Periodontology 2000, Vol. 0, 2017, 1–8 © 2017 John Wiley & Sons A/S.
ley & Sons A/S. Published by John Wiley & Sons Ltd
Printed in Singapore. All rights reserved
Development of the gingival
sulcus at the time of tooth
eruption and the influence of
genetic factors
LUIGI NIBALI
Tooth formation and eruption
In embryos, following the migration of cells from the
neural crest into the first branchial arch, cells of
the newly formed epithelial dental lamina grow into
the underlying mesenchymal tissue, where they form
enamel organ (epithelial component) and dental
papilla and dental follicle (mesenchymal compo-
nent), starting the process of tooth morphogenesis.
The dental follicle is a sac composed of connective
tissue that surrounds the unerupted tooth, gives rise
to the periodontal-supporting tissues and has a piv-
otal role in the process of tooth eruption (34), which
is a fascinating unique human event inasmuch as a
developing organ exits the boundaries of its bony
crypt (62). In humans, the primary dentition starts
forming at 6 weeks in utero and eruption is usually
complete at between 2 and 3 years of age. The sec-
ondary dentition starts forming in the 20-week-old
embryo and eruption occurs between 6 and 25 years
of age. This is characterized by exfoliation of the
deciduous teeth, which are gradually replaced with
the permanent dentition. The permanent anterior
teeth and premolars are successional, deriving from
the dental lamina of their primary predecessors, while
the secondary molar dentition is accessional, deriving
from an extension of the dental lamina (12). The for-
mation of an eruption pathway as a consequence of
bone resorption is crucial for successful tooth erup-
tion, and this process is genetically guided through a
template called the gubernacular canal. Interesting
experiments show that if the dental follicle is surgi-
cally removed then the tooth will not erupt (9), but
crucially if the dental follicle is left intact and the
PERIODONTOLOGY 2000
tooth is removed and replaced with a metallic replica,
the replica tooth will actually erupt (37). Molecular
events are also crucial for eruption to occur, as pro-
ven by the fact that injection of epidermal growth fac-
tor and transforming growth factor-alpha accelerates
incisor eruption in rodents (13, 54), whereas colony-
stimulating factor-1 stimulates molar eruption in
mice (11). Among other molecules, parathyroid-hor-
mone-related protein, interleukin-1 and osteoclast
differentiation factor have been shown to play a role
in tooth eruption in mice. A recent experiment in
patients with cleidocranial dysplasia affected by
delayed tooth eruption, showed elevated levels of
mRNA for RANK, osteoprotegerin and colony stimu-
lating factor-1 in the dental follicle, confirming the
role of bone remodeling guided by the dental follicle
in tooth-eruption disturbances (17).
The dental follicle eventually develops into the
periodontal ligament, which drives the final stages of
tooth eruption (see Fig. 1). While the basal lamina is
in contact with the enamel by hemi-desmosomes, the
reduced ameloblasts, together with other cells from
the enamel organ, form the reduced dental epithe-
lium, which surrounds the crown of the tooth until
eruption. Immediately before eruption, cells of the
reduced dental epithelium and cells of the basal layer
of the oral epithelium proliferate and migrate into the
connective tissue (56). As the tooth breaches the oral
mucosa to enter the oral cavity, the reduced enamel
epithelium develops into the junctional epithelium, a
nonkeratinized epithelium that starts covering the
incisal area of the enamel, forming a continuum with
the oral epithelium, while reduced epithelium and
ameloblasts still cover the more apical part of the
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Fig. 1. Schematic representation of the process of tooth
eruption. (A) The reduced dental epithelium (formed by
ameloblasts) surrounds the crown, while the basal lamina
is in contact with the enamel by hemi-desmosomes. (B)
Upon emergence of the tooth into the oral cavity, the
reduced enamel epithelium develops into the junctional
epithelium, which is in contact with the oral epithelium
coronally and with reduced epithelium and ameloblasts
enamel. This process of formation of junctional
epithelium continues for up to 4 years during erup-
tion (56). A space, termed the gingival sulcus, is
formed between the enamel and the free gingiva. The
sulcus is covered by a specific type of epithelium, ter-
med oral sulcular epithelium, which is very similar to
oral epithelium (34). Even before tooth eruption,
potentially pathogenic oral bacteria, such as strepto-
cocci, start colonizing the oral cavity (55, 61). Upon
tooth eruption, plaque colonization occurs on the
tooth surface, and colonization with mutans strepto-
cocci seems to increase with the number of teeth
erupted (22). Subclinical signs of inflammation, with
the presence of a subclinical inflammatory infiltrate,
exist in the junctional epithelium, even in a physio-
logical state (7). This physiological state can be dis-
rupted by processes leading to periodontal
attachment loss (Fig. 1D), which are characterized by
gingival inflammation, deepening of the gingival sul-
cus and creation of pathological periodontal pockets.
Therefore, in periodontitis, upon bacterial coloniza-
tion subgingivally, the junctional epithelium converts
into ‘pocket epithelium’ with loss of cellular continu-
ity in its coronal portion (48). This is probably
2
more apically. (C) Physiological status upon completion of
tooth eruption, with junctional epithelium in continuity
with the oral epithelium and formation of gingival sulcus
covered by oral sulcular epithelium. (D) Formation of a
periodontal pocket, with proliferation and inflammation
of the junctional epithelium, loss of epithelial tissue–con-
nective tissue attachment and formation of pocket epithe-
lium.
because of the effect of bacteria able to invade the
epithelial tissues and the effect of cells involved in the
local host response (6). In brief, the presence of bac-
terial products subgingivally triggers the release of
inflammatory mediators by the host (42), initially by
vascular endothelial responses, including neutrophil
migration into the gingival crevice, which is regulated
by cytokines and chemokines and accompanied by
proliferation of the junctional epithelium (‘early gin-
givitis’). If the accumulation of bacteria within dental
plaque in the sulcus continues, there is a shift in the
composition of inflammatory infiltrate toward a
higher number of plasma cells, together with T-lym-
phocytes, macrophages and neutrophils, gradually
moving to ‘established gingivitis’ and eventually to
the ‘periodontitis’ lesion, with a predominance of
plasma cells and the presence of tissue damage. In
addition to leukocytes, resident fibroblasts and junc-
tional epithelial cells can participate in the tissue-
destruction process, with the activation of metallo-
proteinases leading to connective tissue destruction,
apical migration of the epithelial attachment and the
formation of a pocket, typical of the established peri-
odontal lesion (42). During tooth eruption, the

