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Role of genetic factors in the

pathogenesis of aggressive
periodontitis
ALEXANDRE R. VI EI RA & JASI M M. ALBANDAR
Both genetic and environmental factors have roles in
the development of chronic diseases. Some of the
most common chronic disorders, such as heart dis-
ease, diabetes and Alzheimers disease, are associated
with mutations in multiple genes, combined with
environmental effects (116). Available data suggest
that, similarly to these common chronic disorders,
chronic periodontitis and aggressive periodontitis are
also caused by the combined effects of environmental
and genetic factors.
Following a periodontal infection an inammatory
process will ensue in order to fend off the infectious
assault and protect the host. However, this process
may also result in loss of the supporting tissues of
teeth, which may occur through an up-regulation
of pro-inammatory mediators (140) or as a result of
particular defects in the host response to the infec-
tious assault (62). To that extent, both of these mech-
anisms appear to be genetically determined. This
article critically reviews the evidence for a role of
genetic factors in the pathogenesis of aggressive peri-
odontitis and discusses the approaches commonly
used in studies designed to identify genetic risk fac-
tors for this disease.
Role of genetic factors in
periodontal diseases
Syndromic periodontal diseases
Certain monogenic disorders, or single-gene muta-
tions, are associated with severe forms of periodonti-
tis (48), whereas other periodontal disease
phenotypes seem to occur through different genetic
associations. Aggressive forms of severe periodontitis
associated with single-gene diseases or syndromes
are described elsewhere (65). These syndromes are
etiologically diverse and their genetic triggering fac-
tors have been identied (Table 1).
The PapillonLefevre syndrome is an example of
the monogenic disorders that have a periodontal
component. This disease is an autosomal-recessive
trait characterized by a diffuse palmar-plantar kerato-
sis and rapid loss of the periodontal tissue attach-
ment and alveolar bone, and the primary and
permanent teeth are lost at a young age (26). In
patients with PapillonLefevre syndrome periodontal
pathogens do not seem to play a signicant role in
the pathogenesis of the periodontal tissue loss (3). On
the other hand, these patients show immune defects
that are thought to predispose these individuals to
the severe loss of periodontal tissue (65). Studies
show that in the PapillonLef evre syndrome there is a
loss-of-function mutation affecting the cathepsin C
gene (CTSC; MIM 245000) on chromosome 11q14.2,
and this inuences a key enzyme essential in the acti-
vation of certain immune cells and in the regulation
of epithelial cells (30).
Studies have reported the identication of CTSC
mutations in families with prepubertal children
exhibiting aggressive forms of periodontal destruction
but no other systemic clinical manifestations (47, 105,
107). It should be noted that the CTSC mutation
reported by Hart et al. (47) in prepubertal children
with periodontitis is the same mutation previously
reported in a patient with PapillonLef evre syndrome
for which a complete loss of cathepsin C activity was
demonstrated (138). These data suggest that aggres-
sive periodontitis, in some families, represents a par-
tially penetrant PapillonLef evre syndrome (52).
There is evidence that in prepubertal children
exhibiting aggressive periodontitis, mutations segre-
gate in an autosomal-recessive manner, similarly to
92
Periodontology 2000, Vol. 65, 2014, 92106 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Printed in Singapore. All rights reserved
PERIODONTOLOGY 2000
the segregation pattern in the PapillonLef evre
syndrome. It is possible that the reported cases of
periodontitis in prepubertal children (47, 105, 107)
may be associated with a yet-undetected systemic
disorder, and this may explain the autosomal-reces-
sive pattern observed in these subjects. Another
explanation, however, is that these children indeed
exhibited aggressive periodontitis, and as such the
reported inheritance pattern is particular to these
subjects.
Hewitt et al. (52) did not nd a statistically signi-
cant difference in cathepsin C enzyme activity
between a group of 30 subjects with aggressive peri-
odontitis and age- and gender-matched controls. The
study, in addition, found three CTSC mutations and
negligible cathepsin C enzyme activity in one subject
with aggressive periodontitis, suggesting complete
loss of function of cathepsin C.
ChediakHigashi syndrome is another monogenic
disease transmitted in an autosomal-recessive man-
ner and characterized by involvement of teeth with
severe periodontitis (63, 64). In patients with Chediak
Higashi syndrome, mutations have been identied
in the CHS1/LYST gene on chromosome 1q42.3 (MIM
214500), and the proteins encoded by this gene are
thought to be associated with the signicant immune
defects seen in these patients.
Severe periodontal manifestations are also associ-
ated with congenital neutropenia (MIM 202700), cyc-
lic neutropenia (MIM 162800), leukocyte adhesion
deciency type I (MIM 116920) and type II (MIM
266265), glycogen storage disease (MIM 232220),
EhlersDanlos syndrome (MIM 130000) and Cohen
syndrome (MIM 216550) (65). There is also a report of
aggressive periodontitis associated with Fanconi ane-
mia (109). Fanconi anemia is an autosomal-recessive
disorder affecting all bone marrow elements and is
associated with cardiac, renal and limb malforma-
tions as well as with dermal pigmentary changes
(MIM 227650). Fanconi anemia can be caused by
mutation in one of the Fanconi anemia complemen-
tation group genes: FANCA (16q24.3), FANCB
(Xp22.31), FANCC (9q22.3), FANCD1 (13q12.3),
FANCD2 (3p25.3), FANCE (6p22-p21), FANCF (11p15),
FANCG (9p13), FANCJ (17q22), FANCL (2p16.1) and
FANCM (14q21.3). Aggressive periodontitis was also
reported in a Turkish patient with tetraploid/diploid
mosaicism (139), but was not described in another 14
subjects previously reported with tetraploid/diploid
mosaicism (5).
