating modes of inheritance
trapping. Once the gene has been isolated it can then
2) Detecting the effects of admixture and
be sequenced and the coding regions (exons) and
inbreeding
non-coding regions (introns) identified. Fol l o wi n g
3) Performing linkage analyses
this, mutations in affected individuals can be
identified using techniques such as single strand chain 4) Estimating heritabilities
po l y m o r phisms (SSCP) or direct sequencing. 5) Comparing population differences
Australian Dental Journal 1998;43:4. 000
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Modes of inheritance bite, large maxillary overjet, distal molar occlusion
and tendency to open bite in 45,X females reflecting
As already mentioned, occlusal variation appears
(or is assumed) to conform to a multifactorial mode imbalanced growth of the craniofacial skeleton.25 It
is suggested that the X chromosome may alter
of inheritance, although strong familial similarities
morphology of the cranial base by affecting growth
may be due to single major genes. For example, the
at the synchondroses, that is, cartilaginous joints,
famous ‘Hapsburg jaw’ seen in consecutive genera-
and it also appears to have a direct effect on
tions of an Austrian royal family may have been
mandibular shape.
caused by a small number of segregating major
genes. It is also possible that epistatic factors, that is, Of particular interest is the finding that the human
the interaction between genes at different loci, may dental enamel amelogenin gene is located on both
play a more important role than most researchers the X and Y chromosomes,26 although the gene on
the X chromosome is predominant. Using molecular
have thought.
genetic techniques, the amelogenin gene has been
localized to the distal portion of the short arm of the
Admixture and breeding effects
X chromosome and to the peri-centromeric region
Although many workers have suggested that racial
of the Y. Amelogenin is one of the major matrix
admixture increases the occurrence of malocclusion,
proteins secreted by ameloblasts and it is thought to
Smith and Bailit3 have pointed out that the only
direct the growth of hydroxyapatite crystals. This
detailed study aimed at testing this hypothesis by
finding fits in with studies at a phenotypic level. It
Chung and colleagues19 failed to show any increased
also appears that mutation of the human amelogenin
risk associated with admixture. The notion that
gene is associated with some X-linked types of
admixture might lead to an increased frequency of
amelogenesis imperfecta, a finding that will be
malocclusion in humans appears to have originated
discussed in more detail subsequently. This provides
from the work of Stockard and Johnson20 in which
an excellent example of how studies at both molecular
gross deformities of the jaws of dogs were produced
and phenotypic levels can complement each other
by cross-breeding different inbred strains. It has
and also have important clinical implications.
subsequently been noted that Stockard’s results
reflected the segre g a tion of a gene for achondroplasia Heritability
which is present in many breeds of small dogs but
Early traditional twin studies27 and intrafamilial
rare in humans, and therefore the results of Stockard’s
comparisons28 indicated that occlusal traits were
animal experiments cannot be extrapolated directly
under reasonably strong genetic control. However,
to humans with any validity.13
more recent reports in twins29 and in first-degree
re l a ti v es 3 0 , 3 1 h ave emphasized the importance of
The X and Y chromosomes
environmental factors.
Linkage studies in humans have been mainly
Studies of tooth size in Australian twins have
restricted to studies of the sex chromosomes and the indicated a relatively strong genetic influence on
work of Gorlin and his colleagues,21 together with o b s e rved va ri a b i l i t y, and a model incorp o r at i n g
the on-going research of Professor Lassi Alvesalo in a d d i t i ve genetic and individual env i r o n m e n t a l
Finland, have clarified the roles of the X and Y influences provided a good fit to the data. In addi-
chromosomes on craniofacial morphology. Pattern tion, significant or near significant contributions of
profiles of dental crown size show the dosage effect non-additive genetic variance were noted for the
of the sex chromosomes,22 with both the X and Y mesiodistal crown dimension of canines and first
chromosomes appearing to exert growth-promoting premolars, and a significant shared environmental
effects on human tooth crown size. component of variation to maxillary first molar
The X chromosome appears to mainly regulate dimensions. The findings for the canine and first
enamel thickness. On the other hand, the Y chromo- premolar mesiodistal dimensions are consistent with
some seems to affect both enamel and dentine. The e x p e c t ations deri ved from evo l u t i o n a ry theory
X and Y chromosomes also seem to influence concerning the presence of dominance variation in
cr a n i o f acial gro wth and development. Cephalometric morphological features that have been subjected to
analysis of a sample of 47,XXY males indicates strong selective pressures in the past.32
pronounced facial prognathism in the Klinefelter The best model for Carabelli trait includes
males, especially in the mandible. Mandibu l a r additive genetic effects, together with general and
corpus length is significantly increased and there is a specific environmental components. An estimate of
tendency for reduction of the cranial base angle.23 heritability around 90 per cent indicates a very
Studies of 45,X females indicate a retrognathic face, strong genetic contribution to observed variation. It
with short mandible and flattened cranial base also seems possible that features like Carabelli trait
angle.24 There is an increased prevalence of cross- may be influenced by genes interacting at the same
