958710 JOO Journal of OrthodonticsCunha et al.

Scientific Section

Journal of Orthodontics

Human permanent tooth sizes are 1­–9

https://doi.org/10.1177/1465312520958710
DOI: 10.1177/1465312520958710
© The Author(s) 2020
associated with genes encoding Article reuse guidelines:
sagepub.com/journals-permissions
oestrogen receptors journals.sagepub.com/home/joo

Arthur S Cunha1 , Luiza Vertuan dos Santos2,

Samantha Schaffer Pugsley Baratto3,*, Zerrin Abbasoglu4,
Jennifer Tsi Gerber3, Aleysson Paza5,
Mírian Aiko Nakane Matsumoto2, Rafaela Scariot3,**,
Maria Bernadete Stuani2 and Erika Calvano Küchler3,***

Abstract
Objective: To evaluate if genetic polymorphisms in the oestrogen receptor 1 (ESR1) and oestrogen receptor 2 (ESR2)
genes encoded for oestrogen receptors alpha (ERα) and beta (ERβ) are involved in permanent tooth size.
Design: Cross-sectional study.
Setting: Orthodontic Clinic at School of Dentistry of Ribeirão Preto, University of São Paulo.
Participants: A total of 108 orthodontic patients.
Materials and Methods: Pre-treatment orthodontic records were evaluated. Dental casts were used to determine
the maximum crown measurements of fully erupted permanent teeth in the mesiodistal dimensions. Second and third
molars were not included in the analysis. Genomic DNA samples were used for the genotyping of four genetic poly-
morphisms: ESR1 (rs9340799 and rs2234693) and ESR2 (rs1256049 and rs4986938). The associations between tooth
size and sex were evaluated using t test. The associations between tooth size and genotype were analysed with linear
regression and adjusted by sex at an alpha of P⩽0.05.
Results: Female patients presented smaller tooth size than male patients. A statistically significant difference was
observed in almost all teeth (P<0.05). The genetic polymorphisms in rs9340799, rs2234693, rs1256049 and rs4986938
were associated with some tooth sizes in both the maxilla and mandible (P<0.05).
Conclusion: This study provides evidence that genetic polymorphisms in ESR1 and ESR2 could be associated with tooth
size in permanent teeth.

Keywords
Receptors, oestrogen, oestrogen receptor alpha, oestrogen receptor beta, tooth size, dental development

Date received: 30 March 2020; revised: 14 July 2020; accepted: 24 August 2020

1
 epartment of Orthodontics, School of Dentistry, State University of Rio de Janeiro, Rio de Janeiro, Brazil
D
2
Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
3
School of Health and Biological Sciences, Universidade Positivo, Curitiba, Brazil
4
Department of Pediatric Dentistry, Yeditepe University, Istanbul, Turkey
5
School of Dentistry, Univille University, Joinville, Brazil

*Current affiliation: Parana Construction Union, Curitiba, Paraná, Brazil.

**Current affiliation: Dental School, Federal University of Paraná, Department of Stomatology, Curitiba, Brazil.
***Current affiliation: Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.