Nonsyndromic periodontal diseases
There is strong evidence for a role of genetic factors
in increasing the host susceptibility to periodontal
diseases (13, 74), particularly aggressive forms of peri-
odontitis. An analysis of clinical parameters of peri-
odontal disease was performed in 75 families to
assess the familial aggregation of indices of periodon-
tal disease (15). The study found evidence for a famil-
ial aggregation of dental plaque measurements after
adjustment for age, gender, race and oral hygiene
habits. The plaque index showed greater familial
resemblance compared with other measures of peri-
odontal disease. Sizable fractions of the variances in
gingival index and attachment loss were also attrib-
uted to differences among families, although these
two variables did not attain statistical signicance in
the study.
The relative contribution of environmental and
host genetic factors to clinical measures of periodon-
tal disease was investigated in twins reared together
or reared apart (88). Probing depth, clinical attach-
ment loss, gingival inammation and dental plaque
Table 1. Syndromes with clinical manifestations of severe periodontitis
Syndrome Mutated gene Chromosome region
PapillonLef evre Cathepsin C (CTSC) 11q14.1q14.3
ChediakHigashi Lysosomal trafcking regulator CHS1/LYST 1q42.1q42.2
Hypophosphatasia ALPL 1p36.12
Congenital and cyclic neutropenia ELANE 19p13.3
Leukocyte adhesion deciency type I Beta-2 integrin chain 21q22.3
Leukocyte adhesion deciency type II GDP-fucose transporter-1 11p11.2
Glycogen storage disease SLC37A4 11q23.3
EhlersDanlos Collagen alpha-1(V) gene (COL5A1) or the
collagen alpha-2(V) gene (COL5A2)
9q34, 2q31
Genetic factors in aggressive periodontitis
93
were assessed in 110 pairs of adult twins consisting of
63 monozygous and 33 dizygous twin pairs reared
together, and 14 monozygous twin pairs reared apart.
A statistically signicant genetic component was
found for gingivitis, probing depth, attachment loss
and dental plaque. Furthermore, it was estimated that
3882% of the population variance for these clinical
measures of periodontal disease may be attributed to
genetic factors. In the latter study group the genetic
variance of alveolar bone height was assessed using
panoramic radiographs, and the estimates of the in-
traclass correlations of alveolar bone heights for the
twin groups were 0.70, 0.52 and 0.55 for the monozy-
gous and dizygous twins reared together and the
monozygous twins reared apart, respectively, suggest-
ing that there is a signicant genetic variance in the
population for alveolar bone height (89).
It has been estimated that approximately half of
the population variance in chronic periodontitis
could be accounted for by genetic factors and that
the inheritance mainly inuences biological, and not
behavioral, variables (90). A large population study in
4,908 twin pairs found that the concordance rates
were 0.38 for monozygotic twins and 0.16 for dizy-
gotic twins, implying that genetic factors make an
important contribution to the risk of chronic peri-
odontitis (24). A more recent population study in
10,000 twin pairs reported that genetic factors con-
tributed to 14% of the variation in tooth loss among
women and to 39% of the variation in tooth loss
among men (95). Furthermore, the study concluded
that genetic factors have a moderate role in the path-
ogenesis of oral diseases and suggested that interac-
tions of genetic and environmental factors may have
an important role.
Several studies investigated gene polymorphisms in
patients with chronic periodontitis. The gene poly-
morphisms explored typically encoded proteins
involved in immune regulation or in other periodon-
tal tissue defects. The rst report of an association of
a specic gene polymorphism with chronic periodon-
titis was for interleukin-1 (72), and several studies
have been published since that report associations
between an array of gene polymorphisms and
increased risk for periodontitis (68). Evidence using a
mouse model suggests discrete sets of differentially
expressed genes are associated with genetically deter-
mined susceptibility or resistance to alveolar bone
loss following infection with the periodontal patho-
gen Porphyromonas gingivalis (43). Other mecha-
nisms of genetic predisposition to chronic
periodontitis have also been investigated and docu-
mented in animal models (13).
Genetic associations in aggressive
periodontitis
The genetic association study approach is useful for
identifying genetic variants that affect susceptibility
to common complex diseases (66, 121). A leading
hypothesis of increased susceptibility to aggressive
periodontitis entails decient host response to peri-
odontal infection (87, 129), particularly infections
with virulent periodontal pathogens (73). It is now
established that genetic factors regulate the innate
immune system (6, 146) and that certain genetic poly-
morphisms may render the immune system defective
and unable to successfully fend off assaults by infect-
ing microorganisms. Genetic factors may play a more
signicant role in the pathogenesis of aggressive peri-
odontitis than in chronic periodontitis (133), and this
may be attributed, to a certain extent, to the signi-
cance of the innate immune system in the pathogen-
esis of this disease (122). Although local etiological
factors are less prevalent in aggressive periodontitis
than in chronic periodontitis (12), alveolar bone loss
and tooth loss are signicantly more pronounced in
aggressive periodontitis. Periodontal tissue destruc-
tion in aggressive periodontitis commences at an
early age, shows a rapid rate of progression and has a
unique pattern where it affects multiple teeth and
occurs bilaterally (4). In addition, differences in the
microbiologic ora or in other environmental factors
do not fully explain the variance in the severity and
age of onset between these two diseases (8, 50).