000 Australian Dental Journal 1998;43:4.
6
or different loci.33 Dental arch shape also appears to Population differences
be under relat i vely strong genetic influence,
Variations in dental occlusion between different
although there is evidence of some independence
human populations have been described and
between the maxilla and mandible.34
interpreted in genetic terms.
Studies of occlusal variation in Australian twins
Growth records of Aborigines living at Yuendumu
have shown that heritability estimates for various
in the North e r n Ter rit o r y of Australia have provi d e d ,
occlusal features are generally low in magnitude,
and continue to provide, a unique resource for
emphasizing the importance of env i r o n m e n t a l
clinicians, anthropologists and geneticists. The
influences.35 The trend noted by other workers for
special value of this material for clinicians is that it
genetic components of variance to be greatest for
provides the essential perspective upon which to
overjet, less for overbite and least for molar relation-
base preventive and treatment decisions. From a
ships has also been confirmed by these studies.
genetic viewpoint it has been shown that a fairly
There is also an apparent lack of genetic determi n a ti o n
large percentage of the variation observed in tooth
for crossbite, a relationship in the coronal plane.
size is due to genetic fa c t o rs. For example,
Although most genetic studies of craniofa c i a l
h e ritability estimates are around 60 per cent.4 3
gr owth and morphology have concentrated on
Certain teeth are more variable than others in their
osseous structures, the functional matrix concept
size, shape, timing of emergence, etc, and this
proposes that the morphology of the craniofacial
pattern follows Butler’s field theory.
skeleton is determined by the surrounding soft
t i s s u e s.3 6 Although a relationship has been Midfacial growth, alveolar bone development and
demonstrated between the morphology of cranio- tooth migra tion associated with vigorous masticato r y
facial features and the amount of muscular function tends to provide space for unimpeded
activity,37,38 little is known about the genetic basis to emergence and alignment of permanent teeth in
variation in soft tissue structure or function. In this A b o ri gi n a l s. This is in contrast to commonly
regard the finding of significant genetic variance in observed crowded dental arches in industrialized
masseter muscle electrical activity and morphology populations. A feature of dental arch growth in many
in recent twin studies is of considerable interest.39,40 A b o ri ginal children, especially males, is the
Comparisons of MZ twins who show different tendency for a greater increase in maxillary arch
expressions of va rious dental or facial feat u r e s breadth than mandibular arch breadth. This growth
provide a useful means of unravelling the influence pattern leads to a variation of dental occlusion
of genes and environment to observed variability. termed alternate intercuspation which resembles the
For example, several pairs of MZ twins who display dental relationship found in many species of
different expressions of missing, peg-shaped and herbivores. It is suggested that alternate intercus-
diminutive upper lateral incisors have been noted.41 pation, which would be regarded as a malocclusion
These findings support the view of a relationship and termed ‘scissors bite’ according to the modern
between tooth size and agenesis. A multifactorial clinical concepts, is in fact an efficient adaptation to
threshold model for tooth development is proposed vigorous masticatory function.
that links tooth size and tooth number. Presumably,
Studies of genetic contri butions to arch size
developmental influences may modify phenotypic
variability indicate that the heritability for maxillary
expression of lateral incisor crown form in those MZ
arch breadth in Aborigines is low, that is, that
twins whose genetic make-up places them near the
variation is largely due to environmental factors.44
threshold for agenesis.