Corresponding author:
Erika Calvano Küchler, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil. Department of Pediatric Dentistry,
Orthodontics and Public Health. Av. do Café, s/n Monte Alegre, Ribeirão Preto, SP, 14040-904, Brazil.
Email: erikacalvano@gmail.com
2 Journal of Orthodontics 
Introduction
Tooth development, also known as odontogenesis, is a
complex mechanism regulated by sequential and reciprocal
epithelial-mesenchymal interactions controlled by many
genetic factors. The mesenchyme derives from the neural
crest, whereas the epithelium may be ectodermal or endo-
dermal (Fraser et al., 2009; Soukup et al., 2008). The genes
expressed during tooth development are responsible for the
determination of the position (Chattopadhyay and Srinivas,
1996), number (Küchler et al., 2013), shape (Lee et al.,
2012) and size of teeth (de Saboia et al., 2013; Kirac et al.,
2016; Lee et al., 2012; Thesleff, 2018).
To date, the mechanism involved in tooth development
demonstrated that many proteins can have different func-
tions during the various processes of organogenesis and
during the development of primary and permanent teeth
(Kolenc-Fusé, 2004). In past decades, active research in
many groups worldwide has led to the understanding of the
steps of tooth morphogenesis (Jernvall and Thesleff, 2012)
and the discovery of some hundreds of genes that regulate
tooth development (Thesleff, 2018).
Studies with animal models, human teeth samples and in
vitro studies have demonstrated that oestrogen receptors
(both ERα and ERβ) are expressed in dental tissues and
cells (Alhodhodi et al., 2017; Ferrer et al., 2005; Hietala
et al., 1998; Jukić et al. 2003), including ameloblasts (Ferrer
et al., 2005; Jedeon et al., 2016), odontoblasts (Hietala
et al., 1998) and dental pulp (Alhodhodi et al., 2017; Jukić
et al.. 2003). Although both sexes express oestrogen recep-
tors, some gender differences might exist. For example,
Jukić et al. (2003) showed higher expression of oestrogen
receptors in female dental pulp than male pulp. Jedeon
et al. (2016) demonstrated that the quality of enamel could
be explained by the preferential impact of endocrine-dis-
rupting chemical on the enamel of male rats, raising the
issue of the hormonal influence on amelogenesis and pos-
sible sexual dimorphism in enamel quality.
ERα and ERβ also play an important role in the growth,
development and morphology of the dental arches after
birth (Marquez Hernandez et al., 2011). Oestrogen binds to
either ERα or ERβ, activating other oestrogen-responsive
genes and stimulating ER-positive cell lines. It is via ERα
and ERβ that oestrogen plays its diverse function in many
tissues, including cell proliferation and differentiation
(Klinge et al., 2004; Li et al., 2014).
There is some evidence suggesting that oestrogen is
involved in tooth dimension. This evidence is based on the
well-known sexual dimorphism in human permanent denti-
tion (Angadi et al., 2013; da Silva et al., 2019; Sabóia et al.,
2013; Sorenti et al., 2019) and the fact that female patients
with Turner syndrome, which is a chromosomal condition
that presents a lack of endogenous oestrogen, also present
reduced crown size (Faggella et al., 2006). Then, it is reason-
able to hypothesise that the oestrogen receptor 1 (ESR1) and
oestrogen receptor 2 (ESR2) genes encode for ERα and ERβ,
respectively, and are involved in tooth size. The genetic
polymorphisms rs9340799 (XbaI) and rs2234693 (PvuII) in
ESR1 and rs1256049 and rs4986938 in ESR2 are single
nucleotide polymorphisms frequent in different populations
and highly explored in different health conditions (NCBI,
2009). XbaI and PvuII have been associated with different
conditions, such as osteoporosis (van Meurs et al., 2003) and
shorter stature (Schuit et al., 2004). These polymorphisms
are located in the intronic region and may affect the binding
of the transcription factor, resulting in the alteration of pro-
tein expression (Herrington et al., 2002). Therefore, the aim
of the present study was to investigate if genetic polymor-
phisms in ESR1 and ESR2 are associated with human perma-
nent tooth size.
Materials and Methods
The human research ethics committee of the Ribeirão
Preto Dental School, University of São Paulo (no.
50765715.3.0000.5419) approved this cross-sectional study.
STrengthening the REporting of Genetic Association ­studies
(STREGA) criteria were used to report the data presented
here (Little et al., 2009).
Patient screening and tooth dimensions
Pre-treatment orthodontic records (X-rays and dental casts)
from the Orthodontic Clinic of São Paulo University were
evaluated before patient recruitment. The patients were con-
secutively recruited during the years 2016–2018. Patients
were invited to participate in the study. Biologically unrelated
patients with no syndromes were included. The anamnesis and
radiographic records were assessed; patients with chronic dis-
eases, hypodontia/oligodontia, congenital alterations (includ-