In the quest to identify genetic risk markers of
aggressive periodontitis, association studies have
focused on genetic factors that regulate the immune
response. We carried out a systematic review of asso-
ciation studies of major gene polymorphisms in
aggressive periodontitis by performing a comprehen-
sive search of the biomedical literature published in
PubMed up to May 2012 using a combination of the
subject heading terms aggressive periodontitis,
periodontal disease, gene, genetic and polymor-
phism.
Neutrophil chemotaxis and functions
Neutrophils represent the rst line of defense against
infection and are an essential component of the
human innate immune system (70). Neutrophils are
attracted to the site of infection in an attempt to elim-
inate or reduce the infectious load, and they kill bac-
teria by oxidative bursts and phagocytose bacteria
and antigens. In an early study, Suzuki et al. (136)
studied neutrophil functions in subjects with different
Vieira & Albandar
94
forms of aggressive periodontitis and in controls. In
addition to uncovering abnormalities in peripheral-
blood neutrophil chemotaxis in more than half of the
subjects with aggressive periodontitis, they also found
abnormalities in other neutrophil functions in signi-
cant numbers of the subjects with aggressive peri-
odontitis. In-vitro assays using radiolabeled bacterial
spores detected defects in phagocytosis in 62% and
29% of subjects with localized and generalized forms
of the disease, respectively, and spore-germination
assays identied defects in the killing of bacteria by
neutrophils in 65% and 38% of such subjects, respec-
tively (136). Subsequent studies provided more infor-
mation on the various neutrophil abnormalities in
patients with aggressive periodontitis, and a compre-
hensive review of this topic has recently been
published (122).
These studies suggest that defects in neutrophil
chemotaxis and function may be key etiological fac-
tors in the pathogenesis of aggressive periodontitis
because these defects impede the host immune
response and contribute to pronounced loss of peri-
odontal tissue. Formyl peptide receptors on the cell
surface of leukocytes are involved in mediating
immune-cell responses to infection. The bacteria-
derived N-formyl-methionyl peptides have high afn-
ity to the N-formyl-methionyl peptide cell receptor,
and after binding to the neutrophil receptor the neu-
trophils become activated, thus triggering them to
migrate to the site of infection. Early studies sug-
gested that neutrophils from the serum of patients
with aggressive periodontitis show impaired chemo-
taxis to these antigens (20, 23) and these ndings
were later validated by several other studies (62, 122).
Conversely, some reports suggest that the abnormal
neutrophil chemotactic response to N-formyl-me-
thionyl peptides is limited to some, but not to all,
cases of aggressive periodontitis (114).
It is believed that major aspects of the innate
immune system are genetically determined (6, 146).
However, certain defects in the innate immune
response to infection may also be induced, such as
defects in neutrophil chemotaxis, phagocytosis and
other functions (1, 9, 10, 69). The human FPR1 gene,
which encodes the N-formyl peptide receptor, was
cloned and sequenced in 1992/1993 (28, 96). Gwinn
et al. (41) studied the frequency of two single nucleo-
tide polymorphisms, 329T>C and 378C>G, in the
FPR1 in a group of African-American patients with
aggressive periodontitis compared with controls, and
reported that 29 of those patients had one or both
single nucleotide polymorphisms, but that the single
nucleotide polymorphisms were not present in any of
the controls. They concluded that these alterations
may play a role in the decreased chemotactic activity
of neutrophils in this disease. By contrast, Zhang
et al. (150) tested the latter hypothesis in a group of
226 ethnically diverse individuals, comprising 111
subjects with aggressive periodontitis and 115 ethni-
cally matched controls, but neither of these two single
nucleotide polymorphisms were detected in the
452 chromosomes sequenced in their study. The
authors therefore concluded that these two polymor-
phisms may not play an etiologic role in aggressive
periodontitis.
A different FPR1 polymorphism (single nucleotide
polymorphism c.348T>C) has also been investigated;
an association of this polymorphism was noted with
aggressive periodontitis in African-American patients,
and mainly the 348T/T genotype was associated with
signicantly impaired polymorphonuclear cell che-
motaxis (81). An in-vitro experiment showed that
phosphoinositide-dependent kinase-1 regulates neu-
trophil chemotaxis (145); this suggests that the
expression and activation levels of phosphoinositide-
dependent kinase-1 which are signicantly reduced
in aggressive periodontitis may explain the impaired
neutrophil chemotaxis in such patients. Another
study in Japanese subjects found signicant associa-
tions of aggressive periodontitis with polymorphisms
at ve functional FPR1 variants (12915C>T,
10056T>C, 8430A>G, 301G>C and 546C>A) and
one haplotype (-12915T-301G-546C) (39).
Several studies have investigated the signicance of
genetic polymorphisms that affect neutrophil func-
tions in aggressive periodontitis. Nebali et al. (103)
studied the genetic basis of neutrophil functions in
Caucasian patients and their results suggest that the
C242T polymorphism of the CYBA gene (which
encodes p22
phox
) was associated with an oxidative
burst in response to challenge with Aggregatibacter
actinomycetemcomitans and that the FccIIa polymor-
phism was associated with the phagocytic index of
Escherichia coli. Ho et al. (53) studied, in Taiwanese
patients, the association of polymorphism of FccIIIb
the neutrophil-specic receptor involved in the
phagocytosis of IgG-opsonized bacteria and found
signicant association with aggressive periodontitis.
