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Further, note that the human genome is not the only Pathological factors, which include cariogenic bacteria,
genome involved in caries, i.e. the oral microbiome clear- frequent ingestion of fermentable carbohydrates and sal-
ly plays a role in pathogenesis, and a number of groups ivary dysfunction, drive the caries process toward demin-
are simultaneously working on the metagenomic contri- eralization. Protective factors, which include salivary
butions to caries. The oral cavity contains more than 700 components, fluoride and remineralization, and targeted
species of bacteria, which grow primarily in multi-species biofilm control drive the caries process toward reminer-
biofilms (for example, dental plaque) that play vital roles alization [Featherstone, 2004]. If pathological factors out-
in homeostasis of the mouth and in diseases of the oral weigh protective factors, caries progresses as a conse-
cavity [Zarco et al., 2012]. Although caries is strongly as- quence [Featherstone, 2006]. Behaviors related to oral hy-
sociated with differences in diet and environmental fac- giene practices, dietary choices and decisions involving
tors, a study of the taxonomy of the salivary microbiome seeking professional oral health care also contribute to
of 120 individuals selected from 12 different locations caries, and defining these factors and including them
worldwide (10 per location) found little geographic struc- along analyses of biological underpinnings is a major
ture; only 13.5% of the variance in genera composition challenge.
observed between populations was explained by differ- The American Academy of Pediatric Dentistry [2012]
ences among individuals [Nasidze et al., 2009]. This sug- currently recommends that caries risk assessment based
gests that microbial taxonomy alone even after adjust- on a childs age, biological factors, protective factors and
ing for environmental exposures is insufficient to ex- clinical findings should be a routine component of new
plain individual, familial and regional variations in oral and periodic examinations by oral health and medical
microbiota and particularly caries susceptibility. providers.
In this paper, we focus on recent human genetic stud- There is no single test that takes into consideration all
ies, provide an overview of where the field stands and these factors and accurately predicts an individuals sus-
summarize the promise of these studies in devising new ceptibility to caries. The caries risk may be determined by
strategies to prevent and manage caries. analyzing and integrating several factors such as caries
experience (initial caries lesions and established caries de-
fects, secondary caries and present caries activity), fluo-
Pathogenesis ride use, extent of plaque present, diet, bacterial and sali-
vary activity and social and behavioral factors [Reich et
The term caries is thought to derive from words mean- al., 1999]. Although the best tool to predict future caries
ing rottenness, decay, injure, break, death, destruction, is past caries experience, this risk factor is not applicable
withered or faded. It alludes to a disease process, but does for young children due to the need to determine caries
not describe it. According to Fejerskov et al. [2008], caries risk before the disease is present [American Academy of
describes the signs and symptoms of a disease. In other Pediatric Dentistry, 2012].
words, it is the result of a localized chemical dissolution Host susceptibility is underlined by a potential genetic
of the tooth surface caused by metabolic events that take contribution for caries risk. The understanding of genet-
place in the biofilm (dental plaque) that covers the af- ic contributions to caries can be highly valuable for dental
fected area. Carious lesions result from a shift in the ecol- practitioners. In the future, clinicians might be able to
ogy and metabolic activity of the biofilm, whereby an im- explain to patients that some forms of caries are more
balance in the equilibrium between tooth mineral and strongly associated with inherited risk. This could offer
biofilm fluid has developed. Although the biofilm is a pre- an explanation for both the patient and dental practi-
requisite for carious lesions to occur, its presence on sol- tioner why persons with similar behavioral risks (i.e.
id surfaces does not necessarily result in the development tooth brushing frequency or dietary habits) have different
of clinically visible carious lesions. Some chemical modi- caries risk and/or caries activity [Bretz et al., 2003].
fications are so subtle that they can only be recorded mi-
croscopically. When cumulative numerous pH fluctua-
tions result in a net loss of calcium and phosphate of an Early Evidence for a Genetic Component of Caries
extent that makes the enamel porous and visible, it is con-
sidered a white spot lesion. Although a genetic contribution to caries in humans
Featherstone [2006] explains the caries process as has been controversial, even the earliest studies of family
a balance between pathological and protective factors. patterns in twins [Boraas et al., 1988; Conry et al., 1993],
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families [Klein and Palmer, 1940] and animal breeding to caries/Filled Teeth or Surfaces) is the most widely used
[Hunt et al., 1944] were consistent with a genetic compo- index and gives a good estimate of the prevalence of the
nent. The most compelling early evidence for a genetic disease, as well as an estimate of the severity of the affec-
component to caries comes from studies of twins reared tion based on the number of teeth (or surfaces) affected
apart. In two related studies, investigators found signifi- by caries. The DMFT distribution in 12-year-olds across
cant resemblance for percentage of teeth and surfaces re- many countries shows that there is a skewed distribution
stored or carious within monozygotic but not dizygotic of caries prevalence [Nishi et al., 2002]. While a propor-
twin pairs reared apart and estimated the genetic contri- tion of 12-year-olds are caries-free, a considerable num-
bution to caries as 40% [Boraas et al., 1988; Conry et al., ber still have DMFT values higher than the goal of 3 set
1993]. More recent studies of twins reared together [Bretz by the Health Assembly of the World Health Organiza-
et al., 2003, 2005] or of families [Wang et al., 2010] esti- tion (Bratthall [2000]; see also fig.1). Caries prevalence
mated the heritability for caries measured by the DMFT/S assessed in the third of the population with higher DMFT
as ranging from 45 to 64%, with primary dentition caries scores (Significant Caries Index) brings to attention the
in general showing higher heritability than permanent individuals that are experiencing most severe disease. It
dentition caries. Heritability studies alone are not suffi- has been proposed that the Significant Caries Index for
cient to demonstrate a genetic component in caries be- countries should be less than 3 DMFT in 12-year-olds by
cause shared behavior and other environmental factors the year 2015 [Bratthall, 2000].