ing cleft lip with/without cleft palate) and/or syndromes were
excluded. Finally, 108 patients were included (53 male
patients, 55 female patients; mean age = 15.0 ± 7.2 years).
Orthodontic diagnostic casts of both dentitions (maxilla
and mandible) were used to determine the maximum crown
measurements in millimetres in the mesiodistal direction at
an accuracy of 0.1 mm using a digital calliper (Mitutoyo
500-752-20 Digimatic Digital Calliper). Measurements
were established as the greatest distances among the mesial
and distal anatomical proximal points of contact of the tooth
on a line perpendicular to the long axis of the tooth. All fully
erupted permanent teeth were measured; the only excep-
tions were the second and third molars, which were not
included in this analysis due to the mean age of the sample.
Teeth with cavitated dental caries in the mesial or distal sur-
faces, occlusal wear, restorations in the mesial or distal sur-
faces and dental abnormalities were not evaluated.
All measurements were undertaken with a rigorous crite-
rion to minimise variation as reported by Fess (Fess, 1995) by
a single calibrated operator, as demonstrated in Figure 1. The
dental cast analyses were performed as previously reported
(Cunha et al., 2020). Over four months, five dental casts were
analysed every day to avoid fatigue of the operator. Each
tooth was measured three consecutive times and the
Cunha et al. 3
Figure 1.  Dental cast measurement.
arithmetic mean was calculated for further analyses.
Measurements were repeated another three times if results
differed by > 0.2 mm. To assess the reliability of the analy-
ses, dental casts of 10 patients were chosen and all tooth
measurements were assessed twice at a minimum of two
weeks apart in order to test the repeatability of the operator.
An intraclass correlation coefficient (ICC 95%) was esti-
mated to evaluate the random error of intra-observer variabil-
ity, which was in the range of 0.87–0.99 in the present study.
Collection of saliva, extraction of DNA and
genotyping
Samples of saliva were collected from the included patients
and the genomic DNA was extracted from buccal epithelial
cells with an established protocol previously described
(Küchler et al., 2012). Quantification of the concentration of
the DNA was evaluated by spectrophotometer (Nanodrop
1000; Thermo Scientific, Wilmington, DE, USA). Table 1
Table 1.  Characteristics of the studied genetic variants.
Gene Gene official full name Chromosome
ESR1 Oestrogen receptor alpha 6 rs2234693†
ESR1
ESR2 Oestrogen receptor beta 14
ESR2
*Base change in bold means polymorphic allele.
†
Also known as PvuII.
‡
Also known as XbaI.
MAF, minor allele frequency
Sources: dbSNP from: https://www.ncbi.nlh.nih.gov/snp/; http://genome.uscs.edu/ and https://www.thermofisher.com.
describes the studied genetic polymorphisms in ESR1
(rs9340799 and rs2234693) and in ESR2 (rs1256049 and
rs4986938), which were blindly genotyped by real-time pol-
ymerase chain reactions (RT-PCR) and TaqMan technology
on a StepOnePlus™ sequence detection system (Applied
Biosystems™, Foster City, CA, USA) according to a proto-
col (Ranade et al., 2001). RT-PCRs were made in a total vol-
ume of 3.0 μL (5.0 ng DNA/reaction, 1.5 μL Taqman PCR
master mix, 0.095 SNP assay; Applied Biosystems, Foster
City, CA, USA). Thermal cycling was performed by starting
with a hold cycle of 95 °C for 10 min, followed by 40 ampli-
fication cycles of 92 °C for 15 s and 60 °C for 1 min.
Statistical analysis
The Chi-square test was used to calculate the Hardy-
Weinberg equilibrium. Mesiodistal tooth sizes among sexes
were compared using the t-test. Mesiodistal tooth size pre-
sented a normal distribution in the Kolmogorov–Smirnov
test and in the evaluation of histograms. The associations
between tooth size and genotypes were analysed using lin-
ear regression and adjusted by sex, once permanent tooth
size presents a sexual dimorphism. Beta coefficient (β) was
calculated using the software Statistical Package for Social
Science (IBM, USA). The beta coefficients (β) can be neg-
ative or positive and represent the change of the outcome
variable for every unit of change in the predictor variable.
Therefore, the beta coefficients (β) represented increased
tooth sizes in millimetres (positive values) or decreased
tooth sizes (negative values) in millimetres of each tooth
measurement (outcome variable).
The alpha was established at an alpha of P ⩽ 0.05.
Results
Figure 2 demonstrates that female patients presented
smaller tooth sizes than male patients in all teeth, and a
statistically significant difference was observed in almost
all teeth (P < 0.05). The measurements (in mm) according
to sex are presented in Supplementary Table 1.
Reference sequence Type of alteration Base change* Global MAF
Intron variant C/T 0.446/2235
‡
rs9340799 Intron variant A/G 0.281/1409
rs1256049 Intron variant C/T 0.129/649
rs4986938 Intron variant C/T 0.259/1301
4 Journal of Orthodontics 

