Periodontology 2000, Vol.

32, 2003, 3649

Printed in Denmark. All rights reserved

Copyright # Blackwell Munksgaard 2003

PERIODONTOLOGY 2000
ISSN 0906-6713

The genetic relationship to

periodontal disease
Salvador Nares

Early in 2001, man heralded one of its greatest scientific achievements: a draft of the human genome.
This sequence contains the genetic code at the center
of each of our 10 trillion cells influencing our bodies,
our behavior, and our minds. It has the potential to
provide unparalleled insights into the diagnosis and
treatment of numerous diseases affecting mankind
including those affecting the oral cavity. This is particularly important in periodontitis as oftentimes the
severity of the disease process cannot be explained
simply by the quantity and types of bacteria present
(46, 48). The most common form of periodontitis,
chronic periodontitis, has been reported to affect
up to 30% of the adult population with approximately 713% of adults affected with severe disease
(6, 12, 68). Moreover, predicting the course of
destruction can be a difficult task due to the variable
nature of the disease process and the significant
influence of environmental factors.
Completion of the human genome has great
implications for both medicine and dentistry. In
periodontitis, the host-activated inflammatory and
immunological cascades responding to predominantly gram-negative microorganisms that result in
the destruction of connective tissue and bone are
under genetic control. Also under this control is the
innate ability of the host tissues to respond to both
non-surgical and surgical therapy. Although not discussed in the present article, it has been previously
noted that systemic health and environmental factors including smoking and oral hygiene can also
greatly impact on the patients innate ability to
respond to therapy. Previously reported findings
involving genetic factors and periodontitis have been
excellently reviewed by Hart and Kornman (31).
The present review will focus on recent findings
relating genetics to periodontitis and will summarize
recent technological advances in the sequencing of

36

the human genome. What follows is a brief glossary

of various terms frequently used in discussions involving genetics.
Allele one of several possible alternative forms of a
given gene differing in DNA sequence assumed to
arise by mutation and often affecting the function
of a single product. Humans carry two sets of chromosomes, one from each parent. Single nucleotide
polymorphisms may render two sets of equivalent
genes different.
Alternative splicing the generation of multiple protein isoforms from a single gene via the splicing
together of nonconsecutive exons during RNA processing of some but not all of RNA transcripts.
Believed to the mechanism involved with the high
number of proteins produced from a smaller number
of genes in humans.
Autosome chromosomes other than sex chromosomes.
Autosomal dominant the dominant effect of one
gene located on an autosome regardless of the presence of the other, normal copy.
Autosomal recessive A gene on an autosome that is
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
that gene.
Complementary DNA (cDNA) the DNA sequence
produced by the enzyme called reverse transcriptase
from messenger RNA. Very frequently used in cloning experiments.
Chromosome a nuclear structure carrying genetic
information arranged in a linear sequence. Humans
have 23 pairs (including a pair of sex chromosomes
XX or XY).
Cloning the generation of sufficient copies of a
target DNA sequence that allows it to be sequenced
or studied further.

The genetic relationship to periodontal disease

Dizygotic twin fraternal twins as a result of fertilization of two separate eggs. They are no more similar
genetically than are siblings.
Exon the expressed portion of DNA or RNA that will
ultimately be translated into protein. Multiple exons
are spliced together to remove introns during RNA
processing.
Frameshift mutation A type of mutation as a result
of an insertion or deletion of one or more nucleotides
into a gene causing the coding regions to be read in
the wrong frame.
Gene a hereditary unit that occupies a specific
position (locus) within a genome or chromosome
that has one or more specific effects upon the phenotype of the organism.
Gene expression the process involving use of the
information in a gene via transcription and translation leading to production of a protein affecting
the phenotype of the organism determined by that
gene.
Genetic code in RNA and DNA, the consecutive
nucleotide triplets (codon) that specify the sequence
of amino acids for protein synthesis (translation).
Genome a term used to refer to all the genes carried
by an individual or cell.
Genotype the genetic makeup of an organism or cell
distinct from its expressed features or phenotype.
Haplotype the collection of one allele of each gene
comprising the genotype.
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).
Intron the intervening (non-coding) portion of
DNA or RNA that is removed during RNA processing.
Isoforms a protein with equivalent function and
similar or identical sequence but derived from a different and usually tissue-specific gene.
Ligand any particular molecule that binds to
another such as a hormone to its receptor.
Linkage the tendency for certain genes to be inherited together due to their presence on the same chromosome.
Linkage disequilibrium the occurrence of some
genes together more often than would be expected
by random distribution.
Locus (plural loci) the physical location a gene
occupies within a chromosome or portion of genomic DNA.
Monozygotic twin identical twins having identical
sets of nuclear genes as a result of separation of
blastomeres.