Al s o , recent studies have shown that occlusal var ia ti o n
The study of Australian twins and their families
increased significantly in the Yuendumu people
has been extended recently to include young children
within one generation after adoption of a more
with deciduous dentitions. It is planned to follow
westernized diet.45
these children through the mixed dentition stage
There seems to have been an increase in the
until all permanent teeth are present. A longitudinal
frequency of malocclusion during the period of
approach should overcome many of the problems
human evolution. Although examples of crowding
associated with previous cross-sectional studies and
provide information that can be applied clinically for and malalignment of teeth have been found in
predictive purposes. There is now increasing interest prehistoric specimens, the prevalence appears to be
in early intervention to correct incipient malocclusions lower than in modern day societies.46 Whether this
and based on the preliminary findings of clinical increase in malocclusion is a reflection of genetic or
trials in Finland, Varrela and Alanen42 claim that non-genetic effects is still not completely resolved
‘orthodontics may be on the verge of a fundamental but there is apparently an association betwe e n
change in its clinical practice which could be of increased occlusal variation and the adoption of
benefit to dental health as a whole’. modern industrialized lifestyles.46
Australian Dental Journal 1998;43:4. 000
7
Future developments and applications to Table 2. Classification of the periodontal
clinical dentistry diseases
One of the major deficiencies in most genetic I Gingivitis
II Early onset periodontitis
studies of common dental disorders to date has been
Prepubertal – localized or generalized
the use of inappropriate systems of classification for Juvenile – localized or generalized
the conditions or traits being studied. It is little III Adult onset periodontitis
Adult-type periodontitis
wonder that genetic analyses of malocclusion based
Rapidly progressive periodontitis
on Angle’s classification, dental caries expressed as Refractory periodontitis
IV Periodontal abscess
DMF scores, or periodontitis measured by pocket
V Periodontitis associated with systemic or inherited diseases
depth have been largely uninformative, given the HIV– gingivitis
complex aetiologies and continuous distributions of HIVperiodontitis
Neutropenias
these conditions. Po t t e r4 7 has emphasized the Diabetes, etc
im p o r tance of clarifying unrecognized heterogeneities
in the aetiology of diseases such as periodontitis
or disorder under investigation need to be included
before attempting genetic analyses. She believes that
in studies to avoid introducing bias. For example,
a combined biologic-genetic approach is most likely
most studies of craniofacial growth and morphology,
to prove fruitful in discovering major susceptibility
with the exception of a recent investigation by King,
genes that might then be mapped.
Harris and Tolley52 have excluded individuals who
An important basis for inves t i g a tions of craniofac i a l
h ave received orthodontic treatment. Thirdly,
growth is to establish the appropriate developmental
longitudinal studies are more likely to be informative
units for study. Atchley and Hall48 have emphasized
for predictive purposes than cross-sectional
that before any comprehensive theory for develop-
approaches, but the cost of the former is often
mental change can be form u l ated, fundamental
prohibitive.
developmental units need to be identified along with
The critical questions that need to be answered
their underlying controlling factors. These authors
before real progress can be made are: ‘How many
have provided a quantitative genetic model for the
genes are involved?’ and ‘Where are the genes
evolution of mandibular development in the mouse
located?’.
that might eventually be applied to the craniofacial
A gene that influences a continuously variable or
structures of humans. They have drawn on the work
so-called quantitati v e feature is termed a quantitati v e
of Moss49 and Cheverud et al.50 who used finite
trait locus or QTL. For traits that display a multi-
element scaling analysis to compare mandibular
factorial mode of inheritance, it would be expected
morphology in inbred strains of mice. Rather than
that several QTLs will be involved together with
computing linear and angular variables as usually
various environmental effects. Although traditional
occurs in conventional craniometric or cephalo-
approaches have usually been unable to identify
metric analyses, finite element analysis uses data
these genes because of the superimposed effects of
derived from sets of interconnected landmarks or
other genes and environmental va ri ation, it is
nodes to provide triangles or quadrangles that are
theoretically possible to locate them if they are
t e rmed ‘finite elements’. These elements then
linked with genetic markers, for example, RFLPs or
become the basic units for analysis.
VNTRs. Considerable progress has been made in
Application of 3D methods for visualizing hard mapping QTLs in rodents using either segregating
and soft tissues in the craniofacial region (for populations or recombinant inbred strains together
example, magnetic resonance imaging), together with genetic markers.53VNTRs are ideally suited for
with morp h o m e t ric techniques such as finite linkage studies of quantitative traits in humans as
element analysis that focus on particular regions of they are very common, often have multiple co-
the skull, promise to provide a more realistic assess- dominant alleles, and are distributed throughout the
ment of craniofacial morphology and growth than human genome.54 Although recent genetic mapping
the conventional 2D methods used up until now.11,51 of hypodontia in Finnish families has excluded a
These data could then be analysed using multi- number of candidate genes that are known to be
variate genetic modelling methods such as Mx to i m p o rtant in dental development, for example,
investigate their covariance structure. epidermal and fibroblast growth factors,55the search
Another problem to overcome in human studies of is on in earnest!