Figure 2.  Tooth size distribution according to sex. *Statistically significant difference between sexes (P ⩽ 0.05).

Table 2.  Genotype frequency in the studied population.

Gene/polymorphism Common homozygote Heterozygote Rare homozygote

ESR1 rs2234693 (T>C) 45 45 14

ESR1 rs9340799 (A>G) 39 57 7

ESR2 rs1256049 (C>T) 100 8 0

ESR2 rs4986938 (C>T) 33 50 15

In rs2234693, four samples did not amplify. In rs9340799, five samples did not amplify. In rs4986938, 10 samples did not amplify.

The distribution of genotypes is presented in Table 2. The
associations of the maxillary teeth according to the geno-
types are presented in Table 3. On the right side, rs1256049
in ESR2 was associated with the mesiodistal size of the upper
second premolar (P = 0.050/ß = −0.301). While on the left
side, both polymorphisms in ESR1 (rs9340799 and
rs2234693) were associated with the mesiodistal size of the
upper lateral incisor (P = 0.018/ß = −0.301 and P = 0.045/ß
= −0.412, respectively). The GG genotype in ESR1
(rs9340799) was associated with the mesiodistal size of the
upper lateral incisor (P = 0.029/ß = −0.655). For ESR2, an
association was found on the upper first premolar (rs4986938)
(P = 0.038/ß = −0.297) and the upper second premolar
(rs1256049) (P = 0.050/ß = −0.286 for the right side and P
= 0.009/ß = −0.514 for the left side).
Table 4 presents the measurements of the mandibular
teeth according to the genotypes. On the right side, rs1256049
in ESR2 was significantly associated with the size of the
lower first premolar (P = 0.031/ß = −0.428). On the left
side, the GG genotype in ESR1 (rs9340799) was associated
with the size of the lower second premolar (P = 0.033/ß =
0.540). For ESR2 (rs1256049), a significant association was
found on the lower lateral incisor (P = 0.003/ß = −0.432)
and lower first premolar (P < 0.001/ß = −0.644).
 Cunha et al.

Table 3.  Association between genotypes and tooth measurement in the upper teeth on the right and left sides.

Gene/rs Reference Genotype Central incisor Lateral incisor Canine First premolar Second premolar First molar

  P value β P value β P value β P value β P value β P value β

Right
ESR1 rs9340799 GG AA 0.940 0.018 0.897 0.038 0.802 −0.047 0.395 0.175 0.236 0.294 0.749 −0.088
  AG 0.494 0.161 0.529 0.195 0.908 −0.230 0.864 0 0.035 0.550 0.148 0.876 −0.043
ESR1 rs2234693 TT CC 0.423 0.174 0.907 −0.030 0.552 −0.081 0.537 −0.111 0.322 −0.169 0.987 −0.003
  CT 0.210 0.180 0.261 0.188 0.633 0.063 0.517 −0.083 0.671 0.066 0.585 0.067
ESR2 rs1256049 CC* CT 0.400 −0.182 0.512 −0.162 0.768 0.049 0.029 −0.301 0.050 −0.286 0.482 −0.180
ESR2 rs4986938 CC TT 0.779 −0.066 0.868 0.047 0.397 0.156 0.671 0.077 0.610 −0.103 0.963 −0.008
  CT 0.270 −0.154 0.124 −0.221 0.753 −0.048 0.808 −0.033 0.976 −0.005 0.614 −0.070

Left
ESR1 rs9340799 GG AA 0.870 −0.056 0.018 0.424 0.785 0.070 0.554 0.146 0.481 0.182 0.029 −0.655
  AG 0.763 0.101 0.076 0.321 0.655 0.116 0.417 0.209 0.994 0.002 0.150 −0.420
ESR1 rs2234693 TT CC 0.517 0.157 0.045 −0.412 0.077 −0.295 0.265 −0.192 0.850 −0.039 0.153 0.273
  CT 0.214 0.180 0.865 0.025 0.658 0.057 0.434 0.104 0.673 −0.076 0.282 0.152
ESR2 rs1256049 CC* CT 0.386 −0.208 0.618 −0.117 0.786 −0.048 0.087 −0.254 0.009 −0.514 0.197 −0.381
ESR2 rs4986938 CC TT 0.640 −0.116 0.556 0.161 0.302 0.213 0.739 −0.066 0.261 0.254 0.706 0.072
  CT 0.141 −0.215 0.280 −0.161 0.776 −0.037 0.038 −0.297 0.271 0.188 0.764 −0.050

Linear regression model adjusted by sex. Reference genotypes means the genotype that was used for comparison. Bold values indicate statistical significance (P ⩽ 0.05).
*There were no individuals TT.
5
 6

Table 4.  Association between genotypes and tooth measurement in the inferior teeth on the right and left sides.