Mutation alteration of the genomic sequence compared to a reference state. Not all mutations have
harmful events (silent mutation).
Phenotype the observable characteristics displayed
by an organism as influenced by environmental factors and independent of the genotype of the organism.
Polymorphism a region on the genome that varies
between individual members of a population present
in a significant number of individuals.
Sequencing the linear arrangement of nucleotides
(in RNA or DNA) or amino acids (in protein).
Silent mutation a mutation resulting in no noticeable change in the biological activity of the protein
encoded by the affected gene.
Single nucleotide polymorph (SNP) a polymorphism
caused by the change in a single nucleotide believed
to be the most common genetic variation between
individual humans.
Signal transduction the cascade of cellular events
by which an extracellular signal such as a hormone or
growth factor interacting with a receptor on the cell
surface triggers an internally-directed response. This
stepwise occurrence usually results in changes in
gene expression in the nucleus.
Splicing the removal of introns from transcribed
RNAs. The removal of exons results in the formation
of splice variants or alternatively spliced protein
isoforms allowing different proteins to be produced
from the same initial RNA or gene.
X-linked disease a disease of genetic origin as a
result of a mutation on the X-chromosome.
Vector common term for a carrier of and organism,
DNA, RNA, or protein to be transferred from one
organism to another. Examples include plasmids,
viruses, and mosquitoes.
Wild type the non-mutated, naturally-occurring
form of a gene.

The Human Genome Project and

periodontics
For many, the technological advances stemming
from the Human Genome Project have changed the
face of biological investigations and have placed
genomics at the forefront of biomedical science.
The availability of genetic blueprints of organisms
important to mankind including experimental models (mice, yeast, fruit fly, etc.) as well as infectious
pathogens (microorganisms, viruses) and disease
vectors (mosquito, viruses) will lead to important

37

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advances in the understanding of pathological conditions with a genetic basis. It has been reported that
the individual risk for disease as well as the response
to drugs will be heavily influenced by genetic prediction, resulting in changes in the delivery of healthcare and the creation of designer drugs based on a
genomic approach to targeting molecular pathways
disrupted in disease (14). However, access to personal genetic information must also be safeguarded if
we are to be protected from those who would use this
information to discriminate against susceptible individuals in the workplace or those who would deny
the opportunity of one to obtain health insurance
(35, 76).
Presently two versions of the genome are available.
A product of the International Human Genome
Sequencing Consortium (36) (the public project) is
available in draft form via the Internet: http://
www.ncbi.nlm.nih.gov; http://genome.ucsc.edu. This
multinational project united scientists and researchers from 20 groups including China, France, Germany, Japan, the United Kingdom and the United
States. In fact, in the United States, The National
Institutes of Health (NIH) created a new institute,
The National Human Genome Research Institute
(NHGRI), funding $1.4 billion dollars over 10 years.
In Great Britain, The Wellcome Trust funded $300
million for this project (73). In a sense, the information contained in the human sequence is our common legacy. In fact, The United Nations has declared
that the human genome is, in a symbolic sense,
humans common heritage (73).
It was once reasoned that as the most complex
species on Earth, the human genome must contain
the greatest number of genes found in nature. Early
estimates on the number of genes ranged from
80,000 to 150,000 genes (86). However, it is now
apparent that the human genome contains only
approximately 30,00040,000 genes (3). The sequence has also raised questions regarding the
uniqueness of our species and how similar humans
are to other species. This is apparent considering the
fact that the 26,00038,000 genes in our own genome
amount to only approximately two to three times the
13,600 genes in the fruit fly genome (3, 86). In
humans, approximately 5% of the genome actually
codes for genes with some chromosomes containing
a higher density of genes compared to other chromosomes. The function of the remaining DNA is unclear. Moreover, approximately 10% of human
genes are clearly related to particular genes in the
fly. Thus it appears that we share much of our genetic
heritage with even very distant relatives. We already

38

know that we share approximately 99% of the overall

DNA sequence similarity with chimpanzees (39).
However, the relatively low number of genes in
humans is consistent with the idea that variations
in gene regulation and the splicing of gene transcripts results in different protein isoforms and distinct functions in different types of tissue (72, 73).
Indeed, it is likely that sequence variations between
individuals may affect gene splicing and regulation,
resulting in differing susceptibility to disease between individuals, while mutations in the coding
sequences of genes may be responsible for only a
small percentage of the differences in disease susceptibility.
In periodontics, as well as in medicine, we are interested in the genetics of both humans and pathogens
and the genetic interaction between them. As of this
printing, the complete genome sequences of more
than 60 species are available in databases with many
more to come. Presently, the complete sequence of a
putative periodontal pathogen, Porphyromonas gingivalis has been sequenced in its entirety (www.pgingivalis.org). Other microorganisms of dental and
periodontal relevance with ongoing genomic sequencing include Actinobacillus actinomycetemcomitans,
Streptococcus mutans, Streptococcus sanguis, Treponema denticola, Candida albicans, and Fusobacterium
nucleatum (www.nidcr.nih.gov).
Over the past 10 years it has become apparent that
studies involving the influence of genetics on periodontics have gained momentum. This is most notable
in the number of publications available on public
online databases (i.e. PubMed, Fig. 1). With available
sequence data as a result of the Human Genome
Project, this trend will most likely continue.
Of importance is the increasing awareness that
most of the destructive processes involved in periodontitis are host-derived. These inflammatory processes leading to destruction of periodontal tissues
as well as the properties that result in their regeneration and the responses to implanted material are of
great interest to both researchers and clinicians alike.
The information contained within the human genome can potentially lead to a better understanding of
these control mechanisms modulating the production of inflammatory mediators as well as provide
potential therapeutic targets for periodontal regeneration.
Most investigations concerning complex diseases
(like periodontitis) examine known metabolic pathways and candidate genes. Unfortunately, our
incomplete biological knowledge limits our understanding of the contribution of other essential genes