can contribute to covariance between relatives and mim- Over the life course, populations tend to have in-
ic genetic correlation. Notably however, genetic studies in creased DMFT/DMFS scores (fig.2), in part due to un-
animal models (see e.g. Nariyama et al. [2004]) and recent treated caries disease, in part due to restorative proce-
human molecular genetic studies bear out the heritability dures and other reasons. Therefore, genetic studies defin-
results. A full summary of the long history of animal ing the phenotype based on caries experience scores will
model studies in caries is beyond the scope of this review, have to deal with the limitation that these scores provide
but note that many of the candidate gene studies done in an estimate of the prevalence of the disease, but not nec-
humans (see table1 for a summary) were motivated by essarily directly determine the individual factors involved
the findings in animal models. This review focuses in in its pathogenesis. DMFT scores have limited ability to
large part on the recent strides in caries molecular genet- provide insight into the severity or pathogenesis of the
ic studies in human populations. caries experience in an individual. With the widespread
utilization of fluorides, carious lesions have become more
difficult to detect and many are incipient. Epidemiologi-
Caries Phenotypes cal assessments usually have study participants at only
one time and judgment of lesion status needs to be made
Shared behavior, practice and habits within families at the visit. Dentists in their practices have the ability to
can be expected to contribute to covariance between rela- follow up cases and make decisions based on how an ap-
tives and to mimic genetic correlation if not controlled by parent lesion progresses or stays arrested, and treatment
the experimental design [Potter, 1990]. This is particu- decisions can be planned accordingly. To sophisticate the
larly true for caries, which can be profoundly affected by power of discrimination of caries experience evaluations
dietary sugar intake and/or oral hygiene practices within at the population level, another index was proposed, the
families. This effect can explain results that suggest a ma- International Caries Detection and Assessment System
jor gene effect [Werneck et al., 2011], despite the fact that (ICDAS; https://www.icdas.org/; Pitts [2004]). This in-
one would not expect that to be the case for caries. dex provides a more sophisticated assessment of the car-
Successful genetic studies require careful measure- ies experience, but at the same time brings to attention the
ment of the phenotype of interest (i.e. the disorder or difficulties of discerning between specific codes of early
physical characteristic under study), ideally in a biologi- alteration of the enamel (codes 03) and the feasibility of
cally meaningful way. Genetic studies of caries are thus applying this approach to large settings.
inherently difficult because the usual disease measures Both DMFT/DMFS and ICDAS are used to obtain in-
originally developed for clinical and epidemiological formation on primary dentition, which is ideally exam-
studies more directly assess the consequence of the dis- ined after complete eruption, after 4 and before 6 years of
ease rather than its pathogenesis. The DMFT/DMFS age. Caries experience data have been generated for indi-
score (i.e. a count of the number of Decayed/Missing due viduals older than 12 years of age as well, but in these
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Table 1 (continued)
Human leukocyte antigen; presents peptides derived from frequency of allele 4 of Lehner et al. [1981]; Altun et al.
major histocompatibility extracellular proteins DRB1 is increased in [2008]; Bagherian et al. [2008];
complex, class II, DR beta children with early Valarini et al. [2012]
1 (HLA-DRB1) and DQ childhood caries; also allele
beta 1 (HLA-DQB1) 2 of DQB1 is increased in
adolescents affected by
caries; DRB1 allele 1 and
DQB1 allele 3 frequencies
are increased in the
presence of Streptococcus
mutans
no evidence of association de Vries et al. [1985]
Beta defensin 1 (DEFB1) antimicrobial peptide implicated in distinct DEFB1 haplotypes Ozturk et al. [2010]; Krasone
the resistance of epithelial surface to are associated with low and et al. [2013]
microbial colonization high caries experience
Lactotransferrin (LTF) major iron-binding protein in associated with lower caries Azevedo et al. [2010]; Fine et al.
milk and body secretions with experience [2013]
antimicrobial activity
no mutations found in the Brancher et al. [2011]
promoter region
Mucin 7 (MUC7) facilitates the clearance of bacteria associated with higher Pol [2011]
in the oral cavity caries experience with poor
oral hygiene
no evidence of association Buczkowska-Radliska et al.
