Archives of Oral Biology 152 (2023) 105716

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Archives of Oral Biology

journal homepage: www.elsevier.com/locate/archoralbio

Association between genetic factors and molar-incisor hypomineralisation

or hypomineralised second primary molar: A systematic review
Raíssa da Silva Figueira a, 1, Francisco Wilker Mustafa Gomes Muniz b, 2, Lara Carvalho Costa a, 3,
Marcoeli Silva de Moura a, 4, Lúcia de Fátima Almeida de Deus Moura a, 5,
Bibiana Mello de Oliveira c, d, 6, Cacilda Castelo Branco Lima a, 7, Cassiano
Kuchenbecker Rösing e, 8, Marina de Deus Moura de Lima a, *, 9
a
Department of Pathology and Dental Clinic, Federal University of Piauí, Teresina, Piauí, Brazil
b
Department of Periodontology, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
c
Post Graduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
d
Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
e
Department of Periodontology, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: To determine the association between genetic factors and molar-incisor hypomineralisation (MIH)
Molar-incisor hypomineralisation and/or hypomineralised second primary molars by means of a systematic review.
Hypomineralised second primary molars Design: A search was performed in Medline-PubMed, Scopus, Embase and Web of Science databases; manual
Genetics
search and search in gray literature were also performed. Selection of articles was performed independently by
two researchers. A third examiner was involved in cases of disagreement. Data extraction was performed using
an Excel® spreadsheet and independent analysis was performed for each outcome.
Results: Sixteen studies were included. There was an association between MIH and genetic variants related to
amelogenesis, immune response, xenobiotic detoxification and other genes. Moreover, interactions between
amelogenesis and immune response genes, and SNPs in the aquaporin gene and vitamin D receptors were
associated with MIH. Greater agreement of MIH was found in pairs of monozygotic twins than dizygotic twins.
The heritability of MIH was 20 %. Hypomineralised second primary molars was associated with SNPs in the
hypoxia-related HIF-1 gene and methylation in genes related to amelogenesis.
Conclusion: With very low or low certainty of evidence, an association was observed between MIH and SNPs in
genes associated with amelogenesis, immune response, xenobiotic detox and ion transport. Interactions between
genes related to amelogenesis and immune response as well as aquaporin genes were associated to MIH. With
very low certainty of evidence, hypomineralised second primary molars was associated to a hypoxia-related gene
and to methylation in genes related to amelogenesis. Moreover, higher agreement of MIH in pairs of monozygotic
twins than dizygotic twins was observed.

* Correspondence to: Campus Universitário Ministro Petrônio Portella – Bloco 5 – Programa de Pós-Graduação em Odontologia, Bairro Ininga, CEP: 64049-550
Teresina, Piauí, Brazil.
E-mail address: mdmlima@gmail.com (M.D.M. de Lima).
1
ORCiD: 0000-0003-3684-9965.
2
ORCID: 0000-0002-3945-1752.
3
ORCiD: 0000-0003-0374-5676.
4
ORCiD: 0000-0002-9044-9025.
5
ORCiD: 0000-0002-4112-1533.
6
ORCID: 0000-0002-2679-6858.
7
ORCiD: 0000-0002-2977-6035.
8
ORCID: 0000-0002-8499-5759.
9
ORCID 0000-0002-7641–6331.