Gene/rs Reference Genotype Central incisor Lateral incisor Canine First premolar Second premolar First molar

  P value β P value β P value β P value β P value β P value β

Right
ESR1 rs9340799 GG AA 0.499 0.158 0.358 0.202 0.812 0.073 0.245 0.229 0.401 0.245 0.086 0.360
  AG 0.447 0.177 0.404 0.182 0.956 −0.017 0.858 0.034 0.915 −0.030 0.273 0.234
ESR1 rs2234693 TT CC 0.724 −0.052 0.440 −0.111 0.635 −0.087 0.359 −0.143 0.489 −0.152 0.396 −0.163
  CT 0.763 0.028 0.838 −0.020 0.747 −0.032 0.235 −0.175 0.223 −0.235 0.979 −0.004
ESR2 rs1256049 CC* CT 0.116 −0.211 0.073 −0.256 0.709 0.069 0.031 −0.428 0.238 −0.272 0.662 −0.123
ESR2 rs4986938 CC TT 0.295 0.138 0.529 0.101 0.606 −0.075 0.618 −0.097 0.496 −0.123 0.339 −0.172
  CT 0.793 0.023 0.346 −0.093 0.231 −0.126 0.954 0.008 0.604 −0.089 0.047 −0.325

LEFT
ESR1 rs9340799 GG AA 0.127 0.284 0.375 0.173 0.964 −0.011 0.565 0.138 0.033 0.540 0.719 0.108
  AG 0.208 0.243 0.453 0.147 0.951 −0.016 0.945 −0.017 0.075 0.467 0.831 0.064
ESR1 rs2234693 TT CC 0.315 −0.151 0.496 −0.096 0.838 −0.035 0.241 −0.218 0.131 −0.288 0.817 0.043
  CT 0.848 −0.018 0.898 −0.013 0.764 0.032 0.844 −0.025 0.942 −0.013 0.965 −0.006
ESR2 rs1256049 CC* CT 0.671 −0.083 0.003 −0.432 0.560 −0.114 <0.001 −0.644 0.066 −0.327 0.393 −0.200
ESR2 rs4986938 CC TT 0.400 0.129 0.759 0.054 0.858 −0.025 0.955 0.010 0.183 −0.276 0.709 −0.065
  CT 0.415 −0.081 0.257 −0.112 0.058 −0.205 0.724 −0.047 0.184 −0.223 0.107 −0.239