A systematic review of 17 studies investigated the
association of three Fcc receptor polymorphisms
(FccRIIA H131R, FccRIIIA F158V and FccRIIIB NA1/
NA2) with susceptibility to aggressive periodontitis
(32). The study concluded that the FccRIIIB NA1/NA2
polymorphism was associated with aggressive peri-
odontitis as well as with chronic periodontitis,
whereas the two other polymorphisms showed only a
Genetic factors in aggressive periodontitis
95
weak association or were not associated with a higher
risk for aggressive periodontitis.
Albandar et al. (2) reported that the serum levels of
IgA reactive to periodontal pathogens were signi-
cantly higher in patients with generalized aggressive
periodontitis compared with healthy controls. Fur-
thermore, neutrophils from patients with periodonti-
tis show increased levels of expression of the FcaRI
receptor (71). Cross-linking of IgA with the Fca recep-
tor on phagocytes triggers an array of host cellular
responses, such as phagocytosis, antibody-dependent
cell-mediated cytotoxicity, superoxide generation and
the release of inammatory mediators (93). Hence, it
may be hypothesized that individuals with increased
expression levels of FcaRI receptor on phagocytes,
and elevated levels of IgA reactive to periodontal
pathogens, may be at higher risk for aggressive
periodontitis.
Relative to this, Kaneko et al. (61) identied a novel
FcaRI gene polymorphism at nucleotide position 324
in the EC1 domain that was associated with a signi-
cantly increased rate of carriage of aggressive peri-
odontitis (65.2%) vs. a control group (42.5%).
Furthermore, they found that neutrophils from
patients with the nt 324 A/A genotype exhibited
decreased phagocytosis compared with patients with
the nt 324 G/G genotype.
Cytokines
Several studies have investigated the association of
aggressive periodontitis with polymorphisms in the
interleukin-1 (IL1) gene cluster and the ndings were
inconsistent. Generally, there is either limited or no
evidence of association between this genotype and
this disease in Caucasian subjects (34, 38, 55, 125).
Meanwhile, some studies maintain that signicant
associations were detected in other race-ethnicity
groups (40, 75).
Interleukin-4 and interleukin-13 are closely related
cytokines and have similar functions and anti-inam-
matory properties (18, 84). It has been shown that
patients with aggressive periodontitis and the 34 TT
and 590 TT interleukin-4 genotypes have signi-
cantly increased expression of IL4 and STAT6 genes
and produce higher concentrations of interleukin-4
in activated CD4
+
cells (36). Two studies investigated
the association of IL4 promoter/intron with compos-
ite genotype (PP
+
/IP
+
) but found no signicant asso-
ciations with aggressive periodontitis in Caucasian,
Brazilian and Japanese patients (35, 115). A study in a
Taiwanese population found an association between
the IL13 1113 CC genotype and a higher frequency
of aggressive periodontitis (144). Furthermore, it has
been shown that T-helper 1 cells from patients homo-
zygous for the 34T and 590T alleles show higher
interferon-c and interleukin-2 expression and signi-
cantly increased interleukin-13 production (37). This
suggests an increased production of interleukin-13 by
the T cells of aggressive periodontitis patients with
the IL4 genotype.
The cytokine interleukin-6 is encoded by the IL6
gene and has pro-inammatory as well as anti-
inammatory functions. One study found that the IL6
polymorphisms 1363 and 1480 may be associated
with increased susceptibility to aggressive periodonti-
tis (99). A meta-analysis of six published studies
found that the IL6 174G allele and 572 C/G poly-
morphisms were associated with aggressive peri-
odontitis (132). Using a large study sample
comprising 534 patients with periodontitis and 231
controls, Nibali et al. (102) concluded that IL6 poly-
morphisms and haplotypes are moderately associated
with periodontitis and that this association was stron-
ger for the localized form of aggressive periodontitis
than for generalized aggressive periodontitis or
chronic periodontitis.
A study in Germans of Caucasian descent evaluated
IL10 polymorphisms at positions 1082G>A,
819C>T and 590C>A, reported that the combina-
tion ATA/ATA was detected only in patients with
aggressive periodontitis and concluded that the hap-
lotype ATA is a low interleukin-10 producer and may
be a risk indicator for this disease (117). A similar
association was reported for the IL10 haplotype ATA
in a group of Taiwanese patients (57). However, three
other studies found no signicant associations
between IL10 polymorphisms and aggressive peri-
odontitis (60, 67, 85). One study, on IL12, reported
signicantly higher frequencies of variant alleles of
IL12Rb2 in Japanese patients with aggressive peri-
odontitis compared with controls (137).
The cytokine interleukin-17 is a central player in
the immune system in complex diseases that inte-
grate innate and adaptive immune mechanisms
(148). This cytokine is secreted by a variety of innate
cells and it has been shown that it exerts a host-
defense role in many infectious diseases, but also pro-
motes inammation and tissue loss in autoimmune
diseases (111). The interleukin-17 receptor (IL-17RA)
is expressed on most host cells and therefore these
cells can potentially respond to this cytokine. The role
of interleukin-17 or its receptor in bone loss triggered
by infection was studied in Il17ra knockout mice
(147). Upon infecting the IL-17RA-decient mice with
the pathogen P. gingivalis, the mice exhibited
Vieira & Albandar
96
reduced serum chemokine levels and reduced neu-
trophil migration to bone, although neutrophils from
these mice functioned normally ex vivo. Furthermore,
the mice showed enhanced periodontal bone loss
reminiscent of a neutrophil deciency.