https://doi.org/10.1016/j.archoralbio.2023.105716
Received 1 March 2023; Received in revised form 1 May 2023; Accepted 5 May 2023
Available online 7 May 2023
0003-9969/© 2023 Elsevier Ltd. All rights reserved.
R. da Silva Figueira et al.
1. Introduction
Molar-incisor hypomineralisation (MIH) and hypomineralised sec­
ond primary molars are qualitative developmental defects of enamel
caused by disorders that occur during the maturation phase of amelo­
genesis (Elfrink et al., 2014; Weerheijm et al., 2001). MIH affects per­
manent first molars, and may affect incisors, premolars, second
permanent molars and the tip of the canines while hypomineralised
second primary molars affects deciduous second molars (Elfrink et al.,
2012; Lygidakis et al., 2022; Weerheijm et al., 2001). The global prev­
alence of MIH is 13.5 % (Lopes et al., 2021) and of hypomineralised
second primary molars is 6.8 % (McCarra et al., 2021).
Hypomineralised enamel is friable, susceptible to post-eruptive
breakdown and dentin hypersensitivity, is a risk factor for dental
caries and makes it difficult for restorative materials to adhere (Acosta
et al., 2022; Alifakioti et al., 2020; Americano et al., 2017; de Castro
et al., 2021; Raposo et al., 2019). In this context, hypomineralised sec­
ond primary molars and MIH negatively impact oral health-related
quality of life of affected individuals and their families (Jälevik et al.,
2021; Silva et al., 2021), in addition to overloading health systems by
demand for replacement of restorations (Schneider & Silva, 2018).
The etiology of MIH/hypomineralised second primary molars is
multifactorial and not fully elucidated, with a possible association of
genetic, epigenetic and environmental factors (Butera et al., 2021).
Some studies have observed an association between MIH/hypominer­
alised second primary molars and genetic variants that cause retention
of organic matrix proteins and a consequent reduction in the mineral
content of dental enamel (Elhennawy et al., 2017; Jeremias et al., 2013,
2016; Pang et al., 2019). Furthermore, immune system genes that
interfere with enamel development have also been associated with
enamel defects (Pang et al., 2019). However, the results of these studies
are contradictory. The evidence points out that certain systemic and
genetic factors act synergistically to produce enamel hypomineralisation
(Lygidakis et al., 2022). According to a systematic review, prematurity,
cesarean delivery, perinatal hypoxia, measles, urinary tract infection,
otitis media, gastric disorders, bronchitis, kidney diseases, pneumonia,
asthma, fever and antibiotic use are the main systemic factors associated
with MIH (Garot et al., 2022). Therefore, MIH seems to follow a
multifactorial model with genetic and/or epigenetic components
becoming more prominent in the most recently published evidence
(Lygidakis et al., 2022).
Considering that information on genetic causes of MIH is scarcely
available in the literature and derived from studies with different de­
signs, a systematic review with comprehensive summary of the available
evidence on the topic is warranted. The identification of polymorphisms
and gene interactions associated with MIH and hypomineralised second
primary molars may guide future research involving gene therapies
aiming to prevent the occurrence of these developmental defects of
enamel. Therefore, this systematic review aims to answer the following
question: “Is there an association between genetic factors and MIH or
hypomineralised second primary molars?”.
2. Methods
2.1. Study design, protocol and registry
This systematic review followed the guidelines of the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses - PRISMA
Statement (Page et al., 2021) and was registered on the PROSPERO
platform (International Prospective Register of Systematic Reviews)
under the number CRD42021251752.
2.2. Review question and PECO strategy
The present study was designed based on the following question: “Is
there an association between genetic factors and MIH or
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Archives of Oral Biology 152 (2023) 105716
hypomineralised second primary molars?”.
Two PECO (P: Population, E: Exposure, C: Comparison, O: Outcome)
models were used according to the outcome studied: PECO 1: P (in­
dividuals with mixed or permanent dentition), E (family inheritance
pattern and/or genetic variants), C (absence of genetic variant), O (MIH
diagnosed by clinical examination) and PECO 2: P (individuals with
primary or mixed dentition), E (family inheritance pattern and/or ge­
netic variants), C (absence of genetic variant), O (hypomineralised
second primary molars diagnosed by clinical examination).
2.3. Bibliographic search and selection strategy
A broad bibliographic search, without restriction of language and
publication date, was performed in four databases: Medline/PubMed
(National Library of Medicine), Scopus (Elsevier), Embase (Elsevier) and
Web of Science (Clarivate Analytics).
The search strategy used in PubMed (listed below) was adapted for
the other databases. The survey was conducted on October 28th, 2022.
#1 – Agenesis, Enamel[Text word] OR Enamel Hypoplasia[Text
word] OR Hypoplasias, Enamel[Text word] OR Molar Incisor Hypo­
mineralization[Text word] OR Hypomineralization OR Hypominerali­
sation[Text word] OR Hypomineralised[Text word] OR
Hypomineralized second primary molar[Text word] OR Hypomineral­
ised Second Primary Molar[Text word] OR Molar Incisor Hypominer­
alisation[Text word] OR Deciduous Molar Hypomineralization[Text
word] OR Deciduous Molar Hypomineralisation[Text word] OR Molar
Incisor[Text word] OR Amelogenesis Imperfecta[Text word] OR enamel
defects[Text word] OR cheese molars[Text word] OR enamel opacities
[Text word].
#2 – Genetics[Mesh Terms] OR Genetics[Text word] OR Genetic
[Text word] OR Genome-Wide Association Study[Mesh Terms] OR Ge­
netic Loci[Mesh Terms] OR Genetic Variation[Mesh Terms] OR Poly­
morphism[Text word] OR Genetic Techniques[Mesh Terms] OR Genetic
profile[Mesh Terms] OR Mutagenicity Tests[Mesh Terms] OR Genes
[Mesh Terms] OR Genes[Text word] OR Gene frequency[Mesh Terms]
OR Pedigree[Text word] OR genetic epidemiology[Text word] OR
Twins[Mesh Terms] OR Twin[Text word] OR Twin Study [Mesh Terms]
OR Diseases in Twins[Mesh Terms] OR Siblings[Mesh Terms] OR Sib­
lings[Text word] OR Sibling[Text word] OR Brother[Text word] OR
Sisters[Text word].
2.3.1. #3 - #1 AND #2
For reference management and removal of duplicated articles,
Endnote Web® software was used. The overlapping of articles was
analyzed both automatically and manually.
2.4. Article selection process and eligibility criteria
Two independent researchers (R.S.F and M.D.M.L) performed the
selection of the articles, and a third examiner (F.W.M.G.M) was involved
in cases of disagreement. Observational studies (cross-sectional, case-
control and cohort) and letters to the editor with unpublished data,
which associated outcomes with family inheritance pattern and/or ge­
netic variants, were considered eligible for inclusion. Studies with no
comparison group; who did not distinguish MIH and hypomineralised
second primary molars from other developmental defects of enamel; and
those with preliminary, incomplete or duplicate results were excluded.
The first phase involved reading titles and abstracts (inter-examiner
kappa = 0.86). In the next phase, articles were read in full and selected
according to the previously described inclusion criteria (inter-examiner
kappa = 0.70). Subsequently, a manual search was performed in the
reference lists of the selected studies and in the publications of the last
five years of journals relevant to the topic (International Journal of Pae­
diatric Dentistry, Pediatric Dentistry and European Journal of Pediatric
Dentistry), whose choice was based on the number of publications and
citations in the field of pediatric dentistry according to the Web of
R. da Silva Figueira et al.
Science.
Reference lists of included studies were manually searched to
retrieve eligible articles that had not been identified through the main
search. In addition, a gray literature search was performed, using the
Opengrey platform, and a manual search on Google Scholar® of the first
300 published articles (Haddaway et al., 2015) using the following
strategy: (“molar incisor hypomineralization” OR “molar incisor hypo­
mineralisation” OR “hypomineralized second primary molar” OR “hypo­
mineralised second primary molar”) AND genetics.
2.5. Data extraction
Data extraction from the studies was performed independently by
the two researchers (R.S.F and M.D.M.L) using an Excel® spreadsheet
developed specifically for this study. Once completed, the researchers
analyzed the results together and, again, a third reviewer (F.W.M.G.M)
was involved in case of discrepancy.
The following data were extracted: first author’s surname, year of
publication, country in which the sample was collected, study design,
sample size (n), sample age, outcome (MIH or hypomineralised second
primary molars), index used for diagnosis of the outcome, assessed ge­
netic factors, measures of association and conflict of interest.
2.6. Assessing the risk of bias and certainty of the evidence
The risk of bias of the selected studies was independently assessed by
the two researchers (R.S.F and M.D.M.L). The criteria proposed by the
Joanna Briggs Institute (JBI Critical Appraisal Checklist) (Moola, 2017)
were used for cross-sectional studies. Eight questions were evaluated,
and the possible answers were “yes”, “uncertain”, “no” or “not appli­
cable”. Decisions on scoring system and cut-off were agreed by all re­
viewers prior to the commencement of critical evaluation, as
recommended by the JBI reviewers manual (Moola, 2017). Studies were