Linear regression model adjusted by sex. Reference genotypes means the genotype that was used for comparison. Bold values indicate statistical significance (P ⩽ 0.05).
*There were no individuals TT.
Journal of Orthodontics 
Cunha et al. 7
Discussion
The present study planned to evaluate the association
between genetic polymorphisms in the encoding oestrogen
receptor genes with the size of permanent teeth of healthy
patients. The action of oestrogen involves the specific inter-
action between the hormone and cellular receptors, which
are highly specific proteins to recognise hormones
(Compston, 2001). Thus, genetic polymorphisms in ESR1
and ESR2 were selected based on the hypothesis that genes
involved in sexual hormones could be involved in tooth size,
since sexual dimorphism is well known in human dentition
and was also observed in our population (Angadi et al., 2013;
da Silva et al., 2019; Sabóia et al., 2013; Sorenti et al., 2019).
Fagella et al. (2006) evaluated the dental characteristics
of individuals affected by Turner syndrome. In their inves-
tigation, they hypothesise that this syndrome most likely
affects the quantitative and qualitative excretion of amelo-
genin such that teeth often present enamel hypoplasia and
reduced tooth size. Amelogenin genes (AMELX and
AMELY) are located in regions of the X and Y chromo-
somes and have been described in different mammalian
species (Fontanesi et al., 2008). Turner syndrome is caused
by monosomy of the X chromosome and, therefore, amelo-
genin is haploinsufficient in this syndrome. It is possible to
assume that enamel thickness strongly contributes to the
male:female differences in tooth size.
Ameloblasts are cells that are primarily responsible for
forming and mineralising the enamel and also produce a
monolayer that is in direct contact with the forming enamel
surface. These cells express many genes responsible for
amelogenesis (Lacruz et al., 2017). It is also possible that
tooth size differences among genotypes observed in the
present study are mainly due to the effect of oestrogen and
its receptors in the enamel. Other studies also supported
that oestrogen and its receptors play an important role in
enamel development (Arid et al., 2019; Ferrer et al., 2005;
Jedeon et al., 2016; Takeshita et al., 2004). Takeshita et al.
(2004) reported that enamel microhardness is significantly
reduced in an animal model as a result of oestrogen defi-
ciency, due to the fact that oestrogen has an important role
in influencing the process of enamel and dentin mineralisa-
tion. Although it is possible that oestrogen levels during
tooth development are involved in enamel size, our study
does not present these data; however, it presents some inter-
esting results regarding oestrogen receptors and genetic
polymorphisms.
Oestrogen receptors were also demonstrated to be
involved in amelogenesis. A study evaluating an immunola-
beling pattern during enamel formation suggested a role of
ERα in ameloblast proliferation and differentiation (Ferrer
et al., 2005). Recent studies also reported that genetic poly-
morphisms in oestrogen receptors are involved in develop-
mental enamel alterations. Genetic polymorphisms in ESR1
were associated with dental fluorosis (Dalledone et al.,
2019) and with enamel defects (Arid et al., 2019). In the
present study, we demonstrated that ESR1 was associated
with tooth size of some maxillary and mandibular teeth. Our
study and these previous studies suggested that ESR1 is
involved in enamel mineralisation and enamel size, depend-
ing on the polymorphism within the gene.
It is also possible that ESR1 and ESR2 were involved in
tooth size through the dentin formation. Xu et al. (2013)
showed that lack of oestrogen has a negative influence on
dentin formation, calcium deposition and compressive
strength, indicating that oestrogen can regulate dentinogen-
esis (Xu et al., 2014). Takeshita et al. (2004) also demon-
strated that oestrogen has an important role in dentin
mineralisation (Takeshita et al., 2004). More recently,
Wang et al. (2013) provided evidence that a deficiency of
oestrogen can downregulate the odontogenic differentia-
tion of dental pulp stem cells (Wang et al., 2013), since
stem cells are pivotal to the regeneration of tooth and den-
tal–pulp complex (Yan et al., 2011). Additionally, some
developmental and experimental studies have demonstrated
the expression of both ERα and ERβ in odontoblasts and
the dental pulp tissue (Hietala and Larmas, 1992; Hietala
et al., 1998; Jukić et al. 2003; Krall et al., 1997; Ojanotko-
Harri et al., 1991). These suggested that the variations in
tooth size observed here could be a result of the effect of
ESR1 and/or ESR2 on dentin development.
It is important to highlight that a statistical difference
among genotypes did not present a left-right symmetry in
some teeth. The reason for this should be interpreted with
caution. Tooth development is a multifactorial process, in
which genes and enviromental factors play a role. It is pos-
sible that some enviromental factors are involved in the
assymetric presentation of tooth size. It is also possible that
some other genes are ivolved in the left–right asymmetry.
Unilateral occurrence of many dental conditions with a
strong genetic background, such as tooth agenesis and
supernumerary teeth, is more common than bilateral pres-
entation (Shimizu and Maeda, 2009).
The tooth is a typical example of an organ in which the
‘programme’ of its development is within genes, while
environmental factors play minimal or no role (Thesleff,
2018). Furthermore, like all organs, teeth develop from dif-
ferent cell types—cells that express many genes (Thesleff,
2018)—including oestrogen receptors (Ferrer et al., 2005;
Jedeon et al., 2016). To the best of our knowledge, this is
the first research to investigate if genetic polymorphisms in
ESR1 and ESR2 are associated with permanent tooth size.
Although we found remarkable results, it is reasonable to
emphasise that more studies in different populations are
required to confirm these results.
Conclusion
The present study provided evidence that genetic polymor-
phisms in ESR1 (rs9340799 and rs2234693) and in ESR2
8 Journal of Orthodontics 
(rs1256049 and rs4986938) are associated with permanent
tooth size.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
work was supported by the São Paulo Research Foundation
(FAPESP) (funding number: 2015/06866-5).
ORCID iDs
Arthur S Cunha https://orcid.org/0000-0001-7592-1507
Erika Calvano Küchler https://orcid.org/0000-0001-5351-2526
Supplemental material
Supplemental material for this article is available online.
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