[2012]
Mannose-binding lectin recognizes mannose and associated with higher Olszowski et al. [2012]
(protein C) 2, soluble N-acetylglucosamine on many caries experience
(MBL2) microorganisms
no evidence of association Yang et al. [2013]
Mannan-binding lectin bactericidal factor that binds to no evidence of association Olszowski et al. [2012]
serine peptidase 2 the Ra and R2 polysaccharides
(MASP2) expressed by certain enterobacteria
Saliva genes
Aquaporin 5 (AQP5) water channel protein that plays associated with higher Wang et al. [2012b]
a role in the generation of saliva, caries experience
tears and pulmonary secretions
Protein-rich protein provide protective environment associated with higher Zakhary et al. [2007]
HaeIII subfamily 1 (PRH1) for the teeth caries experience and
colonization by
Streptococcus mutans
Other genes
Matrix metalloproteinase degrades type IV collagen no evidence of association Tannure et al. [2012a]
2 (MMP2)
Matrix metalloproteinase degrades type IV and V collagens no evidence of association Tannure et al. [2012a]
9 (MMP9)
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Matrix metalloproteinase involved in endochondral associated with lower caries Tannure et al. [2012a]
13 (MMP13) ossification and bone remodeling; experience
this gene is physically close to
MMP20 and maybe evolved at the
same time before the divergence of
ray-finned and lobe-finned fish
[Kawasaki and Suzuki, 2011]
TIMP metallopeptidase possibly critical to the maintenance no evidence of association Tannure et al. [2012a]
inhibitor 2 (TIMP2) of tissue homeostasis by suppressing
the proliferation of quiescent tissues
in response to angiogenic factors,
and by inhibiting protease activity in
tissues undergoing remodeling
of the extracellular matrix
Taste receptor, type 2, controls the ability to taste associated with lower caries Wendell et al. [2010]
member 38 (TAS2R38) glucosinolates experience
Taste receptor, type 1, sweet taste receptor associated with both Wendell et al. [2010]; Kulkarni
member 2 (TAS1R2) lower and higher caries et al. [2013]
experience
Guanine nucleotide- believed to be involved in dietary no evidence of association Wendell et al. [2010]
binding protein, alpha preferences
transducing 3 (GNAT3)
Solute carrier family 2 mediates facilitated bidirectional associated with higher Kulkarni et al. [2013]
(facilitated glucose glucose transport caries experience
transporter), member 2
(SLC2A2)
Dentin involved in the mineralization associated with lower caries Wang et al. [2012b]
sialophosphoprotein process of dentin experience
(DSPP)
Secreted phosphoprotein 1 involved in the attachment of no evidence of association Wang et al. [2012b]
(SPP1) osteoclasts to the mineralized bone
matrix
Carbonic anhydrase IV involved in respiration, calcification, no evidence of association Yarat et al. [2011]
(CA4) acid-base balance, bone resorption
and formation of aqueous humor,
cerebrospinal fluid, saliva and
gastric acid
cases, total caries experience tends to increase due to oth- For human genetic study purposes, research groups
er factors that cannot be easily discerned from caries: have begun to use tooth- and/or surface-specific scores,
sound surfaces may have been prepared to receive tooth for example dividing the surfaces into pit-and-fissure ver-
restorations or are bases for fixed prosthodontics, teeth sus smooth surfaces [Zeng et al., 2013]. An intriguing re-
can be lost due to trauma, periodontal disease or or- cent study used cluster analysis to divide the tooth sur-
thodontic indications, and depending on the study, these faces into groups with similar caries experience [Shaffer
factors cannot be easily detected during the clinical as- et al., 2013b], resulting in five primary clusters summa-
sessment. rized in footnote e of table2. Of note some clusters of
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Color version available online
10
9
8
7
Fig. 1. Graphs showing caries data for two
6
DMFT score
populations of 12-year-olds, expressed as
frequency distribution. a Data (n = 539) 5
from Curitiba, Brazil (principal investiga-
4
tor Paula C. Trevilatto) included in Shi-
mizu et al. [2012]. b Data (n = 368) from 3
the Center for Oral Health Research in Ap- 2
palachia, USA (principal investigator Mary
L. Marazita) included in Wang et al. 1
[2012a]. 48% of children from the Brazilian 0
site (n = 258) and 28% of the children from 0 10 20 30 40 50 60 70 80 90 100
the US site (n = 102) were caries-free. The a Percent of population
mean DMFT was 1.45 (Brazilian site) and
3.45 (US site), respectively. The Significant 24
23
Caries Index calculated from the third of 22
the population with the highest caries 21
20
scores was 3.64 (Brazilian site) and 7.82 19
18
(US site), respectively. The third of the 17
population with the highest caries experi- 16
15
DMFT score
surfaces did not show significant heritability (e.g. maxil- and thus represent a hypothesis-generating procedure.
lary incisors, see table2), indicating that perhaps some DNA variants with genome-wide significant statistical
clusters are not under genetic control while other clusters signals imply that the anonymous variants are near caries
do have genetic contributions to risk of caries. etiologic variants; such positive signals then require fol-
low-up studies for identification of the etiologic variants.
Since genome-wide studies are hypothesis-generating,
Human Genetic Studies of Caries one typically targets for follow-up both strictly genome-
wide significant results and also suggestive results, i.e.
