Single nucleotide polymorphisms in

odontogenesis-related genes associated with

tooth-size discrepancy
Caio Luiz Bitencourt Reis,* Guido Artemio Marañón-Vásquez,†
Mirian Aiko Nakane Matsumoto,* Flares Baratto-Filho,‡
Maria Bernadete Sasso Stuani,* Peter Proff,§ Christian Kirschneck§
and Erika Calvano Küchler§
Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil*
Department of Pediatric Dentistry and Orthodontics, School of Dentistry, Federal University of Rio de Janeiro,
Rio de Janeiro, Brazil†
School of Dentistry, Univille University, Joinville-SC, Brazil‡
Department of Orthodontics, University Medical Centre of Regensburg, Regensburg, Germany §

Introduction: The present study aimed to determine the association between single nucleotide polymorphisms (SNPs) in RUNX2,
SMAD6, BMP2, and BMP4 genes in relation to tooth-size discrepancy (TSD).
Methods: A cross-sectional study of patients undergoing orthodontic treatment measured the mesiodistal width of permanent teeth
from pretreatment dental casts. Sixty-two patients were included in the study and TSD was assessed according to the Bolton
analysis. The patients were allocated into a control group (without a TSD), an anterior excess group and an overall excess group.
Genomic DNA was extracted from saliva samples, and SNPs previously associated with tooth size were evaluated using a real-
time polymerase chain reaction (PCR) system. The Fisher exact test was performed to compare genotype and allele frequencies at
an α = 0.05. An Odds Ratio (OR) and 95% Confidence Interval (95% CI) were calculated.
Results: The rs59983488 SNP in the RUNX2 gene was significantly related to the presence of anterior mandibular tooth-size
excess in allele (T allele: p<0.001; OR = 11.74; 95% CI =2.61–55.80), and genotype models (GT genotype: p = 0.002;
OR = 12.69; 95% CI = 2.47–64.83). The rs3934908 SNP in the SMAD6 gene was significantly associated with the presence
of an overall maxillary tooth-size excess in allele (T allele: p < 0.001) and genotype models (TT genotype: p = 0.010).
Conclusions: The present results suggest that SNPs in RUNX2 (rs59983488) and SMAD6 (rs3934908) genes may be associated
with the presence of tooth-size excess.
(Aust Orthod J 2023; 39: 86 - 95. DOI: 10.2478/aoj-2023-0008)

Received for publication: August, 2022

accepted: January, 2023.

Caio Luiz Bitencourt Reis: caioluizreis@usp.br; Guido Artemio Marañón-Vásquez: guido_amv@hotmail.com;

Mirian Aiko Nakane Matsumoto: manakane@forp.usp.br; Flares Baratto-Filho: fbaratto1@gmail.com;
Maria Bernadete Sasso Stuani: bernadete@forp.usp.br; Peter Proff: peter.Proff@klinik.uni-regensburg.de;
Christian Kirschneck: christian.Kirschneck@klinik.uni-regensburg.de; Erika Calvano Küchler: erikacalvano@gmail.com

the dental arches because accepted overbite, overjet

Introduction
A tooth-size discrepancy (TSD) is characterised by
a dimensional disproportion in the mesiodistal size
between the maxillary and mandibular teeth1,2. A
TSD contributes to an altered relationship between
and interdigitation require a certain proportional
size relationship between the teeth.3,4 Successful
orthodontic treatment with regard to a functional
and aesthetic occlusion also, in part, depends on an
accurate TSD diagnosis and intervention.1,2