judged as follows: 1) low risk of bias, if studies achieved more than 70 %
of “yes” scores; 2) moderate risk of bias, if the “yes” scores were between
50 % and 69 %; and 3) high risk of bias, if “yes” scores were below 49 %
(Melo et al., 2018). For case-control and cohort studies, the
Newcastle-Ottawa quality rating scale was used (Wells et al., 2012).
Studies that received ≥ 9 stars were considered to be of high quality or
low risk of bias. Those with 7 and 8 stars were of medium quality or
moderate risk of bias. Those with a number of stars ≤ 6 had low
methodological quality or high risk of bias (Herzog et al., 2013; Tibúr­
cio-Machado et al., 2021).
The certainty of the evidence was assessed using the Grading of
Recommendations Assessment, Development and Evaluation (GRADE)
(Guyatt et al., 2010) scale recommendations. Independent analyzes
were performed for association between MIH or hypomineralised sec­
ond primary molars and amelogen-related genes, immune
response-related genes, other genes and other analysis. A summary of
findings was generated using online software (GRADEpro GDT; the
GRADE Working Group).
2.7. Synthesis of the evidence
The extracted data were presented in tables with a narrative
approach. An independent analysis was performed for each outcome
(MIH or hypomineralised second primary molars). It was not possible to
perform a meta-analysis, as there was not a minimum of at least two
studies that analyzed the same genetic factor.
3. Results
3.1. Selection of studies
Five thousand five hundred twenty-four (5524) potentially relevant
articles were identified. After removing duplicates, 2536 titles and
3
Archives of Oral Biology 152 (2023) 105716
abstracts were read. Of these, 73 articles were read in full and 16 were
selected (Fig. 1).
3.2. Characteristics of the included studies
Sixteen studies published between 2013 and 2022 were included, of
which 12 had MIH (Bezamat et al., 2021; Bussaneli et al., 2019; Elzein
et al., 2022; Jeremias et al., 2013, 2016, 2021; Hočevar et al., 2020;
Kühnisch et al., 2014; Koruyucu et al., 2018; Pang et al., 2019; Teixeira
et al., 2018; Vieira, 2019) as outcome, three hypomineralised second
primary molars (Fatturi et al., 2021; Silva et al., 2019, 2022) and one
article included both outcomes (Fatturi et al., 2020). The population of
studies that evaluated MIH ranged between 113 and 1065 participants,
aged between five and 34 years. In the studies that evaluated hypo­
mineralised second primary molars, the population varied between 333
and 344 participants, aged between five and eight years.
For the diagnosis of MIH/hypomineralised second primary molars,
the European Academy of Pediatric Dentistry (EAPD) diagnostic criteria
were used in most studies (n = 11) (Bezamat et al., 2021; Bussaneli
et al., 2019; Hočevar et al., 2020; Jeremias et al., 2013, 2016, 2021;
Koruyucu et al., 2018; Kühnisch et al., 2014; Pang et al., 2019; Teixeira
et al., 2018; Vieira & Manton, 2019) followed by modified DDE (n = 2)
(Fatturi et al., 2020; Fatturi et al., 2021) and Ghanim index (n = 3)
(Elzein et al., 2022; Silva et al., 2019, 2022). The included studies
involved cross-sectional (n = 12) (Bezamat et al., 2021; Bussaneli et al.,
2019; Elzein et al., 2022; Hočevar et al., 2020; Jeremias et al., 2013,
2016, 2021; Koruyucu et al., 2018; Kühnisch et al., 2014; Silva et al.,
2022; Teixeira et al., 2018; Vieira, 2019), case-control (n = 3) (Fatturi
et al., 2020, 2021; Pang et al., 2019) and cohort designs (n = 1) (Silva
et al., 2019). The characteristics of the included studies are shown in
Table 1. No conflict of interest was reported in any of the included
studies.
3.3. Risk of bias of selected studies
Risks of bias for each study included in the qualitative analysis are
shown in Fig. 2 and 3. The majority of cross-sectional studies presented a
low risk of bias (91.7 %) (Fig. 2), and 75.0 % of case-control and cohort
studies presented a moderate risk of bias, especially due to compara­
bility and non-response rate criteria (Fig. 3).
3.4. Study results
3.4.1. Studies that evaluated MIH
Of the 13 studies whose outcome was MIH, ten evaluated genetic
variants and interactions between genes (Bezamat et al., 2021; Bussaneli
et al., 2019; Elzein et al., 2022; Fatturi et al., 2021; Hočevar et al., 2020;
Jeremias et al., 2013, 2016; Koruyucu et al., 2018; Kühnisch et al., 2014;
Pang et al., 2019) one evaluated concordance between mono and
dizygotic twins (Teixeira et al., 2018), one calculated heritability (Vieira
& Manton, 2019) and one underwent segregation analysis (Jeremias
et al., 2021).
Genetic variants and interactions between genes related to amelo­
genesis (Bussaneli et al., 2019; Elzein et al., 2022; Hočevar et al., 2020;
Jeremias et al., 2013, 2016; Kühnisch et al., 2014; Pang et al., 2019),
immune response (Bezamat et al., 2021; Bussaneli et al., 2019; Elzein
et al., 2022; Pang et al., 2019), in addition to aquaporins (Pang et al.,
2019), vitamin D receptors (Fatturi et al., 2020) and others (Elzein et al.,
2022; Koruyucu et al., 2018) were identified.
3.4.2. Genes related to amelogenesis
The Single nucleotide polymorphism (SNPs) rs4694075 (AMBN
gene) (Jeremias et al., 2013), rs1711399 (MMP-20 gene) (Jeremias
et al., 2016), rs3790506, rs4970957 (TUFT1 gene) (Jeremias et al.,
2013) and rs5997096 (TFIP11 gene) (Jeremias et al., 2013) were asso­
ciated with a lower occurrence of MIH. On the other hand, SNPs
R. da Silva Figueira et al.
Fig.1. Study development flowchart.
rs13058467 (next to SCUBE1/TTLL12 gene) (Kunisch et al., 2014),
rs34367704 (Jeremias et al., 2016), rs13115627 (Pang et al., 2019)
(AMBN gene), rs2245803 (Hočevar et al., 2020), rs1711423 (Jeremias
et al., 2016), rs1784418 (Pang et al., 2019), rs144425539 (Elzein et al.,
2022) (MMP-20 gene), rs5979395 (AMELX gene) (Jeremias et al., 2016),
rs3796704 (Jeremias et al., 2013), rs7664896 (Jeremias et al., 2016)
(ENAM gene), rs3789334 (BMP-2 gene), rs762642 (BMP-4 gene),
rs6099486 (BMP-7 gene), rs2278163 (DLX3 gene), rs7821494 (FAM83H
gene), rs6996321 (FGFR1 gene) (Jeremias et al., 2013) and rs17676820
(AMTN gene) (Elzein et al., 2022) were associated with a higher
occurrence of MIH (Table 2).
SNPs in genes related to ion transport during amelogenesis were also
associated with a higher occurrence of MIH (Elzein et al., 2022). The
SNPs rs141919534 (ORAI1 gene), rs2289570 (STIM1 gene),
rs569988715, rs569988715, rs75058604 and rs10028164 (STIM2 gene)
are related to calcium accretion (Elzein et al., 2022); rs397963644,
rs77319279 and rs397963644 (SLC34A2 gene), rs28542318,
rs34664302 and rs35699762 (SLC34A3 gene) related to phosphate ac­
cretion (Elzein et al., 2022); rs2001063 (PVALB gene), rs7645 (HSP90B1
gene) and rs490494 (SLC24A4 gene) related to calcium absorption
(Elzein et al., 2022); rs3109894 (TRPM7 gene) related to homeostasis
regulation (Elzein et al., 2022) and rs2229549, rs34403003, rs1050734,
rs2303929 (SLC4A2 gene), rs2274328, rs3765964 (CA6 gene) that act in
pH regulation were associated with MIH (Elzein et al., 2022) (Table 2).
3.4.3. Genes related to the immune response
The presence of the CC allele in the rs1800972 of the DEFB1 (Pang
et al., 2019) gene, rs35211496, rs6567272 (TNFRSF11A) (Elzein et al.,
2022), rs8178561, rs3171425 and rs8178562 SNPs in the IL10RB gene
(Elzein et al., 2022) and the rs10733708 SNP in the TGFBR1 (Bussaneli
et al., 2019) gene were associated with a higher occurrence of MIH
(Table 2).
3.4.4. Other genes
SNPs close to the PPARGC1A/MIR573 (rs17650401), RMI1/
SLC28A3 (rs13288553), CDH5 (rs1126179) and KCNG1/NFATC2
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Archives of Oral Biology 152 (2023) 105716
(rs4811117) (Kunisch et al., 2014) genes were associated with a higher
occurrence of MIH (Table 2).
An association was found between a higher occurrence of MIH and
SNPs in genes related to xenobiotic detoxification (Elzein et al., 2022):
rs3768017 and rs34415707 in the ARNT gene, rs1056837, rs1056827
and rs1056836 in the CYP1B1 gene (Elzein et al., 2022) and rs1801132
in the ESR1 gene (Elzein et al., 2022) (Table 2).
An association was found between genetic polymorphisms in the
VDR gene (rs78783628) and MIH (Elzein et al., 2022). Furthermore, the
presence of at least one G allele (GT/GG) in the SNP (rs739837) was
associated with greater severity of MIH in patients who had hypo­
mineralisation affecting both molars and incisors (Fatturi et al., 2020).
3.4.5. Interaction between genes
Regarding the interaction between genes, an association was
observed between a higher occurrence of MIH and the interaction be­
tween genes related to amelogenesis and those related to the immune
response (Bezamat et al., 2021; Bussaneli et al., 2019), as well as the
interaction of different SNPs of the AQP5 gene (Pang et al., 2019)
(Table 3).
3.4.6. Other analyzes
One study evaluated concordance between twins (Teixeira et al.,
2018) and concluded that there was a higher occurrence of MIH in pairs
of monozygotic twins than in dizygotic twins, both in the analysis by
individuals (p = 0.021) and in the analysis by teeth (p = 0.001). Vieira
(2019), using the sample from Teixeira et al. (2018) defined the heri­
tability of MIH at 20 %.
3.4.7. Studies that evaluated hypomineralised second primary molars
Four selected articles studied hypomineralised second primary mo­
lars. The presence of at least one C allele (CC/CT) in SNP rs2057482 in
the hypoxia-related HIF-1 gene was associated with a higher occurrence
of hypomineralised second primary molars (Fatturi et al., 2021)
(Table 2). On the other hand, it was not observed an association between
hypomineralised second primary molars and SNPs in the VDR gene
R. da Silva Figueira et al. Archives of Oral Biology 152 (2023) 105716