junctional epithelium has a high content of mononu-
clear cells, providing a favorable environment for the
initiation of local immune responses (49). Interest-
ingly, characteristics similar to an ‘early’ periodontal
lesion appear during tooth eruption, with predomi-
nance of T-lymphocytes (49). It is conceivable that
events occurring during dental eruption and during
the formation of the gingival sulcus could potentially
predispose to dental diseases, such as periodontal
diseases and caries.
Genetic influence on tooth
eruption
A complex network of signaling between the epithe-
lium and the mesenchyme in an embryo regulates
events leading to the formation, maturation and
eruption of primary and secondary dentitions.
Genetic factors regulate these processes, so, not sur-
prisingly, genetic defects underlie dental abnormali-
ties, including anomalies in the number of teeth and
anomalies of tooth morphology, structure and erup-
tion (12). Common human genetic variants have
been associated with the process of dental matura-
tion (43) and with the emergence of the primary
dentition (27). As seen in RANKL-co-knockout mice,
in which teeth do not erupt, genetic factors affecting
bone turnover play an important role in tooth
eruption (31). It is thought that a concert of bone-
resorption and osteogenesis genes, regulatory genes,
proto-oncogenes and soluble factors is activated at
specific time points during tooth eruption in the
dental follicle to permit tooth eruption (63). Interest-
ingly, epidemiological studies have revealed that
dental maturation seems to occur independently of
other forms of biological maturation (4, 15). There-
fore, prospective candidate genes for eruption distur-
bances should be explored, possibly by using
genome-wide approaches rather than by studying
other biological maturation traits. Several genetic
conditions involving disturbances in tooth eruption
(including delayed or failed eruption) have been
identified, including, for example, gingival fibro-
matosis, osteopetrosis, oculofaciocardiodental syn-
drome, Hunter’s syndrome and Dubowitz syndrome.
Delayed tooth eruption is also a typical feature of
Down syndrome (12, 30). Nonsyndromic distur-
bances of tooth eruption include natal teeth (33),
primary failure of eruption (1) and familial nonsyn-
dromic primary failure of eruption (14). The last
feature in this list is associated with mutations in the
parathyroid hormone receptor 1 gene (chromosome
Influence of genetic factors on tooth eruption
3p21-p22.1) (45). Similarly, physiological interindivid-
ual differences in the patterns of tooth eruption may
be caused by yet-unknown common genetic variants
(62). Table 1 shows some of the genes, genetic loci
and cells suspected to play a role in the process of
tooth eruption and potentially affecting nonsyn-
dromic variations in tooth-eruption patterns.
Recently, the results of a genome-wide association
study investigating the genetic influence on the tim-
ing of permanent tooth eruption were published
(21). The study was based on records of 5,104
women from the Danish National Birth Cohort and
was then replicated in an independent sample. Four
genetic loci associated with delayed tooth eruption
(with p < 10 -11) were identified. Two of the four
loci (rs12424086 on chromosome 12q14.3 and
rs4491709 on chromosome 2q35) had previously
been associated with primary tooth eruption (44),
confirming possible parallel mechanisms for the
eruption of primary and permanent teeth. These
two single-nucleotide polymorphisms are also in
linkage disequilibrium with genome-wide significant
single-nucleotide polymorphisms associated with
adult and childhood height and with breast cancer,
respectively (21). The remaining two novel loci
(rs2281845 and rs7924176) belonged to genomic
regions without any previous significant genome-
wide association study results and were linked to
expression of transmembrane protein 9 and adeno-
sine kinase in monocytes respectively (21). The
combined effect of the four genetic variants was
most pronounced in children between 10 and
12 years of age, in which children with six to eight
alleles for delayed tooth eruption had, on average,
3.5 fewer permanent teeth than did children with
none or only one of these alleles (20). More
recently, another population-based genome-wide
association study was conducted on a total of 9912
individuals from the Avon Longitudinal Study of
Parents and Children and from the 1966 Northern
Finland Birth Cohort. The authors tested 2,446,724
single-nucleotide polymorphisms in both cohorts
and analyzed the results using fixed-effects inverse-
variance meta-analysis. They identified 10 indepen-
dent loci for which genome-wide significance for
‘age at first tooth’, and 11 loci for ‘number of teeth’,
had been recorded, including genes known to play
a role in tooth and other developmental pathways,
and genes showing evidence of association with
craniofacial measurements (18). Some of the single-
nucleotide polymorphisms identified were in agree-
ment with previous reports (21, 44), confirming
their probable role in influencing tooth eruption.
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Table 1. Some of the genetic loci or genes and molecules suspected to have a role in tooth eruption