A study in 102 patients with aggressive periodontitis
and 67 periodontally healthy controls showed that
interleukin-17 was present at signicantly higher con-
centrations in sera from the patients and was barely
detectable in the control individuals (130). The study
concluded that interleukin-17 may play a role in the
pathogenesis of aggressive periodontitis. Another
study, however, found that the concentration of inter-
leukin-17 in the gingival crevicular uid was signi-
cantly lower in the group of patients with aggressive
periodontitis than in the healthy control group (11).
Studies assessing the relationship between IL17 geno-
types and this disease are still lacking.
Vitamin D
Vitamin D plays an important role in bone metabo-
lism and in calcium and phosphorus homeostasis,
and also regulates the expression of a large number of
genes (80, 141). The blood concentration of the pre-
hormone calcifediol (calcidiol) is considered as the
best indicator of a subjects level of vitamin D (49). A
study found higher plasma levels of calcifediol and
osteocalcin and lower serum levels of inorganic phos-
phorus in subjects with aggressive periodontitis than
in healthy controls (78).
The vitamin D receptor (VDR) gene is found not
only in tissues involved in calcium homeostasis, but
also in a variety of cell lines involved primarily in
immune regulation, including mononuclear cells,
dendritic cells, antigen-presenting cells and activated
B lymphocytes and CD4
+
T cells, and it is therefore
thought to play an important role in the pathogenesis
of autoimmune and inammatory diseases (42). A
number of studies investigated the association of
VDR polymorphisms and aggressive periodontitis.
Carriage of the less frequent allele (t) of the VDR TaqI
gene was found to be signicantly associated with
localized aggressive periodontitis in Caucasian sub-
jects from the UK (51) and in Chinese and Italian sub-
jects with aggressive periodontitis (83, 134). Two
studies found signicant associations of the VDR FokI
gene polymorphism with generalized aggressive peri-
odontitis in Korean (113) and Chinese (76) patients.
The latter two studies did not nd signicant associa-
tions with the VDR BsmI or TaqI gene polymorphisms
in Korean patients, or with the VDR BsmI, TaqI or
ApaI gene polymorphisms in Chinese patients. A
recent study reported a meta-analysis of data from 15
studies of aggressive periodontitis, as well as of
chronic periodontitis (29). The study evaluated four
VDR polymorphisms BsmI, TaqI, ApaI and FokI
and concluded that there were no signicant associa-
tions between any of these VDR gene polymorphisms
and aggressive periodontitis. A second study that also
used a meta-analysis methodology to evaluate the
same four VDR polymorphisms concluded that the
four gene loci did not have a statistically signicant
association with aggressive periodontitis when all
race-ethnicity groups were combined (22). However,
the mutant allele F of the FokI locus was associated
with aggressive periodontitis in Asian subjects (odds
ratio = 1.6).
Pattern recognition receptor genes
Pattern recognition receptors are an array of proteins,
expressed by cells of the innate immune system,
which identify patterns associated with pathogen
molecules, yet are distinguishable from host mole-
cules, and therefore contribute to the rapid host
response to microbial pathogens (91). Toll-like recep-
tors comprise a subgroup of pattern recognition
receptors. For example, toll-like receptor-4 detects
lipopolysaccharide from gram-negative bacteria and
is thus important in the activation of the innate
immune system. CD14 is a subgroup of pattern recog-
nition receptors involved in recognition and phagocy-
tosis of bacteria and acts as a co-receptor to toll-like
receptor-2 and toll-like receptor-4 (131, 149).
A study in 73 Caucasian subjects concluded that the
Asp299Gly TLR4 gene polymorphism is associated with
a decreased risk of aggressive periodontitis in western
European patients, whereas no association was found
for the CD14 single nucleotide polymorphisms 159
and 1359 (59). Other studies found no signicant
associations for the Arg753Gln and Arg677Trp poly-
morphisms of the TLR2 gene, or for the Asp299Gly and
Thr399Ile polymorphisms of the TLR4 gene, in Turkish
(33), Chinese (151) or European (106, 120) patients
with aggressive periodontitis. In a meta-analysis of
four studies comprising 295 patients with aggressive
periodontitis and 456 controls, Ozturk & Vieira (112)
concluded that the TLR4 399Ile polymorphism
(TLR4+1196 C>T) may have a protective effect against
aggressive periodontitis (odds ratio = 0.29).
Other polymorphisms
Calprotectin is an antimicrobial protein released from
activated leukocytes, particularly neutrophils, and it
Genetic factors in aggressive periodontitis
97
belongs to the family of calcium-binding S100 pro-
teins encoded by the S100A8 gene in humans. Mem-
bers of this protein family have been implicated in
the calcium-dependent regulation of a variety of
intracellular activities, and it is thought that this pro-
tein is involved in inammation. An enzyme immu-
noassay showed that the plasma concentration of
calprotectin was signicantly higher in patients with
aggressive periodontitis than in controls (135). A
study of 73 Chinese families found that the single
nucleotide polymorphism rs3795391 (A>G) of the
S100A8 gene might contribute to increased suscepti-
bility to aggressive periodontitis (118).
Cyclooxygenases are enzymes involved in the for-
mation of important inammatory mediators, includ-
ing prostaglandins. Cyclooxygenase-2 plays an
important role in mediating periodontal inamma-
tion (94). A study found a signicant association of
the rare G allele of the COX2 haplotype, rs6681231,
with aggressive periodontitis in a large group of Euro-
peans (odds ratio = 1.6 after adjusting for smoking,
diabetes and gender) (94).
A genome-wide analysis found a statistically signi-
cant association of aggressive periodontitis with the
intronic single nucleotide polymorphism rs1537415,
which is located in the glycosyltransferase gene
GLT6D1 (127). Glycosyltransferases are enzymes that
catalyze glycosidic bond formation.