Table 1
Description of studies included in this systematic review.
Author, Participants’ Kind of Sample size Outcome Index for Studied Gene SNP (rs) or CpG (cg)
year country (s) study diagnosis genetic
factor

Bezamat Brazil and Cross- N = 1065 Molar-incisor EAPD Genes/genetic IRF6 rs2073487
et al. Turkey sectional hypomineralisation variants and TGFA rs2013162
(2021) nested to a (MIH) gene interaction rs17015215
cohort rs861019
rs642961
rs2902345 rs2166975
rs1523305 rs930655
Bussaneli Brazil Cross- 101 families, MIH EAPD Genes/genetic IL10 rs1800872
et al. sectional N = 391 variants related IL1A rs1800587
(2019) to immune IL1B rs1143634
response and STAT1 rs3771300
interaction with TGFBR1 rs10733708
amelogenesis IL8 rs4073
genes IL4 rs2070874
TNF rs1800629
IL17A rs2275913
IL6 rs1800795
TGFB1 rs1800470
AMEL X rs6654939
TUFT1 rs7526319
BMP2 rs2355767
Elzein et al. Lebanon Cross- N = 37 MIH Ghanim Polymorphisms MMP-20 rs144425539
(2022) sectional in genes ARNT rs34415707
expressed during ESR1 rs3768017
enamel SLC4A2 rs1801132
mineralization or CA6 rs2229549
potentially HSP90B1 rs34403003
modulating MIH PVALB rs1050734
risk factors SLC24A4 rs2303929
SLC34A2 rs2274328
SLC34A3 rs3765964
ORAI1 rs7645
STIM1 rs2001063
STIM2 rs4904942
VDR rs397963644
TRPM7 rs77319279
IL10RB rs2854231
TNFRSF11A rs356997628
rs34664302
rs28591989
rs141919534
rs2289570
rs569988715
rs10028164
rs75058604
rs78783628
rs3109894
rs8178561
rs3171425
rs8178562
rs35211496
rs6567272
Fatturi Brazil Case-control N = 352 MIH and Modified Vitamin D VDR rs2228570
et al. Hypomineralised DDE receptor genes/ rs739837
(2020) second primary molars genetic variants
Fatturi Brazil Case-control N = 326–333 Hypomineralised Modified Genes / genetic HIF-1α rs2301113 rs2057482
et al. second primary molars DDE variants
(2021)
Hočevar Slovenia Cross- N = 113 MIH EAPD Genes/genetic HLA (allele rs3796704
et al. sectional variants related DQ2 and rs546778141
(2020) to amelogenesis DQ8) rs2106416
ENAM rs7660807
AMBN rs35286445
AMELX rs4870723
AMTN rs2245803
COL14A1 rs3828054
MMP20
TUFT1
Jeremias Brazil and Cross- N = 405 MIH EAPD Genes/genetic AMBN rs496502 rs4694075
et al. Turkey sectional variants related AMELX rs17878486 rs946252
(2013) nested to to amelogenesis ENAM rs3796704
rs12640848
(continued on next page)

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Table 1 (continued )
Author, Participants’ Kind of Sample size Outcome Index for Studied Gene SNP (rs) or CpG (cg)
year country (s) study diagnosis genetic
factor

cohorts TUFT1 rs3790506 rs233736

studies TFIP11 rs4970957
rs134136
rs5997096
Jeremias Brazil Cross- 101 nuclear families, MIH EAPD Genes/genetic MMP20 rs2280211 rs1784410
et al. sectional N = 391 variants related TUFT1 rs1711399 rs1711441
(2016) to amelogenesis FAM83H rs1784438 rs1711422
DSPP rs1784423 rs1784441
AMELX rs1784440 rs1711423
ENAM rs4970956 rs7526319
AMBN rs11204848 rs3790506
AMTN rs7821494
DLX3 rs7463064 rs12681370
KLK4 rs2615487 rs3750025
BMP2 rs2615489
BMP4 rs6530435
BMP7 rs6654939
TIMP2 rs5979395
FGFR1 rs946252
FGFR2 rs5934996
FGF1 rs17878486
FGF2 rs2609426 rs7664896
PTH rs1055660
PTHR1 rs34367704
TGFB1 rs4694075
rs17676820
rs13151614
rs17149007
rs2278163
rs3891034
rs2235091
rs198968
rs3789334
rs235767
rs15705
rs1005464
rs17563
rs762642
rs2071047
rs6099486
rs927836
rs12479955
rs230191
rs2376999
rs7218729
rs6987534
rs6996321
rs4752566
rs2981427
rs1078806
rs34010
rs1048201
rs307253
rs7652849
rs6442307 rs11568785
rs4803455
Jeremias Brazil Cross- 101 nuclear families MIH EAPD Segregation - -
et al. sectional including a child or Analysis for MIH
(2021) adolescent with MIH
and parents and
siblings
N = 391
Koruyucu Turkey Cross- N = 228 MIH EAPD Genes/genetic IGSF9B rs10798049
et al. sectional variants HCMN1 rs622260
(2018)
Kühnisch Germany Cross- N = 668 MIH EAPD Genes/genetic
et al. sectional variants
(2014) nested to a (2.013.491
cohort SNPs)
Pang et al. China Case- N = 430 MIH EAPD Genes/genetic ENAM rs12640848
(2020) control variants and AMBN rs13115627
gene interaction AMELX rs946252
in involved genes TFIP11 rs134143
in amelogenesis, MMP20 rs2097470 rs1612069
(continued on next page)

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Table 1 (continued )
Author, Participants’ Kind of Sample size Outcome Index for Studied Gene SNP (rs) or CpG (cg)
year country (s) study diagnosis genetic
factor

immune system TUFT1 rs1784418

and aquaporins DEFB1 rs17640579
LTF rs3790506
MBL2 rs11362 rs1800972
MASP2 rs4547741
AQP5 rs1800450
rs10779570
rs1996315 rs923911
Silva et al. Australia Cohort N = 344 Hypomineralised Ghanim Concordance of - -
(2019) second primary molars mono and
dizygotic twins
Silva et al. Australia Cross- N = 54 Hypomineralised Ghanim DNA GPR123 cg12340219
(2022) sectional second primary molars methylation ACAT2 cg14145175
MIR25; cg00734931
MCM7 cg07232895
TSSC4 cg08470031
CYP1A1 cg17059694
HIST1H4C cg17059694
PSMC3IP cg24453353
TFR2 cg03701005
DAB1 cg11238371
NVL cg26345888
TBP cg07706038
cg08681726
Teixeira Brazil Cross- N = 167 pairs of MIH EAPD Concordance of - -
et al. sectional twins mono and
(2013) dizygotic twins
Vieira Brazil Cross- N = 167 pairs of MIH EAPD Heritability - -
et al. sectional twins between mono
(2013) and dizygotic
twins

DDE – developmental defects of enamel; EAPD – European Academy of Paediatric Dentistry.