Gene variants suspected to affect timing of nonsyndromic Molecules suspected to affect tooth eruption
tooth eruption (chromosome) (ref. no.)
Parathyroid hormone receptor-1 (chromosome 3) (12) Parathyroid-hormone-related protein

Adenosine kinase (chromosome 10) (20) Epidermal growth factor (13)

Ectodysplasin A (X chromosome) (44) Transforming growth factor-alpha (52)

Homeobox B (chromosome 12) (44) Colony-stimulating factor-1 (11)

RAD51B (chromosome 14) (44) Interleukin-1

rs 12424086 (chromosome 12) (21) Osteoclast differentiation factor, RANK (17)

rs 4491709 (chromosome 2) (21) Osteoprotegerin (17)

rs2281845 (chromosome 1) (21)

rs8079702 (chromosome 17) (44)

rs 4844096 (X chromosome) (44)

rs 9674544 (chromosome 17) (44)

ADKVCLAP3M1 (chromosome 10) (18)

MSRB3 (chromosome 12) (18)

HMGA (chromosome 12) (18)

BMP4 (chromosome 14) (18)

KCNJ2KCNJ16 (chromosome 17) (18)

FAM155E-EDA (X chromosome) (18)

Unfortunately, no data on periodontal conditions of

the individuals examined were presented. Further-
more, no functional insights into the effects of these
gene variants on tooth development could be iden-
tified in these studies.

Genetic influence on periodontitis

risk
The concept of interindividual variability in the pre-
disposition to periodontal diseases has been sus-
pected at least over the last 4 decades (3). Studies on
twins estimate that half of the variance in the risk for
periodontitis is attributable to host genetic factors
(38). Expansion of knowledge of the host genome and
of the laboratory techniques for genetic analysis have
produced a wealth of evidence on genetic variants
affecting disease predisposition in the last decades.
Host genetic variants could potentially influence the
onset and progression of periodontal diseases by
affecting behavioral factors (such as oral-hygiene Fig. 2. Genetic pathways likely to have an effect on the
behaviors and/or smoking addiction), inflammatory development of periodontitis, segregated into broad mech-
and immune responses to microbial biofilms, wound anisms of action.