The genetic relationship to periodontal disease

Fig. 1. Graph of query results from

PubMed
(www.ncbi.nlm.nih.gov/
entrez/) with the keywords Genetics
and Periodontal Disease from years
19922001 demonstrating an increasing trend for publications related to
genetics.

and pathways. No one gene operates exclusively or is

completely free from environmental or lifestyle influences. A gene interacts directly or through its protein
product with many other genes and gene products in
coordinated networks, often resulting in striking variations in symptoms among patients with the same
disease. It is known that the phenotypic expression of
simple monogenic diseases such as cystic fibrosis
can be influenced by modifier genes. Understanding
these relationships will require further analysis in
humans as well as in animal models before we can
understand why the severity of monogenic diseases
fluctuates not only with different mutations in the
same gene, but also between affected individuals
within the same family. Unfortunately, only a small
percentage of these networks have been identified
and characterized through classical biochemistry,
structural analyses, and assays of activity. With the
availability of the human genome sequence and
knowledge of the full complement of our genes, it
should now be possible to identify all of the metabolic pathways in the human body, including those
involved in periodontal destruction and regeneration.
Most common forms of periodontitis represent a
lifelong account of interactions between our genome,
our behavior, and our environment. Accurately predicting all the genes and pathways involved in periodontal destruction (or regeneration) as well as their
interactions with these modifiers represents a daunting task. Humans share 99.9% of their genetic information, which is why every human belongs to the
same species. The final 0.1% differs from one person
to the next (80). This seemingly small variation may
very well be involved in disease susceptibility, and
drug and treatment response in periodontitis. Many
clinicians hope to be able to group individuals by the
presence and variety of gene types to someday offer

highly personalized treatments that will have been

predetermined at the genetic level (80).
The incidence of periodontitis also appears to vary
among differing genetic backgrounds. Race, while
culturally important, appears to be the result of only
a few continuous traits determined by only a very
small percentage of our genes. However, this may not
give any indication as to variations in other parts of
the genome. Thus, from a genetic standpoint, two
individuals from the same part of the world who
appear to look alike may actually be more related
to persons from other parts of the world than they
are to each other, even though they may look very
different. Of 313 genes that were examined from
unrelated individuals in one study including Caucasians, African Americans, Asians, and Latinos, 3,899
distinct genetic variations for each gene were discovered. In fact, there were no variations that could be
used to define an ethnic group. Geographic origin of
one group compared to another was associated with
an increased frequency among groups (80).
Recently, the genes responsible for two pathological
conditions affecting the oral cavity were reported. Dentinogenesis imperfecta, an autosomal dominant condition, was reported to be caused by mutations in the
DSSP gene (93, 96). DSSP is unusual in that two proteins
are produced from this gene, dentin phosphoprotein
and dentin sialoprotein. Both are key elements of dentin extracellular matrix. The mutation turns out to
affect only the dentin sialoprotein portion of the gene,
suggesting that it alone may be a key player in dentogenesis imperfecta. Hereditary gingival fibromatosis
type 1, also an autosomal dominant form of gingival
overgrowth, was found to be associated with a mutation
in the SOS (Son of sevenless-1) gene (32). The insertion
mutation introduces a frameshift creating a truncated protein that abolishes a vital portion of the protein. The authors suggest that a clear understanding

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of the role of this mutant has implications for the management of gingival tissue management. These and
other articles on syndromes affecting the oral cavity
serve as important reminders of the influence of genetics on disease manifestations.

Single nucleotide polymorphisms

Single nucleotide polymorphisms are the subject of
intense research in medicine and periodontics. They
occur as a single base-pair site in the human genome
every 1001,000 base pairs differing from person to
person as a result of deletions, insertions, or substitutions (Fig. 2). Single nucleotide polymorphisms are
frequently studied because they are the most common type of genetic marker in the human genome
and because the mutation rate of single nucleotide
polymorphisms is low from generation to generation
(47). One recent study identified 1.42 million single
nucleotide polymorphisms in a map of human
genome (77).
Not all single nucleotide polymorphisms result in a
distinct phenotype, while others are apparent clinically. In humans, blood type is determined by genes
that encode the A, B, or O antigens on red blood cells
as a result of four single nucleotide polymorphisms
and the deletion of a single nucleotide present in
these genes (Fig. 2). The DNA sequence CGTGGTGACCCCTT will produce antigen A. Antigen B results
from the same gene when a parent passes on four
single nucleotide polymorphisms to the offspring,
resulting in the sequence CGTCGTCACCGCTA. A

Fig. 2. Common types of mutations resulting in single

nucleotide polymorphisms. In humans, blood type is
determined by the presence of either A, B, or O antigens.
A four base-pair substitution in the A-antigen sequence
gives rise to blood type B, while a single nucleotide
deletion in the A-antigen sequence results in the nonfunctional antigen (O antigen) as a result of a frameshift
mutation. The AB blood type results when both antigens
are present on red blood cells. An insertion at any point
along the sequence would also result in a frameshift
mutation (not shown).