dental disorders relates to sampling. Firstly, there is
a difficulty in obtaining data from large numbers of The periodontal diseases
related individuals to provide sufficient statistical Currently, the periodontal diseases are considered
power for genetic analyses. Secondly, individuals as a group of related, but vastly different, inflammato r y
representing the entire range of variation of the trait diseases affecting the support structures of the
000 Australian Dental Journal 1998;43:4.
8
periodontium. While many different classifications two diseases were of similar origin. Today it is
have been proposed, the American Academy of recognized that gingivitis and periodontitis are quite
Pe riodontology has adopted a relat i vely simple separate diseases with separate aetiologies and thus
classification related to age of onset and severity of an y extrapolation between gin g ivitis and perio d o n t i t i s
disease (Table 2). These diseases range in severity is of little value.
from gingivitis which is largely a reversible condition Differences in periodontal disease experi e n c e
if the causative agents are removed and controlled, b e t ween different populations have also been
to the very aggressive forms of early onset periodon- studied. Chung et al.60,61 found that different racial
titis, which manifest in several forms all of which groups residing in Hawaii demonstrated different
d e m o n s t r ate early and rapid destruction of the levels of disease, with Caucasians and Japanese
periodontium and can be extremely difficult to s h owing a high level of oral health while the
manage. In the middle ground lies the relatively Hawaiians had a poor level of health. In a study of
benign form of adult-type periodontitis which two Pacific Island populations who have relatively
affects many individuals but is generally regarded as separate gene pools yet are ethnically similar, have
being of less long-term threat to the well-being of the similar diets, lifestyle and oral hygiene practices,
periodontium and is relatively easily treated. Cutress, Powell and Ball62 found that these two
populations varied significantly in their experience
Without question, all of the above conditions are
of progressive disease. This observation has been
associated with bacterial plaque accrual adjacent to
suggested to implicate a role for genetic factors in
the gingival tissues. However, although disease will
determining disease susceptibility.63
not develop in the absence of plaque it is apparent
that plaque alone is not sufficient to lead to disease. Family studies have also provided insights into
For example, there are many instances where d e t e rmining the genetic contri bution to va ri o u s
individuals may have significant plaque and calculus diseases. While these are useful for diseases that
deposits yet manifest little overt evidence of disease. manifest with a single discrete trait (or set of traits)
asMendelian segregation, in multifactorial or multi-
The conve rse holds true also in that some
p r e s e n t ation diseases such as the peri o d o n t a l
individuals appear to have very minimal plaque and
diseases, such analyses cannot distinguish between
calculus deposits yet manifest significant periodontal
environmental and genetic influences on disease
destruction.
trait manifestation.
The most likely explanation for the above
N e ve rtheless, for some forms of peri o d o n t a l
dilemma lies in the multifactorial nature of the
disease, localized juvenile periodontitis (LJP) in
disease in which host and environmental factors play
particular, pedigree patterns have been determined
a significant role in the development of disease. If
that seem to indicate a genetic component to this
this paradigm is accepted, then it is likely that some
specific disease. However, this concept has been
individuals will be at higher risk of developing
complicated by reports that have variously indicated
disease. Thus, within this framework the issue of a
localized juvenile periodontitis to be X-linked
genetic component to the disease experience of
d o m i n a n t ,6 4 autosomal recessive ,6 5 or autosomal
different individuals must be taken into account. In
dominant.66 These findings indicate that even this
recent years there have been several very good
clinically well-defined condition may have significant
published reviews on the subject of genetics and
genetic heterogeneity. One study has even gone so
periodontitis to which the reader is referred for a
far as to suggest that the putative localized juvenile
more detailed discussion of this topic.56-59
periodontitis gene is located on chromosome 4q12-
q13.67However, more recently, this finding has been
Host genome considerations
questioned as not being representati v e of all localized
Epidemiology
juvenile periodontitis cases and further serves to
Population studies can be used to study groups of highlight the genetic heterogeneity of this disease.