4

healing and structural factors affecting the periodon-
tium (see Fig. 2). As we stand, very few truths are set
in stone in the periodontal genetic literature and,
unlike other diseases, a consensus on a genetic risk
profile is lacking. Single gene defects with a Men-
delian pattern of transmission are responsible for a
small subset of early-onset syndromic forms of peri-
odontitis (24). However, most cases of periodontitis
originate from an increased susceptibility profile (as a
result of the presence of a combination of common
gene variants) and its interaction with bacterial colo-
nization and environmental factors (29). Linkage
analyses, candidate gene analyses with case–control
designs and, more recently, genome-wide association
studies have investigated genetic factors associated
with the periodontitis trait. The results have been
affected by small sample sizes, inclusion of subjects
of different ethnicities and lack of focus on functional
single-nucleotide polymorphisms. Currently, single-
nucleotide polymorphisms in genes affecting the
inflammatory and immune responses, such as inter-
leukin-1, interleukin-6, human leukocyte antigen,
vitamin D receptor, antisense noncoding RNA in the
INK4 locus (also known as ANRIL) and cyclooxyge-
nase-2 perhaps offer the best evidence for association
with periodontitis (16, 28, 47, 50, 52, 53), although lar-
ger, more definitive, studies in different populations
are still lacking. These candidate variants affect the
response to the subgingival biofilm in the periodontal
sulcus, thus predisposing to the loss of cellular conti-
nuity in the junctional epithelium (Fig. 1D) and the
subsequent pathogenic process leading to periodonti-
tis. For example, commonly occurring interleukin-1
and interleukin-6 single-nucleotide polymorphisms
and haplotypes have been associated with many dis-
eases, such as cardiovascular disease (26, 58), owing
to the effect of these gene variants on increasing pro-
duction of these cytokines (interleukin-1 and inter-
leukin-6 respectively) (10, 19). This proinflammatory
state could predispose to a constitutively excessive
inflammatory cascade, with the ability to lead to col-
lateral periodontal tissue damage upon subgingival
bacterial insults, or to create an excessively ‘inflamed’
environment, which could, in turn, predispose to the
growth of particularly pathogenic bacteria, such as
Aggregatibacter actinomycetemcomitans (41). Another
example is given by matrix metalloproteinases, which
are calcium-dependent zinc-containing endopepti-
dases implicated in cell proliferation, collagen degra-
dation and rupture of the extracellular matrix in
physiological processes, such as tissue remodeling
and embryonic development, but also in pathological
conditions, such as periodontitis (46). A balance
Influence of genetic factors on tooth eruption
between the six main groups of matrix metallopro-
teinases and endogenous inhibitors, such as tissue
inhibitors of metalloproteinase, regulate periodontal
tissue turnover. The levels of matrix metallopro-
teinases in periodontal tissues, gingival crevicular
fluid and saliva may be one of the main processes
involved in controlling periodontal tissue destruction
(46). Genetic factors affecting matrix metallopro-
teinase activity could potentially predispose to exces-
sive tissue breakdown and more advanced
periodontal destruction. Hence, considerable
research effort has been invested in identifying
genetic variants in matrix metalloproteinase genes
that could lead to the onset and progression of peri-
odontitis. However, limited evidence- mainly in Asian
populations- has been obtained to date (52). Essen-
tially, different genetic variants in different genes,
some common and others rare, are probably able to
predispose to periodontitis, although different ‘ge-
netic forms’ of periodontal diseases are not clinically
differentiable. A better understanding of the genetic
factors predisposing to the formation of periodontal
pockets may also help in diagnosis, as is the case
for other dental diseases, such as amelogenesis
imperfecta, which is characterized by the forma-
tion of abnormal enamel. Amelogenesis imperfecta
is inherited as an autosomal-dominant, recessive,
X-linked or sporadic trait caused by to defects involv-
ing a variety of genes, such as amelogenin X, enam-
elin, distal-less homeobox 3, family with sequence
similarity 83 Member H, matrix metalloproteinase-20,
kallikrein-related peptidase 4 and WD Repeat domain
72 (25, 32, 59), which often result in similar clinical
phenotypes. As more is known about the genetic nat-
ure of amelogenesis imperfecta, genetic classifica-
tions have been introduced (autosomal-dominant
amelogenesis imperfecta, autosomal-recessive amel-
ogenesis imperfecta, X-linked amelogenesis imper-
fecta and enamel abnormalities as part of a
syndrome), although phenotypic–genotypic correla-
tions are not always good (12).
The example of localized aggressive
periodontitis
Localized aggressive periodontitis, previously known
as localized juvenile periodontitis, is a rare form of