40

deletion of a single nucleotide results in the sequence

CGTGGTACCCCTT, resulting in a frameshift and a
gene that produces no antigen at all (i.e. O antigen)
(17). The hereditary disease present in persons of
African descent results in sickle cell anemia when
an adenine to thymine mutation of the beta-globin
gene gives rise to the replacement of a glutamic acid
amino acid residue to a valine residue (52).

Indigenous populations
Recently, the prevalence of periodontitis among indigenous people in remote regions of the Amazon rain
forest and in Guatemala was reported in two separate
studies (20, 75). A cross-sectional evaluation of 244
subjects 2070 years of age evaluated pocket depth,
clinical attachment level, bleeding upon probing,
plaque and calculus assessed using the Ramfjord
index (75). This particular population had high levels
of plaque, calculus and bleeding on probing but
mean probing depth was shallow in both the 20
29-year-olds and in the 50 group (2.45 mm and
2.73 mm, respectively). It was concluded that periodontal disease in this population was mainly associated with gingival recession rather than deep
pockets and that most individuals had clinical
attachment loss rather than severe periodontal
destruction despite poor oral hygiene and extensive
gingival inflammation. In comparison, high disease
prevalence according to full-mouth pocket probing
depths in 239 Guatamalian subjects 1275 years old
was reported with more than 75% of subjects with
one or more pockets of 5 mm (20). A more detailed
examination of 125 unrelated subjects of 18 years or
greater confirmed that 90% of adults 35 years old had
at least one site with clinical attachment levels
6 mm. However, only 10% of this population had
severe disease (20% or more sites with clinical
attachment levels 6 mm) and tooth retention
was high in both studies (26.4 and 28.0 teeth, respectively).

Studies in twins
A better understanding of complex diseases like
periodontitis involves the use of both molecular
and non-molecular approaches to evaluate the interaction between genetics and the environmental
influences exerted upon it. Familial studies or casecontrol approaches together with genetic marker
polymorphisms offer a unique opportunity to assess

The genetic relationship to periodontal disease

whether candidate genes are associated with disease.

It has been suggested that a heritable component to
periodontitis may exist likely due to genetic variations in immunologic host defenses in contrast to
oral health-related behaviors attributed to gingivitis
(62). Recently, 117 pairs of adult twins (64 monozygotic, 53 dizygotic pairs) were evaluated clinically,
including probing depths, attachment loss, plaque,
and gingivitis on all teeth present. Monozygotic twins
were more similar than dizygotic twins for all clinical
measures with estimations of adult periodontitis to
have 50% heritability. Gingivitis did not appear to
have a hereditary component. Instead, it was concluded that approximately half of the variance in
disease in the population is due to genetic variance
and not to behavioral aspects (62), confirming earlier
studies (60). The influence of genetic factors on subgingival plaque in monozygous and dizygous adult
twins was also recently evaluated (61). Microbial and
clinical data was collected from 169 twin pairs. It was
found that with access to routine dental care, any
effects that host genes and the early family environment have on subgingival plaque were not apparent
in adulthood. Comparison of periodontal disease in
identical, systemically healthy female twins was
also evaluated in a case report (55) evaluating both
clinical and microbiological parameters. One twin
exhibited only mild gingivitis and no clinical or
radiographic signs of periodontitis, while the other
had localized mild-to-severe periodontitis. The only
reported variable was a higher plaque score in the
affected twin, suggesting behavioral aspects contributed to the presence of disease.

The immune system

In an otherwise healthy individual, the immune system adequately defends the host from invading
microbes with little or no destruction of host tissue.
The innate defenses of the host include the ability to
opsonize and clear (phagocytize) microorganisms.
Immunoregulation also involves the timely control
of potentially destructive cytokine networks while
defending the host from pathogens. It is becoming
increasingly clear that variations in one or more of
these functions can lead to differences in host
response and tissue destruction.

Cytokine polymorphisms
Differences in the expression of cytokines, especially
proinflammatory cytokines, are of great interest in