86   Australasian Orthodontic Journal Volume 39 No. 1 2023 ☉ Open Access. Published by Sciendo. cc BY 4.0 © 2023 Author(s). This work is licensed under
the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/)
 REIS, MARAÑÓN-VÁSQUEZ, MATSUMOTO, BARATTO-FILHO, SASSO STUANI, PROFF, KIRSCHNECK AND KÜCHLER
Tooth size is determined at the commencement of the
dental development stage.5 Odontogenesis involves a
complex mechanism of interaction between signalling
networks and growth factors.6–8 Bone morphogenetic
protein 4 (BMP4) is an important growth factor
inducing tooth development as it stimulates the
differentiation of mesenchymal-derived dental-
specific cells from the beginning of tooth formation.6,9
BMP4 also regulates Runt-related transcription
factor 2 (RUNX2), which is a critical transcriptional
regulator of tooth formation.7,10 RUNX2 controls the
morpho-differentiation and growth of the embryonic
epithelium of the enamel organ which precedes the
formation of tooth enamel.8 In addition, RUNX2
stimulates BMP2 production which is a key protein
involved in odontogenic differentiation and the
control of enamel mineralisation.11 Additionally,
SMAD proteins are important mediators affecting
this network of signaling pathways.8,12
Single nucleotide polymorphism (SNP) is a DNA
sequence variation occurring when a single nucleotide
in the genome differs between members or paired
chromosomes of an individual. Recent studies have
investigated SNPs in odontogenesis-related genes and
identified some as possible relevant factors related to
tooth-size variability in humans.13–15 Therefore, SNPs
associated with growth factors that play an important
role in odontogenesis could be a risk factor for TSD.
Therefore, the current study aimed to investigate the
association between SNPs in BMP4, BMP2, RUNX2
and SMAD6 genes and TSD.
Methods
The present cross-sectional study was approved by
the Local Research Ethics Committee (protocol:
01451418.3.0000.5419/3.150.551) and all included
patients and their legal guardians signed written
informed consent according to the Declaration
of Helsinki. The STREGA (STrengthening the
REporting of Genetic Association Studies) checklist
was used to design and report this study.16
The study included pretreatment dental casts and
genomic DNA samples from self-reported white
and biologically unrelated patients undergoing
orthodontic treatment at School of Dentistry of
Ribeirão Preto, University of São Paulo from 2016 to
2018. Patients with a previous history of orthodontic
treatment, congenital syndromes, tooth anomalies,
interproximal caries, restorations or enamel
reduction, occlusal dental wear, fractured or poor-
quality dental casts, and extreme tooth misalignment,
were excluded. The sample was previously described
by Marañón-Vásquez et al.13 Sixty-two patients were
included in the current study.
A single dentist evaluated ten random dental casts
twice within a two-week period to conduct an intra-
examiner reliability test. The intraclass correlation
coefficient (ICC) estimated a high reproducibility
for all teeth (ICC ranging from 0.888 to 0.996).
Mesiodistal tooth width was obtained by the
largest crown distance between the lateral contact
point parallel to the occlusal plane (maximum
side-distal distance). A digital calliper (Digimatic
CD-15DCX; Mitutoyo, Kawasaki, Japan) was
used for measurements. All teeth of each maxillary
and mandibular cast were consecutively measured
three times and, when the difference between the
measurements was more than 0.2 mm, the tooth was
remeasured.
TSD was assessed using the Bolton analysis.17
Bolton ratios were calculated according to the pre-
existing formula for the establishment of an anterior
discrepancy ratio and overall discrepancy ratio, as