There are two major ways to study the genetics of a those results that are near strict significance.
complex trait such as caries, and both have been applied
to caries: candidate gene studies (summarized below and Candidate Gene Studies
in table1) and genome-wide studies (summarized below Most of the genetic studies of caries to date approach
and in table 2). Candidate gene studies test hypotheses the problem of detecting a genetic factor contributing to
regarding association between specific genes or gene vari- caries by testing genetic variation in specific genes, based
ants and caries experience. Genome-wide studies test ei- on their assumed or known function which is thought to
ther linkage or association between anonymous DNA be relevant to the disease, using the standard statistical
variants with known locations throughout the genome, approach of testing for association between specific vari-
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10
dramatic progression of the lesion into dentin than oth-
8 ers, and these lesions can involve the pulp to a point that
6 these cases can be more susceptible to developing periapi-
4
cal lesions detected radiographically. MMP2 expression
is higher in dentin affected by caries [Toledano et al.,
2
2010]. When the presence of periapical lesions associated
0 with deep carious lesions in dentin was used as a pheno-
612 1318 1925 2635 3644 45
type (in comparison to absence of periapical lesions de-
Age range (years)
spite the presence of deep carious lesions in dentin), as-
sociations were found with MMP2 and MMP3 [Menezes-
Fig. 2. DMFT scores tend to grow as individuals grow older. The
effect of age in any caries experience score will potentially add un-
Silva et al., 2012], demonstrating the promise of exploring
detectable bias since it is not possible to account for all factors con- phenotypes related to the severity of the carious lesions.
tributing to increasing levels of tooth loss and affection, and these
likely impact genetic analyses (data from Jindal et al. [2011]). Genome-Wide Linkage Studies
With early molecular genetic tools such as restriction
fragment polymorphisms and single nucleotide polymor-
ants or alleles at a genetic locus and caries. These genes phisms (SNPs), genome-wide studies began to identify
can be grouped in certain categories, based on the factor regions in the genome likely to harbor caries risk genes.
influencing caries. The major candidate gene categories The first genome-wide attempt to identify genetic con-
studied to date include enamel formation genes, immune tributors to caries used the linkage approach [Vieira et al.,
response genes, genes related to saliva, genes related to 2008] (see also table2). Linkage studies utilize the recom-
taste and others (table1). Associations have not always bination that occurs between genetic loci that are near
been replicated in other independent studies and these each other on the same chromosome during crossing
conflicting results are probably due to population hetero- over of homologous chromosomes during meiosis I. The
geneity and issues with statistical power. Due to such recombination frequency is a function of distance be-
study design issues, the associations described in table1 tween loci, and the larger the estimated recombination
cannot yet be fully refuted by the negative reports [Branch- frequency, the lower the likelihood that the loci are linked
er et al., 2011; Yarat et al., 2011; Buczkowska-Radliska et (i.e. close to each other). If a genetic marker is physically
al., 2012; Olszowski et al., 2012; Gasse et al., 2013; Yang et close or in the vicinity of the genetic variant causing the
al., 2013] that followed the original studies. disease, there will be statistically significant evidence of
The most studied group of candidate genes includes linkage, as estimated by a statistic termed LOD score,
the enamel formation genes. The aggregate association which has a value of 3.4 for genome-wide statistically sig-
data [Slayton et al., 2005; Deeley et al., 2008; Patir et al., nificant linkage or between 2 and 3.4 for suggestive evi-
2008; Shimizu et al., 2012; Ergz et al., 2013; Jeremias et dence of linkage.
al., 2013] have only one mostly consistent result, the lack The genome-wide linkage scan performed for caries
of association between TFIP11 and caries (Jeremias et al. controlled for several key environmental factors that in-
[2013] is the exception). However, an association with fluence caries. The 46 families studied shared similar cul-
this gene was found when the phenotype tested was mi- tural habits, were all from a specific geographic area in the
crohardness of enamel after the creation of an artificial Philippines and had very limited access to dental care.
caries lesion [Shimizu et al., 2012]. These data suggest The analysis was done twice, once utilizing a definition
that the bulk of candidate gene studies can suffer from the for high caries experience and the second for low caries
definition of the phenotype as discussed earlier. Most experience. The definitions of caries experience relied on
studies compare individuals who are caries-free to indi- DMFT scores but took into consideration the age of the
viduals with at least one affected tooth. The obvious ques- subjects to overcome the limitations of DMFT scores (see
tion is Are individuals with DMFT = 1 the same as indi- footnote d in table2).
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Table 2. Summary of genome-wide studies of dental caries
genome-wide association utilizes standard association analysis methods to detect the relationship between a trait and anonymous bi-allelic SNP vari-
ants.
b Significant = genome-wide significant, i.e. for genome-wide linkage: LOD scores 3.4; for genome-wide association: p value 107, additional
high (DMFT 5); in teenagers (1318 years): caries experience very low (DMFT = 02), low (DMFT = 35), moderate (DMFT = 68), high (DMFT 9);
in adults: caries experience very low (DMFT = 04), low (DMFT = 58), moderate (DMFT = 913), high (DMFT 14).
e Hierarchical clusters (see Shaffer et al. [2013b]): DMFS1 (DMFS scored from the occlusal surfaces of molars; heritability (h2) = 27%, p = 0.06),
DMFS2 (mandibular incisors, canines and first premolars; h2 = 54%, p = 0.002), DMFS3 (molars and maxillary premolars excluding occlusal molar
surfaces; h2 = 43%, p = 0.004), DMFS4 (maxillary incisors; h2 = 0%, p = 0.5) and DMFS5 (canines and premolars; h2 = 40%, p = 0.008).
f DMFS calculated on pit and fissure surfaces, and DMFS calculated on smooth surfaces, with each score adjusted for age, sex, presence of Strepto-
number in parentheses is the number of genes tested within the set [Wang et al., 2013]; selected gene names with known/suspected involvement in oral
or dental phenotypes are also listed. Terms included in this table are those significant after adjustment for multiple testing (FDR <0.05) under at least
one of four statistical methods utilized for the gene set analyses (GenGen, Alligator, SNP ratio test, mixed model; see Wang et al. [2013]). Bold terms
are those that were significant under more than one statistical method. FDR = False discovery rate.