periodontal research. Cytokines such as (IL)-1 and

tumor necrosis factor (TNF) have important roles in
bony destruction and inflammatory stomatitis and
attempts have been made to elucidate the association of single nucleotide polymorphisms between
patient populations.
Among one of the more studied genetic associations with periodontal disease is that of the IL-1
genotype. This genetic marker includes two polymorphism of the IL-1 gene cluster on chromosome
2 (46). The IL-1 family consists of at least three wellstudied genes: IL-1B (IL-1b), IL-1A (IL-1a), and IL-RN
(IL-1 receptor antagonist). Recently IL-1B and IL-6
polymorphisms were found to be associated with
the development of recurrent apthous stomatitis
(4). Ninety-one patients suffering from recurrent
apthous stomatitis and 91 controls were genotyped
for known IL-1A, IL-1B, IL-1RN, and IL-6 gene polymorphisms. Both the IL-1B511 and the IL-6174
polymorphisms were found to be significantly associated with recurrent apthous stomatitis. Inheritance
of the G/G genotype for both genes was reported to
be a strong predictor for this condition (Odds
ratio 8.5). The authors note that effective therapeutic agents used in the treatment of recurrent
apthous stomatitis including corticosteroids and thalidomide are inhibitors of IL-1b and IL-6 production.
In humans, IL-1b has been identified as a key
cytokine involved in destruction of extracellular
matrix and resorption of bone. Laine et al. (48) investigated the distribution of polymorphisms in the IL-1
gene family among periodontitis patients and controls considering both smoking and microbiological
parameters including the presence of P. gingivalis
and A. actinomycetemcomitans. Results indicated a
higher frequency of allele 2 carriage in IL-1A, IL-1B,
and IL-1RN in non-smoking periodontitis patients in
whom P. gingivalis and A. actinomycetemcomitans
were undetectable. Using checkerboard DNADNAhybridization, Socransky et al. (79) investigated the
presence of periodontal pathogens in genotype-positive patients. Higher levels of the red and orange
complexes including Bacteroides forsythus, T. denticola, the F. nucleatum subspecies, Fusobacterium
periodonticum, Campylobacter gracilis, Campylobacter showae and Streptococcus constellatus were
detected in genotype-positive subjects more frequently than genotype-negative patients. In a similar
study, Papapanou et al. (69) investigated the relationship between genotype status, periodontal parameters, subgingival bacteria, and systemic antibody
response to periodontal microbiota concluding that
the composite genotype (allele 2 of the IL-1A4845

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and IL-1B3954 loci) was unable to distinguish

between patients and controls. However, the composite genotype did correlate with the severity of disease when assessed by clinical attachment levels.
Moreover, genotype-positive patients had a lower
systemic IgG antibody response to periodontal bacteria than genotype-negative patients. The results of
this study contradicted that of Socransky et al. (79) in
that no definitive relationship between genotype status and the mean bacterial load or their colonization
by specific bacterial clusters could be identified (69).
Another study investigated the incidence of the
periodontitis-associated genotype (PAG) (46) in
young New Zealanders (26 years old). It was reasoned that this population with a lower exposure to
environmental factors was well suited for the study of
the early natural history of periodontitis and the
influence of genetic polymorphisms (85). After controlling for sex, smoking status, and plaque levels,
patients with the IL-1A4845/ IL-B3953-positive genotype had 12.3 times the odds of being in the severe
group (as measured by probing depths).
Recent investigations regarding the correlation
between IL-1 genotype status and gingival crevice
fluid (GCF) levels of IL-1a and IL-1b have provided
evidence of a genetic influence on the levels of these
inflammatory mediators in GCF. Carriage of the IL1A gene at position 889 was associated with about a
four-fold increase in GCF IL-1a (78), while in shallow
sites (<4 mm), total IL-1b in GCF was 2.5 times
higher for PAG() patients prior to treatment and
2.2 times higher after treatment. A reduction in IL1b concentration in GCF was seen for PAG() but not
for PAG() patients after treatment (22). In a followup study, the presence of GCF IL-1b in patients with
periodontal disease were assessed in 29 non-smoking
adults with mild, moderate, or severe periodontal
disease at baseline, 2, and 24 weeks following scaling
and root planning. Once again, patients with severe
disease exhibited higher IL-1b GCF levels in shallow
sites. Taken together, these findings suggest that the
expression of IL-1b is partly a result of a host trait and
not due solely to clinical parameters (23). Moreover,
genotype-positive patients were reported to have a
significantly elevated chance of presenting with
higher bleeding upon probing scores, while genotype-negative patients had a 50% smaller chance of
showing increases in bleeding upon probing scores
over a 4-appointment recall, indicating the possibility of a genetically determined hyperinflammatory
response during periodontal maintenance (49).
Longitudinal evaluation of 60 consecutive nonsmoking patients with moderate to severe periodon-

42

titis treated either surgically or non-surgically and

enrolled in a periodontal maintenance program over
10 years were examined retrospectively (9). In this
European population, 23/60 patients (38.3%) were
IL-1 genotype-positive. Of the 1,566 teeth examined,
a total of 52 teeth (3.3%) were lost due to periodontitis between baseline and 10 years; 28 of 957
(2.9%) in the IL-1 genotype-negative group and 24
of 609 (3.9%) in IL-1 genotype-positive group. However, some patients showed significant differences in
response to therapy based on initial bone levels and
genotype. In this study, a non-smoking, well-maintained periodontal population, failed to show a significant difference related to IL-1 genotype in tooth
loss after 10 years. The authors noted that on an
individual patient basis, the IL-1 genotype, in combination with the initial bone level, appears to be
useful at the beginning of therapy for predicting bone
level variation (9). A 5-year study investigating the
relationship between the IL-1 genotype and periodontitis in essentially a European heritage reported an
interaction of the IL-1 genotype with age, smoking,
and, P. gingivalis (16). These findings indicated that
the IL-1 genotype is a contributory but non-essential
risk factor for periodontal disease progression. This
study was further supported by Meisel et al. (59) who
concluded that the IL-1 gene cluster combined with
smoking was associated with an increased risk of
attachment loss. In this population, non-smoking
subjects were not at increased risk, even if they are
genotype-positive.
The influence of IL-1 gene polymorphisms on the
maintenance of regenerated clinical attachment following guided tissue regeneration of deep intrabony
defects using polytetrafluoroethylene membranes
after 4 years in 40 patients was recently reported
(19). Forty deep (4 mm) interproximal angular
defects with clinical attachment loss >8 mm were
subject to guided tissue regeneration (GTR), the
membranes were removed at 46 weeks, and the
patients placed on monthly recall for the first year
and every 3 months for the following 3 years. At
1 year, it was determined that genotype expression
did not affect the treatment response. However, when
compared to oral hygiene-matched genotype-negative patients in the 3 years following, genotype-positive patients lost about 50% of the clinical
attachment levels gained in the first year and were
approximately 10 times as likely to experience
2 mm clinical attachment levels loss, demonstrating a decreased stability of the clinical gains (19).
The relationship between ethnicity and cytokine
gene polymorphism distribution among 300 Whites,