follows:
TSD was classified according to Bolton17 as
Anterior TSD: Bar < 75.55 and Bar > 78.85 were
considered as maxillary and mandibular tooth-size
anterior excess, respectively. Bar ranging from 75.55
to 78.85 was classified as an absence of anterior TSD.
Overall TSD: Bor < 89.39 and Bor > 93.21 were
considered as maxillary or mandibular overall tooth-
size excess, respectively. Bor ranging from 89.39 to
93.21 was classified as an absence of overall TSD.
DNA was extracted from saliva according to the
protocol previously published by Küchler et al.18
and was used for the molecular analysis. SNPs in
RUNX2, SMAD6, BMP2, and BMP4 genes that
were previously associated with permanent tooth
size14 were selected for genotyping analysis. The
SNP characteristics are shown in Table I. Probes
(Applied Biosystems, Foster City, CA, USA) were
used for genotyping in a real-time polymerase
chain reaction (PCR) system (Applied Biosystems,
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SINGLE NUCLEOTIDE POLYMORPHISMS IN ODONTOGENESIS-RELATED GENES ASSOCIATED WITH TOOTH-SIZE DISCREPANCY
Table I. Characteristics of SNPs.
Genes SNPs Type of Alteration
RUNX2 rs59983488 Upstream Variant
Rs1200425 Intron Variant
SMAD6 rs3934908 Intron Variant
Rs211261 Intron Variant
BMP2 rs1005464 Intron Variant
rs235768 Missense Variant
BMP4 Rs17563 Missense Variant
A, adenine; C, cytosine; G, guanine; MAF, Minor Allele Frequency; T, thymine.
Data are available in https://www.ncbi.nlm.nih.gov/snp.
Foster City, CA, USA) according to the Taqman
method.19 All reactions were performed blindly and
10% of the sample was genotyped twice to test for
reproducibility, which was 100%.
Statistical analysis
The Hardy–Weinberg equilibrium of each SNP was
evaluated by the chi-square test. Genotype and allele
distributions were compared using Fisher’s exact test.
Odds Ratios (OR) and 95% Confidence Intervals
(95% CI) were also calculated. A Bonferroni
adjustment was applied for the total number of SNPs
(0.05/7 = 0.007). IBM SPSS Version 25.0 (IBM
Corp, Armonk, USA) software was used for all
analyses.
Results
The number of excluded patients from the study and
associated reasons are shown in Figure 1. Sixty-two
patients participated, 33 females (53.2%) and 29
(46.8%) males. The mean age of the patients was
15.65 years (Standard Deviation = 6.82 years).
The genotyping success rate of each SNP is presented
in Table I. The Hardy–Weinberg equilibrium (HWE)
was assessed by a chi-square test (clinicalc.com),
and all SNPs were within the HWE (p>0.05). This
indicated that allele frequencies in this population
did not change from generation to generation.
Table II demonstrates the allele and genotype
distribution between the groups for the overall TSD
analysis. The rs59983488 SNP in the RUNX2 gene
was significantly associated with the presence of an
88   Australasian Orthodontic Journal Volume 39 No. 1 2023
Base Change Global MAF* Genotyping success rate
G > T 0.15 88.7%
G > A 0.44 87.0%
C > T 0.41 91.9%
C > T 0.19 90.3%
G > A 0.19 91.9%
T > A 0.32 90.3%
A > G 0.42 88.7%
anterior mandibular tooth-size excess in allele (T
allele: p<0.001; OR = 11.74; 95% CI =2.61–55.80),
and genotype models (GT genotype: p = 0.002;
OR = 12.69; 95% CI = 2.47–64.83).
Table III demonstrates the allele and genotype
distribution between the groups for the anterior Bolton
analysis. The rs3934908 SNP in the SMAD6 gene was
significantly associated with the presence of overall
maxillary tooth-size excess in allele (T allele: p < 0.001)
and genotype models (TT genotype: p = 0.010).
Discussion
Predictions of skeletal and tooth patterns is a challenging
aspect of orthodontic practice.20 Knowledge regarding
the genes involved in tooth morphology that could be
used to predict tooth-size excess in each patient will