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a
Is there a microcavity
Is there an opacity/ or obvious cavity?
discoloration at the
entrance to the fissure? Is dentin visible at the
No Yes
base of the cavity?
Fig. 3. Questionable carious lesions can be managed with minimal going to bed. b After 5 years, there were no signs of lesion progres-
intervention. a A 9-year-old patient with discoloration on an oc- sion, both clinically and radiographically, which suggests the deci-
clusal fissure of the right maxillary first molar. Radiographic exam sion of not performing restorative treatment was for the benefit of
showed no signs of dentine affection. The dental explorer was used the child. c Diagram of the decision making tree of the ICDAS
gently and suggested the fissure was retentive. The mother of the (modified from https://www.icdas.org). The surface of the tooth
child was instructed to carefully brush that tooth with an over the above would have been possibly coded as 3 in a larger-scale study,
counter fluoridated toothpaste every day at least before the child even though it was sound.
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sure caries, and suggested associations with three genes (1) Very little overlap exists across studies, but the prom-
that were observed in previous studies: MPPED2 (p value ising associations with 1p36.32 and 10p11.23 should be
= 6.9 106), AJAP1 (p value = 1.6 106) and RPS6KA2 prioritized for future studies for the identification of ge-
(p value = 7.3 106). netic factors contributing to caries. (2) Phenotype defini-
In addition to the above association analyses of indi- tions for caries warrant further refinement because sug-
vidual SNPs with caries, a recent analysis [Wang et al., gestive but not formally significant results were obtained
2013] applied a new statistical methodology to the pri- for the traditional DMFS/T caries definitions, but ge-
mary dentition association results from Shaffer et al. nome-wide significant results were found for surface-
[2012]. Instead of analyzing SNPs one by one, they used specific caries scores. (3) Utilizing approaches that look
gene set-based analysis, which has recently emerged as a for joint effects of DNA variants across sets of related
useful approach to examine the joint effects of multiple genes (such as the gene set enrichment approach of Wang
risk loci in complex human diseases or phenotypes such et al. [2013]) appear to hold promise for identifying pos-
as caries. Wang et al. [2013] used four complementary sibly functional relationships between caries-associated
gene set statistical analysis methods and analyzed 1,331 genetic factors.
gene sets under Gene Ontology terms [Ashburner et al., Interestingly, as mentioned above, the significant or
2000]. Identified were 13 significantly associated Gene suggestive signals to date from genome-wide association
Ontology terms/gene sets (table 2). 17 additional sets studies of caries are different from the significant signals
were further identified as marginally relevant. The identi- found from genome-wide linkage analyses. This fact em-
fied gene sets encompass broad functions that potentially phasizes that the two approaches have different strengths:
interact and contribute to the oral immune response re- association studies are more sensitive in detecting com-
lated to caries development, which have not yet been re- mon variants of small effect size than are linkage studies,
ported in any standard single marker-based analysis. but linkage is more robust in detecting etiologic genes
These approaches are under development, but it appears that exhibit allelic heterogeneity if multiple different
that the gene set enrichment analysis approach can pro- variants (especially rare variants) within a gene can lead
vide complementary insights into the molecular mecha- to caries, linkage is much more likely to detect such genes
nisms and polygenic interactions in caries. [Risch and Merikangas, 1996]. Thus further follow-up
As summarized by Wang et al. [2013], five genes from studies of the results from both types of studies are neces-
either ligase activity (WWP2 and RNF217), neuronal de- sary to confirm genetic loci for caries.
velopment (ROBO2 and SLIT2) or cytokine/protein se-
cretion (INS) gene sets listed in table2 might be poten-
tially associated with dental traits. WWP2 is a member of Final Remarks
ligase activity pathways and functions as a ligase for and
mediates degradation of PTEN, whose gene is expressed Advances in molecular genetics, engineering, manage-
in mouse oral development. RNF217 is located at 6q22.31, ment, research and education offer many new ways to
a genomic region reported to be associated with oral treat patients regarding caries management and preven-
clefts. ROBO2 is a receptor for SLIT2 and possibly SLIT1 tion. Advancement is underway in caries risk assessment,
genes, which appear to work cooperatively to establish carious lesion detection, genetic predisposition technolo-
anatomical midlines during neuronal development and gies and restorative techniques [Berg, 2013]. The under-
establishment of olfactory organization. SLIT1 is also ex- standing of genetic contributions to caries can be highly
pressed in the primary and secondary enamel knots dur- valuable for dental practitioners as the starting point of
ing molar tooth cusp formation. INS can impact caries host susceptibility. In the future, clinicians might be able
through insulin sensitivity. Insulin receptor binding sites to explain to patients that some forms of caries are more
are present on rat incisors. None of these relationships are strongly associated with inherited risk, offering an expla-
apparently relevant for caries development, but the gene nation for both the patient and dental practitioner why
sets and the subset of tooth-related genes raise interesting similar behavioral risks (i.e. tooth brushing frequency or
possible mechanisms for caries. dietary habits) have different caries risk [Bretz et al.,
2003]. Individuals at higher genetic risk could then be
Summary of Genome-Wide Analyses monitored more closely and provided with more aggres-
When we compare the results across all these ge- sive caries management and prevention programs [Bretz
nome-wide analyses there are three notable conclusions: et al., 2003].