Polymorphism in the promoter region of the sero-
tonin transporter 5-HTT gene is linked to certain psy-
chological conditions such as depression, anxiety and
stress, and was found to be associated with aggressive
periodontitis in Brazilian subjects (25).
Genegene and geneenvironment
interactions
Aggressive as well as chronic forms of periodontitis
are complex diseases that have multifactorial etiology
and in which the effects of various etiological factors
are modied via a complex mechanism of interac-
tions. Genes encode the information for building pro-
teins, and proteins regulate various processes of the
host. While one gene may make only one protein, the
effects of those proteins may interact, and thereby
the expression of one gene may interfere with or
enhance the expression of another gene. Hence, epis-
tasis (or genegene interaction) plays a role in suscep-
tibility to common human diseases (92), including
periodontal diseases.
Most studies of the genetic associations of peri-
odontitis assessed one or a few related variants
(haplotypes). However, aggressive periodontitis
appears to be associated with a few loci, each with
relatively small effects (27). Only a few studies have
investigated the co-occurrence of multiple polymor-
phisms, although more studies may be forthcoming.
A large study of 224 patients and 231 healthy controls
estimated that there is a strong association of the
concomitant presence of the C242T p22phox NADPH
oxidase T allele and FccRIIIb NA1 homozygosity with
generalized aggressive periodontitis in Caucasian
subjects (odds ratio = 30.4) (97). Another study exam-
ined 124 cases and 94 controls and concluded that
the co-occurrence of polymorphisms of CCR2-V64I
and MCP-1-2518A/G genes may be associated with
generalized aggressive periodontitis in female
Chinese subjects, in whom the VV and G+ genotypes,
respectively, apparently impart a protective effect
(odds ratio = 0.2) (152).
A recent study investigated a potential epistasis
among functional gene variants affecting either the
amount or the activity of the protein produced from
each gene and that had previously shown signicant
associations with aggressive periodontitis when
tested individually (126). The study found evidence of
statistically signicant genegene interaction effects
associated with this disease in a group of Italian Cau-
casian subjects comprising 122 cases and 246 con-
trols. The analysis revealed a main independent effect
of the IL6 (572) gene polymorphism (P = 0.0008)
and interactions of IL6 (6106) and IL6 (1480) poly-
morphisms with IL18 (P < 0.0001) and IL4
(P = 0.0001) and with IL2 (P = 0.038). The study also
detected associations of the disease with the seleno-
protein S (SEPS1) gene, independently (P = 0.005)
and in association (P = 0.0002) with IL2. The SEPS1
gene is involved in the stress response in the endo-
plasmic reticulum, redox signaling and inammation
control. Yet another nding in the study is a signi-
cant association of the disease with an interaction
between TNFRSF1B and IL2 genes (P = 0.0008). The
TNFRSF1B gene encodes the tumor necrosis factor
receptor superfamily member 1B protein in humans.
Disease phenotypes are also affected by their envi-
ronment (119). For instance, smoking may potentiate
the associations of CCR2 VV (odds ratio = 7.4) and
MCP1 G+ (odds ratio = 4.9) genotypes with aggres-
sive periodontitis in male Chinese subjects (152).
Also, an interaction between smoking and the VDR
gene 1056 TaqI polymorphism has been shown to
be associated with periodontitis (odds ratio = 1.3)
and with severe disease progression (odds
ratio = 15.2) in Caucasian subjects (100). There is also
evidence suggesting that complex interactions may
Vieira & Albandar
98
take place between the periodontal microbiota and
the host genome. For example, Fcc receptor and IL6
gene polymorphisms have been associated with
increased odds of detecting A. actinomycetemcomi-
tans, P. gingivalis and Tannerella forsythia in patients
with aggressive periodontitis (98, 101).
Major-effect genes vs. small-effect
genes
Traditionally, the prevailing view was that aggressive
periodontitis is transmitted by a Mendelian pattern of
inheritance, and early studies used this assumption
to investigate genetic markers of the disease; for
instance, the study by Amer et al. (7) in which the sig-
nicance of the HLA locus was assessed. Based on
these studies a hypothesis was put forward that
aggressive periodontitis may be caused by a genetic
variant that has a major effect. However, most of the
associations initially reported between genes and the
disease were not conrmed in subsequent studies.
It has been shown that in several complex traits an
initial study often suggests a stronger genetic effect
than is found by subsequent studies (58). In these ini-
tial studies, the overestimation of the disease predis-
position, or protection, conferred by a genetic
polymorphism may be attributed to study bias, as well
as to genuine population diversity. Results from asso-
ciation studies have been systematically revisited, and
reports of meta-analyses of specic candidate genes,
although useful in increasing the understanding of
the variances in the reported literature, have not pro-
vided conclusive evidence in favor of, or against, spe-
cic genetic contributions (32, 68, 104, 106, 122, 132).
More recently, some studies have shifted their
focus towards a genome-wide approach, rather than
a candidate gene approach, thereby contemplating
the possibility that perhaps multiple genes may con-
tribute as causal factors to aggressive periodontitis.