assist an individual orthodontic treatment plan and
prognosis as well as in the screening of patients. In the
present study, the association between SNPs in RUNX2
and SMAD6 genes and TSD, is identified for the first
time which may, in the future, be used in orthodontic
finishing strategies to optimise TSD-dependent
treatment outcomes.21
RUNX2 was selected in the study due to its
important role in tooth development and, potentially,
in final tooth morphology.8 Besides regulating
odontoblast differentiation, RUNX2 also plays a
role in the later stages of odontogenesis, mainly
before crown formation. RUNX2 mRNA is strongly
expressed in immature and mature ameloblasts and
is also known to regulate the transcription of the
Amelobastin (Ambn) gene, one of the major proteins
of enamel matrix.8 SNPs in RUNX2 have been
 REIS, MARAÑÓN-VÁSQUEZ, MATSUMOTO, BARATTO-FILHO, SASSO STUANI, PROFF, KIRSCHNECK AND KÜCHLER
Figure 1. Patient flow of the study.
previously associated with tooth development and
size.14 In the present study, the recessive allele (T)
of rs59983488 was associated with the presence of
anterior mandibular tooth-size excess. This SNP
is located in a binding site of an intronic region of
the RUNX2 gene and has already been associated
with cleidocranial dysplasia,22 and also with tooth-
size variability.14 The exact functional effect of this
SNP on Runx2 is still unknown; however, Napierala
et al.22 showed that the recessive allele prevents
binding between the RUNX2 gene and the Myeloid
Zinc-Finger transcription factor 1 (MZF1). MZF1
is a factor that acts as a transcriptional repressor in
stem cells, which may subsequently modify RUNX2
expression and affect tooth development.
SMAD6 is characterised by an inhibitory SMAD
protein that restricts the cellular response to BMPs and
transforming growth factor β  (TGFβ ).6,23 This mediator
is present in all tooth-formation stages, but mainly at
the initiation stage of tooth development.12 Therefore,
it is hypothesised that SNPs in SMAD6 are involved
in tooth morphogenesis. In addition, SNPs in SMAD6
have already been associated with other craniofacial
traits, as craniosynostosis,24 skeletal patterns,25 palatal
rugae,26 and tooth agenesis.27 Of note, some of these
factors have been associated with tooth size variation,14
suggesting that these different phenotypes share a
common genetic background. The present results
suggest an association between rs3934908 in SMAD6
and overall maxillary tooth-size excess. Although
Gerber et al.14 did not find an association between this
SNP and mesiodistal and buccal-lingual tooth sizes, it
is important to consider that previous studies focused
on the evaluation of TSD/tooth excess and therefore
differed from the present study and possibly explains
this divergence of results. Further research is indicated
to clarify the exact role of SMAD6 in odontogenesis
and tooth-size determination.
The findings of the present study indicated that
rs59983488 in RUNX2 was associated with anterior
tooth-size excess, but not with overall tooth-size
excess. Similarly, the rs3934908 in SMAD6 was
associated with overall tooth-size excess, but not with
anterior tooth-size excess. Furthermore, the SNPs
were associated with tooth-size excess in only one of
the arches, and not in both arches. Previous studies
have indicated that the morphogenesis of each type
of tooth is regulated by different growth factors and
different sets of genes.6,8,12 Therefore, it is reasonable
to suggest that SNPs in growth factor decoder genes
can influence the tooth size of only one type, one
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 Table II. Allelic and Genotypic distribution between anterior TSD groups and comparison by Fisher Test.