The genetic relationship to periodontal disease

Blacks, Hispanics, and Asians requiring renal transplantation was recently investigated (34). Striking
differences were noted in the distribution of cytokine
polymorphisms among differing ethnic populations.
This study exemplifies the apparent influence of ethnicity on allograft outcomes (34). In periodontics a
very similar situation may exist. Investigators have
detected decreased frequencies of the IL-1 polymorphism in a Chinese population (2) or have failed
to identify an association in European Caucasians
with either generalized early onset periodontitis
(33) or adult periodontitis (21). The association
between early-onset periodontitis and IL-1 polymorphisms was investigated in several recent studies. Diehl et al. (18) evaluated the association
between early-onset periodontitis and genotype status in 28 African American and 7 Caucasian families,
concluding that early-onset periodontitis is a complex, oligogenic disorder in which the IL-1 genotype
is an important but non-exclusive influence on disease risk. Moreover, in an African American population, it was concluded that the 3953 polymorphism
would provide only a small amount of diagnostic or
predictive information for this population (90). In
Caucasians, Parkhill et al. (70) suggested that smoking together with the IL-1b genotype and a combined
IL-1b and IL-1RA genotype are risk factors for earlyonset periodontitis. In Hispanics, it was reported
that the prevalence of genotype-positive patients
was 26% (7) which compares to the 30% prevalence
among white Europeans. It was concluded that periodontal health can be maintained in this group with
proper preventative care. In addition, the mean response to mucogingival surgery to cover localized
recession defects was similar in both genotype-positive and genotype-negative groups. The authors noted,
however, that full coverage was achieved more frequently in genotype-negative patients (8). Positive
correlations between disease severity and IL-1 genotype-positive patients have also been reported by
other investigators (25, 26, 56, 78). However, Mark
et al. (54), using cultured peripheral blood monocytes from PST-positive and PST-negative patients,
found no difference in the production of IL-1b between
the two groups when these cells were incubated with
periodontal pathogens. They concluded that genetic
loci other than the PST polymorphisms contribute to
the regulation of monocyte IL-1 responses.
It is apparent from these findings that while IL-1
genotype status may influence the susceptibility and
expression of periodontal disease for many patients,
no one individual fits into the universal genotype
box as yet some other undetermined genetic

factors may also influence periodontal outcomes.

In addition, the effects of environmental factors
including smoking, oral hygiene and maintenance
schedules appears to greatly influence periodontal
outcomes determined by the genotype. Further studies on the molecular pathways and candidate genes
involved in periodontal disease are required, as are
studies involving the complex interactions between
host and pathogen.

Implants
Implants are now an integral part of periodontal and
restorative dentistry. However, due to the somewhat
recent introduction of predictable therapies in
implant dentistry, very few studies have been reported addressing the influence of genetics on
implant survival. The effects of the IL-1 genotype,
smoking status, and patients age on failed or failing
implants was recently compared to successfully integrated implants (91). Although smoking increased
the risk of implant failures by approximately 2.5
times, statistical testing failed to indicate a relationship between implant failure, age, or IL-1 genotype
status. This was further validated by another study
that failed to demonstrate a relationship between
implant failure and the IL-1A (899), IL-1B (3953)
composite genotype in Caucasian patients (74).
However, it was suggested that the absence of these
alleles may not indicate a reduced risk of periodontitis or peri-implantitis.
Calcitonin is a hormone produced in the thyroid
that causes a reduction of calcium ions in the blood.
The relationship between the calcitonin receptor
genotype and mandibular buccal marginal bone loss
at stage II surgery in 237 implants was recently
reported in Japanese patients (66). Although there
were no significant differences in the distribution
of age, smoking status, postmenopausal women,
and bone quality, patients with the calcitonin receptor polymorphism were 20 times more likely to suffer
buccal marginal bone loss than patients who were
calcitonin receptor genotype-negative.