individuals with differing levels of inbreeding or Since MZ twins have an identical genetic
outbreeding to determine the influence of genetics composition and DZ twins share approximately 50
on the manifestation of disease in known populati o n s . per cent of their genome, twin studies utilizing both
This method has been used with some success in the MZ and DZ twins enable determination of both
study of periodontal disease. An effect of racial hereditary variability and the influence of environ-
mixing as well as inbreeding has been noted for ment on genetic expression. As with all hereditary
gingivitis.60,61 This has led to the proposal that studies, those involving twins have limitations that
recessive genes might be associated with increased must be recognized. Firs t l y, for twins reared
risk for development of periodontitis. Nonetheless, together, this method of study presupposes that the
these early studies mistakenly assumed that environment during development and maturation is
gingivitis progressed to periodontitis and that these ve ry similar and thus any differences noted in
Australian Dental Journal 1998;43:4. 000
9
Table 3. Monogenetic and chromosomal defects associated with periodontal defects
Condition Tissue/cell/ Periodontal condition Mode of inheritance
biochemical defect
Connective tissue disorders
Ehlers-Danlos syndrome
Type IV Collagen type III Fragile tissues and EOP AR or AD
Type VII Procollagen peptidase Fragile tissues and EOP AR or AD
TypeIX Collagen Fragile tissues and EOP X-linked
Mucopolysaccharidoses Proteoglycans Gingival overgrowth
Mannosidosis Mannose Gingival overgrowth
Familial fibromatoses Collagen Gingival overgrowth Variable
Metabolic disorders
Acatalasia Catalase Gingival necrosis and EOP AR
Hypophosphatasia Alkaline phosphatase Poorly mineralized bone and AR (?AD)
cementum and EOP
Leukocyte defects
Chediak Higashi syndrome Neutrophil EOP AR
Chronic neutropenia Neutrophil EOP AD
Cyclic neutropenia Neutrophil EOP AD
Leukocyte adhesion defect Neutrophil EOP AD
Dermatological defects
Papillon Lefevre syndrome Keratin/epithelium EOP AR
Chromosomal disorders
Trisomy 21 Multiple biochemical CIPD, EOP
Abbreviations:EOP=Early onset periodontitis. AR=Autosomal recessive. AD=Autosomal dominant. CIPD=Chronic inflammatory periodontal
disease.
phenotype between MZ and DZ twins must be due incidence of various class I and II HLA antigens in
to genetic differences. Howev er, subtle envi r o n m e n t a l patients with early onset periodontal disease. In
differences between MZ and DZ twins do exist particular, the HLA antigens A9, A28, BW15 and
during both prenatal development (for example, DR4 have been found to be associated with early
b i rth weight) and postnatal development (for onset forms of periodontitis.68-70
example, parenting differences) that may have a Of interest is the observation that the HLA-A9
significant bearing on phenotype which is extremely and HLA-BW15 antigens have been associated with
difficult to control in such studies. the generalized but not localized forms of juvenile
Although environmental factors are considered to periodontitis implying differing genetic factors may
be important in the establishment of periodontitis, be responsible for these two conditions.71 Further-
individuals reared or living in similar environments more, unique intronic gene variations have been
may manifest significantly different disease patterns. noted in the gene for HLA-DQb in patients (and
However, MZ twins reared either together or apart some other normal family members) with early
have been found to have a more similar periodontal onset periodontitis.71 However, other studies have
disease experience than DZ twins reared in the same indicated that there are no HLA associations with
manner with respect to both disease severity and m a n i f e s t ations of va rious types of peri o d o n t a l
distribution.57These findings have possibly provided disease.72,73 Thus, it is unclear whether there is an
the most convincing data to date that some, as yet to association between HLA antigens and periodontal
be identified, genetic factors may influence the disease due to an inherited periodontal disease
manifestation of periodontal disease. susceptibility factor which is close to the gene for
From these various epidemiological studies it may HLA, or segregation of HLA antigens in families
be concluded that the early onset forms of who have a high risk for developing early onset forms
periodontal disease such as LJP probably have a of periodontitis.
distinct host genomic component to their Genetic segregation analyses of serum IgG2 levels
manifestation. However, there are little convincing have indicated that some forms of early onset perio-
data to support a similar conclusion for adult-type dontitis have a clear, albeit va riable, genetic
periodontitis. linkage.74 The results from this study indicated the
possibility of a two locus model explaining the
Genetic markers for periodontal diseases manifestation of early onset forms of periodontal
Genetic risk fac t o r s may be studied by establishing disease in which there may be an autosomal dominant
an association between the disease and inherited major locus for early onset periodontitis conferring
tissue markers. In an infectious disease such as disease susceptibility.74 Additionally, other alleles
periodontal disease, the association between the which control IgG2 responses may regulate some
HLA antigens and various forms of the disease has features of the disease. Thus, an interesting model
been of interest with several studies reporting the has been proposed whereby an individual with the