90  
Control vs. Maxillary tooth-size anterior excess Control vs. Mandibular tooth-size anterior excess

95%
Comparison Alleles or Maxillary Mandibular Odds Confidence
Gene SNP Type Genotypes Control (%) (%) p-value OR 95% CI (%) p-value Ratio Interval
RUNX2 rs59983488 Allelic G 60 (96.8) 14 (87.5) Ref. 23 (71.9) Ref.
T 2 (3.2) 2 (12.5) 0.184 4.28 0.61–28.44 9 (28.1) <0.001** 11.74 2.61–55.80
Genotypic GG 29 (93.5) 6 (75.0) Ref. 8 (50) Ref.
GT 2 (6.5) 2 (25.0) 0.180 4.83 0.62–33.70 7 (43.8) 0.002** 12.69 2.47–64.83
TT 0 (0.0) 0 (0.0) >0.999 - - 1 (6.3) 0.236 - -
rs1200425 Allelic G 37 (63.8) 13 (81.3) Ref. 21 (61.8) Ref.
A 21 (36.2) 3 (18.7) 0.237 0.40 0.11–1.56 13 (38.2) >0.999 1.09 0.47–2.64

Australasian Orthodontic Journal Volume 39 No. 1 2023

Genotypic GG 14 (48.3) 6 (75.0) Ref. 6 (35.3) Ref.
GA 9 (31.0) 1 (12.5) 0.371 0.25 0.02–2.47 9 (52.9) 0.320 2.33 0.61–7.90
AA 6 (20.7) 1 (12.5) 0.633 0.38 0.02–2.87 2 (11.8) 0.268 4.66 0.44–71.52
SMAD6 rs3934908 Allelic C 33 (53.2) 7 (43.7) Ref. 19 (52.8) Ref.
T 29 (46.8) 9 (56.3) 0.580 1.46 0.47–4.12 17 (47.2) >0.999 1.01 0.45–2.25
Genotypic CC 9 (29.0) 2 (25.0) Ref. 4 (22.2) Ref.
CT 15 (48.4) 3 (37.5) >0.999 0.90 0.15–5.84 11 (61.1) 0.728 1.65 0.38–5.76
TT 7 (22.6) 3 (37.5) 0.635 1.92 0.31–12.80 3 (16.7) 0.134 0.25 0.06–1.12
rs211261 Allelic C 29 (55.8) 10 (62.5) Ref. 19 (55.9) Ref.
T 23 (44.2) 6 (37.5) 0.774 0.75 0.22–2.42 15 (44.1) >0.999 0.99 0.39–2.41
Genotypic CC 10 (32.3) 2 (25.0) Ref. 3 (17.6) Ref.
CT 19 (61.3) 6 (75.0) >0.999 1.57 0.27–8.71 13 (76.5) 0.322 2.28 0.53–8.75
SINGLE NUCLEOTIDE POLYMORPHISMS IN ODONTOGENESIS-RELATED GENES ASSOCIATED WITH TOOTH-SIZE DISCREPANCY

TT 2 (6.5) 0 (0.0) >0.999 - - 1 (5.9) >0.999 1.66 0.08–18.07

BMP2 rs1005464 Allelic G 52 13 Ref. 29 Ref.
A 10 3 0.723 1.20 0.31–4.59 5 >0.999 0.89 0.31–2.82
Genotypic GG 23 (74.2) 6 (75.0) Ref. 12 (70.6) Ref.
GA 6 (19.4) 1 (12.5) >0.999 0.63 0.04–4.54 5 (29.4) 0.721 1.59 0.41–5.53
*p < 0.05. **p < 0.007.
 Table II. Allelic and Genotypic distribution between anterior TSD groups and comparison by Fisher Test.

Control vs. Maxillary tooth-size anterior excess Control vs. Mandibular tooth-size anterior excess

95%
Comparison Alleles or Maxillary Mandibular Odds Confidence
Gene SNP Type Genotypes Control (%) (%) p-value OR 95% CI (%) p-value Ratio Interval
AA 2 (6.5) 1 (12.5) 0.536 1.91 0.11–18.28 0 (0.0) >0.999 - -
rs235768 Allelic T 47 (75.8) 11 (68.7) Ref. 26 (72.2) Ref.
A 15 (24.2) 5 (31.3) 0.539 1.42 0.46–4.88 10 (27.8) 0.810 1.20 0.44–2.92
Genotypic TT 16 (51.6) 4 (50.0) Ref. 9 (50.0) Ref.
TA 15 (48.4) 3 (37.5) >0.999 0.80 0.17–3.41 8 (44.4) >0.999 0.94 0.30–2.84
AA 0 (0.0) 1 (12.5) 0.23 - - 1 (5.6) 0.384 - -
BMP4 rs17563 Allelic A 39 (62.9) 9 (64.3) Ref. 21 (61.8) Ref.
G 23 (37.1) 5 (35.7) >0.999 0.94 0.31–3.11 13 (38.2) >0.999 1.05 0.46–2.47
Genotypic AA 13 (41.9) 2 (28.6) Ref. 7 (41.2) Ref.
AG 13 (41.9) 5 (71.4) 0.413 2.50 0.37–13.97 7 (41.2) >0.999 1.00 0.25–3.96
GG 5 (16.1) 0 (0.0) >0.999 - - 3 (17.6) >0.999 1.11 0.23–5.39
*p < 0.05. **p < 0.007.

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 Table III. Allelic and Genotypic distribution between overall TSD groups and comparison by Fisher Test.