(Fatturi et al., 2020). The agreement of hypomineralised second primary
molars between monozygotic and dizygotic twins found no difference
between the groups (p > 0.05) (Silva et al., 2019).
In the analysis of the association between methylated cytosine-
guanine dinucleotide (CpG) and hypomineralised second primary mo­
lars found that cg12340219 in the GPR123 gene, cg14145175 and
cg00734931 (ACAT2 gene), cg22638766 (MIR25 and MCM7 genes),
cg08470031 and cg17059694 (TSSC4 gene), cg05010179 (CYP1A1
gene), cg24453353 (HIST1H4C gene), cg03701005 (PSMC3IP gene),
cg11238371 (TFR2 gene), cg26345888 (DAB1 gene), cg07706038 (NVL
gene) and cg08681726 (TBP gene) are associated with higher occur­
rence of hypomineralised second primary molars (Silva et al., 2022)
(Table 2).
3.5. Certainty of evidence
The certainty of the evidence was very low, considering the studies
that evaluated amelogenesis, immune response, other genes. However,
it was considered low when considering the other analyzes to evaluate
the genetic influence on MIH. The certainty of the evidence was very low
in the analysis of studies that evaluated hypomineralised second pri­
mary molars (Table 4).
4. Discussion
To the best of our knowledge, the present systematic review is the
first to focus on the association between genetic aspects and MIH/
hypomineralised second primary molars. An association was observed
between MIH and genetic variants and interactions between amelo­
genesis genes, immune response, as well as SNPs in aquaporin gene.
There was also greater agreement in the occurrence of MIH between
monozygotic than dizygotic twins. Furthermore, hypomineralised sec­
ond primary molars has been associated with mutations in the hypoxia-
related HIF-1 gene and DNA methylation. These results suggest an as­
sociation of genetic factors in the occurrence of MIH and hypominer­
alised second primary molars.
Dental enamel consists of hydroxyapatite crystals and organic con­
tent formed by the proteins amelogenin (AMELX), ameloblastin
(AMBN), enamelin (ENAM), amelotin (AMTN) and those related to the
odontogenic ameloblast (ODAM) (Poulter et al., 2014; Xie et al., 2016;
Vieira & Manton, 2019). Most of the included studies evaluated genes
related to amelogenesis (Bussaneli et al., 2019; Elzein et al., 2022;
Hočevar et al., 2020; Jeremias et al., 2016; Kunisch et al., 2014; Pang
et al., 2019), because the enamel formation is a complex process
genetically determined (Alaluusua, 2010) and mediated by environ­
mental factors (Garot et al., 2022). SNPs in genes related to amelo­
genesis are associated with a higher (Elzein et al., 2022; Hočevar et al.,
2020; Jeremias et al., 2013, 2016; Kunisch et al., 2014; Pang et al.,
2019) or lower occurrence of MIH (Jeremias et al., 2013, 2016).
Therefore, individuals with genetic alterations present a predisposition
or protection for the development of MIH/hypomineralised second
primary molars, when exposed to pre-, peri- and post-natal environ­
mental factors (Garot et al., 2022; Hočevar et al., 2020).
SNPs in the genes BMP2, BMP4, BMP7 (Jeremias et al., 2016), AMTN
(Elzein et al., 2022), MMP20 (Elzein et al., 2022; Jeremias et al., 2016;
Hočevar et al., 2020; Pang et al., 2019), AMBN (Jeremias et al., 2016;
Pang et al., 2019), AMELX (Jeremias et al., 2016), ENAM (Jeremias
et al., 2013, 2016), FAM83H, DLX3 (Jeremias et al., 2016) and in the
region of SCUBE1/TTLL1 (Kunisch et al.,2014) were associated with a
higher occurrence of MIH. Mutations in the AMBN (Butera et al., 2021)
and MMP20 (Vieira & Manton, 2019) genes were associated with a
lower occurrence of MIH. These results should be interpreted with
caution, since the association of a SNP with a higher occurrence of a
condition does not necessarily mean that the causative variant cannot be
linked to other SNPs that have not yet been identified (Pang et al., 2019).
BMP2 and BMP4 proteins have the function of regulating the expression

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Fig. 2. Risk of bias assessment of the cross-sectional studies included (JBI critical appraisal scale).

Fig. 3. Risk of bias assessment of included case-control and cohort studies (Newcastle-Ottawa Scale).

of MMP20 and KLK4 proteins that participate in the cleavage of extra­ previously occupied by proteins (Lu et al., 2008), in addition to allowing
cellular matrix proteins (Xie et al., 2016). This important stage of adequate enamel mineralization (Lu et al., 2008). Therefore, failure in
amelogenesis allows enamel crystals to progressively grow in the space the degradation of enamel matrix proteins can interfere with the

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Table 2
Genes associated with higher and/or lower occurrences of molar-incisor hypomineralisation (MIH) and/or hypomineralised second primary molars.
Genes SNP (rs)/CpG (cg) Author, year Outcome Significant association

Higher occurrence of the Lower occurrence of the

outcome outcome
OR (95 % CI) or p-value OR (95 % CI)

Related to amelogenesis
*close to the SCUBE1/ rs13058467 Kunnish et al. MIH 4.4 (2.5–7.8) -
TTLL12 genes (2014)
AMBN (ameloblastin)
rs4694075 Jeremias et al. MIH - 0.46 (0.26–0.80)
(when the severity of MIH was (2013)
considered)
rs34367704 Jeremias et al. MIH 2.7(1.16–6.58) -
(2016)
rs13115627 Pang et al. MIH Allele GG p = 0.042 -
(2020)
MMP20 (enamelisin) rs144425539 Elzein et al. MIH 10.31 (4.559–23.31) -
rs2245803 (2022) MIH 2.796 (1.075–4.783) -
Hočevar et al.
(2020)
rs1711399 Jeremias et al. MIH - 0.4 (0.20–0.72)
(2016)
rs1711423 Jeremias et al. MIH 2.1 (1.18–3.61) -
(2016)
rs1784418 Pang et al. MIH Allele TT 2,02 -
(2020) (1.63–3.52)
TUFT1 (tuftelin) rs3790506 Jeremias et al. MIH - 0.19 (0.11–0.33)
(2013)
rs4970957 Jeremias et al. MIH - 0.12 (0.08–0.19)
(2013)
AMELX (amelogenin) rs5979395 Jeremias et al. MIH 11.7 (1.63–8.74) -
(2016)
BMP2 rs3789334 Jeremias et al. MIH 2.9 (1.34–6.35) -
(2016)
ENAM (enamelin) rs3796704 Jeremias et al. MIH Brazil: 0.28 (0.06–1.0) -
(2013) (when the severity of MIH was Turkey: 17.36
considered) (5.98–56.78)
rs7664896 Jeremias et al. MIH 2.1 (1.19–3.51) -
(2016)
TFIP11 (tuftelin-interacting rs5997096 Jeremias et al. MIH - 0.49 (0.49–0.74)
protein) (2013)
FAM83H rs7821494 Jeremias et al. MIH 3.7 (1.75–7.78) -
(2016)
BMP7 rs6099486 Jeremias et al. MIH 2.2 (1.14–4.38) -
(2016)
BMP4 rs762642 Jeremias et al. MIH 2.3 (1.38–3.65) -
(2016)
DLX3 rs2278163 Jeremias et al. MIH 2.8 (1.26–6.41) -
(2016)
FGFR1 rs6996321 Jeremias et al. MIH 2.7 (1.20–5.88) -
AMTN rs17676820 (2016) MIH 2.098 (1.071–4.110) -
Elzein et al.
(2022)
ORAI1 rs141919534 Elzein et al. MIH 35,69 (2175–∞) -
(2022)
STIM1 rs2289570 Elzein et al. MIH 2152 (0,9932–4663) -
(2022)
STIM2 rs569988715 Elzein et al. MIH 8.968 (4192–19,19) -
(2022)
rs10028164 Elzein et al. MIH 6983 (1645–29,26) -
(2022)
rs569988715 Elzein et al. MIH 3426 (1633–7191) -
(2022)
rs75058604 Elzein et al. MIH 2744 (1178–6393) -
(2022)
SLC34A2 rs397963644 Elzein et al. MIH 2338 (1191–4589) -
(2022)
rs77319279 Elzein et al. MIH 4,21 (1767–10,05) -
(2022)
rs397963644 Elzein et al. MIH 3417 (1595–7320) -
(2022)
SLC34A3 rs28542318 Elzein et al. MIH 5573 (1319–23,54) -
(2022)
rs35699762 Elzein et al. MIH 6,59 (2525–15,20) -
(2022)
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Table 2 (continued )
Genes SNP (rs)/CpG (cg) Author, year Outcome Significant association