destructive periodontal disease that affects young
individuals. Epidemiological studies suggest a preva-
lence of localized aggressive periodontitis of less than
1% in the general population, with a higher incidence
in African-American subjects (2, 36). Localized
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aggressive periodontitis is unique among periodontal
diseases as it has a very rapid progression but is con-
fined to specific teeth. Progressive attachment loss
and progression of some cases diagnosis of localized
to generalized agressive periodontitis has been
reported (8). However, a 14- to 19-year follow-up
study of 11 subjects with localized aggressive peri-
odontitis, with no consistent maintenance therapy,
concluded that not all cases of localized aggressive
periodontitis show progression, even in the absence
of therapy, suggesting possible ‘burn-out’ of the local-
ized lesions (39). The characteristic severe periodon-
tal attachment and bone loss on first molars and
incisors, with no destruction on neighboring teeth,
has long puzzled researchers. The pattern of destruc-
tion coincides with the sequence of eruption of per-
manent teeth (first molars and incisors are the first
teeth to erupt) and is exemplified in the radiograph
shown in Fig. 3, which demonstrates extensive alveo-
lar bone loss localized to first molars and incisors in a
16-year-old nonsmoking and medically healthy sub-
ject of North African descent. It is interesting that pre-
molars, and even second molars, show very little, if
any, signs of periodontitis-associated bone loss. Given
the patterns of destruction, it is plausible that distur-
bances of tooth eruption (for example, because of
hormonal disorders or colonization of the newly
formed gingival sulcus with specific bacteria) could
play an important role in the pathogenesis of local-
ized aggressive periodontitis. A strong association has
been found between the presence of A. actino-
mycetemcomitans subgingivally and active disease
phases and the risk of periodontal disease progres-
sion (20). A possible role of cytomegalovirus infection
during root formation (causing malformation of the
attachment apparatus) has been hypothesized as a
possible cause of localized aggressive periodontitis
(57). Hormonal changes at the time of puberty could
Fig. 3. Dental panoramic tomogram of a 16-years-old non-
smoking patient of North African descent, showing the
typical features of radiographic bone loss of localized
aggressive periodontitis, affecting first (upper and lower)
molars and incisors.
6
then stimulate re-activation of a periodontal cytome-
galovirus infection, causing reduction in antibacterial
immune defenses and a disease-causing shift in the
normal subgingival microbiota (51). Other authors
identified cementum hypoplasia using scanning elec-
tron microscopy in subjects with localized aggressive
periodontitis and observed a correlation between
hypoplastic areas and alveolar bone loss, suggesting
that this could be responsible for weakness in the
attachment apparatus predisposing to early-onset
periodontal destruction (5, 35). They hypothesized
that such cementum defects could be attributable to
hereditary systemic factors. Similarly, aplasia and
hypoplasia were observed in teeth extracted from two
patients with leukocyte-adhesion deficiency and
early-onset periodontitis, suggesting that alterations
in cementum formation and maturation may play a
role in the etiology of early-onset periodontitis (60).
As a result of the low prevalence of localized aggres-
sive periodontitis, genetic association studies in
patients with localized aggressive periodontitis are
few and far between (23, 40, 47). In this context,
genetic factors affecting tooth eruption could poten-
tially be responsible for determining susceptibility to
colonization with specific periodontopathogenic bac-
teria and periodontal tissue damage in a short period
during tooth eruption. In other words, genetic vari-
ants that affect the timing of tooth eruption (as dis-
cussed in previous paragraphs) could, in theory,
predispose to localized aggressive periodontitis by
shifting tooth eruption to less-favorable times of host
development. This, coupled with specific microbial
colonization occurring at the time of the formation of
the subgingival sulcus in the permanent teeth, could
be a determinant factor for the onset of localized
aggressive periodontitis and perhaps even the gener-
alized form of aggressive periodontitis. However, at
this stage this remains in the realm of theory because
no published study has investigated associations
between the timing of tooth eruption or genetic vari-
ants affecting tooth maturation and localized aggres-
sive periodontitis or other more common forms of
periodontitis.
Conclusions
Tooth eruption is characterized by the sequential
replacement of primary teeth with the permanent
dentition. Microbes start colonizing the tooth surface
and the newly formed junctional epithelium immedi-
ately upon eruption. Events occurring during tooth
formation and eruption could predispose to such