Sch aefer et al. (127) performed a genome-wide asso-
ciation study in two independent phases. In the rst
phase, the genome-wide analysis was performed in a
group of German subjects consisting of 141 patients
with aggressive periodontitis and 500 controls, and in
the second phase the same analysis was performed in
a separate group of German subjects comprising 142
patients and 472 controls. The results of the two inde-
pendent analyses were then compared, and only one
genetic variant (rs1537415) showed a statistically
signicant association with aggressive periodontitis
in both study groups. This single nucleotide
polymorphism is located within intron 2 of the glyco-
syltransferase 6 domain containing 1 (GLT6D1) gene
on chromosome 9 (9q34.3). The authors then validated
the results by replicating their ndings in a third group
of Dutch subjects comprising 164 patients and 368 con-
trols. The results of the latter study are consistent with
the hypothesis that aggressive periodontitis is passed
by a complex mode of inheritance, rather than by a
major gene Mendelian mode. Notably, however, the
latter study did not identify known disease-causing
coding mutations in the gene. Moreover, the GLT6D1
gene was not expressed differently in healthy tissues vs.
inamed gingival tissues. Hence, it is challenging to
interpret the results of this study with respect to a pos-
sible role of this gene in aggressive periodontitis.
Careful ne mapping of a locus previously linked to
aggressive periodontitis also yielded novel results.
One linkage study in African-American families (77)
showed that aggressive periodontitis is linked to the
marker D1S492, located on chromosome 1q, and
identied a susceptibility locus between the markers
D1S196 and D1S533. This region of chromosome 1
(from base pair 165,770,752 to base pair 192,424,848)
includes the cytogenetic regions from 1q24.2 to
1q31.3. The goal was to ne map this region to inves-
tigate the hypothesis that genetic variation located
between 1q24.2 and 1q31.3 contributes to susceptibil-
ity to aggressive periodontitis (21).
There is evidence that the family with sequence
similarity 5, member C [FAM5C (now called bone
morphogenetic protein/retinoic acid inducible
neural-specic 3 or BRINP3)] gene contributes to
aggressive periodontitis, and it is likely that the
markers rs1935881 and rs1342913 are candidate
functional variants (based on multispecies nucleo-
tide sequence comparisons and electronic tran-
scription-binding site predictions). Notably, the
FAM5C gene is only 3 megabases from the COX2
gene (Fig. 1) located on chromosome 1q. The COX2
gene has previously been associated with localized
aggressive periodontitis in affected individuals in
four African-American multigenerational families
(77). Interestingly, gene markers near the FAM5C
locus showed borderline statistical signicance in a
German study group [see Sch aefer et al. (127);
Table 2]. The pattern of FAM5C functional expres-
sion in aggressive periodontitis was found to be sig-
nicantly higher in diseased periodontal tissues,
and to present a modest, but statistically signi-
cant, correlation with the expression of interleukin-
1beta, interleukin-17A, interleukin-4 and RANKL.
Therefore, it is likely that the FAM5C gene may
modulate or interfere in the cytokine network in
diseased periodontal tissues, and may inuence the
Genetic factors in aggressive periodontitis
99
disease outcome. However, the mechanism of its
effect is still unknown.
Proposed modes of inheritance of
aggressive periodontitis
In 1969, Butler (19) described periodontal ndings in a
family where two of ve siblings had clinical and radio-
graphic features of aggressive periodontitis, the mother
of the children had lost all her teeth in her late teens,
and an aunt and the grandfather of the siblings on the
mothers side had lost their teeth at an early age. Other
early studies (14, 56, 110, 124, 142, 143) also described
aggressive periodontitis case reports clustered in fami-
lies, suggesting a signicant genetic contribution.
The heritability of aggressive periodontitis is esti-
mated to be approximately 30% (31). Segregation
analysis is an important research tool in human
genetics and it tests whether an observed pattern of
phenotypes in families (ratios) is compatible with an
explicit mode of inheritance. Early studies investi-
gated whether Mendelian models of inheritance are
adequate to explain the relationship of genetic factors
and aggressive periodontitis. Aggressive periodontitis
has been described as both X-linked and autosomal.
The rst important validation of the X-linked mode of
transmission of aggressive periodontitis was provided
by Melnick et al. (86), who presented the most com-
plete study to that date and concluded that the
inheritance mode is X-linked dominant with reduced
penetrance. This conclusion was based on their
assessment that the female:male ratio among affected
persons was approximately 2:1 and that there was no
father-to-son transmission of the disease.
However, the results of most other studies are not
consistent with the X-linked mode of transmission,
and subsequent studies with larger and more com-
plete samples documented father-to-son transmis-
sion of aggressive periodontitis, supporting an
autosomal mode (45). Also, female subjects were
shown to be three times more likely than male sub-
jects to be initially ascertained as aggressive peri-
odontitis probands (44) and this bias may have
contributed to the difculties in validating the mode
of inheritance of the disease.
Hodge et al. (54) characterized the inheritance
mode in their study sample as either autosomal domi-
nant or X-linked dominant. Long et al. (79) compared
the likelihood of autosomal-recessive and X-linked
dominant inheritance patterns and concluded that
the X-linked dominant hypothesis is inadequate.