Higher occurrence of the Lower occurrence of the

outcome outcome
OR (95 % CI) or p-value OR (95 % CI)

rs34664302 Elzein et al. MIH 11,63 (4282–30,12) -

(2022)
PVALB rs2001063 Elzein et al. MIH 2388 (1071–5321) -
(2022)
HSP90B1 rs7645 Elzein et al. MIH 3172 (1562–6441) -
(2022)
SLC24A4 rs490494 Elzein et al. MIH 60,14 (3669–∞) -
(2022)
TRPM7 rs3109894 Elzein et al. MIH 3038 (1490–6196) -
(2022)
SLC4A2 rs2229549 Elzein et al. MIH 4,3 (2128–8688) -
(2022)
rs34403003 Elzein et al. MIH 3492 (1629–7488) -
(2022)
rs1050734 Elzein et al. MIH 3,65 (1765–7548) -
(2022)
rs2303929 Elzein et al. MIH 2.122 (1042–4321) -
(2022)
CA6 rs3765964 Elzein et al. MIH 4276 (2135–8564) -
(2022)
rs2274328 Elzein et al. MIH 2616 (1309–5227) -
(2022)
GPR123 cg12340219 Silva et al. Hypomineralised second p = 0,025 -
(2022) primary molars
ACAT2 cg14145175 Silva et al. Hypomineralised second p = 0,040 -
(2022) primary molars
cg00734931 Silva et al. Hypomineralised second p = 0,017 -
(2022) primary molars
MIR25; MCM7 cg22638766 Silva et al. Hypomineralised second p = 0,010 -
(2022) primary molars
TSSC4 cg08470031 Silva et al. Hypomineralised second p = 0,007 -
(2022) primary molars
cg17059694 Silva et al. Hypomineralised second p = 0,003 -
(2022) primary molars
CYP1A1 cg05010179 Silva et al. Hypomineralised second p = 0,014 -
(2022) primary molars
HIST1H4C cg24453353 Silva et al. Hypomineralised second p = 0,013 -
(2022) primary molars
PSMC3IP cg03701005 Silva et al. Hypomineralised second p = 0,039 -
(2022) primary molars
TFR2 cg11238371 Silva et al. Hypomineralised second p = 0,024 -
(2022) primary molars
DAB1 cg26345888 Silva et al. Hypomineralised second p = 0,039 -
(2022) primary molars
NVL cg07706038 Silva et al. Hypomineralised second p = 0.028 -
(2022) primary molars
TBP cg08681726 Silva et al. Hypomineralised second p = 0,035 -
(2022) primary molars
Genes related to immune response
DEFB1 rs1800972 Pang et al. MIH Allele CC 2,28 -
(2020) (1.27–4.11)
TGFBR1 rs10733708 Bussaneli et al. MIH 3.5 (1.1–10.6) -
IL10RB rs8178561 (2019) MIH 3.272 (1.493–7.171) -
rs3171425 Elzein et al. MIH 4.806 (2.376–9.722) -
rs8178562 (2022) MIH 2.617 (1.126–6.085) -
Elzein et al.
(2022)
Elzein et al.
(2022)
TNFRSF11A rs35211496 Elzein et al. MIH 2384 (1182–4807) -
(2022)
rs6567272 Elzein et al. MIH 1969 (0,9995–3864) -
(2022)
Other genes
ARNT rs3768017 Elzein et al. MIH 3360 (1602–7046) -
(2022)
rs34415707 Elzein et al. MIH 3667 (1818–7398) -
(2022)
CYP1B1 rs1056837 Elzein et al. MIH 2782 (1422—5443) -
(2022)
rs1056827 Elzein et al. MIH 2566 (1282–5133) -
(2022)
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Table 2 (continued )
Genes SNP (rs)/CpG (cg) Author, year Outcome Significant association

Higher occurrence of the Lower occurrence of the

outcome outcome
OR (95 % CI) or p-value OR (95 % CI)

rs1056836 Elzein et al. MIH 2052 (1047–4024) -

(2022)
ESR1 rs1801132 Elzein et al. MIH 2974 (1436–6161) -
(2022)
VDR rs78783628 Elzein et al. MIH 3127 (1387–7048) -
(2022)
rs739837 Fatturi et al. MIH 2.40 (1.08–5.31)
(2020)
close to the genes rs17650401 Kunnish et al. MIH 6.9 (3.1–15.4) -
PPARGC1A/MIR573 (2014)
close to the genes RMI1/ rs13288553 Kunnish et al. MIH 4.2 (2.3–7.8) -
SLC28A3 (2014)
close to the gene CDH5 rs1126179 Kunnish et al. MIH 2.1 (1.6–2.9) -
(2014)
close to the genes KCNG1/ rs4811117 Kunnish et al. MIH 3.1 (1.9–5.1) -
NFATC2 (2014)
HIF-1 rs2057482 Fatturi et al. Hypomineralised second - Allele C (CC/CT)
(2021) primary molars 0.51 (0.27–0.99)

MIH – molar-incisor hypomineralisation, EAPD – European Academy of Pediatric Dentistry.

The DLX3 gene regulates the AMELX, ENAM, ODAM and KLK4 genes
Table 3
by directly binding to their enhancer regions (Zhang et al., 2015). Mu­
Significant results of the analysis of interaction between genes and molar-incisor
tations in DLX3 disrupt this regulatory function (Zhang et al., 2015).
hypomineralisation.
Deletion of this gene in the enamel organ was associated with the
Interaction between genes Author, year significant association
development of hypomineralised enamel in rats (Duverger et al., 2017).
OR (95 % CI) and/or
p-value
The SNP rs 13058467, located close to the SCUBE1/TTLL12 genes, was
associated with a higher occurrence of MIH (Kühnisch et al., 2014). The
• TGFA (rs1523305) and ◆IRF6 Bezamat et al. 1.77 p = 0.03
SCUBE1 gene participates in craniofacial development (Tu et al., 2008),
(rs 642961) (2021)
• TGFA (rs2902345) and ◆IRF6 Bezamat et al. 1.60 p = 0.04 in addition to acting in the mechanisms of suppression of BMP signals in
(rs2073487) (2021) mesenchymal regions of the developing tooth germ (Xavier et al., 2009).
• TGFA (rs930655) and ◆IRF6 Bezamat et al. 1.33 (1.25–1.42) Therefore, polymorphism in SCUBE1 seems to interfere with the
(rs17015215) (2021)
mineralization of dental enamel causing developmental defects of
• TGFA (rs930655) and ◆IRF6 (rs Bezamat et al. 1.25 (1.16–1.34)
2013162) (2021)
enamel.
• TGFA (rs930655) and ◆IRF6 (rs Bezamat et al. 1.34 (1.26–1.42) An association between a higher occurrence of MIH and mutations in
861019) (2021) FAM83H and FGFR1 (Jeremias et al., 2016) genes which are related to
• TGFA (rs930655) and ◆IRF6 (rs Bezamat et al. 1.24 (1.16–1.34) amelogenesis was observed, but they do not have a well-defined role in
2073487) (2021)
this process. Alterations in the FAM83H gene affect ameloblasts during
• TGFA (rs930655) and ◆IRF6 Bezamat et al. 1.39 (1.32–1.42)
(rs642961) (2021) the secretory stage of amelogenesis (Zheng et al., 2021) and has been
• AMELX (rs6654939) and ◆IL4 Bussaneli et al. p = 0.006 associated with amelogenesis imperfecta (Wang et al., 2021) and auto­
(rs2070874) (2019) somal dominant hypocalcification (Zheng et al., 2021). In addition,
• AMELX (rs6654939) and ◆IL17A Bussaneli et al. p = 0.003
enamel mineral density in individuals affected by mutations in this gene
(rs2275913) (2019)
• AMELX (rs6654939) and ◆IL10 Bussaneli et al. p = 0.009
is reduced (Takamori et al., 2008). It has been observed that the secre­
(rs1800872) (2019) tory function of ameloblasts is compromised in mice with mutations in
• AMELX (rs6654939) and ◆IL1A Bussaneli et al. p = 0.03 FGFR1, resulting in enamel with defects similar to amelogenesis
(rs1800587) (2019) imperfecta (Takamori et al., 2008).
• AMELX (rs6654939) and Bussaneli et al. p = 0.009
SNPs in genes related to ion transport (VDR, ORAI, STIM1, STIM2,
◆STAT1 (rs 3771300) (2019)
• TUFT1 (rs7526319) and ◆IL4 Bussaneli et al. p = 0.03 SLC34A2, SLC34A3, PVALB, HSP90B1, SLC24A4, TRPM7) were associ­
(rs2070874) (2019) ated with a higher occurrence of MIH (Elzein et al., 2022). SNPs in the
• BMP2 (rs2355767) and ◆IL4 Bussaneli et al. p = 0.001 genes responsible for incorporating calcium and phosphate into the
(rs2070874) (2019) enamel matrix can lead to hypomiralization (Elzein et al., 2022). In
• AQP5 (rs 1996315) and Pang et al. 2.12 (1.12–3.99)
(rs923911) (2020)
addition, SNPs in pH regulatory genes SLC4A2 and CA6 may decrease or
• AQP5 (rs 1996315- AG) and Pang et al. 3.60 (1.15–11.32) increase the amount of carbon available at the initial moment of tooth
(rs923911- AC) (2020) mineralization, which would justify their association with a higher
• genes related to amelogenesis, ◆ related to immune response, ▪ other genes. occurrence of MIH (Elzein et al., 2022).
Common variations in TUFT1 and TFIP11 genes were associated with
a lower occurrence of MIH (Butera et al., 2021). The allelic frequencies
progressive thickening of enamel crystals, leading to a porous enamel,
of the investigated SNPs are: rs3790506 Allelic frequency on gnomAD
with reduced mineral density, and susceptible to post-eruptive break­
v2.1.1: 0.2449; rs4970957: 0.1639; and rs5997096: 0.4862. As these are
down (Papagerakis et al., 2008), characteristics of hypomineralised
common polymorphisms, it may not be possible to draw definitive
teeth (Guo et al., 2015). Imbalances in the levels of KLK4 and MMP20
conclusions about their impact on the trait or disease. Understanding
have important consequences on enamel mineralization, as they cause
these findings is challenging, as TUFT1 is a constituent of the enamel
an increase in albumin levels, preventing the proper growth of hy­
matrix and plays a role in initiating the formation, regulating the shape
droxyapatite crystals (Mukhtar et al., 2022).
and size of hydroxyapatite crystals (Deutsch et al., 1997; Gerreth et al.,

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Table 4
Certainty of the evidence of the included studies according to the GRADE.
Assessment of certainty Impact Certainty Importance

No. of Study design Risk of Inconsistency Indirect Imprecision Other

studies bias evidence considerations

Molar-incisor hypomineralisation (MIH) - Amelogenesis genes

7 Observational Seriousa Not serious Not Not serious None All included studies demonstrated a ⨁◯◯◯ CRITICAL
studies serious significant association between very low
amelogenesis-related genes and MIH.
MIH - Genes related to the immune response
5 Observational Seriousb Not serious Not Not serious None All included studies demonstrated a ⨁◯◯◯ CRITICAL
studies serious significant association between genes very low
related to immune response and MIH.
MIH - Other genes
6 Observational Seriousc Seriousd Not Not serious None Five studies demonstrated significant ⨁◯◯◯ CRITICAL
studies serious associations with other genetic traits very low
and MIH. However, one of the studies
did not identify significant
associations.
MIH - Other analyzes
3 Observational Not Not serious Not Not serious None All included studies demonstrated a ⨁⨁◯◯ CRITICAL
studies serious serious significant association between MIH low
and the other analyzes of genetic traits.
Hypomineralised second primary molars
4 Observational Very Seriousf Not Not serious None Of the four included studies, only one ⨁◯◯◯ CRITICAL
studies seriouse serious demonstrated a significant association very low
with hypomineralised second primary
molars and genetic factors.

CI: confidence interval;

a. Of the seven studies evaluated, two had a moderate risk of bias and five of them had a low risk of bias.
b. Of the five studies evaluated, one had a moderate risk of bias and four of them had a low risk of bias.
c. Of the six studies evaluated, three had a moderate risk of bias and three of them had a low risk of bias.
d. There is divergence in the direction of the findings among the evaluated studies.
e. Of the three studies evaluated, two had a moderate risk of bias and one had a high risk of bias.
f. Two studies did not identify a significant association between hypomineralised second primary molars and genetic traits. However, two studies identified a sig­
nificant association.

2017). Moreover, tuftelin-interacting protein (TFIP11) also participates
in the formation of the enamel matrix (Chisini et al., 2020; Wen et al.,
2005). Further studies are needed to validate their association with the
trait or disease and to determine their effect size. It is also essential to
consider the potential interactions between these polymorphisms and
other factors that influence the phenotype.
The association between MIH and genes related to the immune
response, such as DEFB1, responsible for activating the immune system
(Pang et al., 2019; Sun et al., 2006) and TGFBR1 (Bussaneli et al., 2019),
involved in apoptosis processes (Gao et al., 2009), can be explained by
the role of these genes in inflammatory processes, such as asthma
(Butera et al., 2021), high fever (Alaluusua, 2010; Dantas-Neta et al.,
2018) and pneumonia (Willmott et al., 2008), which has been associated
with MIH. In addition, TGF-β cytokines expressed by T cells and related
to the TGFBR1 gene induce inflammatory signals, including the forma­
tion of new blood vessels (Bussaneli et al., 2019; Haruyama et al., 2006;
Palomo et al., 2015). Therefore, it is plausible to suppose that poly­
morphisms in genes related to the immune system can alter their
expression profile, resulting in greater vascularization of the germ and,
consequently, in an increased risk of serum albumin leakage, which
would impair the process of formation of the germ enamel (Bussaneli
et al., 2019).
The present study reported that the interaction between immune
response genes (TGFA, IL-4, IL-17A, IL-10, IL-1A and STAT1) and genes
related to amelogenesis and craniofacial development (IRF6 and
AMELX) are associated with a higher occurrence of MIH (Bezamat et al.,
2021; Bussaneli et al., 2019; Elzein et al., 2022). The relationship be­
tween immune response genes and genes involved in amelogenesis and
craniofacial development is an active area of research in dental and
medical genetics. Immune response genes play a vital role in protecting
against oral pathogens. Studies suggest that certain immune response
genes may regulate the expression of genes involved in tooth
development, while others may influence the growth of jaws by regu­
lating bone formation and remodeling, such as RANKL and OPG. These
interactions are complex and may have significant implications for
dental and oral health. However, further studies are needed to fully
comprehend the nature and significance of these interactions in both
health and disease (Bussaneli et al., 2019; Gachova et al., 2022; Santana
et al., 2020).
Interaction between SNPs in AQP5 genes are also associated with
MIH (Pang et al., 2019). This gene is responsible for aquaporin 5, a
protein expressed in salivary and lacrimal glands and epithelial cells
(Felszeghy et al., 2004). Polymorphisms in AQP5 have already been
associated with a lower occurrence of dental caries (Anjomshoaa et al.,
2015) and it has been suggested that this gene may interact with ame­
loblasts and with the fluorine ion and, consequently, alter susceptibility
to MIH (Pang et al., 2019).
The HIF-1 gene, a hypoxia-inducible factor, participates in the pro­
cess of transcription and regulation of oxygen homeostasis, coordinating
the response to hypoxia in normal and tumor tissues, allowing adapta­
tion and survival in a hostile environment (Mukhtar et al., 2022). In
hypoxic conditions, HIF-1α stabilizes, dimerizes with HIF-1β, and
translocates to the nucleus where it activates transcription of genes
involved in cellular processes such as angiogenesis, metabolism, eryth­
ropoiesis, and apoptosis. HIF-1α also promotes new blood vessel for­
mation and oxygen delivery to hypoxic tissues. Studies have shown that
HIF-1α is expressed in dental pulp cells and is involved in the regulation
of dentin formation by promoting the differentiation of odontoblasts
(Choi et al., 2014). Additionally, HIF-1α has been shown to regulate the
expression of genes involved in tooth development and mineralization.
Dysfunction of HIF-1α has been associated with abnormalities in den­
tinogenesis and amelogenesis (Han et al., 2022; Kim et al., 2021; Orikasa
et al., 2022). However, further studies are needed to fully understand
the role of HIF-1 in dental mineralization. Variations in the HIF-1 gene

12
R. da Silva Figueira et al.
can potentially be associated with MIH and hypomineralised second
primary molars, as hypoxia can be caused by problems during birth,
such as prematurity, respiratory problems and prolonged labor (Fatturi
et al., 2021), factors associated with MIH and hypomineralised second
primary molars in previous studies (Butera et al., 2021; Elfrink et al.,
2014; Silva et al., 2019).
In the present study, several SNPs were associated with a higher
occurrence of MIH, but they are not directly related to amelogenesis or
the immune response, such as the SNP rs17650401 close to the
PPARGC1A /MIR573 region, rs13288553 close to the RMI1/SLC28A3
genes, rs1126179 close to the gene CDH5 and rs4811117 close to the
KCNG1/NFATC2 genes (Kühnisch et al., 2014). CDH5 gene produces
cadherin-5, a transmembrane protein that helps form adherends junc­
tions between endothelial cells. Cadherin-5 plays a vital role in the
development and maintenance of the vasculature, particularly in
angiogenesis (OMIM, https://www.omim.org/entry/601120). Addi­
tionally, cadherins have been found to be suppressed in response to
mechanical stress on teeth, suggesting a potential role in the adaptive
response of teeth to stress (Feng et al., 2017; Deng et al., 2021).
The NFATC2 gene encodes for the nuclear factor of activated T-cells
(NFAT) family member NFATc2, primarily expressed in immune cells
and involved in the regulation of both T and B-cell activation and dif­
ferentiation (OMIM, https://www.omim.org/entry/614525). NFATc2
has been shown to be involved in skeletal development and bone ho­
meostasis, suggesting a potential role in tooth development (Zanotti &
Canalis, 2015; Yu et al., 2018). However, there is currently no evidence
linking NFATC2 to dental mineralization.
The KCNG1 gene encodes for the potassium voltage-gated channel
subfamily G member 1, also known as Kv6.1. This gene plays a role in
modulating of synaptic transmission (OMIM, https://www.omim.
org/entry/603788). Currently, there is no known direct relation be­
tween the KCNG1 gene and dental mineralization and further studies are
necessary.
SNPs in genes related to xenobiotic detoxification were associated
with a higher MIH occurrence (Elzein et al., 2022). ARNT, ESR1 and
CYP1A1 are genes responsible for the process of metabolizing polycyclic
aromatic hydrocarbons and are expressed after exposure to environ­
mental pollutants (Badran et al., 2020). Polymorphisms in these genes
may alter the kinetic binding capacity of pollutants and, consequently,
the metabolism and amount of chemical excreted (Elzein et al., 2022).
Three included studies used concordance data between monozygotic
and dizygotic twins, which allows the practical assessment of the genetic
influence on the etiology of alterations (Silva et al., 2019; Teixeira et al.,
2018; Vieira & Manton, 2019). The results were divergent for MIH and
hypomineralised second primary molars, since no difference was
observed in the occurrence of hypomineralised second primary molars
between monozygotic and dizygotic twins. However, the low number of
included twins may have affected the power of the study (Fatturi et al.,
2021). Regarding MIH, a greater agreement was observed in mono­
zygotic twins (84 %) than in dizygotic (65 %) (Teixeira et al., 2018),
demonstrating the genetic influence in its development. Based on the
data from Teixeira et al. (2018), Vieira and Manton (2019) calculated
the heritability of MIH and achieved an estimate of 20 %.
The study that performed segregation analysis indicated that more
than one gene may be involved in the MIH phenotype, but did not
determine the exact pattern of inheritance (Jeremias et al., 2021). The
authors argued that the number of families studied was lower than the
necessary to assess an alteration of multifactorial origin such as MIH. A
fact that may have influenced the results, which suggests that studies
with ethnically diverse populations should be performed to obtain more
consistent results.
One study evaluated the influence of DNA methylation on the
development of hypomineralised second primary molars (Silva et al.,
2022). DNA methylation is the process in which methyl groups are
added to cytosine in DNA, which can cause reduced gene expression (Wu
et al., 2012). This mechanism is involved in the pathogenesis of different
13
Archives of Oral Biology 152 (2023) 105716
general disorders (Wu et al., 2012) and has been associated with
hypomineralised second primary molars when amelogenesis genes are
affected (Silva et al., 2022), however additional studies are needed to
determine this association (Silva et al., 2022).
This systematic review has the advantage of providing an overview
of the literature addressing genetic aspects associated with the occur­
rence of MIH/hypomineralised second primary molars. However, it has
limitations. Despite the significant number of publications, the vari­
ability of factors under study makes more specific conclusions difficult.
The methodological heterogeneity of the included studies impairs their
comparability, precluding a meta-analysis. Most of the included studies
presented low risk of bias, but the certainty of the evidence was very
low/low. In addition, the low number of longitudinal studies limits
temporality assessment and causality determination of the detected
findings.
It is recommended that further longitudinal studies assess the in­
fluence of genetics on MIH/ hypomineralised second primary molars.
The identification of genes associated with these conditions is important
to elucidate the mechanisms that lead to the formation of hypominer­
alised enamel and can help in the development of future research
involving gene therapies that can prevent the occurrence of these
developmental defects of enamel.
5. Conclusion
With very low or low certainty of evidence, an association was
observed between MIH and SNPs in genes associated with amelogenesis,
immune response, xenobiotic detox and ion transport. Interactions be­
tween genes related to amelogenesis and immune response as well as
aquaporin genes were associated to MIH. In addition, with very low
certainty of evidence hypomineralised second primary molars was
associated to a hypoxia-related gene and to methylation in genes related
to amelogenesis. Moreover, higher agreement of MIH in pairs of
monozygotic twins than dizygotic twins was observed.
CRediT authorship contribution statement
Raíssa da Silva Figueira: Conceptualization, Investigation, Data
curation, Writing – original draft. Francisco Wilker Mustafa Gomes
Muniz: Conceptualization, Methodology, Formal analysis, Writing –
review & editing. Lara Carvalho Costa: Writing – review & editing,
Visualization. Cassiano Kuchenbecker Rösing: Methodology, Formal
analysis, Writing – review & editing. Bibiana Mello de Oliveira:
Formal analysis, Writing – review & editing. Cacilda Castelo Branco
Lima, Marcoeli Silva Moura and Lúcia de Fátima Almeida de Deus
Moura: Writing – review & editing, Supervision. Marina de Deus
Moura de Lima: Project administration, Term, Conceptualization,
Investigation, Writing – original draft, Supervision.
Ethics Approval and Consent to Participate
Not applicable.
Funding
No funding was obtained for this study.
Declaration of Competing Interest
All authors declare that there is no conflict of interest.
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