colonization with specific bacteria and potentially
contribute to the onset of periodontal diseases. Initial
evidence suggests that genetic variants may affect the
sequence of primary and permanent teeth eruption.
Further research is needed to identify if these or other
genes that are active during tooth eruption could also
influence an individual’s susceptibility to develop
periodontitis, especially localized aggressive peri-
odontitis.
References
1. Ahmad S, Bister D, Cobourne MT. The clinical features and
aetiological basis of primary eruption failure. Eur J Orthod
2006: 28: 535–540.
2. Albandar JM, Tinoco EM. Global epidemiology of periodon-
tal diseases in children and young persons. Periodontol
2000 2002: 29: 153–176.
3. Baer PN. The case for periodontosis as a clinical entity. J
Periodontol 1971: 42: 516–520.
4. Beunen GP, Rogol AD, Malina RM. Indicators of biological
maturation and secular changes in biological maturation.
Food Nutr Bull 2006; 27(4 Suppl Growth Standard): S244–
S256.
5. Blomlof L, Hammarstrom L, Lindskog S. Occurrence and
appearance of cementum hypoplasias in localized and gen-
eralized juvenile periodontitis. Acta Odontol Scand 1986:
44: 313–320.
6. Bosshardt DD, Lang NP. The junctional epithelium: from
health to disease. J Dent Res 2005: 84: 9–20.
7. Brecx MC, Gautschi M, Gehr P, Lang NP. Variability of his-
tologic criteria in clinically healthy human gingiva. J Peri-
odontal Res 1987: 22: 468–472.
8. Brown LJ, Albandar JM, Brunelle JA, Lo € e H. Early-onset
periodontitis: progression of attachment loss during
6 years. J Periodontol 1996: 67: 968–975.
9. Cahill DR, Marks SC Jr. Tooth eruption: evidence for the cen-
tral role of the dental follicle. J Oral Pathol 1980: 9: 189–200.
10. Chen H, Wilkins LM, Aziz N, Cannings C, Wyllie DH, Bingle
C, Rogus J, Beck JD, Offenbacher S, Cork MJ, Rafie-Kolpin
M, Hsieh CM, Kornman KS, Duff GW. Single nucleotide
polymorphisms in the human interleukin-1B gene affect
transcription according to haplotype context. Hum Mol
Genet 2006: 15: 519–529.
11. Cielinski MJ, Jolie M, Wise GE, Marks SC Jr. The contrasting
effects of colony-stimulating factor-1 and epidermal growth
factor on tooth eruption in the rat. Connect Tissue Res 1995:
32: 165–169.
12. Cobourne MT, Sharpe PT. Diseases of the tooth: the genetic
and molecular basis of inherited anomalies affecting the
dentition. Wiley Interdiscip Rev Dev Biol 2013: 2: 183–212.
13. Cohen S. Isolation of a mouse submaxillary gland protein
accelerating incisor eruption and eyelid opening in the
new-born animal. J Biol Chem 1962: 237: 1555–1562.
14. Decker E, Stellzig-Eisenhauer A, Fiebig BS, Rau C, Kress W, Saar
K, Ru€ schendorf F, Hubner N, Grimm T, Weber BH. PTHR1 loss-
of-function mutations in familial, nonsyndromic primary failure
of tooth eruption. Am J Hum Genet 2008: 83: 781–786.
Influence of genetic factors on tooth eruption
15. Demirjian A, Buschang PH, Tanguay R, Patterson DK. Inter-
relationships among measures of somatic, skeletal, dental,
and sexual maturity. Am J Orthod 1985: 88: 433–438.
16. Deng H, Liu F, Pan Y, Jin X, Wang H, Cao J. BsmI, TaqI,
ApaI, and FokI polymorphisms in the vitamin D receptor
gene and periodontitis: a meta-analysis of 15 studies
including 1338 cases and 1302 controls. J Clin Periodontol
2011: 38: 199–207.
17. Dorotheou D, Gkantidis N, Karamolegkou M, Kalyvas D,
Kiliaridis S, Kitraki E. Tooth eruption: altered gene expres-
sion in the dental follicle of patients with cleidocranial dys-
plasia. Orthod Craniofac Res 2013: 16: 20–27.
18. Fatemifar G, Hoggart CJ, Paternoster L, Kemp JP, Proko-
penko I, Horikoshi M, Wright VJ, Tobias JH, Richmond S,
Zhurov AI, Toma AM, Pouta A, Taanila A, Sipila K,
La€hdesma €ki R, Pillas D, Geller F, Feenstra B, Melbye M,
Nohr EA, Ring SM, St Pourcain B, Timpson NJ, Davey Smith
G, Jarvelin MR, Evans DM. Genome-wide association study
of primary tooth eruption identifies pleiotropic loci associ-
ated with height and craniofacial distances. Hum Mol Genet
2013: 22: 3807–3817.
19. Fife MS, Ogilvie EM, Kelberman D, Samuel J, Gutierrez A,
Humphries SE, Woo P. Novel IL-6 haplotypes and disease
association. Genes Immun 2005: 6: 367–370.
20. Fine DH, Markowitz K, Furgang D, Fairlie K, Ferrandiz J, Nasri
C, McKiernan M, Gunsolley J. Aggregatibacter actinomycetem-
comitans and its relationship to initiation of localized aggres-
sive periodontitis: longitudinal cohort study of initially healthy
adolescents. J Clin Microbiol 2007: 45: 3859–3869.
21. Geller F, Feenstra B, Zhang H, Shaffer JR, Hansen T, Esser-
lind AL, Boyd HA, Nohr EA, Timpson NJ, Fatemifar G, Pater-
noster L, Evans DM, Weyant RJ, Levy SM, Lathrop M, Smith
GD, Murray JC, Olesen J, Werge T, Marazita ML, Sørensen
TI, Melbye M. Genome-wide association study identifies
four loci associated with eruption of permanent teeth. PLoS
Genet 2011: 7: e1002275.
22. Gudino S, Rojas N, Castro C, Rodriguez M, Vega M, Lopez
LM. Colonization of mutans streptococci in Costa Rican
children from a high-risk population. J Dent Child (Chic)
2007: 74: 36–40.
23. Guzeldemir E, Gunhan M, Ozcelik O, Tastan H. Interleukin-
1 and tumor necrosis factor-alpha gene polymorphisms in
Turkish patients with localized aggressive periodontitis. J
Oral Sci 2008: 50: 151–159.
24. Hart TC, Atkinson JC. Mendelian forms of periodontitis.
Periodontol 2000 2007: 45: 95–112.
25. Hart TC, Hart PS, Gorry MC, Michalec MD, Ryu OH, Uygur
C, Ozdemir D, Firatli S, Aren G, Firatli E. Novel ENAM
mutation responsible for autosomal recessive amelogenesis
imperfecta and localised enamel defects. J Med Genet 2003:
40: 900–906.
26. He F, Teng X, Gu H, Liu H, Zhou Z, Zhao Y, Hu S, Zheng Z.
Interleukin-6 receptor rs7529229 T/C polymorphism is
associated with left main coronary artery disease pheno-
type in a Chinese population. Int J Mol Sci 2014: 2: 5623–
5633.
27. Hughes TE, Bockmann MR, Seow K, Gotjamanos T, Gully
N, Richards LC, Townsend GC. Strong genetic control of
emergence of human primary incisors. J Dent Res 2007: 86:
1160–1165.
28. Karimbux NY, Saraiya VM, Elangovan S, Allareddy V, Kin-
nunen T, Kornman KS, Duff GW. Interleukin-1 gene
7
Nibali
polymorphisms and chronic periodontitis in adult whites: a
systematic review and meta-analysis. J Periodontol 2012:
83: 1407–1419.
29. Kinane DF, Hart TC. Genes and gene polymorphisms asso-
ciated with periodontal disease. Crit Rev Oral Biol Med
2003: 14: 430–449.
30. Klein OD, Oberoi S, Huysseune A, Hovorakova M, Peterka
M, Peterkova R. Developmental disorders of the dentition:
an update. Am J Med Genet C Semin Med Genet 2013: 163:
318–332.
31. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli
C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W,
Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ,
Penninger JM. OPGL is a key regulator of osteoclastogene-
sis, lymphocyte development and lymph-node organogene-
sis. Nature 1999: 397: 315–323.
32. Lau EC, Mohandas TK, Shapiro LJ, Slavkin HC, Snead ML.
Human and mouse amelogenin gene loci are on the sex
chromosomes. Genomics 1989: 4: 162–168.
33. Leung AK, Robson WL. Natal teeth: a review. J Natl Med
Assoc 2006: 98: 226–228.
34. Lindhe J, Karring T, Araujo M, editors. The anatomy of peri-
odontal tissues. In: Clinical periodontology and implant
dentistry. Oxford, UK: Blackwell Munksgaard, 2008: 3–49.
35. Lindskog S, Blomlof L. Cementum hypoplasia in teeth
affected by juvenile periodontitis. J Clin Periodontol 1983:
10: 443–451.
36. Loe H, Brown LJ. Early onset periodontitis in the United
States of America. J Periodontol 1991: 62: 608–616.
37. Marks SC Jr, Cahill DR. Experimental study in the dog of the
non-active role of the tooth in the eruptive process. Arch
Oral Biol 1984: 29: 311–322.
38. Michalowicz BS, Aeppli D, Virag JG, Klump DG, Hinrichs JE,
Segal NL, Bouchard TJ Jr, Pihlstrom BL. Periodontal find-
ings in adult twins. J Periodontol 1991: 62: 293–299.
39. Mros ST, Berglundh T. Aggressive periodontitis in chil-
dren: a 14-19-year follow-up. J Clin Periodontol 2010:
37: 283–287.
40. Nibali L, Griffiths GS, Donos N, Parkar M, D’Aiuto F, Tonetti
MS, Brett PM. Association between interleukin-6 promoter
haplotypes and aggressive periodontitis. J Clin Periodontol
2008: 35: 193–198.
41. Nibali L, Ready DR, Parkar M, Brett PM, Wilson M, Tonetti
MS, Griffiths GS. Gene polymorphisms and the prevalence
of key periodontal pathogens. J Dent Res 2007: 86: 416–420.
42. Page RC, Kornman KS. The pathogenesis of human peri-
odontitis: an introduction. Periodontol 2000: 1997: 9–11.
43. Pelsmaekers B, Loos R, Carels C, Derom C, Vlietinck R. The
genetic contribution to dental maturation. J Dent Res 1997:
76: 1337–1340.
44. Pillas D, Hoggart CJ, Evans DM, O’Reilly PF, Sipila € K,
La€hdesma €ki R, Millwood IY, Kaakinen M, Netuveli G, Blane D,
Charoen P, Sovio U, Pouta A, Freimer N, Hartikainen AL, Laiti-
nen J, Vaara S, Glaser B, Crawford P, Timpson NJ, Ring SM,
Deng G, Zhang W, McCarthy MI, Deloukas P, Peltonen L, Elliott
P, Coin LJ, Smith GD, Jarvelin MR. Genome-wide association
study reveals multiple loci associated with primary tooth devel-
opment during infancy. PLoS Genet 2010: 6: e1000856.
45. Risom L, Christoffersen L, Daugaard-Jensen J, Hove HD,
Andersen HS, Andresen BS, Kreiborg S, Duno M. Identifica-
tion of six novel PTH1R mutations in families with a history
of primary failure of tooth eruption. PLoS ONE 2013: 8:
e74601.
46. Sapna G, Gokul S, Bagri-Manjrekar K. Matrix metallopro-
teinases and periodontal diseases. Oral Dis 2014: 20: 538–550.
47. Schaefer AS, Richter GM, Nothnagel M, Laine ML, Ru € hling
A, Scha €fer C, Cordes N, Noack B, Folwaczny M, Glas J,
Do€ rfer C, Dommisch H, Groessner-Schreiber B, Jepsen S,
Loos BG, Schreiber S. COX-2 is associated with periodonti-
tis in Europeans. J Dent Res 2010: 89: 384–388.
48. Schluger S. Periodontics today: dentistry tomorrow. J Dist
Columbia Dent Soc 1977: Fall: 6–8.
49. Schroeder HE, Listgarten MA. The gingival tissues: the
architecture of periodontal protection. Periodontol 2000
1997: 13: 91–120.
50. Shao MY, Huang P, Cheng R, Hu H. Interleukin-6 polymor-
phisms modify the risk of periodontitis: a systematic review
and meta-analysis. J Zhejiang Univ Sci B 2009: 10: 920–927.
51. Slots J. Periodontal herpesviruses: prevalence, pathogenic-
ity, systemic risk. Periodontol 2000 2015: 69: 28–45.
52. Song GG, Kim JH, Lee YH. Toll-like receptor (TLR) and
matrix metalloproteinase (MMP) polymorphisms and peri-
odontitis susceptibility: a meta-analysis. Mol Biol Rep 2013:
40: 5129–5141.
53. Stein JM, Machulla HK, Smeets R, Lampert F, Reichert S.
Human leukocyte antigen polymorphism in chronic and
aggressive periodontitis among Caucasians: a meta-analy-
sis. J Clin Periodontol 2008: 35: 183–192.
54. Tam JP. Physiological effects of transforming growth factor
in the newborn mouse. Science 1985: 229: 673–675.
55. Tankkunnasombut S, Youcharoen K, Wisuttisak W, Vichan-
rayat S, Tiranathanagui S. Early colonization of mutans
streptococci in 2- to 36-month-old Thai children. Pediatr
Dent 2009: 31: 47–51.
56. Ten Cate AR. The role of epithelium in the development,
structure and function of the tissues of tooth support. Oral
Dis 1996: 2: 55–62.
57. Ting M, Contreras A, Slots J. Herpesvirus in localized juvenile
periodontitis. J Periodontal Res 2000: 35: 17–25.
58. Tsimikas S, Duff GW, Berger PB, Rogus J, Huttner K, Clop-
ton P, Brilakis E, Kornman KS, Witztum JL. Pro-Inflamma-
tory interleukin-1 genotypes potentiate the risk of coronary
artery disease and cardiovascular events mediated by oxi-
dized phospholipids and lipoprotein(a). J Am Coll Cardiol
2014: 63: 1724–1734.
59. Urzu  a B, Ortega-Pinto A, Morales-Bozo I, Rojas-Alcayaga G,
Cifuentes V. Defining a new candidate gene for amelogene-
sis imperfecta: from molecular genetics to biochemistry.
Biochem Genet 2011: 49: 104–121.
60. Waldrop TC, Hallmon WW, Mealey BL. Observations of root
surfaces from patients with early-onset periodontitis and leuko-
cyte adhesion deficiency. J Clin Periodontol 1995: 22: 168–178.
61. Wan AK, Seow WK, Purdie DM, Bird PS, Walsh LJ, Tude-
hope DI. A longitudinal study of Streptococcus mutans col-
onization in infants after tooth eruption. J Dent Res 2003:
82: 504–508.
62. Wise GE, Frazier-Bowers S, D’Souza RN. Cellular, molecu-
lar, and genetic determinants of tooth eruption. Crit Rev
Oral Biol Med 2002: 13: 323–334.
63. Wise GE, Yao S. Regional differences of expression of bone
morphogenetic protein-2 and RANKL in the rat dental folli-
cle. Eur J Oral Sci 2006: 114: 512–516.