Sax en (124) examined a study group comprising 31
subjects with aggressive periodontitis, 60 parents, 64
siblings and three offspring children, and concluded
that the disease inheritance pattern is consistent with
an autosomal-recessive trait. The same authors later
published a second report (123) in 30 families and
again concluded that their data concurred with the
hypothesis of autosomal-recessive inheritance of
aggressive periodontitis. Beaty et al. (14) studied this
relationship in 28 families, and also suggested that
Table 2. Single nucleotide polymorphisms associated with the FAM5C gene in German patients with aggressive peri-
odontitis
Single nucleotide polymorphism P-value Odds ratio 95% condence interval Phenotype
rs2789394 0.00021 1.66 1.272.17 Generalized aggressive periodontitis
rs10798049 0.00026 1.99 1.372.88 Localized aggressive periodontitis
rs10911886 0.00039 1.94 1.342.82 Localized aggressive periodontitis
rs10911887 0.00015 2.02 1.402.93 Localized aggressive periodontitis
rs6681231 0.00032 1.86 1.322.61 Localized aggressive periodontitis
185000000 186000000 189000000
1q31.1
190000000
rs10737562 rs10911902
rs4140564
NHGRI Catalog of Published Genome-Wide Association Studies
UCSC Genes Based on RefSeq , Uniport , GenBank, CCDS and Comparative Genomics
RNF2
AF508905
AF510427
HMCN1
TPR
PLA2G4A
C1orf99 PTGS2
PRG4
HMCN1 EDEM3
EDEM3
rs1400544
rs1935881
DBCCR1L
FAM5C
188000000
Chromosome Bands Localized by FISH Mapping Clones
187000000
2 Mb
1q25.3
Fig. 1. The family with sequence similarity 5, member C (FAM5C) gene is about 3 megabases from the cyclooxygenase 2
(COX2 or PTGS2) gene on chromosome 1q. Obtained from the UCSC Genome Browser on Human, February 2009 assembly.
Vieira & Albandar
100
aggressive periodontitis is inherited in an autosomal-
recessive manner. However, the latter authors noted
a relatively high (40%) type II error in their data when
comparing simulations of competing models.
An autosomal-dominant mode of transmission of
aggressive periodontitis was rst suggested in a large
ve-generation extended-family study (16). Further-
more, a robust study that included 100 families ascer-
tained through 104 probands with aggressive
periodontitis (both localized and generalized forms)
was consistent with an autosomal-dominant locus,
with 70% penetrance for African-American subjects
and 73% for Caucasian subjects (82). Also, ndings of
other studies suggest an autosomal-dominant inheri-
tance mode of this disease (44, 45, 54).
Although some studies have suggested an autoso-
mal-recessive inheritance of aggressive periodontitis,
the issue of imposing age limitations when the phe-
notype (aggressive periodontitis) is ascertained may
be confounding the genetic segregation analysis.
Individuals with aggressive periodontitis whose age is
beyond that dened in the case denition may be
assigned a different case category, such as severe
chronic periodontitis, and therefore the subject is
denoted as unaffected in the genetic segregation
analysis. This could result in a dominant form of the
disease appearing to be recessive.
In addition to the age limitations in clinical pheno-
typic diagnosis of the disease, the inconsistent results
regarding the inheritance mode of aggressive peri-
odontitis may also be attributed to a number of other
factors, such as differences in the race and gender
composition of the samples in these studies, the
methods used to ascertain the phenotypes and other
factors. It has been acknowledged that problems exist
with regards to the methodology of genetic modeling
used in these studies, including the availability of lim-
ited family data, problems with phenotype assign-
ment of adults by the use of previous dental records
and a presumed gender bias in the participation in
these studies (17, 45). Hence, adequately designed
studies are needed for exhaustive evaluation and test-
ing to verify the validity of these inheritance models.
If one would infer from this review that aggressive
periodontitis has a Mendelian inheritance, then the
assumption is that this disease is caused by one or
more major genes. However, over the past decade
several studies have investigated potential candidate
genes to test this hypothesis, but no major causal
gene has been identied (128). de Carvalho et al. (27)
performed a study in 74 extended families and found
an excess of heterozygous transmission as the best-t
model explaining the inheritance pattern of the
families segregating aggressive periodontitis. This
suggests that a limited number of genes, each with a
relatively small effect, may contribute to the develop-
ment of the disease. Hence, instead of chasing a sin-
gle major gene, research should be focused on a few
gene variants that may be contributing to the disease
occurrence, and with each gene variant potentially
affecting a small percentage of the cases. It should be
noted that genetic studies of aggressive periodontitis
have often examined limited numbers of families
(typically, 10 or fewer), and this may partly explain
the inconsistent ndings in previous studies reviewed
above, and the conjecture that autosomal Mendelian
models may be the best-t models. On the other
hand, studies with larger numbers of families suggest
differently. For instance, Marazita et al. (82), who
examined 104 families, reported that incomplete pen-
etrance of 30% was present, clearly suggesting that
typical Mendelian models are not the best-t models
for aggressive periodontitis.
To that extent, there is some evidence of associa-
tions between the gene loci 1q25, 4q and 11q14 and
aggressive periodontitis. A haplotype analysis detected
an association between localized aggressive peri-
odontitis and a locus on chromosome 1q25 region
D1S492 in four out of eight African-American families
studied (77). Although this chromosomal region also
includes the COX2 gene (the precursor of prostaglan-
din E) which plays a role in the pathogenesis of peri-
odontal diseases (108), the study did not nd a
mutation in the COX2 gene in these patients (39).
Boughman et al. (16) demonstrated linkage of a
polymorphism in the gene encoding vitamin D-bind-
ing protein (GC) located on chromosome 4q12q13,
with an apparently dominant form of aggressive peri-
odontitis, which co-segregates with dentinogenesis
imperfecta in one large kindred. However, Hart et al.
(46) assessed linkage with 11 markers on chromo-
some 4q, including the GC gene, in 19 extended kin-
dreds (15 African American and four Caucasian) with
aggressive periodontitis , and the statistical analysis
excluded linkage between susceptibility for the dis-
ease and this chromosomal region. Hence, it is likely
that the subjects studied by Boughman et al. (16)
may have had an uncommon form of aggressive peri-
odontitis associated with the chromosome 4q region.
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