000 Australian Dental Journal 1998;43:4.
10
‘at risk’ genotype for early onset periodontitis but acatalasia both gingival necrosis and severe alveolar
who has a strong IgG2 response may manifest the bone destruction have been noted.83
localized form of early onset periodontitis. On the Hypophosphatasia is a monogenetic condition
other hand, an individual with the ‘at risk’ genotype characterized by deficient production of alkaline
for early onset periodontitis who also fails to mount p h o s p h atase leading to significant skeletal
a strong IgG2 response may manifest a more a b n o rm a l i t i e s. Along with diminished bone
generalized form of the disease.75 mineralization, defects in cementum formation have
Other genetic markers which have been studied been noted. Hypophosphatasia and its associated
include the markers associated with the ABO blood cementum defect have been implicated in forms of
group. While several reports have indicated that early onset periodontitis.84
some blood groups may be associated with an
increased incidence of periodontal disease,76,77others Leukocyte defects
have not been able to confirm these findings.78 In most forms of periodontal disease there is a
significant rise in the circulating antibodies to
Inherited disorders with associated periodontal diseases
various periodontal pathogens. However, individual
There are many inherited diseases and syndromes variation is very high in these responses and this may
that have periodontal disease in one form or another be related to differences in levels of individual gene
as one of their distinct clinical features (Table 3). expression for various immunoglobulins. High IgG2
Whether these conditions are monogenetic, chromo- levels to antigens of various periodontal pathogens
somal or multifactorial, they all serve to demonstrate have been noted in localized juvenile periodontitis
that genetic mutations affecting a broad range of and rapidly progressive periodontitis,85 indicating
tissues, cells, biochemical processes and host that the humoral response to periodontal pathogens
defence processes are affected to varying degrees, is not very efficient in eliminating these organisms.
leading to increased susceptibility to developing A p a rt from lymphocytes, polymorp h o n u c l e a r
pe r iodontal disease. Significantly, the genes responsible leukocytes (PMN) are also critical in providing host
for all of these conditions do not appear to cluster on defence against bacterial infections. Indeed, poly-
one particular chromosome and this further high- morphonuclear leukocytes are considered to be the
lights the multifactorial and polydisperse nature of primary line of host defence and if defective in their
the periodontal diseases. Although many of these function can lead to significant and severe problems
conditions are relatively rare, they have provided with controlling infections. The most striking link
some important insights into various components of
between neutrophils and onset of aggressive forms of
host susceptibility to periodontal infections.
periodontal disease is seen in patients suffering from
the var ious forms of neutropenia. In these conditions
Connective tissue disorders there is a significant reduction in neutrophil numbers
Conditions affecting connective tissue metabolism such that these individuals are very susceptible to
include various forms of Ehlers Danlos syndrome,79 recurrent bacterial infections of which periodontal
the mucopolysacchari d o s e s ,8 0 m a n n o s i d o s i s8 1 a n d infections are very common.86 While some forms of
familial fibromatoses.82 Of these, all but the fibro- neutropenia occur spontaneously, others appear to
matoses are monogenetic syndromes. Ehlers Danlos be of a familial nature and may be transmitted via an
syndrome types IV, VII and IX have all been associate d autosomal dominant mode. Apart from the problems
with an early onset form of periodontitis. The with adequate numbers of neutrophils in neutropenia,
m u c o p o l y s a c c h a ridoses and mannosidosis are qualitative defects in neutrophil function have also
generally associated only with gingival overgrowth been noted to contri bute to severe peri o d o n t a l
and little evidence of significant peri o d o n t a l de s t r uction. For example, Chediak-Higashi syndrome
destruction. Similarly, the familial fibromatoses do is a genetically transmitted disease characterized by
not tend to demonstrate any association with reduced neutrophil function and extreme
destructive periodontal disease. susceptibility to recurrent bacterial infections of
which rapidly progressive early onset periodontitis is
Metabolic disorders a characteristic feature.87
Acatalasia is a monogenetic condition affecting A p a rt from these systemic conditions which
the production of catalase which is important in manifest an identifiable neutrophil deficiency,
r e m oving hydrogen peroxide generated duri n g defects in PMN function such as chemotaxis have
normal cell metabolism. Since hydrogen peroxide also been noted in approximately 75 per cent of
can be toxic, and also leads to generation of super- patients with early onset forms of periodontitis.88 A
oxide radicals, tissue destruction is a common genetic component to this defect is considered likely
sequela to its accumulation. In patients manifesting in these conditions since the PMNs in these
Australian Dental Journal 1998;43:4. 000