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Control vs. Maxillary tooth-size overall excess Control vs. Mandibular tooth-size overall excess

95% 95%
Alleles or Maxillary Odds Confidence Mandibular Odds Confidence
Gene SNP Model Genotypes Control (%) (%) p-value ratio Interval (%) p-value Ratio Interval
RUNX2 rs59983488 Allelic G 56 (93.3) 8 (80.0) Ref. 33 (82.5) Ref.
T 4 (6.7) 2 (20.0) 0.201 3.50 0.57–17.98 7 (17.5) 0.110 2.97 0.83–9.51
Genotypic GG 26 (86.7) 3 (60.0) Ref. 14 (70.0) Ref.
GT 4 (13.3) 2 (40.0) 0.195 4.33 0.58–25.79 5 (25.0) 0.281 2.32 0.53–8.40
TT 0 (0.0) 0 (0.0) >0.999 - - 1 (5.0) 0.365 - -
rs1200425 Allelic G 35 (60.3) 8 (80.0) Ref. 28 (70.0) Ref.
A 23 (39.7) 2 (20.0) 0.303 0.38 0.07–1.88 12 (30.0) 0.393 0.65 0.28–1.49

Australasian Orthodontic Journal Volume 39 No. 1 2023

Genotypic GG 14 (48.3) 3 (60.0) Ref. 9 (45.0) Ref.
GA 7 (24.1) 2 (40.0) >0.999 1.33 0.19 – 7.73 10 (50.0) 0.337 2.22 0.64–7.51
AA 8 (27.6) 0 (0.0) 0.527 - - 1 (5.0) 0.210 0.19 0.01–1.58
SMAD6 rs33408 Allelic C 38 (59.4) 0 (0.0) Ref. 21 (52.5) Ref.
T 26 (40.6) 10 (100) <0.001** ∞ 3.75 - ∞ 19 (47.5) 0.544 1.32 0.57–2.85
Genotypic CC 10 (31.3) 0 (0.0) Ref. 5 (25.0) Ref.
CT 18 (56.3) 0 (0.0) >0.999 - - 11 (55.0) >0.999 1.22 0.34–4.33
TT 4 (12.4) 5 (100) 0.010* ∞ 1.96–∞ 4 (20.0) 0.657 2.00 0.39–10.88
rs211261 Allelic C 38 (61.3) 6 (60.0) Ref. 24 (60.0) Ref.
T 24 (38.7) 4 (40.0) >0.999 1.05 0.31–3.72 16 (40.0) >0.999 1.05 0.47–2.28
Genotypic CC 9 (29.0) 1 (20.0) Ref. 5 (25.0) Ref.
CT 20 (64.5) 4 (80.0) >0.999 1.80 0.22–24.21 14 (70.0) >0.999 1.26 0.36–4.31
SINGLE NUCLEOTIDE POLYMORPHISMS IN ODONTOGENESIS-RELATED GENES ASSOCIATED WITH TOOTH-SIZE DISCREPANCY

TT 2 (6.5) 0 (0.0) >0.999 - - 1 (5.0) >0.999 0.90 0.05–9.37

BMP2 rs1005464 Allelic G 50 (80.6) 8 (80.0) Ref. 36 (90.0) Ref.
A 12 (19.4) 2 (20.0) >0.999 1.04 0.20–5.72 4 (10.0) 0.269 0.46 0.15–1.44
Genotypic GG 22 (71.0) 3 (60.0) Ref. 16 (80.0) Ref.
GA 6 (19.3) 2 (40.0) 0.573 2.44 0.35–13.91 4 (20.0) >0.999 0.91 0.25–3.29
Notes: *p < 0.05. **p < 0.007.
 Table III. Allelic and Genotypic distribution between overall TSD groups and comparison by Fisher Test.

Control vs. Maxillary tooth-size overall excess Control vs. Mandibular tooth-size overall excess

95% 95%
Alleles or Maxillary Odds Confidence Mandibular Odds Confidence
Gene SNP Model Genotypes Control (%) (%) p-value ratio Interval (%) p-value Ratio Interval
AA 3 (9.7) 0 (0.0) >0.999 - - 0 (0.0) 0.268 - -
rs235768 Allelic T 48 (75.0) 8 (80.0) Ref. 28 (70.0) Ref.
A 16 (25.0) 2 (20.0) >0.999 0.75 0.14–3.84 12 (30.0) 0.651 1.28 0.55–3.18
Genotypic TT 17 (53.1) 3 (60.0) Ref. 9 (45.0) Ref.
TA 14 (43.8) 2 (40.0) >0.999 0.80 0.13–4.44 10 (50.0) 0.771 1.34 0.40–3.89
AA 1 (3.1) 0 (0.0) >0.999 - - 1 (5.0) >0.999 1.88 0.09–37.71
BMP4 rs17563 Allelic A 34 (55.7) 6 (60.0) Ref. 29 (72.5) Ref.
G 26 (43.3) 4 (40.0) >0.999 11 (27.5) 0.139 0.49 0.21–1.13
Genotypic AA 10 (33.3) 2 (40.0) Ref. 10 (50.0) Ref.
AG 14 (46.7) 2 (40.0) >0.999 0.71 0.10–5.21 9 (45.0) 0.547 0.64 0.19–1.99
GG 6 (20.0) 1 (20.0) >0.999 0.83 0.05–8.47 1 (5.0) 0.183 0.16 0.01–1.64
Notes: *p < 0.05. **p < 0.007.