Fc, FMLP receptor polymorphisms

The Fc portion of an antibody is responsible for
binding to receptors present on immune cells independent of the antigen-binding, Fab portion. These
cellular Fc receptors, especially IgG Fc receptors
designated FcgRs have been the subject of numerous
investigations in periodontal research. They are
found on cells capable of binding the Fc portion of

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IgG antibody such as macrophages, monocytes, and

PMNs and are important in the phagocytosis, antibody-dependent cell-mediated cytotoxicity, endocytosis, enhancement of antigen presentation, and the
release of inflammatory mediators (87). FcgRs are
currently classified into FcgRI (CD64), FcgRII (CD32),
and FcgRIII (CD16) each containing isoforms within
each class that affect cellular distribution and binding affinity to IgG subclasses (88). Polymorphisms in
the genes encoding the low affinity receptors
FcgRIIa, FcgRIIb, FcgRIIIa, and FcgRIIIb may result
in variations in antibody binding and phagocytosis
and hence susceptibility to periodontitis.
The existence of several FcgR polymorphisms of
periodontal relevance has been documented and
appears to be involved in microbial clearance. The
FcgRIIa-131 H/R polymorphism (histidine, H or arginine, R) at position 131 in the membrane proximal
Ig-like domain results from a single G to A nucleotide
substitution. IgG2-opsinized particles are phagocytized much more efficiently in PMNs from FcgRIIaH/H genotypes than from FcgRIIa-R/R genotypes.
The FcgRIIIa-158F/V polymorphism in the high affinity receptor involves a phenylalanine, F to valine, V
amino acid substitution at position 158 in the Ig-like
domain as a result of a G to T substitution at nucleotide 559 in the DNA sequence (45). The V/V variant is
capable of efficient binding of IgG1, IgG3, and IgG4
relative to the F/F variant in both monocytes and
natural killer cells (45, 92). This substitution was also
associated with recurrence of adult periodontitis
compared to individuals without recurrence in Japanese patients (81). In PMNs the low affinity FcgRIIIb
exists as two allelic forms, NA1 and NA2, as a consequence of various nucleotide substitutions resulting in changes in four amino acids. However, the
FcgRIIIb-NA1 displays a more efficient interaction
with IgG1- and IgG3-opsonized bacteria compared
with the FcgRIIIb-NA2 and was found to be associated with increased resistance to periodontitis in
an elderly Japanese patient population (82).
African Americans have been reported to be 15
times more likely than Caucasians to suffer from
localized aggressive periodontitis (53). Moreover,
localized aggressive periodontitis tends to cluster
within families, suggesting that it could be an inherited trait. Recent studies have concluded that the
FcgRIIIb NA2 allele and/or NA2/NA2 genotype may
represent risk markers for localized aggressive periodontitis in both African American (24) and Japanese
patient populations (40, 41, 42, 43). The FcgRIIIbNA1 but not FcgRIIIb-NA2 was recently found to
be associated with resistance to periodontitis in an

44

elderly Japanese population (82). In addition, both

the FcgRIIIa and the FcgRIIIb genotypes were found
to be associated with additional risk of bone loss in
Caucasians (58). However, in one study, differences
in the FcgRIIa and FcgRIIIb IgG2 haplotype were not
related to clinical status in a population of refractory
patients (15). The authors speculated that inadvertent pooling of subjects may have contributed to the
lack of relationships.
The n-formyl-l-methionyl-l-leucyl-l-phenylalanine
(fMLP) peptides are thought to be structural analogs
of bacterial products involved in chemotaxis of neutrophils to areas of bacterial infection. Depressed
chemotactic response to fMLPs in localized juvenile
periodontitis (LJP) patients has been confirmed by
several investigators (10, 11, 50, 89). DNA sequence
analysis of a heterogeneous population of 30 LJP
patients revealed two single nucleotide polymorphisms in the fMLP receptor in LJP patients compared
to control patients (30). Both alterations resulted in
amino acid changes in a region of the fMLP receptor
involved in ligand binding and signal transduction.
The authors suggest that the presence of the single
nucleotide polymorphisms may play a role in
decreased chemotactic activity seen in some patients
with LJP.

HLA genetics
Human leukocyte antigens (HLA) are involved in
genetically predetermined humoral immune response via recognition of foreign antigens. In humans,
the classical major histocompatibility complex
(MHC) Class I molecules (HLA-A, -B, and -C) are
expressed on most nucleated cells while MHC Class
II molecules (HLA -DP, -DQ, -DR) are expressed on
cells that immunosurvey host cells including B and T
cells, macrophages and accessory cells for the presence of foreign peptides. In conjunction with foreign cell antigens, MHC Class I molecules are
important in T-cell killing and are important considerations in transplant medicine. The MHC genes are
the most polymorphic genes present in the genome
of every species analyzed (1). MHC molecules play a
central role in immune responses to protein antigens
and in autoimmunity. In periodontics, research has
focused on identifying alleles associated with disease. Studies have suggested that patients with the
HLA-DRB11501-DQB10602 genotype may have an
accelerated T cell response to P. gingivalis and an
increased susceptibility to EOP in Japanese patients
(84). This study was in agreement with previous findings that DQB1 molecule plays a critical role in the