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References
Altun C, Guven G, Orkunoglu F, Cehreli ZC, Berg J: Keep it simple. Emphasizing effective Silva RM, Cooper ME, Seymen F, Costa MC,
Karaasian A, Basak F, Akbulut E: Human leu- toothbrushing technique and compliance can Granjeiro JM, Trevilatto PC, Orioli IM, Cas-
kocyte antigen class II alleles and dental caries make all the difference in caries prevention. tilla EE, Marazita ML, Vieira AR: Role of
in a child population. Pediatr Dent 2008; 30: Dimens Dent Hyg 2013;11:2629. TRAV locus in low caries experience. Hum
150159. Bergandi L, Defabianis P, Re F, Preti G, Aldieri E, Genet 2013;132:10151025.
American Academy of Pediatric Dentistry: Garetto S, Bosia A, Ghigo D: Absence of sol- Buczkowska-Radliska J, Pol J, Szmidt M,
Guideline on caries risk assessment and man- uble CD14 in saliva of young patients with Biczak-Kuleta A: The influence of polymor-
agement for infants, children, and adoles- dental caries. Eur J Oral Sci 2007;115:9396. phism of the MUC7 gene on the teeth and
cents. Pediatr Dent 2012;34:118125. Boraas JC, Messer LB, Till MJ: A genetic contribu- dental hygiene of students at a faculty of den-
Ashburner M, Ball CA, Blake JA, Botstein D, But- tion to dental caries, occlusion, and morphol- tistry in Poland. Postepy Hig Med Dosw 2012;
ler H, Cherry JM, Davis AP, Dolinski K, ogy as demonstrated by twins reared apart. 66:204209.
Dwight SS, Eppig JT, Harris MA, Hill DP, Is- J Dent Res 1988;67:11501155. Conry JP, Messer LB, Boraas JC, Aeppli DP,
sel-Tarver L, Kasarskis A, Lewis S, Matese JC, Brancher JA, Pecharki GD, Doetzer AD, Me- Bouchard TJ Jr: Dental caries and treatment
Richardson JE, Ringwald M, Rubin GM, Sher- deiros KG, Cordeiro CA Jr, Sotomaior VS, characteristics in human twins reared apart.
lock G: Gene ontology: tool for the unification Bauer P, Trevilatto PC: Analysis of polymor- Arch Oral Biol 1993;38:937943.
of biology. The Gene Ontology Consortium. phisms in the lactotransferrin gene promoter Deeley K, Letra A, Rose EK, Brandon CA, Resick
Nat Genet 2000;25:2529. and dental caries. Int J Dent 2011; 2011: JM, Marazita ML, Vieira AR: Possible asso-
Azevedo LF, Pecharki GD, Brancher JA, Cordeiro 571726. ciation of amelogenin to high caries expe-
CA Jr, Medeiros KG, Antunes AA, Arruda ES, Bratthall D: Introducing the Significant Caries In- rience in a Guatemalan-Mayan population.
Werneck RI, de Azevedo LR, Mazur RF, Moy- dex together with a proposal for a new oral Caries Res 2008;42:813.
ss SJ, Moyss ST, Faucz FR, Trevilatto PC: health goal for 12-year-olds. Int J Dent 2000; Deutsch D, Leiser Y, Shay B, Fermon E, Taylor A,
Analysis of the association between lacto- 50:378384. Rosenfeld E, Dafni L, Charuvi K, Cohen Y,
transferrin (LTF) gene polymorphism and Bretz WA, Corby P, Hart TC, Costa S, Coelho Haze A, Fuks A, Mao Z: The human tuftelin
dental caries. J Appl Oral Sci 2010; 18: 166 MQ, Weyant RJ, Robinson M, Schork NJ: gene and the expression of tuftelin in mineral-
170. Dental caries and microbial acid production izing and nonmineralizing tissues. Connect
Bader JD, Vollmer WM, Shugars DA, Gilbert GH, in twins. Caries Res 2005;39:168172. Tissue Res 2002;43:425434.
Amaechi BT, Brown JP, Laws RL, Funkhouser Bretz WA, Corby P, Schork N, Hart TC: Evidence de Vries RR, Zeylemaker P, van Palenstein Hel-
KA, Makhija SK, Ritter AV, Leo MC: Results of a contribution of genetic factors to dental derman WH, Huis in t Veld JH: Lack of as-
from the xylitol for adult caries trial (X-ACT). caries risk. J Evid Based Dent Pract 2003; 3: sociation between HLA-DR antigens and den-
J Am Dent Assoc 2013;144:2130. 185189. tal caries. Tissue Antigens 1985;25:173174.
Bagherian A, Nematollahi H, Afshari JT, Mo- Briseo-Ruiz J, Shimizu T, Deeley K, Dizak P, Ergz N, Seymen F, Gencay K, Tamay Z, Deeley
heghi N: Comparison of allele frequency for Ruff TD, Faraco IM Jr, Poletta FA, Brancher K, Vinski S, Vieira AR: Genetic variation in
HLA-DR and HLA-DQ between patients JA, Pecharki GD, Kchler EC, Tannure PN, Ameloblastin is associated with caries in asth-
with ECC and caries-free children. J Indian Lips A, Vieira TC, Patir A, Koruyucu M, matic children. Eur Arch Paediatr Dent 2013,
Soc Pedod Prev Dent 2008;26:1821. Mereb JC, Resick JM, Brandon CA, Letra A, Epub ahead of print.