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SINGLE NUCLEOTIDE POLYMORPHISMS IN ODONTOGENESIS-RELATED GENES ASSOCIATED WITH TOOTH-SIZE DISCREPANCY
arch or one group of teeth, and impact the occlusal
relationship,13–15 depending on the group of genotypes
and alleles that the patient carries. The investigated
SNPs in BMP2 and BMP4 were not associated with
tooth-size excess in the present study. Gerber et
al.14 evaluated tooth size in a Brazilian sample and
showed that the same SNPs in BMP2 and BMP4
were associated with size variability of some groups
of permanent teeth and so these genes were selected
for examination. However, the present results did not
demonstrate that the SNPs in BMP2 and BMP4 were
involved in TSD. More studies are indicated with
larger sample sizes in other populations to analyse
these and other SNPs to confirm the findings.
The method of assessing tooth-size discrepancies
proposed by Bolton17 was adopted for the current study
due to its accuracy and long-standing acceptance by
the dental profession.4 It is possible that conventional
plaster casts may not accurately reproduce exact
tooth size, which is a likely limitation of this study.
Nevertheless, carefully prepared impressions and
plaster casts should have negligible size errors. The
absence of positive associations for other analysed SNPs
may also be due to the small sample size. However, the
present study contributes to the identification of some
genes and SNPs that may affect tooth development
and impact directly on the occlusal relationship of the
individual, and therefore provides valuable information
for future studies.
Conclusions
The present results suggest that SNPs in RUNX2
and SMAD6 may be associated with the presence of
tooth-size excess.
Corresponding author
Priv.-Doz. Dr. Dr. Christian Kirschneck and Dr.
Erika Calvano Küchler, Department of Orthodon-
tics, University of Regensburg. Franz-Josef-Strauss-
Allee 11, 93053 Regensburg, Germany. Tel. +49
941/944 – 6095/6093, Fax. +49 941/944 – 6169
Email: christian.kirschneck@klinik.uni-regensburg.
de and erikacalvano@gmail.com
Conflict of interest
The authors declare that there is no conflict of
interest.
94   Australasian Orthodontic Journal Volume 39 No. 1 2023
Ethics approval and consent to participate
Informed consent/assent was obtained from all
participants and/or their legal guardians where age-
appropriate.
Availability of data and material
The data generated in the present study are included
within the manuscript.
Funding
This study was financed in part by the Coordenação
de Aperfeiçoamento de Pessoal de Nível Superior–
Brasil (CAPES)–Finance Code 001 and Alexander-
von-Humboldt-Foundation (Küchler/Kirschneck
accepted in July 4th, 2019). The São Paulo Research
Foundation (FAPESP) financed an individual
scholarship (CLBR, process 2021/02704-1).
Authors’ contributions
Conceptualisation, E.C.K., P.P., C.K.; M.A.N.M;
M.B.S.S. Methodology, M.A.N.M; M.B.S.S.;
G.A.M.V; Formal Analysis, C.L.B.R, G.A.M.V;
Resources, E.C.K., P.P., C.K.; Data Curation,
C.L.B.R.; Writing— Original Draft Preparation,
C.L.B.R.; Writing—Review & Editing, C.L.B.R.,
E.C.K., P.P., C.K.; M.A.N.M; M.B.S.S., G.A.M.V.
Funding Acquisition, E.C.K., P.P., C.K.
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