The genetic relationship to periodontal disease

pathogenesis and susceptibility of EOP in Japanese

patients (67). In a case-control study investigating
the role of HLA-DR4 in severe and rapidly progressive periodontitis, it was determined that subtypes
0401, 0404, 0405, and 0408 should be considered a
risk factor for rapidly progressive periodontitis (5).
Interestingly, these same determinants have also
been implicated in rheumatoid arthritis. HLA-DR
antigens have been associated with insulin-dependent diabetes mellitus (IDDM) as well as periodontitis. The association of HLA-DR3, -DR4, and -DR53
with possible impairment of neutrophil chemotaxis
was evaluated in IDDM patients (29). No association
was found between the two parameters investigated.
The authors suggested that neutrophil chemotaxis
and IDDM is independent of HLA-DR3, -DR4, and
-DR53 genes.
A comprehensive study investigated the associations among multiple host immunologic risk factors
in EOP, suspected EOP, adult periodontitis and periodontally healthy subjects (83). The variables examined included neutrophil functions, phenotypic and
functional characterization of peripheral lymphocytes, cytokine productivity, serum IgG antibody
titers against 12 periodontal bacteria, and HLA class
II genotype. The results indicated wide interindividual variations in each of the tests among patients
and healthy groups, confirming the complex, multifactorial pathogenesis and difficulty in explaining the
pathogenesis based on a single host risk factor.
Activation of thrombin and the kallikreinkinin
system induced by inflammation has been reported
to stimulate bone resorption in vitro (51). The presence of lymphotoxina (TNF-b), angiotensin-converting enzyme (ACE), and endothelin-1 (ET-1)
gene polymorphs was recently evaluated in Caucasian patients with adult periodontitis (37). ET-1 is a
vasoactive, mitogenic peptide detected in increased
quantities in patients with chronic periodontitis (94).
It acts synergistically with growth factors to stimulate
mitogenesis in fibroblasts and osteoblasts (38, 71)
and may contribute to cellular infiltration in chronically diseased sites. Significant differences were
reported with regard to the three locus combination
of genotypes between diseased and healthy subjects.
Differences were also noted for two locus combinations of ACE and TNF-b genotypes and between ET-1
and TNF-b. The authors suggested that the interactions between the three genes may be involved in
disease susceptibility to adult periodontitis.
Bone metabolism and polymorphisms in the vitamin D receptor gene have been associated with
osteocalcin levels and associations with bone

mineral density in both twin and population studies

(27, 64, 65). Research on 69 Caucasian early-onset
periodontitis patients into the association between
this polymorphism and early-onset periodontitis
concluded that for some patients, this polymorphism
significantly increases the risk of developing localized early-onset periodontitis. In a Japanese study,
no correlation was found between vitamin D receptor genotype and generalized early-onset periodontitis (95). However, a significant correlation was
reported between the vitamin D receptor and
FcgRIIIb genotype combination and susceptibility
to G-early-onset periodontitis.
The individual ability to metabolize the arylamines
found in tobacco has been the subject of recent
investigations. Genetic polymorphism results in slow
and rapid acetylators according to the rate at which
patients metabolize isoniazid, sulfamethazine or
procaine amide (63). It was theorized that ineffective
acetylation of xenobiotics found in tobacco smoke
that increase the risk of periodontal disease in smokers may be influenced by the polymorphism of Nacetyltransferase. A total of 154 Caucasian subjects
were assigned to three groups based on degree of bone
and attachment loss: none, moderate, and severe.
Genotyping of these patients demonstrated that the
N-acetyltransferase slow phenotype was significantly
associated with the severity of bone loss. The results
suggested that polymorphisms in the ability to metabolize xenobiotics may contribute to the individual
susceptibility to develop periodontitis (44, 57).

Conclusions
In 1892, Sir William Osler noted, If it were not for
the great variability among individuals medicine
might as well be a science and not an art. This
statement now a century old still embodies the influence of genetic variability on treatment outcomes
both in medicine and in periodontics. In reality, it
can be reasoned that short of trauma, virtually every
human illness has a hereditary component (13).
Although periodontitis does not follow Mendelian
inheritance patterns, evidence is mounting of important hereditary influences. In fact, in developed
countries, the strongest risk predictor for many common illnesses including diabetes, heart disease, and
cancer is family history. Knowledge of the hereditary
influence of disease is not a new finding and it seems
unlikely that the oral cavity is excluded from genetic
factors. However, added to the efforts of medical
and dental surveillance and suggestion will be the

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uncovering of the molecular basis of inheritable diseases. This will not be a trivial task as the complexities underlying the pathogenesis of periodontal
diseases slowly begin to be unraveled. Nevertheless,
genes do not work in a vacuum, nor does it appear
that one gene is overwhelmingly responsible for this
disease. As such, the search for the master gene
responsible for periodontitis in an otherwise healthy
individual has not been realized. What is evident
is that periodontal disease is a consequence of
the complex interactions between host factors,
genetics, and the environment. Thus, interpretation
of genotype status must not be used solely to
alter treatment regimens and maintenance schedules
(28). Treatment outcomes will still be heavily influenced by environmental and behavioral factors
whether an individual is genetically susceptible to
disease or not.

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