114.125.31.247 - 7/4/2017 9:24:03 AM
DOI: 10.1159/000358333
Downloaded by:
Featherstone JD: The caries balance: the basis for tilla EE, Orioli IM, Marazita ML, Vieira AR: patterns in the permanent dentition. J Dent
caries management by risk assessment. Oral Genetic mapping of high caries experience on Res 2013a;92:3844.
Health Prev Dent 2004;2(suppl 1):259264. human chromosome 13. BMC Med Genet Shaffer JR, Feingold E, Wang X, Weeks DE, We-
Featherstone JD: Caries prevention and reversal 2013;14:116. yant RJ, Crout R, Daniel W, McNeil DW,
based on the caries balance. Pediatr Dent Kulkarni GV, Chng T, Eny KM, Nielsen D, Wess- Marazita ML: Clustering tooth surfaces into
2006;28:128132. man C, El-Sohemy A: Association of GLUT2 biologically-informative caries outcomes. J
Fejerskov O, Kidd E, Nyvad B, Baelum V: Defin- and TAS1R2 genotypes with risk for dental Dent Res 2013b;92:3237.
ing the disease: an introduction; in Fejerskov caries. Caries Res 2013;47:219225. Shaffer JR, Wang X, Feingold E, Lee M, Begum F,
O, Kidd E (eds): Dental Caries. The Disease Lehner T, Lamb JR, Welsh KL, Batchelor RJ: As- Weeks DE, Cuenco KT, Barmada MM, Wen-
and Its Clinical Management. Oxford, Black- sociation between HLA-DR antigens and dell SK, Crosslin DR, Laurie CC, Doheny KF,
well Munksgaard, 2008, pp 36. helper cell activity in the control of dental car- Pugh EW, Zhang Q, Feenstra B, Geller F,
Fine DH, Toruner GA, Velliyagounder K, Sam- ies. Nature 1981;292:770772. Boyd HA, Zhang H, Melbye M, Murray JC,
pathkumar V, Godboley D, Furgang D: A Menezes-Silva R, Khaliq S, Deeley K, Letra A, Weyant RJ, Crout R, McNeil DW, Levy SM,
lactotransferrin single nucleotide polymor- Vieira AR: Genetic susceptibility to periapical Slayton RL, Willing MC, Broffitt B, Vieira AR,
phism demonstrates biological activity that disease: conditional contribution of MMP2 Marazita ML: Genome-wide association scan
can reduce susceptibility to caries. Infect Im- and MMP3 genes to the development of peri- for childhood caries implicates novel genes. J
mun 2013;81:15961605. apical lesions and healing process. J Endod Dent Res 2012;90:14571462.
Gasse B, Grabar S, Lafont AG, Quinquis L, Opsahl 2012;38:604607. Shimizu T, Deeley K, Briseo-Ruiz J, Faraco IM Jr,
Vital S, Davit-Bal T, Moulis E, Chabadel O, Nariyama M, Shimizu K, Uematsu T, Maeda T: Poletta FA, Brancher JA, Pecharki GD, Kchler
Hennequin M, Courson F, Droz D, Vaysse F, Identification of chromosomes associated EC, Tannure PN, Lips A, Vieira TC, Patir A,
Laboux O, Tassery H, Al-Hashimi N, Boillot with dental caries susceptibility using quanti- Yildirim M, Mereb JC, Resick JM, Brandon
A, Carel JC, Treluyer JM, Jeanpierre M, Beld- tative trait locus analysis in mice. Caries Res CA, Cooper ME, Seymen F, Costa MC, Gran-
jord C, Sire JY, Chaussain C: Common SNPs 2004;38:7984. jeiro JM, Trevilatto PC, Orioli IM, Castilla EE,
of AmelogeninX (AMELX) and dental caries Nasidze I, Li J, Quinque D, Tang K, Stoneking M: Marazita ML, Vieira AR: Fine-mapping of
susceptibility. J Dent Res 2013;92:418424. Global diversity in the human salivary micro- 5q12.113.3 unveils new genetic contributors
Hunt HR, Hoppert CA, Erwin WG: Inheritance biome. Genome Res 2009;19:636643. to caries. Caries Res 2013;47:273283.
of susceptibility to caries in albino rats (Mus Nishi M, Stjernswrd J, Carlsson P, Bratthall D: Shimizu T, Ho B, Deeley K, Briseo-Ruiz J, Fara-
norvegicus). J Dent Res 1944;23:385401. Caries experience of some countries and areas co IM Jr, Schupack BI, Brancher JA, Pecharki
Isaksson H, Alm A, Koch G, Birkhed D, Wendt expressed by Significant Caries Index. Com- GD, Kchler EC, Tannure PN, Lips A, Vieira
LK: Caries prevalence in Swedish 20-year- munity Dent Oral Epidemiol 2002;30:296301. TC, Patir A, Yildirim M, Poletta FA, Mereb
olds in relation to their previous caries experi- Olszowski T, Adler G, Janiszewska-Olzowska J, JC, Resick JM, Brandon CA, Orioli IM, Cas-
ence. Caries Res 2013;47:234242. Safranow K, Kaczmarczyk M: MBL2, MASP2, tilla EE, Marazita ML, Seymen F, Costa MC,
Jeremias F, Koruyucu M, Kchler EC, Bayram M, AMELX, and ENAM gene polymorphisms Granjeiro JM, Trevilatto PC, Vieira AR:
Tuna EB, Deeley K, Pierri RA, Souza JF, Fra- and dental caries in Polish children. Oral Dis Enamel formation genes influence enamel
gelli CM, Paschoal MA, Gencay K, Seymen F, 2012;18:389395. microhardness before and after cariogenic
Caminaga RM, dos Santos-Pinto L, Vieira Ozturk A, Famili P, Vieira AR: The antimicrobial challenge. PLoS One 2012;7:e45022.
AR: Genes expressed in dental enamel devel- peptide DEFB1 is associated with caries. J Slade GD, Sanders AE, Do L, Roberts-Thomson
opment are associated with molar-incisor hy- Dent Res 2010;89:631636. K, Spencer AJ: Effects of fluoridated drinking
pomineralization. Arch Oral Biol 2013; 58: Patir A, Seymen F, Yildirim M, Deeley K, Cooper water on dental caries in Australian adults. J
14341442. ME, Marazita ML, Vieira AR: Enamel forma- Dent Res 2013;92:376382.
Jindal A, McMeans M, Narayanan S, Rose EK, tion genes are associated with high caries ex- Slayton RL, Cooper ME, Marazita ML: Tuftelin,
Jain S, Marazita ML, Menezes R, Letra A, Car- perience in Turkish children. Caries Res 2008; mutans streptococci, and dental caries sus-
valho FM, Brandon CA, Resick JM, Mereb JC, 42:394400. ceptibility. J Dent Res 2005;84:711714.
Poletta FA, Lopez-Camelo JS, Castilla EE, Pitts N: ICDAS an international system for car- Stanek D, Pridalov-Hnilicov J, Novotn I,
Orioli IM, Vieira AR: Women are more sus- ies detection and assessment being developed Huranov M, Blazkov M, Wen X, Sapra AK,
ceptible to caries but individuals born with to facilitate caries epidemiology, research and Neugebauer KM: Spliceosomal small nuclear
clefts are not. Int J Dent 2011;2011:454532. appropriate clinical management. Commu- ribonucleoprotein particles repeatedly cycle
Kang SW, Yoon I, Lee HW, Cho J: Association nity Dent Health 2004;21:193198. through Cajal bodies. Mol Biol Cell 2008; 19:
between AMELX polymorphisms and dental Pol J: Association of the polymorphism of MUC7 25342543.
caries in Koreans. Oral Dis 2011;17:399406. gene encoding the low-molecular-weight mu- Tannure PN, Kchler EC, Falagan-Lotsch P,
Kawasaki K, Suzuki T: Molecular evolution of cin MG2 with susceptibility to caries. Ann Amorim LMF, Raggio Luiz R, Costa MC,
matrix metalloproteinase 20. Eur J Oral Sci Acad Med Stetin 2011;57:8591. Vieira AR, Granjeiro JM: MMP13 polymor-
2011;119:247253. Potter RH: Twin half-sibs: a research design for phism decreases risk for dental caries. Caries
Klein H, Palmer CE: Dental caries in brothers and genetic epidemiology of common dental dis- Res 2012a;46:401407.
sisters of immune and susceptible children. orders. J Dent Res 1990;69:15271530. Tannure PN, Kchler EC, Lips A, Costa MC, Luiz
Milbank Mem Fund Q 1940;18:6782. Reich E, Lussi A, Newbrun E: Caries-risk assess- RR, Granjeiro JM, Vieira AR: Genetic varia-
Krasone K, Lce B, Akota I, Care R, Deeley K, ment. Int Dent J 1999;49:1526. tion in MMP20 contributes to higher caries
Kchler EC, Vieira AR: Genetic variation in Risch N, Merikangas K: The future of genetic experience. J Dent 2012b;40:381386.
the promoter region of beta-defensin 1 (DEFB studies of complex human diseases. Science Toledano M, Niero-Aguilar R, Osorio R, Campos
1) is associated with high caries experience in 1996;273:15161517. A, Osorio E, Tay FR, Alaminos M: Differen-
children born with cleft lip and palate. Acta Roa NS, Chaves M, Gmez M, Jaramillo LM: As- tial expression of matrix metalloproteinase-2
Odontol Scand 2013, Epub ahead of print. sociation of salivary proteins with dental car- in human coronal and radicular sound and
Kchler EC, Deeley K, Ho B, Linkowski S, Meyer ies in a Colombian population. Acta Odontol carious dentine. J Dent 2010;38:635640.
C, Noel J, Kouzbari MZ, Bezamat M, Gran- Latinoam 2008;21:6975. Valarini N, Maciel SM, Moura SK, Poli-Frederico
jeiro JM, Antunes LS, Antunes LA, de Abreu Shaffer JR, Feingold E, Wang X, Lee M, Cuenco RC: Association of dental caries with HLA
FV, Costa MC, Tannure PN, Seymen F, Ko- KT, Weeks DE, Weyant RJ, Crout R, McNeil class II allele in Brazilian adolescents. Caries
ruyucu M, Patir A, Mereb JC, Poletta FA, Cas- DW, Marazita ML: GWAS of dental caries Res 2012;46:530535.
114.125.31.247 - 7/4/2017 9:24:03 AM
DOI: 10.1159/000358333
Downloaded by: