Single Nucleotide Polymorphisms of Enamel.2

Systematic Review and Meta-Analysis
Single nucleotide polymorphisms of enamel formation

genes and early childhood caries - systematic review,
Downloaded from http://journals.lww.com/jped by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
gene-based, gene cluster and meta-analysis

Aruna Sharma1,2, Sneha S. Patil3,4, M. S. Muthu1,5, Vettriselvi Venkatesan6, Richard Kirubakaran7,
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 06/13/2023
Sivakumar Nuvvula8, Selva Arockiam9

Department of Pediatric and Preventive Dentistry, Centre for Early Childhood Caries and Research, Sri Ramachandra Institute of Higher
1
Education and Research, 3Department of Environmental Health Engineering, Faculty of Public Health, Sri Ramachandra Institute of Higher
Education and Research, 6Department of Human Genetics, Sri Ramachandra Institute of Higher Education and Research, 9Department of
Orthodontics, Meenakshi Ammal Dental College and Hospital, Chennai, 7South Asian Cochrane Network and Centre, Christian Medical
College, Vellore, Tamil Nadu, 2Department of Pediatric and Preventive Dentistry, Indira Gandhi Institute of Dental Sciences, Sri Balaji
Vidyapeeth, Puducherry, 4Department of Pediatric and Preventive Dentistry, Dr. D.Y. Patil Dental College and Hospital, Dr. D.Y. Patil
Vidyapeeth, Pune, Maharashtra, 8Department of Paediatric and Preventive Dentistry, Narayana Dental College and Hospital, Nellore,
Andhra Pradesh, India, 5Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
ABSTRACT Address for correspondence:

Dr. M. S. Muthu,
Introduction: Genetic polymorphisms of genes
Centre for Early Childhood Caries Research, Department of
regulating amelogenesis can alter susceptibility to
Pediatric and Preventive Dentistry, Sri Ramachandra Institute
Early Childhood Caries (ECC). This systematic review of Higher Education and Research, Chennai, Tamil Nadu, India.
aims to analyze associations between single‑nucleotide E‑mail: muthumurugan@sriramachandra.edu.in
polymorphisms of enamel formation genes and ECC.
Methods: Search was conducted across PUBMED,
CINAHL, LILACS, SCOPUS, EMBASE, Web of Science,
Genome‑Wide Association Studies databases from Access this article online
January 2003 to September 2022. This was supplemented Quick response code Website:
by hand search. Totally 7124 articles were identified https://journals.lww.com/jped
and 21 articles that satisfied the inclusion criteria DOI:
proceeded to data extraction. Quality assessment was 10.4103/jisppd.jisppd_78_23
done using the Q‑Genie tool. Results: Quantitative
PMID:
synthesis revealed that homozygous genotype AA
******
of rs12640848 was significantly higher in children
with ECC with an odds ratio of 2.36. Gene‑based
analysis revealed significant association between KEYWORDS: Dental caries, enamel formation genes,
six variants of AMBN, four variants of KLK4, two single‑nucleotide polymorphisms
variants of MMP20, and a single variant of each of
MMP9 and MMP13 genes and ECC. The Bonferroni
corrected‑log10 P value of amelogenesis gene Cluster This is an open access journal, and articles are distributed under the terms
of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0
was 2.25 (0.05/88 = 5.6 × 10−4). Search Tool for Retrieval
License, which allows others to remix, tweak, and build upon the work
of Interacting Genes and Proteins plot constructed to
non‑commercially, as long as appropriate credit is given and the new
comprehend the protein‑protein interaction revealed
creations are licensed under the identical terms.
the presence of four functional clusters. Gene function
prediction using Multiple Association Network For reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com
Integration Algorithm revealed that physical interaction
between these genes was 69.3%. Conclusion: How to cite this article: Sharma A, Patil SS, Muthu MS,
Polymorphisms of genes regulating amelogenesis Venkatesan V, Kirubakaran R, Nuvvula S, et al. Single nucleotide
can influence the susceptibility to ECC. AA genotype polymorphisms of enamel formation genes and early childhood
caries - systematic review, gene-based, gene cluster and meta-
of rs12640848 may increase the susceptibility to ECC.
analysis. J Indian Soc Pedod Prev Dent 2023;41:3-15.
Gene‑based analysis revealed a significant association
between multiple polymorphisms of genes regulating Submitted: 15‑Feb‑2023 Revised: 11‑Mar‑2023
Accepted: 19‑Mar‑2023 Published: 01-Jun-2023
amelogenesis and ECC.
© 2023 Journal of Indian Society of Pedodontics and Preventive Dentistry | Published by Wolters Kluwer - Medknow 3
Sharma, et al.: Enamel formation genes and early childhood caries
Introduction Reviews (PROSPERO) under protocol CRD42020179922.

It has been reported per the Preferred Reporting Items
Early childhood caries (ECC) is a public health concern for Systematic Reviews and Meta‑analysis (PRISMA)
affecting more than 600 million children globally.[1] It checklist 2020.[22] We deviated from the protocol
adversely impacts their quality of life, family, society, by including only the polymorphisms of enamel
and health care systems.[2] ECC is a multifactorial formation genes in the present review.
disease caused by a chronic imbalance between the risk
and protective factors[3] and is characterized by acidic Eligibility criteria

demineralization of dental enamel. Amelogenesis is a The research question posed by the present review
highly organized phenomenon consisting of secretory, was to ascertain the SNPs of enamel formation genes
transition and maturation stages and is genetically associated with ECC. The review followed the PECO
controlled. framework: (1) participants/population: children up to
6 years of age; (2) exposure: SNPs of enamel formation

Single‑nucleotide polymorphisms (SNPs) are the genes; (3) comparison: children without SNPs of
most common variations in the human genome. enamel formation genes; and (4) outcome being ECC.
Polymorphisms of enamel formation genes can alter
the protein content, quantity, quality of the enamel Observational studies (case‑control, cohort,
formed.[4] SNPs can also reduce the microhardness of cross‑sectional design) that analyzed the association
enamel resulting in the formation of “caries predisposing of SNPs in enamel formation genes with ECC were
enamel”[5] or “weak enamel.”[6] Amelogenins are the included. Studies conducted on animals, case reports,
most abundant of the enamel matrix proteins and are case series, and those not in English were excluded.
encoded by AMELX gene. Polymorphisms of AMELX
gene can alter the protein content and alter susceptibility Search strategy
to caries.[6‑11] Positive and significant association An extensive search was conducted across various
between polymorphisms of AMELX gene and ECC electronic databases such as MEDLINE via PubMed,
has been reported.[5,8,11] However, certain studies did CINAHL via EBSCO, LILACS, Web of Science,
not report significant association between SNPs of SCOPUS, EMBASE, Cochrane Central, Google
AMELX gene and ECC.[3,12‑15] Polymorphisms of ENAM Scholar, and Opengrey. This was supplemented by a
gene can cause alterations in enamel microstructure search of GWAS databases. The search was conducted
and thus affect the susceptibility to caries.[3,8,9,13‑19] SNPs from January 2003, which marked the completion
of TUFT1 gene and TFIP11 can interact with mutans of The Human Genome Project, till September
streptococci, altering the predisposition to carious 2022. The search strategy has been summarized in
demineralization.[3,8,12] Polymorphisms of TUFT1 gene Supplementary Table 1. The references of the existing
can be associated with increased caries experience in reviews were assessed for relevant studies. A hand
children.[9] T allele and TT genotype of rs34538475 of search of Pediatric Dentistry, Journal of Dentistry for
AMBN gene have been found to be more susceptible Children, International Journal of Paediatric Dentistry,
to ECC.[16] Genetic variants of MMP20, TIMP1, TIMP2, European Journal of Pediatric Dentistry, European
KLK4 can adversely affect the maturation process of Archives of Pediatric Dentistry, Pediatric Dental Journal,
enamel, increasing the protein content and reducing Journal of Clinical Pediatric Dentistry, Caries Research,
the mineral content of matured enamel.[3,11,20,21] Journal of Indian Society of Pedodontics and Preventive
Dentistry, American Journal of Epidemiology, and Genetic
SNPs may be responsible for diversity among ethnic Epidemiology Journal were also conducted.
traits, variations in individual responses to pathogens,
toxins, drugs, and susceptibility to pathological Selection of studies
conditions, including ECC. They thus can serve as The titles and abstracts of the selected studies were
potential biomarkers of the disease. Studies have independently screened by two authors (PA and SP).
attempted to understand the effect of polymorphisms They were grouped into three categories as included,
in various enamel formation genes and predisposition excluded, and uncertain studies (if the abstract was
to ECC, albeit with conflicting and inconclusive ambiguous or unavailable). The full texts of the
results, thus creating a lacuna in comprehending the included studies and studies in uncertain categories
polymorphisms of enamel formation genes which were retrieved and evaluated. The studies which did
influence ECC susceptibility. Therefore, this systematic not satisfy the eligibility criteria were excluded from the
review aims to evaluate the effect of SNPs of enamel review. Disagreements about the studies were resolved
formation genes on susceptibility to ECC. either by consensus or by the third author (MSM).
The corresponding author was contacted to elicit any
Methods missing, unreported data.
Registration of protocol and reporting guidelines Data extraction

The systematic review was registered with the Two authors (PA and SP) recorded the data
International Prospective Register of Systematic independently in a data extraction form. Data regarding
4 Journal of Indian Society of Pedodontics and Preventive Dentistry | Volume 41 | Issue 1 | January-March 2023 |
Table 1: Risk of bias assessment of included studies

Author and Rationale Selection Selection and Technical Nontechnical Other Sample A priori Statistical Testing of Appropriateness Final Quality
year for study and comparability classification classification sources size and planning methods and assumptions of inferences score of the
definition of comparison of the of the of bias power of control for and drawn from study
of outcome groups exposure exposure analyses confounding inferences results
of interest for genetic
analyses
Slayton 6 5 5 5 1 1 4 6 6 5 6 50 Good
et al., 2005[12]
Ouryouji 6 5 5 6 1 1 1 5 3 3 6 42 Moder
et al., 2008[13] ate
Patir et al., 6 6 6 1 3 1 5 5 5 5 6 49 Good
2008[8]
Olszowski 6 5 5 5 1 1 5 5 5 5 6 49 Good
et al., 2012[14]
Shimizu 6 5 5 5 1 1 3 6 6 6 6 50 Good
et al., 2012[5]
Tannure et al., 6 6 6 5 1 1 1 6 6 4 6 48 Good
2012(a)[29]
Tannure et al., 6 6 6 5 1 1 1 6 5 4 6 47 Good
2012(b)[35]
Abbasoğlu 6 6 6 1 1 4 4 5 5 4 6 48 Good
et al., 2015 [3]
Shaffer et al., 6 5 6 5 1 1 4 5 6 5 6 50 Good
2015[9]
Antunes 6 6 6 5 1 1 1 6 5 5 6 48 Good
et al., 2016[20]
Gerreth 6 6 6 5 1 1 1 5 5 6 6 48 Good
et al., 2016[16]
Filho et al., 6 6 5 5 1 1 5 6 5 3 6 49 Good
2017[34]
Gerreth 6 6 6 6 1 1 1 6 5 5 6 49 Good
et al., 2017[11]
Lewis et al., 6 5 5 4 1 1 3 5 5 6 6 47 Good
2017[32]
Linhartova 6 5 5 5 5 1 1 5 4 4 6 47 Good
et al., 2018[30]
Wang et al., 6 5 5 6 1 1 4 6 6 2 6 48 Good
2017[19]
Weber et al., 6 5 6 5 1 1 1 5 6 6 6 48 Good
2018[21]
Journal of Indian Society of Pedodontics and Preventive Dentistry | Volume 41 | Issue 1 | January-March 2023 |
Linhartova 6 5 5 3 1 3 3 6 5 5 6 48 Good
et al., 2020[31]
Al‑Marshad 6 6 5 3 1 1 5 5 5 6 6 49 Good
et al., 2021[27]
5
Zaorska 6 6 6 4 1 1 1 6 6 6 6 49 Good
et al., 2021[28]
Wu et al., 5 6 6 4 1 1 5 5 5 5 6 49 Good
2022[15]
author’s name, institutional affiliation, journal were performed using “GeneGeneInteR 1.22.0,” “BS
name, year of publication, study design, ethnicity genome,” “Biobase,” “Biocgenerics,” “Biocmanager,”
of participants, sample size, chromosome, gene/ and “ARTP2” packages. Gene pair association using
genetic locus, SNPs analyzed, genotype frequencies, the “LD attenuating rank sum test” was performed to
allele frequencies, covariates, odds ratio (OR) at 95% determine any significant gene pairs associated with
confidence intervals (CI), and P value were obtained. ECC. The multiple testing for pathway P values was
performed using “Benjamini and Hochberg 1995” with
Assessment of risk of bias a false detection rate threshold set at 0.05.[24]

The quality of the included studies was assessed
independently by the two authors (PA and SP) using The functional impacts of differentially expressed
the Q‑Genie tool,[23] which has been designed and genes were also evaluated in system level enrichment
validated to evaluate the quality of studies analyzing analysis with Protein‑Protein Interaction (PPI)
the genetic association. It is a likert‑type scale, consisting network construction. Search Tools for Retrieval of
of eleven questions with a maximum score of 7 and a Integrating Genes and Proteins (STRING)[25] plot
minimum score of 1 for each question. For studies with was constructed wherein network nodes represent
a control group, a score of <35 indicates poor‑quality genes and lines of different colors represent different
studies, >35 but <45 indicates moderate quality types of evidence used in predicting associations.
studies, and >45 indicates good‑quality studies. For Red line represents gene fusion evidence; green line
studies without control groups, a score <32 indicates depicts gene neighborhood evidence; blue line reveals
low‑quality studies, >32, but <40 indicates moderate gene co‑occurrence evidence; purple line shows
quality studies, and >40 indicates good‑quality studies. experimental evidence; yellow line indicates text
Any difference of opinion was resolved by consensus mining evidence; light blue line suggests database
or by another author (VV). evidence; black line characterizes co‑expression
evidence. Functional interactions with interaction
score >0.7 was only plotted. Gene interaction and gene
Data synthesis network association was predicted using gene function
The results of the included studies were assessed using prediction using Multiple Association Network
the Review Manager statistical software (RevMan 5.4, Integration Algorithm (geneMANIA) where genes are
The Cochrane Collaboration, London, UK). Data from prioritised for functional assays. On entering a list of
various studies were combined if the same SNP was query genes, geneMANIA extends the list by including
analyzed and genotype frequencies were reported. other functionally similar genes from the available
Forest plots were generated and the pooled OR at 95% genomics and proteomics data.[26]
CI was calculated to estimate the effect sizes, and the
inverse‑variance method was used to estimate the weight
of the study. Heterogeneity was assessed by studying Results
the population and study characteristics. The Chi‑square
test and I2 analysis were conducted if considerable Search outcome
heterogeneity was observed. For statistical heterogeneity, The initial search of databases, registers and
I2 value >50% was considered, and a random‑effects citations yielded 7124 articles. After removal of
model was used to conduct the meta‑analysis. duplicates (n = 309), titles and abstracts of 6815 articles
were evaluated. This initial screening resulted in
Gene‑based analysis and gene pair‑based associations exclusion of 6702 articles and 113 articles qualified
were performed using “R statistical software” and Plink for full text screening. As per the selection criteria, 92
software. The base pair data (gene coordinates) for articles were excluded and 21 articles were included
each corresponding reference SNP cluster ID (RSIDs) in the review and 12 for quantitative synthesis. This
were extracted using “BiomaRt” and “BS genome. has been depicted in the PRISMA flowchart [Figure 1].
Homosapiens. UCSC.hg38” packages. The linkage The included studies have been tabulated in
disequilibrium r2 value was computed using Plink. Supplementary Table 2, and the excluded studies have
Gene‑based analysis was performed using Fisher’s been tabulated in Supplementary Table 3.
exact approach, Simes approach, extended Chi‑square
approach, Gene‑based Association Test using extended Description of studies
Simes procedure (GATES), inverse method, weighted The studies were published from 2005 to 2021. The
truncated product method (TPM), unweighted TPM, number of participants varied from 53 to 1005. The
and Adaptive rank Truncated Product (ARTP) with an studies were performed on diverse population groups
error rate of 0.05. The largest test statistic from all the such as Chinese, Turks, Norwegians, Czechs, Polish,
SNP‑based tests in a gene was used as a gene‑based Afro‑Americans, Caucasians, Hispanic Whites and
test statistic. Blacks, Non‑Hispanic Whites and Blacks, Japanese,
Brazilians, and Saudi Children.
The gene cluster analysis was performed to determine
the significant association within the enamel formation Ten studies[3,8,11,13,15,17,19,20,27,28] were conducted on
gene cluster. All gene‑based and gene cluster analyses children through 6 years. Eleven studies analyzed the
Figure 1: PRISMA flow diagram. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta‑analysis
association between genetic variants and dental caries MMP2 gene. One coding sequence and one upstream
in wider age groups, with data for children till 6 years transcript variant of MMP3 gene and one coding
being reported.[5,9,12,14,21,29‑34] For the studies conducted sequence variant of MMP9 gene and one upstream
on children in mixed age group, efforts were made to transcript variant of MMP13 were assessed. Five
contact the authors by electronic mail to retrieve data polymorphisms each of MMP10 (one each of coding
for children below 6 years; However, one author shared sequence and downstream transcript variant and
the data.[29] The studies for which data for children up three intron variants) and MMP14 (four intron and
to 6 years could not be retrieved were excluded from one upstream transcript variant) were evaluated.
the review. Eighteen polymorphisms of MMP16 gene were
analyzed of which 13 were intron variants, one was
Twenty‑one studies assessed the association between upstream transcript variant and four were intergenic
88 SNPs of 16 genes regulating enamel formation variants. One intron and one upstream transcript
and maturation with ECC in 4990 participants across variant were assessed in MMP20 gene. One each
various countries. Seven polymorphisms of AMELX of upstream transcript variants were analyzed for
gene were analyzed of which four were coding TIMP1 and TIMP2 genes.
sequence variants and three were intronic variants.
Five polymorphisms of AMBN gene were evaluated
Quality assessment
of which one was a coding sequence variant and two
The 21 included studies scored in the range of 42–50
each were intronic and upstream transcript variants.
with the Q‑Genie tool. Twenty studies were of good
Nine SNPs of ENAM gene were assessed with
five being coding sequence variants, one being an quality and one study was of moderate quality.[13] The
intron variant and three being upstream transcript quality assessment has been tabulated in Table 1.
variants. Eight intron and five upstream transcript
variants were analyzed in TUFT1 gene. Three Quantitative synthesis
coding sequence, seven intron and one upstream Among the 21 included studies, 12 studies that
transcript variants were evaluated in TFIP11 gene. analyzed 11 SNPs have been included in the
Two upstream transcript, and one each of intron meta‑analysis.[11,13,17,19‑21,28‑31,33,34] In studies where caries
and downstream transcript variants were assessed was reported as per the severity, the total number of
in KLK4. One each of coding sequence, intron and affected children was summed up for quantitative
upstream transcript variants were analyzed in synthesis. Studies with various designs were pooled
Journal of Indian Society of Pedodontics and Preventive Dentistry | Volume 41 | Issue 1 | January-March 2023 | 7
Table 2: Gene‑based analysis of enamel formation genes
8
Symbol Chromosome Start position Group SNP Position Gene feature Meta‑P
AMBN 4 70586884 Protein coding rs34538475 70605459 Intronic 0.00001
rs3924573 70593531 Intronic 0.04
rs7439186 70603887 Intronic 0.1179
rs4694075 70601197 Intronic 0.23732
TUFT1 1 151512784 Protein‑coding rs2337360 151542127 Intronic 0.00001
rs1045298 151538349 Intronic 0.1952
rs7526319 151552082 Intronic 0.255
rs8934 151538633 Intronic 0.31
rs4970957 151544912 Intronic 0.373
rs10158855 151543178 Intronic 0.4
rs2337359 151523320 Intronic 0.4963
TUFT1 151584525 Protein‑coding gene rs12749 151583265 Upstream 0.248
TUFT1 151518271 Noncoding RNA rs2337359 151523320 Intronic 0.4963
MMP13 11 102921414 Protein‑coding gene rs2252070 102955810 Intronic 0.00027
MMP9 20 46011509 Noncoding RNA rs17576 46011586 ncRNA 0.006
KLK4 19 50902108 Protein‑coding gene rs2235091 50907215 Intronic 0.0003
rs198969 50910546 Intronic 0.0049
rs198968 50910072 Intronic 0.037
rs198966 50908754 Intronic 0.041

rs17720688 88092013 Intronic 0.02
rs16878625 88113761 Intronic 0.02
rs6469206 88072463 Intronic 0.03
rs1824717 88063751 Intronic 0.04
rs7826929 88072609 Intronic 0.07
rs10103111 88062998 Intronic 0.07
rs2616487 88072056 Intronic 0.14249596
rs10089111 88107077 Intronic 0.18
rs17718917 88018262 Intronic 0.29
rs1382104 88091097 Intronic 0.3
rs1551893 88090138 Intronic 0.32
rs2054415 88075130 Intronic 0.39
rs1477907 88021387 Intronic 0.4
rs16876790 88023436 Intronic 0.4
89044241 Protein‑coding rs2046315 89198871 Intronic 0.21
MMP2‑AS1 16 55460708 Noncoding RNA rs243865 55477894 ncRNA 0.248
TIMP1 X 47566589 Pseudogene rs4898 47585586 ncRNA 0.32
Contd...
Table 2:Contd...
Symbol Chromosome Start position Group SNP Position Gene feature Meta‑P
AMELX X 11161516 Protein‑coding gene rs946252 11294907 Intronic 0.04
rs5934997 11295613 Intronic 0.058
rs6639060 11298857 Intronic 0.143
rs17878486 11295828 Intronic 0.289202
rs104894738 11294799 Intronic 0.29
rs104894733 11298243 Intronic 0.35
rs2106416 11298622 Intronic 0.356
rs104894737 11294790 Intronic 0.45
rs2287074 55493201 ncRNA 0.314
Symbol Fischers Simes GATES ECS Inverse variance Weighted TPM Unweighted TPM ARTP
AMBN 0.0005336 0.00004 0.0006 0.0006 0.0988075 0.0004248 0.00004 0.00004
TUFT1 0.3311 0.24813 0.306368 0.306368 0.289942 0.263752265 0.2555739 0.20445912
MMP13 0.00027 0.00027 0.00135 0.00135 0.00027 0.00027 0.00027 0.00027
MMP9 0.006 0.006 0.018 0.018 0.006 0.006 0.006 0.006
KLK4 0.0016 0.0012 0.0045 0.0045 0.0208 0.001275552 0.001236 0.0009888
MMP20 0.002 0.02 0.05 0.05 0.02 0.002 0.02 0.02
MMP16 0.310050509 0.2323515 0.3002895 0.300289286 0.218653538 0.246980882 0.23932256 0.191458048
MMP2-AS1 0.4190016 0.314 0.4 0.4 0.281 0.33376944 0.32342 0.258736
TIMP1 0.32 0.32 0.4 0.4 0.32 0.32 0.32 0.32
AMELX 0.3095808 0.232 0.372 0.372 0.24702525 0.24660672 0.23896 0.191168
SNP=Single‑nucleotide polymorphism; GATES=Gene‑based association test using extended Simes procedure; ECS=Extended Chi‑square; TPM=Truncated product method; ARTP=Adaptive rank truncated product
9
Table 3: Gene cluster analysis of enamel formation genes

Gene cluster Fischers Simes GATES ECS Inverse Weighted TPM Unweighted TPM ARTP
Enamel formation gene cluster 0.17001 0.13743 0.18531 0.185311 0.15024 0.13779 0.14048 0.11934
GATES=Gene‑based association test using extended Simes procedure; ECS=Extended Chi‑square; TPM=Truncated product method; ARTP=Adaptive rank
truncated product
together as the genetic association was analyzed tabulated in Table 2. The Bonferroni corrected‑log10
using the inverse variance method with random‑effect P value for the enamel formation gene cluster was
models. 2.25 (0.05/88 = 5.6 × 10−4). Six SNPs (rs3453475, rs2337360,
rs2252070, rs2235091, rs144929717, rs198969) showed
Meta‑analysis revealed that the homozygous AA significant genome‑wide association signal. AMBN,
genotype of SNP rs12640848 was significantly higher MMP13, MMP9, and KLK4 genes were significant
in patients affected by ECC and was statistically at a threshold of 3 × 10 − 3. Gene cluster analysis did
significant (OR of 2.36; 95% CI: [1.00–5.57]; P = 0.05). not reveal statistically significant association between
Meta‑analysis of the heterozygous genotype AG of polymorphisms of enamel formation gene cluster
rs12640848 was statistically not significant with a and incidence of ECC [Table 3]. No significant gene
pooled OR of 1.25; 95% CI: 0.27–5.84; P = 0.78. The pairs were determined after performing gene pair
homozygous genotype GG resulted in an OR of 0.85; association using the “LD attenuating rank sum test.”
95% CI: 0.04–4.55 and an insignificant P value. These
forest plots are depicted in Figures 2‑4 respectively. Enrichment analysis
The odds of developing caries for the homozygous The constructed enrichment network consisted of 16
genotype CC of SNP rs3796703 was 1.11; 95% CI: 0.28– nodes (differentially expressed genes) and 38 edges
4.44. The odds for developing caries for heterozygous with strength of interaction score set on >0.8. The
genotype CT was 0.90 [Supplementary Figure 1a and 1b] PPI enrichment coefficient, average node degree and
and for homozygous genotype CC of rs243865 was average local clustering coefficient were <1.0e‑16, 4.75
1.06 with 95% CI ranging from 0.39 to 2.88 and for and 0.734 respectively.
Genotype CT was 0.79 (0.44-1.36) [Supplementary
Figure 2a and 2b] and for genotype TT of rs243865 To define the functional clusters, constructed networks
was 1.40; 95% CI: 0.81–2.43 [Supplementary Figure 2c]. were clustered with the K means hierarchical
The odds of developing caries for the genotype AG clustering algorithm. The generated network showed
of SNP rs2252070 was 1.46 with 95% CI from 0.73 to four functional clusters: Cluster 1 (5 genes, AMBN,
2.94 with a nonsignificant P = 0.28 while the odds of AMELX, ENAM, KLK4, MMP20), cluster 2 (5 genes,
developing caries for AA and AG genotypes was MMP13, MMP14, MMP16, MMP2, TIMP2), cluster 3
0.81 and 0.78 respectively [Supplementary Figure 3a, (4 genes, MMP10, MMP3, MMP9, TIMP1) and cluster
3b and 3c]. The heterozygous genotype CT of SNP 4 (2 genes, TFIP11, TUFT1). The enrichment analysis
rs1711437 displayed an OR of 1.06 and 95% CI: 0.81– with the four clusters is depicted in Figure 5. Among
1.38 with P = 0.67. The homozygous genotypes CC, the biological process associated with ECC, regulation
TT returned an odds ratio of 0.84 ().47-1.51) and 0.84 of enamel mineralization and positive regulation
(0.65-1.08) respectively [Supplementary Figure 4a, 4b of tooth mineralization had highest strength of
and 4c]. Homozygous CC genotype of rs1784418 of the association 2.69 (false discovery rate of 0.0050) and
MMP20 gene with an OR of 1.05; 95% CI: 0.81–1.36. 2.61 (false discovery rate of 0.0064) respectively. The
The heterozygous CT and homozygous TT revealed an strength of disease gene association for dental caries
odds ratio of 1.11 and 0.94 respectively [Supplementary was visualized to be 2.87 with a false discovery rate
Figure 5a, 5b and 5c]. GG genotype of rs2253091 was of 1.82e‑05. Among the reactome pathways, activation
higher in patients with ECC with an OR 2.77 and 95% of MMPs had highest strength of association of
CI ranging from 0.24 to 33.53 and a P value = 0.42. AA around 2.52 (false discovery rate of 9.41 e‑18) followed
and AG genotypes displayed an odds ratio of 0.91 (0.38- by collagen degradation (2.13, false discovery rate
2.50) and 0.91 (0.68-1.22) respectively [Supplementary of 3.68e‑11). In wiki pathways MMPs had strength
Figure 6a,6b and 6c]. The P value for genotypes of SNPs of association of around 2.61 and false discovery rate
rs17576, rs7501477, and rs10429371 was not significant of 2e‑21. In protein domain and features, tissue inhibitor
[Supplementary Figures 7a, 7b, 7c, 8a, 8b, 8c, 9a, 9b, 9c]. of metalloproteinase had strength of association of 2.91.
The pairwise gene interactions were also computed for
Gene‑based and gene cluster analysis individual gene pairs. TIMP 2 and MMP 9, TIMP 2
Gene‑based analysis revealed that joint association and MMP 2 as well as TIMP 2 and MMP 14 expressed
between genetic variants of AMBN gene (6 variants, the maximum interaction with a score of 0.999. This is
all P < 0.0005), MMP13 gene (1 variant, all P < 0.005), depicted in Table 4. geneMANIA revealed that these
KLK4 (4 variants, all P < 0.005), MMP 9 (1 variant, genes were linked through physical interaction, shared
all P < 0.05), MMP20 (2 variants) was statistically protein domain, predicted protein interaction network
significant as shown by all P values (all P < 0.05 and co‑expression to an extent of 69.3%, 13.65%, 8.27%
except GATES and ECS). These results have been and 7.23% respectively [Figure 6].
Figure 2: Forest plots for AA genotype of rs12640848

Figure 3: Forest plot for AG genotype of rs12640848
Figure 4: Forest plot for GG genotype of rs12640848
Figure 5: STRING plot showing the clustering of genes into four

functional clusters. Number of nodes is 16 and number of edges is 38.
STRING: Search Tools for Retrieval of Integrating Genes and Proteins
Discussion
This systematic review assessed the effects of
polymorphisms of enamel formation genes on
susceptibility to ECC. Increasing evidence suggests Figure 6: GeneMANIA plot showing the Interaction between various
that genetic susceptibility plays a definitive role in the enamel formation genes. GeneMANIA: Gene function prediction using
etiology of dental caries.[35] This genetic predisposition Multiple Association Network Integration Algorithm
has been investigated across studies using the
the etiology of ECC. The SNPs in the coding regions
candidate gene approach. Polymorphisms in both
the coding and noncoding sequence regions of genes modify the encoded protein, which can influence the
have been investigated to interpret the genetic basis of susceptibility to acidic demineralization. SNPs in
Table 4: Interactions of enamel formation genes in various biological process and pathways
Biological process GO term Strength
Regulation of enamel mineralization GO:0070173 2.69
Positive regulation of tooth mineralization GO:0070172 2.61
Regulation of tooth mineralization GO:0070170 2.56
Negative regulation of metallopeptidase activity GO:1905049 2.54
Amelogenesis GO:0097186 2.37
Odontogenesis of dentine containing tooth GO:0042475 1.88

Odontogenesis GO:0042476 1.79
Molecular function (GO)
Structural constituents of tooth enamel GO:0030345 2.99
Reactome pathways
Description Pathway Strength
Activation of matrix metalloproteinases HSA‑1592389 2.52
Collagen degradation HSA‑1442490 2.13
Wiki pathways
Matrix metalloproteinases WP129 2.61
Disease‑gene association (diseases)
Dental caries Disease DOID: 216 2.87
Protein domains and features (Interpro)
Peptidase M10A, cysteine switch, zinc binding site Domain IPR021158 2.81
Tissue inhibitor of metalloproteinase, conserved site Domain IPR030490 2.79
Protein domains (SMART)
Tissue inhibitor of metalloproteinase family SM00206 2.91
GO=Gene ontology, SMART=Simple modular architecture research tool
the noncoding regions, can influence transcription nonamelogenin protein encoded by the AMBN gene
site and gene expression, thus potentially altering in the calcium‑binding phosphoprotein cluster on the
the disease susceptibility and influencing the fourth chromosome. The studies included in this review
genotype‑phenotype association. Alternate splicing of did not report a significant association for the genetic
the intron‑exon boundaries also results in the synthesis variants of AMBN gene and ECC.[3,5,8,9,11,15,21] However,
of isoforms of the proteins and can modify the caries in the present review, gene‑based analysis revealed
susceptibility.[33] SNPs have only a “small effect” that six variants in the AMBN gene could be associated
and many such polymorphisms across the gene can with increased ECC susceptibility. Gene‑based analysis
alter the susceptibility. Hence a gene‑based analysis performed by Li et al. revealed that six genetic variants
was performed to comprehend the effect of various of the AMELX gene were associated with a greater
polymorphisms in a single gene and its regulatory susceptibility to dental caries in contrast to the findings
region on ECC susceptibility. Such analyses can aid of this review.[39] This observed difference could be
in apprehending the effect of SNPs as the gene is the attributable to the age disparity of the study participants
functional unit of a genome, and the gene’s position, included in the analysis. Matrix metalloproteinases are
sequence, and function are consistent across the diverse involved in the breakdown of enamel matrix proteins
human populations. Gene‑based analysis also aids in during enamel formation and maturation. Mutations of
understanding the LD structure of the population and MMP20 result in the enamel which is soft, porous, and
can overcome problems associated with nonreplication highly vulnerable to acid dissolution.[20] Gene‑based
due to underlying population differences.[36] analysis has revealed that one variant of each of the
Gene‑Clustering helps in identifying and grouping MMP9 and MMP13 genes, two variants of the MMP20
genes with similar expression patterns and functions. gene, and four variants of the KLK4 gene exhibited
Clustering is based on certain similarity measures for significant association with carious demineralization.
understanding gene expression regulating the various This is similar to the gene‑based analysis of the MMP20
cellular processes.[37] It also assists in classifying genes gene reported by Li et al., wherein two genetic variants
as per their functions and in analyzing diseases by of MMP20 were associated with increased caries risk.[39]
evaluating clusters of protein‑protein interaction as KLK4, a protein‑coding gene on chromosome 19, plays
similar diseases can be caused by proteins with similar an important role in the degradation of enamel matrix
functions.[38] proteins. Mutations in KLK4 and MMP20 have been
implicated in amelogenesis imperfecta.[40]
Amelogenesis is under precise genetic control, and
interaction between various genes and their products To better comprehend the genetic association of ECC,
can alter the susceptibility to ECC. Ameloblastin is a the functional interactions of differently expressed
candidate genes were also evaluated in system‑level data.” Despite studies conducted on many participants
enrichment analysis with PPI network construction. with different ethnic backgrounds, a lack of data for
STRING plot showed numerous differentially children up to 6 years of age prevented their inclusion
expressed genes are involved in predicted and known in this review. Another important observation in
protein‑protein interactions with respect to ECC. these genetic association studies has been “conflicting
results.” These variations in the results observed could
Unlike single gene disorders, complex diseases are be accounted for by differences in the study settings,
characterized by genetic polymorphism having a sample size, the genetic makeup of the individuals,
“small” effect, and the gene‑environment interactions differences in the allele frequencies of the population
can affect the observed phenotype. In the present analyzed, and population stratification in studies
review, it has been observed that most studies conducted on participants with mixed ethnicity.
evaluated the caries phenotype using the dmft/deft
index, and five studies evaluated the presence of Environmental factors may influence the
noncavitated white spot lesions, in addition to the genetic component in multifactorial diseases.
cavitated lesions.[11,17,20,28,29] If the phenotypes were Hence, research focused on understanding gene
analyzed using the same criteria across studies, the expression, gene‑protein, and gene‑environment
effects of genetic variants on the phenotypes could have interactions (epigenetics) is necessary to apprehend
been reported differently. Moreover, dental caries is a genetic contribution to ECC.
chronic and cumulative disease, and different genes
can influence the susceptibility to carious dissolution Conclusion
at different periods of time.[41]
Based on the findings of the present review the
We deviated from the original protocol by including following conclusions can be made:
other electronic databases namely EMBASE, Web of 1. AA genotype of rs12640848 was significantly
Science, Scopus, and Google Scholar to enlarge the higher in children with ECC
specificity and objectivity of the search. Also, due to 2. Gene‑based analysis revealed that polymorphisms
the volume and the SNPs analyzed in the included of AMBN, MMP9, MMP13, MMP20, KLK4 may
studies, only the studies evaluating the association alter the genetic susceptibility
between polymorphisms of enamel formation genes 3. Though the quantitative synthesis yielded a pooled
and ECC were included into the present review. The OR > 1 for certain genotypes, alteration of alleles at
qualitative assessment using the Q‑genie tool revealed a single locus may not yield significant results as
a low risk of bias in most of the studies, with the scores SNPs can have a minor contribution and numerous
being closer to the lower margin. Many studies did not such polymorphisms can contribute toward
report on the “Non‑technical Classification” of genetic the observed phenotype. Hence, the authors
variants, and it was unclear whether a blinded assessor recommend that the polymorphisms across the
did the genotyping. The quality of the isolated DNA, gene can be analyzed as “gene” is the functional
sample size, and power calculations were not reported unit of the genome
in most of the studies. 4. Studies with greater sample sizes on diverse
populations directed toward understanding
The strengths of this study are this is the first the interaction between various genes and
study to analyze the SNPs of genes regulating environmental factors is required to understand
amelogenesis that are associated with ECC and to the genetic underpinnings of ECC
perform gene‑based and gene cluster analysis to 5. Though ECC is a multi‑factorial disease, it is evident
comprehend this plausible genetic contribution. This that certain polymorphisms of genes regulating
systematic review can aid in comprehending the amelogenesis can predispose to this condition.
genetic variations which can contribute to increased Hence, in this era of “Precision Medicine”,
susceptibility to ECC when emphasis is being placed cognizance of variations of enamel formation
on “Personalized and Precision Dentistry.” For genes and their contribution to ECC susceptibility
most of the meta‑analysis, I2 was minimal, showing is essential for clinicians and professionals treating
an absence of heterogeneity, despite studies being children with ECC.
conducted on diverse populations with different study
designs. Only observational studies were incorporated Acknowledgment
for quantitative synthesis, as in genetic association The authors thank Dr. Tannure et al. for sharing the
studies, the genetic “exposure” happens much data.
before the “outcome,” and the allele or genotype,
once established, can never change. Random‑effects Financial support and sponsorship
meta‑analysis was conducted as that would account The authors extend their thanks to the assistance
for within‑study variance and between‑study variance, provided under Founder‑Chancellor, Shri NPV
yield wider CIs, and is more conservative. One of the Ramasamy Udayar Research Fellowship (Ref No.
main limitations of this review has been “missing Founder Chancellor Fellowship 2019‑20‑2) by Sri
Ramachandra Institute of Higher Education and Davit‑Béal T, et al. Dental caries and enamelin haplotype.
Research in conducting this study. J Dent Res 2014;93:360‑5.
17. Gerreth K, Zaorska K, Zabel M, Borysewicz‑Lewicka M,
Conflicts of interest Nowicki M. Association of ENAM gene single nucleotide
There are no conflicts of interest. polymorphisms with dental caries in Polish children. Clin Oral
Investig 2016;20:631‑6.
18. Devang Divakar D, Alanazi SA, Assiri MY,
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Supplementary Table 1: Search strategy
Database Search Strategy
PubMed ((“dental caries”[MeSH Terms] OR (“dental”[All Fields] AND “caries”[All Fields]) OR “dental caries”[All Fields])
OR (“child‑hood”[All Fields] AND (“dental caries”[MeSH Terms] OR (“dental”[All Fields] AND “caries”[All
Fields]) OR “dental caries”[All Fields] OR “caries”[All Fields]))) OR ((“infant”[MeSH Terms] OR “infant”[All Fields])
AND (“dental caries”[MeSH Terms] OR (“dental”[All Fields] AND “caries”[All Fields]) OR “dental caries”[All
Fields] OR “caries”[All Fields])) AND ((“polymorphism, single nucleotide”[MeSH Terms] OR (“polymorphism”[All
Fields] AND “single”[All Fields] AND “nucleotide”[All Fields]) OR “single nucleotide polymorphism”[All Fields]
OR (“single”[All Fields] AND “nucleotide”[All Fields] AND “polymorphisms”[All Fields]) OR “single nucleotide
polymorphisms”[All Fields]) OR (“polymorphism, genetic”[MeSH Terms] OR (“polymorphism”[All Fields] AND
“genetic”[All Fields]) OR “genetic polymorphism”[All Fields] OR “polymorphisms”[All Fields])) OR “genetic”[All
Fields]) AND variants[All Fields]) AND ((((“genes”[MeSH Terms] OR “genes”[All Fields]))))
CINAHL Childhood Caries OR Infant Caries OR Early Childhood Caries AND Single Nucleotide Polymorphisms OR
polymorphisms OR genetic variants AND enamel formation genes OR Enamel genes OR Amelogenesis genes
LILACS Caries AND dental OR Childhood Caries AND Single Nucleotide polymorphisms OR Genetic variants AND Enamel
genes OR Enamel formation genes OR Amelogenesis Genes
EMBASE (Dental Caries) AND (Single Nucleotide Polymorphisms OR polymorphisms OR genetic variants) AND (Enamel genes
OR Enamel formation genes OR Amelogenesis genes))
Web of Science All Fields (Dental Caries OR Caries OR Infant Caries OR Childhood Caries) AND all fields (genetic variants OR genetic
Polymorphisms OR Single Nucleotide Polymorphisms) AND All fields (Enamel formation Genes OR Enamel genes OR
Amelogenesis genes)
Scopus (ALL (dental AND caries) AND TITLE‑ABS‑KEY (single AND nucleotide AND polymorphisms) OR
TITLE‑ABS‑KEY (enamel formation genes OR Amelogenesis genes))
Cochrane Central “dental caries” in Title Abstract Keyword AND “enamel formation genes” in Title Abstract Keyword AND
“polymorphisms” in Title Abstract Keyword OR “genetic variants” in Title Abstract Keyword
GWAS databases Dental caries AND Single Nucleotide Polymorphisms AND Enamel formation genes
Google Scholar Dental caries AND Single nucleotide Polymorphisms OR genetic polymorphisms AND genes OR Genetic Loci AND
and Opengrey genome wide association Scan
Supplementary Table 2: Polymorphisms of enamel formation genes, matrix metalloproteinases, tissue inhibitors of metalloproteinases and their
association to early childhood caries
Gene/SNP Chromosome/functional consequence Author (s)/year Study/design/country/age Sample size
AMELX/rs17878486 Xp22.2/intronic, genic upstream transcript Patir et al./2008[8] Case‑control/ 173: Cases ‑ 91; controls ‑ 82
variant Turkey/3–6 years
Abbasoğlu et al./2015[3] Cross‑sectional/ 259: Caries‑free ‑ 123; caries
Turkey/2–5 years experience ‑ 136
Gerreth et al./2017[11] Case‑control/Poland/20–42 96: Cases ‑ 48; controls ‑ 48
months
Wu et al./2020[15] Case‑control/ 517: No caries ‑ 265; with
Chinese/3–5 years caries ‑ 254 (mild caries ‑ 85, moderate
caries ‑ 83, severe caries ‑ 86)
AMELX/rs946252 Xp22.2/intronic, genic upstream transcript Shimizu et al./2012[5] (only Case‑control/ 172: Cases ‑ 90; controls ‑ 82
variant Turkey cohort considered) Turkey/3–6 years
Weber et al./2018[21] Cohort/Norway/5 years 876: No caries ‑ 647; with caries (low
caries + high caries) ‑ 228
AMELX/rs2106416 Xp22.2/coding sequence, synonymous Ouryouji et al./2008[13] Case‑control/ 147: Cases ‑ 80; controls ‑ 67
missense variant; benign Japan/3–6 years
Olszowski et al./2012[14] Case‑control/Poland/5 years 71: Low caries experience ‑ 34; high
caries experience – 37
AMELX/SNP‑4 CCCAACAGCAC/ Xp22.2/synonymousmissense, coding Slayton et al./2005[12] Case‑control/mixed 184: Cases ‑ 92; controls ‑ 92
TCCCCCGACTC-rs2106416 sequence variant; intron, genic upstream ethnicity/3–5 years
transcript variant
AMELX/rs6639060 Xp22.2/intronic, genic upstream transcript Ouryouji et al./2008[13] Case‑control/ 147: Cases ‑ 80; controls ‑ 67
variant Japan/3–6 years
AMELX/SNP‑1 GTTACGAGCCC/ Xp22.2/exon 5 variant Slayton et al./2005[12] Case‑control/mixed 184: Cases ‑ 92; controls ‑ 92
TATGGGTGGAT ethnicity/3–5 years
AMELX/SNP‑3 CATCCCCGTGC/ Xp22.2/exon 5 variant Slayton et al./2005[12] Case‑control/mixed 184: Cases ‑ 92; controls ‑ 92
GTGTCCCAACA ethnicity/3–5 years
AMELX/rs5934997 Xp22.2/intronic, genic upstream transcript Wu et al./2020[15] Case‑control/ 517: No caries 265; with
variant Chinese/3–5 years caries ‑ 254 (mild caries ‑ 85, moderate
AMBN/rs34538475 4q13.3/intron variant Patir et al./2008[8] Case‑control/ 173: Cases ‑ 91; controls ‑ 82
Turkey/3–6 years
months
AMBN/rs4694075 4q13.3/intron variant Shimizu et al./2012[5] (only Case‑control/ 172: Cases ‑ 90; controls ‑ 82
Turkey cohort considered) Turkey/3–6 years
Contd...
Supplementary Table 2: Contd...

months
Wu et al./2020[15] Case‑control/ 517: No caries 265; with caries 254 (mild
Chinese/3–5 years caries ‑ 85, moderate caries ‑ 83, severe
caries ‑ 86)
4q13.3 Slayton et al./2005[12] Case‑control/mixed 184: Cases ‑ 92; controls ‑ 92
ethnicity/3–5 years
AMBN/rs17149026 4q13.3/upstream transcript variant Shaffer et al./2015[9] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
IFS ‑ 4–6 years IFS ‑ 136)
AMBN/rs17733915 4q13.3/upstream transcript variant Shaffer et al./2015[9] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
AMBN/rs7439186 4q13.3/coding sequence missense variant Shaffer et al./2015[9] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
ENAM/rs3796703 4q13.3/coding missense variant; benign Ouryouji et al./2008[13] Case‑control/ 147: Cases ‑ 80; controls ‑ 67
Japan/3–6 years
Wang et al./2017[19] Case‑control/China/24–48 1005: Caries‑free ‑ 500; severe
months caries ‑ 505
ENAM/rs3796704 4q13.3/coding missense variant; benign Patir et al./2008[8] Case‑control/ 173: Cases ‑ 91; controls ‑ 82
Turkey/3–6 years
months
4q13.3 Slayton et al./2005[12] Case‑control/mixed 184: Cases ‑ 92; controls ‑ 92
ENAM/rs12640848 4q13.3/intron variant Shimizu et al./2012[5] (only Case‑control/ 172: Cases ‑ 90; controls ‑ 82
Shaffer et al./2015[9] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
Abbasoğlu et al./2015[3] Cross‑sectional/ 259: Cariesfree ‑ 123; caries
months
Linhartova et al./2018[30] Case‑controls/ 187: Cases ‑ 109; controls ‑ 78
Czechoslovakia/2–6 years
Al‑Marshad et al./2021[27] Case‑control/Saudi 360: No caries ‑ 98; with caries – 262
Arabia/2–6 years old
Contd...

Chinese/3–5 years caries ‑ 254 (mild caries ‑ 85,
moderate ‑ caries 83, severe caries ‑ 86)
ENAM/rs7671281 4q13.3/coding missense variant; benign Gerreth et al./2016[17] Case‑control/Poland/20–42 96: Cases ‑ 48; controls ‑ 48
months
ENAM/rs144929717 4q13.3/intronic, genic upstream transcript Gerreth et al./2016[17] Case‑control/Poland/20–42 96: Cases ‑ 48; controls ‑ 48
variant months
ENAM/rs139228330 4q13.3/intronic genic upstream transcript Gerreth et al./2016[17] Case‑control/Poland/20–42 96: Cases ‑ 48; controls ‑ 48
variant months
ENAM/rs2609428 4q13.3/coding missense variant; benign Gerreth et al./2016[17] Case‑control/Poland/20–42 96: Cases ‑ 48; controls ‑ 48
months
ENAM/rs36064169 4q13.3/coding, stop gained synonymous Gerreth et al./2016[17] Case‑control/Poland/20–42 96: Cases ‑ 48; controls ‑ 48
variant; benign months
ENAM/rs1967376 4q13.3/intronic, genic upstream transcript Shaffer et al./2015[9] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
variant IFS ‑ 4–6 years IFS 136)
TUFT1/rs3790506 1q21.3/intron variant Gerreth et al./2017[11] Case‑control/Poland/20–42 96: Cases ‑ 48; controls ‑ 48
months
Patir et al./2008[8] Case‑control/ 173: Cases ‑ 91; controls ‑ 82
Turkey/3–6 years
TUFT1/rs4970957 1q21.3/2Kb upstream transcript variant Shimizu et al./2012[5] Case‑control/ 172: Cases ‑ 90; controls ‑ 82
Turkey/3–6 years
months
TUFT1/rs2337360 1q21.3/intron variant Patir et al./2008[8] Case‑control/ 173: Cases ‑ 91; controls ‑ 82
Turkey/3–6 years
months
1q21.3 Wu et al./2020[15] Case‑control/ 517: No caries ‑ 265; with
Chinese/3–5 years caries ‑ 254 (mild caries ‑ 85,
moderate ‑ caries 83, severe ‑ caries 86)
TUFT1/rs2337359 1q21.3/intron variant Shaffer et al./2015[9] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
TUFT1/rs1045298 1q21.3/2Kb upstream transcript variant; 3 Shaffer et al./2015[9] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
prime UTR variant IFS ‑ 4–6 years IFS ‑ 136)
TUFT 1/rs17640579 1q21.3/intron variant Shaffer et al./2015[9] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
Contd...

TUFT1/rs12749 1q21.3/3 prime UTR variant Shaffer et al./2015[9] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
Slayton et al./2005[12] Case‑control/mixed 184: Cases ‑ 92; controls ‑ 92
TUFT1/rs3828054 1q21.3/5 prime UTR; upstream transcript Abbasoğlu et al./2015[3] Cross‑sectional/ 259: Caries‑free ‑ 123; caries
variant Turkey/2–5 years experience ‑ 136
TUFT1/rs946252 1q21.3/intron variant Abbasoğlu et al./2015[3] Cross‑sectional/ 259: Caries‑free ‑ 123; caries
TUFT1/rs7526319 1q21.3/intron variant Abbasoğlu et al./2015[3] Cross‑sectional/ 259: Caries‑free ‑ 123; caries
TUFT1/SNP‑2 TGGGCCGGGCG/ 1q21.3/3 prime UTR variant Slayton et al./2005[12] Case‑control/mixed 184: Cases ‑ 92; controls ‑ 92
ACAGTAGCTCA-rs1376729959; ethnicity/3–5 years
rs6578605
TFIP11/rs134136 22q12.1/intron variant Patir et al./2008[8] Case‑control/ 173: Cases ‑ 91; controls ‑ 82
Turkey/3–6 years
months
TFIP11/rs5997096 22q12.1/intron variant Shimizu et al./2012[5] (only Case‑control/ 172: Cases ‑ 90; controls ‑ 82
months
Weber et al./2018[21] Cohort/Norway/5 years 876: Caries‑free ‑ 647; with caries (low
TFIP11/rs17402286 22q12.1/coding sequence variant; Shaffer et al./2015[9] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
synonymous IFS ‑ 4–6 years IFS ‑ 136)
TFIP11/rs6005060 22q12.1/intron variant Shaffer et al./2015[9] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
TFIP 11/rs2097470 22q12.1/intron variant Shaffer et al./2015[9] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
IFS ‑ 4–6 years IFS 136)
TFIP11/rs134145 22q12.1/noncoding, upstream, 2Kb upstream Shaffer et al./2015[9] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
transcript variant IFS ‑ 4–6 years IFS ‑ 136)
Contd...

TFIP11/SNP‑2 TGATCTACATT/ 22q12.1/coding sequence synonymous, genic Slayton et al./2005[12] Case‑control/mixed 184: Cases ‑ 92; controls ‑ 92
CGACCGGGGAG-rs17850763 downstream transcript, 3’ UTR variant; DTV ethnicity/3–5 years
TFIP11/SNP‑3 TTGTCCAGGGT/ 22q12.1/coding sequence synonymous, genic Slayton et al./2005[12] Case‑control/mixed 184: Cases ‑ 92; controls ‑ 92
CGAGAAGACGT-rs16982207 downstream transcript, 3’ UTR variant ethnicity/3–5 years
KLK4/rs2235091 19q13.41/intron; genic downstream transcript Abbasoğlu et al./2015[3] Cross‑sectional/ 259: Caries‑free ‑ 123; caries
months
KLK4/rs198968 19q13.41/intron, genic upstream transcript Abbasoğlu et al./2015[3] Cross‑sectional/ 259: Caries‑free ‑ 123; caries
Weber et al./2018[21] Longitudinal cohort/ 876: No caries ‑ 647; with caries (low
Norway/5 years caries + high caries) ‑ 228
Wu et al./2020[15] Case‑control/ 517: No caries ‑ 265; with caries ‑ 254
Chinese/3–5 years (mild caries ‑ 85, moderate caries ‑ 83,
severe caries ‑ 86)
KLK4/rs198969 19q13.41/intron, genic upstream transcript Gerreth et al./2017[11] Case‑control/Poland/20–42 96: Cases ‑ 48; controls ‑ 48
variant months
KLK4/SNP‑1 GCGGAGGGCAA/ 19q13.41/intron; coding sequence; Slayton et al./2005[12] Case‑control/mixed 184: Cases ‑ 92; controls ‑ 92
CGACCAGAAGG-rs2569527 synonymous; 3’UTR; missense variant ethnicity/3–5 years
MMP2/rs243847 16q12.2/intron variant Antunes et al./2017[20] Cross‑sectional/Brazil (Nova 786: Caries‑free ‑459; caries
Friburgo)/2–6 years experience ‑ 325
MMP2/rs2287074 16q12.2/coding sequence synonymous Linhartova et al./2020[31] Case‑control/ 153: 101 cases + 52 controls
variant Czechoslovakia/2–6 years
MMP 2/rs243865 16q12.2/2Kb upstream transcript variant Tannure et al./2012(a)[29] Cross‑sectional/ 73: 40 cases + 33 controls
Brazil/3–6 years
Linhartova et al./2020[31] Case‑control/ 153: 101 cases + 52 controls
MMP3/rs522616 11q22.2/upstream transcript variant; 2Kb Antunes et al./2016[20] Cross‑sectional/Brazil (Nova 786: Caries‑free ‑459; caries
UTV Friburgo)/2–6 years experience ‑ 325
MMP3/rs679620 11q22.2/stop gained coding sequence variant; Linhartova et al./2020[31] Case‑control/ 153: 101 cases + 52 controls
missense variant Czechoslovakia/2–6 years
MMP9/rs17576 20q13.12/coding sequence variant; missense Tannure et al./2012(a)[29] Cross‑sectional/ 73: 40 cases + 33 controls
variant Brazil/3–6 years
Antunes et al./2016[20] Cross‑sectional/Brazil (Nova 786: caries‑free ‑ 459; caries
MMP10/rs7948454 11q22.2/500B DTV; downstream transcript Lewis et al./2017[32] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
variant IFS ‑ 4–6 years IFS ‑ 136)
Contd...

MMP10/rs12272341 11q22.2/intron vatiant Lewis et al./2017[32] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
MMP10/rs470154 11q22.2/intron variant Lewis et al./2017[32] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
MMP10/rs17293607 11q22.2/coding sequence missense variant Lewis et al./2017[32] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
MMP13/rs2252070 11q22.2/upstream transcript variant; 2Kb Tannure et al./2012(a)[29] Cross‑sectional/ 73: 40 cases + 33 controls
UTV Brazil/3–6 years
MMP14/rs8003217 14q11.2/2KB UTV; 500B DTV Lewis et al./2017[32] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
MMP16/rs17718917 8q21.3/intergenic Lewis et al./2017[32] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
MMP16/rs2664368 8q21.3/3’ UTR variant Lewis et al./2017[32] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
Contd...

Linhartova et al./2020[31] Case‑control/ 153: 101 cases, 52 controls
MMP16/rs10429371 8q21.3/intergenic variant Lewis et al./2017[32] Cohort/US/IHS ‑ 3–5 years; 200 (IHS ‑ 64 [41 whites + 23 blacks] +
Zaorska et al/2021[28] Case‑control/ 95: No caries ‑ 47; with caries ‑ 48
Poland/2–3 years
MMP20/rs1784418 11q22.2/intron, genic upstream transcript Tannure et al./2012(b)[33] Cross‑sectional/ 53: Cases ‑ 30 (16 Caucasians + 14
variant Brazil/3–6 years Afrodescendants); controls ‑ 23 (15
Caucasians + 8 Afrodescendants)
MMP20/rs1784418 11q22.2/intron variant; genic upstream Abbasoğlu et al./2015[3] Cross‑sectional/ 259: Caries‑free ‑ 123; caries
transcript variant Turkey/2–5 years experience ‑ 137
Antunes et al./2016[20] Cross‑sectional/Brazil (Nova 786: Caries‑free ‑ 459; caries
11q22.2 Gerreth et al./2017[11] Case‑control/Poland/20–42 96: Cases ‑ 48 + controls ‑ 48
months
11q22.2 Filho et al./2017[34] Cross‑sectional/ 56: Cases ‑ 46 + controls ‑ 10
Brazil/4–5 years
11q22.2 Linhartova et al./2020[31] Case‑control/ 153: 101 ‑ cases + 52 ‑ controls
11q22.2 Al‑Marshad et al./2021[27] Case‑control/Saudi 360: No caries ‑ 98; with caries ‑ 262
Arabia/2–6 years old
MMP20/rs1711437 11q22.2/intron variant Antunes et al./2016[20] Cross‑sectional/Brazil (Nova 786: 459 caries free + 325 caries
Friburgo)/2–6 years experience
11q22.2 Linhartova et al./2020[31] Case‑control/ 153: 101 cases + 52 controls
11q22.2 Zaorska et al./2021[28] Case‑control/ 95: No caries ‑ 47; with caries ‑ 48
Poland/2–3 years
Contd...

TIMP1/rs4898 Xp11.3/upstream transcript variant; Antunes et al./2016[20] Cross‑sectional/Brazil (Nova 786: 459 caries‑free + 325 caries
synonymous variant; missense variant; coding Friburgo)/2–6 years experience
sequence variant; intron variant
TIMP2/rs7501477 17q25.3/upstream transcript variant Tannure et al./2012(a)[29] Cross‑sectional/ 73: 40 cases + 33 controls
Brazil/3–6 years
Antunes et al./2016[20] Cross‑sectional/Brazil (Nova 786: 459 caries‑free+325 caries
Friburgo)/2–6 years experience
Gene/SNP Genotype frequencies ‑ cases Allele frequencies ‑ cases versus Statistical test (s) done P Results
versus controls controls
AMELX/rs17878486 CC/CT/TT ‑ frequencies not C/T ‑ frequencies not mentioned Student’s t‑test, Chi‑square test, Genotype ‑ 0.63; allele Over representation of “C”
mentioned Regression analysis ‑ 0.3 allele and CC genotype in
cases (when anterior and
posterior teeth are affected)
CC/CT/TT ‑ frequencies not C/T ‑ frequencies not mentioned Univariate analysis ‑ OR (95% Univariate analysis ‑ No association
mentioned CI): CC=‑ ; CT=1.10 (0.46–2.65); OR (95% CI): CC=‑ ;
TT=1.28 (0.62–2.67) CT=0.823; TT=0.506
Multivariate analysis ‑ OR (95% Multivariate analysis
CI): CC=‑ ; CT=1.04 (0.41–2.64); ‑ OR (95% CI): CC=‑;
TT=1.28 (0.59–2.77) CT=0.534; TT=0.534
CC/CT/TT: Cases ‑ 8/10/30; C/T: 26/70 versus 76/20 OR (95% CI): Genotype ‑ CC=0.11 Genotype ‑ T allele and TT genotype
controls ‑ 31/14/3 (0.04–0.2); TT=25 (6.8–92.4), Allele CC=P<0.0001; significantly more in
– T=10.2 (5.2–20) TT=P<0.0001; allele ‑ caries‑affected children
T=P<0.0001
Not mentioned Not mentioned Chi‑square: Mild caries ‑ 0.106; Mild caries ‑ 0.745; No association
moderate caries ‑ 0.001; severe moderate caries ‑ 0.973;
caries ‑ 0.013; mild + moderate severe caries ‑ 0.910; mild
caries ‑ 0.033; moderate + severe + moderate caries ‑ 0.857;
caries ‑ 0.007; mild + moderate + moderate + severe caries
severe caries ‑ 0.007 ‑ 0.932; mild + moderate
OR: Mild caries ‑ 1.349; moderate + severe caries ‑ 0.932
caries ‑ 0.967; severe caries ‑ 0.892; Additive model: Mild
mild + moderate caries ‑ 1.165; caries ‑ 0.999; moderate
moderate + severe caries ‑ 0.928; caries ‑ 0.999; severe
mild + moderate + severe caries caries ‑ 0.999; mild +
‑ 1.071 moderate caries ‑ 0.999;
OR additive model: Mild caries moderate + severe caries
‑ 3.793E + 04; moderate caries ‑ ‑ 0.999; mild + moderate
3.918E + 04; severe caries ‑ 3.764E + + severe caries ‑ 0.999
04; mild + moderate caries ‑ 2.725E
+ 04; moderate + severe caries ‑
2.714E + 04; mild + moderate +
severe caries ‑ 2.207E + 04
Contd...

OR dominant model: Mild caries Dominant model: Mild
‑ 0.891; moderate caries ‑ 0.475; caries ‑ 0.909; moderate
severe caries ‑ 0.439; mild + caries ‑ 0.548; severe
moderate caries ‑ 0.690; moderate caries ‑ 0.506; mild +
+ severe caries ‑ 0.456; mild + moderate caries ‑ 0.688;
moderate + severe caries ‑ 0.603 moderate + severe caries
OR recessive model: Mild caries ‑ 0.438; mild + moderate
‑ 1.466E + 09; moderate caries ‑ + severe caries ‑ 0.565
1.589E + 09; severe caries ‑ 1.466E +
Recessive model: Mild
09; mild + moderate caries ‑ 7.625E caries ‑ 0.999; moderate
+ 08; moderate + severe caries ‑ caries ‑ 0.999; severe
7.625E + 08; mild + moderate + caries ‑ 0.999; mild +
severe caries ‑ 5.016E + 08 moderate caries ‑ 0.999;
moderate + severe caries
‑ 0.999; mild + moderate
+ severe caries ‑ 0.999
AMELX/rs946252 CC/CT/TT ‑ frequencies not C/T ‑ 47/133 versus 62/110 Transmission Disequilibrium test, Genotype ‑ 0.10; allele T allele significantly more in
mentioned Chi‑square, Fisher’s exact tests ‑ 0.04 caries‑affected group
CC/CT/TT ‑ frequencies not C/T ‑ frequencies not mentioned Univariate analysis ‑ OR (95% CI): Univariate analysis Not in HWE. Was not tested
mentioned CC=‑; CT=1.54 (0.80–2.96); TT=1.59 ‑ OR (95% CI): CC=‑; further
(0.81–3.13) CT=0.189; TT ‑ 0.172
CI): CC=‑; CT=1.59 (0.79–3.18); ‑ OR (95% CI): CC=‑;
TT=1.37 (0.67–2.78) CT=0.188; TT=0.383
Not mentioned Not mentioned NA No association
AMELX/rs2106416 CC/CT/TT: 78/2/0 versus NA Fisher’s exact test Genotype ‑ 0.142 No association
61/6/0
CC/CT/TT: 24/13/0 versus C/T=78/38 versus 76/24; Chi‑square, Fisher’s exact test and Genotype ‑ 0.57; allele No association
21/12/1 carriage of allele T=13/13 OR (95% CI): Allele frequencies ‑ ‑ 0.67; carriage of allele
0.82 (0.36–1.90); carriage of allele T=0.81
T ‑ 0.88 (0.33–2.30)
AMELX/SNP-4 NA C/T=121/45 versus 125/53 Chi‑square test Allele ‑ 0.29 No significant association
CCCAACAGCAC/
TCCCCCGACTC-
rs2106416
AMELX/rs6639060 CC/CT/TT: 80/0/0 versus NA Fisher’s exact test P=0.143 No significant association
67/0/0
AMELX/SNP-1 NA C/T: 102/64 versus 115/63 Chi‑square test Allele ‑ 0.35 No significant association
GTTACGAGCCC/
TATGGGTGGAT
AMELX/SNP-3 NA C/G: 103/63 versus 115/63 Chi‑square test Allele ‑ 0.45 No significant association
CATCCCCGTGC/
GTGTCCCAACA
Contd...

AMELX/rs5934997 Not mentioned Not mentioned Chi square: Mild caries ‑ 3.604; Mild caries ‑ 0.058; No association
‑ 0.884; moderate caries ‑ 1.637; ‑ 0.454; mild + moderate
severe caries ‑ 1.374; mild + + severe caries ‑ 0.614
moderate caries ‑ 1.291; moderate Dominant model: Mild
+ severe caries ‑ 1.514; mild + caries ‑ 0.052; moderate
moderate + severe caries ‑ 1.317 caries ‑ 0.356; severe
OR dominant model: Mild caries caries ‑ 0.516; mild +
‑ 0.260; moderate caries ‑ 0.595; moderate caries ‑ 0.080;
severe caries ‑ 1.363; mild + moderate + severe caries
moderate caries ‑ 0.417; moderate ‑ 0.942; mild + moderate
+ severe caries ‑ 0.968; mild + + severe caries ‑ 0.416
moderate + severe caries ‑ 10.707 Recessive model: Mild
OR recessive model: Mild caries caries ‑ 0.928; moderate
‑ 0.879; moderate caries ‑ 2.949; caries ‑ 0.355; severe
severe caries ‑ 1.812; mild + caries ‑ 0.631; mild +
moderate caries ‑ 1.856; moderate moderate caries ‑ 0.584;
+ severe caries ‑ 2.358; mild + moderate + severe caries
moderate + severe caries ‑ 0.841 ‑ 0.438; mild + moderate
AMBN/rs34538475 GG/GT/TT ‑ frequencies not G/T ‑ frequencies not mentioned Student’s t‑test, Chi‑square test, Allele ‑ 0.1; genotype ‑ No significant association
mentioned Regression analysis 0.26
GG/GT/TT G/T ‑ not mentioned Univariate analysis ‑ OR (95% Univariate analysis: No significant association
CI): GG=‑; GT=0.84 (0.43–1.64); GG=‑; GT=0.660; T=0.170
TT=0.42 (0.12–1.45) Multivariate analysis:
Multivariate analysis ‑ OR (95% GG=‑; GT=0.439;
CI): GG=‑; GT=0.75 (0.36–1.57); TT=0.186
TT=0.41 (0.11–1.54)
GG/GT/TT: Cases ‑ 27/17/4; G/T: 71/25 versus 28/68 OR (95% CI): Genotype ‑ cases Genotype GG ‑ P<0.0003; More T allele and TT
controls ‑ 9/10/29 versus controls GG=5.6 (2.2–14) controls versus genotype in controls
controls versus cases; TT=17 cases ‑ TT=P<0.0001;
(5.2–54.4), Allele ‑ cases versus alleles ‑ cases versus
controls ‑ G=7 (3.7–13) controls controls ‑ G=P<0.0001;
versus cases – T=6.9 [3.7–13] controls versus cases ‑
T=P<0.0001
Contd...

Not mentioned Not mentioned Chi square: Mild caries ‑ 2.305; Mild caries ‑ 0.129; No association
mild + moderate caries ‑ 3.808; caries ‑ NA; moderate
moderate + severe caries ‑ 4.301; caries ‑ NA; severe caries
mild + moderate + severe caries ‑ 0.999; mild + moderate
‑ 4.407 caries ‑ NA; moderate +
OR additive model: Mild caries severe caries ‑ 0.999; mild
‑ NA; moderate caries ‑ NA; + moderate + severe
severe caries ‑ 3.921E + 04; Mild + caries ‑ 0.999; Dominant
moderate caries ‑ NA; moderate + model: Mild caries ‑
severe caries ‑ 2.807E + 04; mild + 0.160; moderate caries
moderate + severe caries ‑ 2.282E ‑ 0.347; severe caries ‑
+ 04 0.160; mild + moderate
OR Dominant model: Mild caries caries ‑ 0.204; moderate +
‑ 4.758; moderate caries ‑ 3.000; severe caries ‑ 0.204; mild
severe caries ‑ 4.758; mild + + moderate + severe
moderate caries ‑ 3.901; moderate caries ‑ 0172
+ severe caries ‑ 3.901; mild + Recessive model: Mild
moderate + severe caries ‑ 4.191 caries ‑ NA; moderate
OR recessive model: Mild caries caries ‑ NA; severe caries
‑ NA; moderate caries ‑ NA; ‑ 0.999; mild + moderate
severe caries ‑ 1.469E + 09; mild + caries ‑ NA; moderate +
moderate caries ‑ NA; moderate + severe caries ‑ 0.999; mild
severe caries ‑ 7.573E + 08; mild + + moderate + severe
moderate + severe caries ‑ 4.971E caries ‑ 0.999
+ 08
AMBN/rs4694075 CC/CT/TT ‑ frequencies not C/T: Cases versus controls ‑ not Transmission Disequilibrium test, Genotype ‑ 0.16; allele No significant association
mentioned mentioned Chi‑square, Fisher’s exact tests ‑ 0.29
CC/CT/TT Not mentioned Univariate analysis ‑ OR (95% CI): Univariate analysis No significant association
CC=‑; CT=1.99 (0.78–5.08); TT=0.51 ‑ CC=‑; CT=0.151;
(0.21–1.28) TT=0.153
CI): CC=‑; CT=1.74 (0.66–4.61); ‑ CC=‑; CT=0.265;
TT=0.58 (0.22–1.49) TT=0.258
CC/CT/TT: Cases ‑ 16/20/12; C/T: 52/44 versus 42/54 OR (95% CI): Genotype ‑ controls OR (95% CI): Genotype No significant association
controls ‑ 12/18/18 versus cases=CC ‑ 1.5 (0.6–3.6); ‑ controls versus cases ‑
CT ‑ 1.2 (0.5–2.7); Allele ‑ controls CC=0.3703; CT=0.6765;
versus cases=C ‑ 1.5 (0.9–2.7); T ‑ allele ‑ controls versus
0.7 (0.4–1.2) cases ‑ C=0.1496;
T=0.1496
Contd...

CC/CT/TT ‑ frequencies not C/T ‑ frequencies not mentioned Chi‑square ‑ NA Not mentioned No significant association
mentioned
Moderate caries ‑ 0.424; severe moderate caries ‑ 0.515;
moderate caries ‑ 1.066; moderate Dominant model: mild
OR Dominant model: Mild caries caries ‑ 0.240; mild +
+ severe caries ‑ 0.952x
Not mentioned Not mentioned Chi‑square test and Regression Not mentioned No heterozygosity and no
analysis further analysis
AMBN/rs17149026 GG/GT/TT ‑ frequencies not G/T ‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ 0.8429; No association
mentioned IHS (blacks) ‑ 0.03458;
IFS ‑ 0.255
AMBN/rs17733915 CC/CT/TT ‑ frequencies not C/T ‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ 0.1681; No association
mentioned IHS (blacks) ‑ 0.1388; IFS
‑ 0.9447
AMBN/rs7439186 AA/AG/GG ‑ frequencies not A/G ‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ NA; IHS No association
mentioned (blacks) ‑ 0.2507; IFS ‑
0.1179
ENAM/rs3796703 CC/CT/TT: 76/4/0 versus CC/CT/TT: Cases ‑ 76/4/0; Chi‑square test P=0.143 No association
59/8/0 controls ‑ 59/8/0
Contd...

CC/CT/TT: Cases ‑ 439/64/2 C/T ‑ 942/68 veraus 958/42 MVA: OR (95% CI) ‑ Genotype Genotype ‑ CT=0.026; CT genotype and T allele
versus 458/42/0 CT ‑ β=0.746; OR=1.609 (1.029– allele ‑ C/T=0.013 increase caries susceptibility
2.518); Genotype TT ‑ β=21.762;
OR=22907.418 (0.000–0.000)
UVA: Chi‑square test ‑ Genotype
CT ‑ χ2=4.683 (compared with CC);
Allele‑C/T ‑ χ2=6.231
ENAM/rs3796704 GG/GA/AA ‑ frequencies not G/A: NA Student’s t‑test, Chi‑square test, Allele ‑ 0.11; Genotype No association
mentioned Regression analysis ‑ 0.11
AA/CT/GG ‑ not mentioned Not mentioned Univariate analysis ‑ OR (95% CI): Univariate analysis ‑ OR No association
AA=‑; CT=‑; GG=0.63 (0.29–1.37) (95% CI): AA=‑; CT=‑;
Multivariate analysis ‑ OR GG=0.247
(95% CI): AA=‑; CT=‑; GG=0.58 Multivariate analysis
(0.25–1.37) ‑ OR (95% CI): AA=‑;
CT=‑; GG=0.217
GG/GA/AA ‑ not mentioned G/A: NA OR (95% CI): Values not given Values not given No association
GG/GA/AA ‑ frequencies NA G/A: 144/28 versus 153/19 Chi‑square test Allele ‑ 0.44 No significant association
ENAM/rs12640848 AA/AG/GG ‑ frequencies not A/G ‑ frequencies not mentioned Transmission Disequilibrium test, Genotype ‑ 0.52; Allele No association
mentioned Chi‑square, Fisher’s exact tests ‑ 0.72
AA/AG/GG ‑ frequencies not A/G ‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ 0.2513; Significant in IHS blacks
mentioned IFS ‑ 0.6152; HIS (blacks)
‑ 0.4074
AA/AG/GG ‑ frequencies not A/G: Cases versus controls ‑ not Univariate analysis ‑ OR (95% Univariate analysis: AG ‑ GG genotype protective for
mentioned mentioned CI): AA=‑; AG=0.65 (0.32–1.30); 0.221; GG ‑ 0.100 ECC
GG=0.53 (0.25–1.13) Multivariate analysis:
Multivariate analysis ‑ OR (95% AG ‑ 0.200; GG ‑ 0.032
CI): AA=‑; AG=0.61 (0.29–1.29);
GG=0.41 (0.18–0.92)
AA/AG/GG: Cases versus A/G: Cases ‑ 53/4 versus 34/62 OR (95% CI): Genotype=Cases Genotype: Cases versus GG genotype protective for
controls ‑ 8/37/3 versus 4/26/18 versus controls ‑ AA=2.2 (0.6–7.9); controls ‑ AA=0.2253; ECC
AG=2.9 (1.2–6.9); Controls AG=0.0199; controls
versus cases ‑ GG=9 (2.4–33.2); versus cases ‑ GG=0.0010
Alleles=A/G ‑ controls versus Alleles: A/G ‑ controls
cases=2.3 (1.3–4) versus cases=0.0062
GG/AG/AA: 46/50/13 versus G/A: 142/76 versus 102/54 Chi‑square and Fisher’s exact tests Not mentioned G allele and GG genotype
28/46/4 protective against caries
Not mentioned Not mentioned Chi‑square ‑ NA Chi‑square: NA No significant association
Not mentioned Not mentioned Univariate analysis ‑ OR (95% Univariate analysis: No association
CI): AA=‑; AG=0.98 (0.565–1.700); AG=0.943; GG=0.198
Multivariate analysis ‑ OR (95% AG=0.952; GG=0.26
CI): AA=‑; AG=1.019 (0.554–1.873);
GG=1.54 (0.726–3.266)
Contd...

OR Additive model: Mild caries moderate + severe caries
ENAM/rs7671281 AA/AG/GG: 4/26/18 versus A/G: 34/62 versus 53/43 Fisher’s exact test, Chi‑square test Not mentioned No significant association
8/37/3
ENAM/rs144929717 NA NA Chi‑square test, Fisher’s exact test, Not given No significant association
OR (95% CI)
ENAM/rs139228330 NA NA Chi‑square test, Fisher’s exact test, Not mentioned No significant association
OR (95% CI)
OR (95% CI)
OR (95% CI)
ENAM/rs1967376 CC/CT/TT ‑ frequencies NA C/T ‑ frequencies NA Linear and logistic regression IHS (whites) ‑ 0.9334; No significant association
IHS (blacks) ‑ 0.7141; IFS
‑ 0.6421
Contd...

TUFT1/rs3790506 AA/AG/GG ‑ 2/18/28 versus A/G: 22/74 versus 30/66 OR (95% CI): Genotype ‑ controls OR (95% CI): Genotype No differences between cases
5/20/23 versus cases ‑ AG=0.8 (0.4–1.9); ‑ controls versus cases ‑ and controls
GG=1.5 (0.7–3.4) AG=0.6765; GG=0.3074;
Allele ‑ controls versus cases – allele ‑ controls versus
G=1.5 (0.8–2.9) cases ‑ G=0.1953
Not mentioned Not mentioned Student‘s t‑test, Chi‑square test, Genotype ‑ 0.1; Allele ‑ CT genotype
Regression analysis P=0.71 overrepresented in cases
AA/AG/GG ‑ frequencies not A/G ‑ frequencies not given Univariate analysis ‑ OR (95% Univariate analysis: Genotype GG protective for
given CI): AA=‑; AG=0.93 (0.3–2.53); AG=0.881; GG=0.039 ECC
GG=0.34 (0.12=0.94) Multivariate analysis:
CI): AA=‑; AG=0.64 (0.21–1.98);
GG=0.23 (0.07–0.74)
TUFT1/rs4970957 AA/AG/GG ‑ frequency not A/G ‑ allele frequency not Transmission Disequilibrium Genotype ‑ 0.75; allele No significant association
mentioned mentioned test, Chi‑square, Fisher’s exact ‑ 0.5
tests
AA/AG/GG ‑ frequencies not A/G ‑ frequencies not mentioned Univariate analysis ‑ OR (95% Univariate analysis ‑ No differences between cases
mentioned CI): AA=‑; AG=0.85 (0.48–1.50); AG=0.577; GG=0.358 and controls
GG=0.64 (0.25–1.63) Multivariate analysis ‑
Multivariate analysis ‑ OR (95% AG=0.952; GG ‑ 0.249
CI): AA=‑; AG=0.98 (0.53–1.79);
GG=0.57 (0.22–1.48)
AA/AG/GG: 18/29/1 versus A/G: 65/31 versus 73/23 OR (95% CI): Genotype ‑ controls Genotype ‑ controls Significant
27/19/2 versus cases – AG=2.3 (1–5.3); versus cases ‑ overrepresentation of AG
GG=0.5 (0.04–5.6) AG=0.0428; GG=0.5651; genotype in children with
Allele ‑ controls versus cases – allele ‑ controls versus caries
G=1.5 (0.8–2.9) cases ‑ G=0.2004
TUFT1/rs2337360 Not mentioned Not mentioned Student t test, Chi‑square test, Genotype ‑ 0.19; allele No significant association
Regression analysis ‑ 0.2
Not in Hardy‑Weinberg Equilibrium. Not tested further
AA/AG/GG: 36/11/1 versus A/G: 83/13 versus 56/40 OR (95% CI): Genotype ‑ controls OR (95% CI): Genotype A Allele and AA genotype ‑
8/40/0 versus cases ‑ AG=0.06 (0.02–0.16); ‑ controls versus risk variants of ECC
AA=15 (0.1–77.1) cases – AG=P<0.0001;
Allele ‑ controls versus cases ‑ AA=P<0.0001; allele
A=4.6 (0.1–0.4) ‑ controls versus
cases=P<0.0001
Not mentioned Not mentioned Chi Square: Mild caries ‑ 0.644; Mild caries‑ 0.422; No association
Contd...

Additive model: Mild
OR: Mild caries ‑ 1.360; moderate caries ‑ 0.999; moderate
caries ‑ 0.801; severe caries ‑ 1.47; caries ‑ 0.999; severe
mild + moderate caries ‑ 1.083; caries ‑ 0.999; mild +
moderate + severe caries ‑ 1.134; moderate caries ‑ 0.999;
mild + moderate + severe caries moderate + severe caries
‑ 1.210 ‑ 0.999; mild + moderate
OR additive model: Mild caries + severe caries ‑ 0.999
‑ 3.936E + 04; moderate caries Dominant model: Mild
‑ 3.785E + 04; severe caries ‑ caries ‑ 0.497; moderate
3.977E + 04; mild + moderate caries ‑ 0.307; severe
caries ‑ 2.728E + 04; moderate + caries ‑ 0.466; mild +
severe caries ‑ 2.742E + 04; mild + moderate caries ‑ 0.908;
moderate + severe caries ‑ 2.250E moderate + severe caries
+ 04 ‑ 0.929; mild + moderate
OR dominant model: Mild caries + severe caries ‑ 0.820
‑ 1.328; moderate caries ‑ 0.614; Recessive model: Mild
severe caries ‑ 1.356; mild + caries ‑ 0.999; moderate
moderate caries ‑ 0.957; moderate caries ‑ 0.999; severe
+ severe caries ‑ 0.967; mild + caries ‑ 0.999; mild +
moderate + severe caries ‑ 1.085 moderate caries ‑ 0.999;
OR recessive model: Mild moderate + severe caries
caries ‑ 1.469E + 09; moderate ‑ 0.999; mild + moderate
caries ‑ 1.615E + 09; severe caries + severe caries ‑ 0.999
‑ 1.515E + 09; mild + moderate
caries ‑ 7.693E + 08; moderate +
severe caries ‑ 7.817E + 08; mild +
moderate + severe caries ‑ 5.101E
+ 08
TUFT1/rs2337359 Frequencies not mentioned Frequencies not mentioned Linear regression Genotype ‑ 0.77; allele ‑ Increased dental caries was
0.4963 observed for participants
carrying the C allele
TUFT1/rs1045298 Frequencies not mentioned Frequencies not mentioned Linear regression Genotype ‑ 0.4741; allele No significant association
‑ 0.1952
TUFT1/rs10158855 Frequencies not mentioned Frequencies not mentioned Linear regression Genotype ‑ 0.4957; Allele No significant association
‑ 0.3202
TUFT 1/rs17640579 Frequencies not mentioned Frequencies not mentioned Linear regression Genotype ‑ 0.9887; allele No significant association
‑ 0.5296
‑ 0.7581
‑ 0.7417
TT/TC/CC ‑ frequencies not T/C: 91/45 versus 100/54 Chi‑square test Allele ‑ 0.37 No significant association
mentioned
Contd...

TUFT1/rs3828054 Frequencies not mentioned Frequencies not mentioned Univariate analysis ‑ OR (95% CI): Univariate analysis: No significant association
AA=‑; AG=1.17 (0.59–2.29); G=0.51 AA=‑; AG=0.649;
(0.05–5.66) GG=0.579
Multivariate analysis ‑ OR (95% Multivariate analysis:
CI): AA=‑; AG=1.06 (0.52–2.17); AA=‑; AG=0.866;
GG=0.44 (0.04–5.06) GG=0.511
CC=‑; CT=1.38 (0.79–2.40); TT=1.32 CC=‑; CT=0.255;
(0.62–2.85) TT=0.473
CI): CC=‑; CT=1.34 (0.73–2.43); CC=‑; CT=0.344;
TT=1.36 (0.60–3.09) TT=0.465
CC=‑; CT=1.38 (0.79–2.40); TT=1.32 CC=‑; CT=0.255;
(0.62–2.85) TT=0.473
CI): CC=‑; CT=1.34 (0.73–2.43); CC=‑; CT=0.344;
TT=1.36 (0.60–3.09) TT=0.465
TUFT1/SNP-2 GG/GA/AA ‑ frequencies not G/A: 108/28 versus 114/40 Chi‑square test Allele ‑ 0.40 No significant association
TGGGCCGGGCG/ mentioned
ACAGTAGCTCA-
rs1376729959;
rs6578605
TFIP11/rs134136 CC/CT/TT ‑ frequencies not C/T ‑ frequencies not mentioned Student‘s t‑test, Chi‑square test, Genotype ‑ 0.79; allele No significant association
mentioned Regression analysis ‑ 0.77
CC/CT/TT ‑ frequencies not C/T ‑ frequencies not mentioned Univariate analysis ‑ OR (95% CI): Univariate analysis: No significant association
mentioned CC=‑; CT=1.18 (0.67–2.06); TT=1.39 CC=‑; CT=0.568;
(0.66–2.9) TT=0.383
CI): CC=‑; CT=1.58 (0.80–3.11); CC=‑; CT=0.185;
TT=1.06 (0.58–1.91) TT=0.860
CC/CT/TT: 15/25/8 versus C/T: 55/41 versus 5/37 OR 95% CI: Genotype ‑ controls Genotype ‑ controls No significant association
18/23/7 versus cases ‑ CT=1.2 (0.5–2.6); versus cases ‑ CT=0.6832;
TT=1.2 (0.5–2.6) TT=0.7788; allele ‑
Allele ‑ controls versus cases – controls versus cases ‑
T=1.2 (0.7–2.1) T=0.5568
TFIP11/rs5997096 CC/CT/TT ‑ frequencies not C/T: Cases versus controls ‑ not Transmission Disequilibrium test, Genotype ‑ 0.77; allele No association
mentioned mentioned Chi‑square, Fisher’s exact tests ‑ 0.61
CC/CT/TT ‑ frequencies not C/T ‑ frequencies not mentioned Univariate analysis ‑ OR (95% CI): Univariate analysis No significant association
mentioned CC=‑; CT=0.75 (0.37–1.51); TT=1.19 ‑ OR (95% CI): CC=‑;
(0.52–2.68) CT=0.414; TT=0.683
CI): CC=‑; CT=0.64 (0.31–1.35); ‑ OR (95% CI) ‑ CC=‑;
TT=1.03 (0.44–2.39) CT=0.242; TT=0.950
Contd...

CC/CT/TT: 36/12/0 versus C/T: 84/12 versus 86/10 OR (95% CI): Genotype ‑ controls OR (95% CI): Genotype No significant association
38/10/0 versus cases ‑ CT=1.3 (0.5–3.3); ‑ controls versus cases
allele ‑ controls versus cases ‑ ‑ CT ‑ P=0.6276; allele ‑
T=1.2 (0.5–3) controls versus cases ‑ T
‑ P=0.6508
CC/CT/TT ‑ no primary C/T: No primary caries versus Chi‑square: No caries versus No caries versus low No significant association
caries versus low primary low primary caries ‑ 501/484 low caries – genotype ‑ χ2=6.182; caries ‑ Genotype ‑
caries ‑ 133/235/125 versus versus 84/114; recessive ‑ 15/84 allele=4.64; low caries versus high P=0.04; Allele ‑ P=0.03;
15/54/30; low caries versus high versus 133/360; low caries versus caries ‑ 4.102 Low caries versus high
caries ‑ frequencies not given high caries ‑ 72/62 versus 84/114 caries ‑ P=0.04
TFIP11/rs17402286 Frequencies not mentioned Frequencies not mentioned Linear regression done IHS (whites) ‑ 0.5176; Suggestive association in
IHS (blacks) ‑ 0.01405; children
IFS ‑ 0.1587
TFIP11/rs6005060 Frequencies not mentioned Frequencies not mentioned Linear regression done IHS (whites) ‑ 0.4884; Suggestive association in
IHS (blacks) ‑ 0.1661; IFS children
‑ 0.4213
TFIP11/rs713900 Frequencies not mentioned Frequencies not mentioned Linear regression IHS (whites) ‑ 0.3399; Suggestive association in
‑ 0.4979
‑ 0.9746
TFIP 11/rs2097470 Frequencies not mentioned Frequencies not mentioned Linear regression IHS (whites) ‑ 0.6187; Suggestive association in
‑ 0.5577
‑ 0.1723
‑ 0.9001
TFIP11/SNP-2 TT/TC/CC ‑ frequencies not T/C: 136/0 versus 152/2 Chi‑square: Value not mentioned. Allele ‑ 0.50 Interacts with S. mutans and
TGATCTACATT/ given P=0.50 increases caries susceptibility
CGACCGGGGAG-
rs17850763
TFIP11/SNP-3 TT/TC/CC ‑ frequencies not T/C: 131/5 versus 153/1 Chi‑square Allele ‑ 0.10 Interacts with S. mutans and
TTGTCCAGGGT/ given increases caries susceptibility
CGAGAAGACGT-
rs16982207
KLK4 /rs2235091 AA/AG/GG ‑ frequencies not A/G ‑ frequencies not mentioned Univariate analysis ‑ OR (95% Univariate analysis: No association
mentioned CI): AA=‑; AG=1.58 (0.38–6.55); AA=‑; AG=0.531;
GG=1.78 (0.46–6.88) GG=0.401
CI): AA=‑; AG=1.65 (0.36–7.57); ‑ OR (95% CI): AA=‑;
GG=1.70 (0.40‑7.18) AG=0.518; GG=0.467
Contd...

AA/GA/GG: 20/18/10 versus G/A: 38/58 versus 21/75 OR (95% CI): Genotype ‑ controls OR (95% CI): Genotype G allele more in children
28/19/1 versus cases – GA=0.9 (0.4–2.1); ‑ controls versus cases with caries
GG: 12.4 (1.5–101); allele ‑ controls – GA=0.8389; GG ‑
versus cases ‑ G=2.3 (1.2–4.4) P=0.0189; allele ‑ controls
versus cases ‑ G=0.0085
AA/AG/GG ‑ no caries versus A/G: No caries versus high Chi‑square ‑ no caries versus No caries versus high Significant in a recessive
high caries ‑ 55/253/281 versus caries ‑ 72/112 versus 363/815; high caries ‑ Genotype ‑12.68; caries ‑ genotype=0.002; model as protective against
20/32/40; low caries versus high recessive ‑ 21/72 versus allele=5.062; low caries versus high allele ‑ 0.02; low caries ECC
caries ‑ 20/32/40 versus 7/52/57 55/534; low caries versus high caries ‑ genotype=11.38; allele=4.85 versus high caries
caries ‑ 72/112 versus 66/166; ‑ genotype=0.003;
recessive ‑ 20/72 versus 7/109 allele=0.03
caries ‑ 0.950; mild + moderate moderate + severe caries
+ severe caries ‑ 0.499; OR: Mild ‑ 0.330; mild + moderate
caries ‑ 1.015; moderate caries ‑ + severe caries ‑ 0.480
1.467; severe caries ‑ 1.165; mild + Additive model: Mild
moderate caries ‑ 1.223; moderate caries ‑ 0.999; moderate
+ severe caries ‑ 1.306; mild + caries ‑ 0.999; severe
moderate + severe caries ‑ 1.203 caries ‑ 0.999; mild +
OR additive model: Mild caries moderate caries ‑ 0.998;
‑ 3.686E + 04; moderate caries ‑ moderate + severe caries
4.256E + 04; severe caries ‑ 3.772E + ‑ 0.998; mild + moderate
04; mild + moderate caries ‑ 2.786E + severe caries ‑ 0.998
+ 04; moderate + severe caries ‑ Dominant model: Mild
2.823E + 04; mild + moderate + caries ‑ 0.639; moderate
severe caries ‑ 2.241E + 04 caries ‑ 0.347; severe
severe caries ‑ 0958; mild + moderate + severe caries
OR recessive model: Mild caries ‑ 0.999; moderate
caries ‑ 1.515E + 09; Moderate caries ‑ 0.999; severe
caries ‑ 1.643E + 09; Severe caries caries ‑ 0.999; mild +
‑ 1.539E + 09; mild + moderate moderate caries ‑ 0.998;
caries ‑ 7.880E + 08; moderate + mod + severe caries ‑
severe caries ‑ 7.945E + 08; mild + 0.998; mild + moderate +
moderate + severe caries ‑ 5.211E severe caries ‑ 0.998
+ 08
Contd...

KLK4/rs198968 AA/AG/GG ‑ frequencies not A/G ‑ frequencies not mentioned Univariate analysis ‑ OR (95% Univariate analysis: Genotypes AG and GG
mentioned CI): AA=‑; AG=0.43 (0.09–1.90); AA=‑; AG=0.265; protective against caries
GG=0.45 (0.11–1.87) GG=0.275
CI): AA=‑; AG=0.15 (0.03–0.89); AA=‑; AG=0.037;
GG=0.17 (0.03–0.92) GG=0.040
Not mentioned Not mentioned Chi‑square: Values not given Chi‑square. Values not G allele protective for caries
given
caries ‑ 2.126; mod + severe caries + moderate caries ‑ 0.145;
‑ 1.731; mild + mod + severe caries moderate + severe caries
‑ 1.956 ‑ 0.188; mild + moderate
OR: Mild caries ‑ 1.368; Moderate + severe caries ‑ 0.162
‑ 1.363 moderate caries ‑0.364;
OR dominant model: Mild caries ‑ 0.206; mild +
caries ‑ 1.913; moderate caries ‑ moderate caries ‑ 0.068;
1.652; severe caries ‑ 1.577; mild moderate + severe caries
+ moderate caries ‑ 1.783; mod ‑ 0.130; mild + moderate
+ severe caries ‑ 1.612; mild + + severe caries ‑ 0.072;
moderate + severe caries ‑ 1.090 ‑ 0.681; Mild + moderate
KLK4/rs198969 CC/CG/GG: Cases ‑ 14/23/11 C/G: 51/45 versus 70/26 OR 95% CI: Genotype ‑ controls Genotype ‑ controls Significantly higher
versus 23/24/1 versus cases ‑ CG: 0.9 (0.4–2); versus cases ‑ 0.8382; incidence of the GG
GG=14 (1.7–113.2); allele ‑ controls GG=0.0135; allele ‑ homozygote and the G allele
versus cases – G=2.4 (1.3–4.3) controls versus cases ‑ in children with caries
G=0.0049
Contd...

KLK4/SNP-1 Not given Not given Chi‑square Not mentioned No association
GCGGAGGGCAA/
CGACCAGAAGG-
rs2569527
MMP2/rs243847 CC/CT/TT ‑ dmft >1 versus C/T: dmft >1 versus Chi‑square test and OR (95% Genotype ‑ dmft >1 No association
dmft=22/81/81 versus dmft=0‑125/243 versus CI): Alleles ‑ dmft >1 versus versus dmft=0‑0.929;
53/203/189 WSL >1 versus 309/581 WSL >1 versus dmft=0=1.03 (0.79–1.35); WSL >1 WSL >1 versus
WSL=0‑19/63/73 versus WSL=0‑101/209 versus versus WSL=0‑1.12 (0.85–1.49); WSL=0‑0.410; dmft
56/220/196 caries (WSL + dmft) 332/612 caries (WSL + dmft) caries (WSL + dmft) >1 versus >1 + WSL >1 versus
>1 versus caries‑free >1 versus caries‑free caries‑free (WSL + dmft)=0‑1.04 dmft=0 + WSL=0‑0.592;
(WSL + dmft)=0‑31/104/110 (WSL + dmft)=0‑166/324 versus (0.82–1.33) alleles ‑ dmft >1 versus
versus 44/178/160 266/498 Multivariate analysis genotypes dmft=0‑0.798; WSL >1
‑ OR (95% CI): dmft ‑ CC versus versus WSL=0‑0.405;
CT=1.18 (0.63–2.21); CC versus caries (WSL + dmft)
TT=1.42 (0.76–2.67); WSL ‑ CC >1 versus caries‑free
versus CT=0.84 (0.46–1.55); CC (WSL + dmft)=0‑0.732;
versus TT=1.19 (0.65–2.17); dmft genotypes ‑ dmft ‑ CC
+ WSL ‑ CC versus CT=0.88 versus CT=0.594; CC
(0.49–1.58); CC versus TT=1.06 versus TT=0.267; WSL
(0.59–1.91) ‑ CC versus CT=0.592;
CC versus TT=0.560;
dmft + WSL ‑ CC versus
CT=0.683; CC versus
TT=0.824
MMP2/rs2287074 GG/AG/AA: 31/56/14 versus A/G: 57/47 versus 118/84 Alleles ‑ Fisher’s exact test; Alleles ‑ 0.314; No association
16/25/11 genotypes ‑ Chi‑square test Genotypes ‑ 0.480
MMP 2/rs243865 CC/CT/TT: 11/13/4 versus Not mentioned OR (95% CI), Regression analysis. Values not mentioned No association
17/14/6 Values not mentioned separately separately for primary
for primary dentition dentition
CC/CT/TT: 62/34/5 versus C/T: 158/44 versus 77/27 Alleles ‑ Fisher’s exact test; Alleles ‑ 0.248; No association
MMP3/rs522616 GG/AG/AA ‑ dmft >1 G/A: dmft >1 versus Chi‑square test and OR (95% Genotype ‑ dmft >1 No association
versus dmft=21/58/96 versus dmft=0‑100/250 versus CI): Alleles ‑ dmft >1 versus versus dmft=0‑0.793;
52/127/240 WSL >1 versus 231/607 WSL >1 versus dmft=0‑0.95 (0.71–1.27); WSL >1 WSL >1 versus
versus 47/108/201 202/510 Multivariate analysis – Genotype: dmft=0‑0.724; WSL >1
dmft ‑ GG versus GA=1.41 versus WSL=0‑0.797;
(0.72–2.76); GG versus AA=1.25 caries (WSL + dmft) >1
(0.66–2.34); WSL ‑ GG versus versus caries‑free (WSL +
GA=1.16 (0.59–2.26); GG versus dmft)=0‑0.663
AA=1.21 (0.65–2.26); dmft + WSL ‑
GG versus GA=1.59 (0.85–2.9) GG
versus AA=1.44 (0.80–2.58)
Contd...

Multivariate analysis:
Genotypes ‑ dmft ‑ GG
versus GA=0.306; GG
versus AA=0.482;
WSL=0.652; GG versus
AA=0.539; dmft + WSL
‑ GG versus GA=0.141;
GG versus AA=0.220
MMP3/rs679620 CC/CT/TT: 24/55/22 versus C/T: 103/99 versus 53/51 Alleles ‑ Fisher’s exact test; Alleles ‑ 0.546; No association
MMP9/rs17576 AA/AG/GG: Cases ‑ 19/11/7; Not mentioned OR (95% CI), Regression analysis. OR (95% CI), Regression No association
controls ‑ 10/15/3 Values not mentioned separately analysis. Values not
for primary dentition mentioned separately for
primary dentition
GG/AG/AA ‑ dmft >1 versus G/A: dmft >1 versus Chi‑square test and OR (95%CI): Genotypes ‑ dmft >1 GG genotype more in
dmft=0‑48/65/6 versus dmft=0‑161/77 versus Alleles ‑ dmft >1 versus versus dmft=0‑0.006; patients without disease
144/118/26 caries (WSL + dmft) 406/170; caries (WSL + dmft) caries (WSL + dmft) >1 versus >1 + WSL >1 versus
(WSL + dmft)=0‑66/85/10 versus (WSL + dmft)=0‑217/105 versus (0.88–1.68) alleles ‑ dmft >1 versus
124/84/24 332/132 Multivariate analysis – genotypes: dmft=0 ‑ P=0.375 WSL
OR (95% CI) ‑ dmft ‑ AA versus >1 versus WSL=0‑0.467;
AG=1.62 (0.97–2.69); AA versus caries (WSL + dmft) >1
GG=0.45 (0.15–1.33); WSL ‑ WSL versus caries‑free (WSL +
‑ AA versus AG=1.31 (0.81–2.12); dmft)=0‑0.211
AA versus GG ‑ 1.03 (0.43–2.48); Multivariate analysis:
dmft + WSL ‑ AA versus AG=1.88 dmft ‑ AA versus
(1.17–3.02); AA versus GG=0.81 AG=0.060; AA versus
(0.34–1.93) GG=0.151; WSL ‑ AA
versus AG=0.254; AA
versus GG=0.935; dmft
+ WSL ‑ AA versus
AG=0.008; AA versus
GG=0.644
AA/AG/GG: 37/54/10 versus A/G: 128/74 versus 63/41 Alleles ‑ Fisher’s exact test; Alleles ‑ 0.361; No association
MMP10/rs7948454 CC/CT/TT ‑ frequencies not C/T ‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ 0.69; IFS ‑ No association
mentioned 0.53; IHS (blacks) ‑ 0.55
MMP10/rs12272341 AA/AG/GG ‑ frequencies not A/G ‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ 0.52; IFS ‑ No association
MMP10/rs470154 CC/CG/GG ‑ frequencies not C/T ‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ 0.04; IFS ‑ No association
Contd...

MMP13/rs2252070 AA/AG/GG: Cases ‑ 20/9/7; Not mentioned OR (95% CI), Regression analysis. Values not mentioned Genotype GG may be
controls ‑ 10/12/6 Values not mentioned separately separately for primary associated with caries
for primary dentition dentition experience
TT/CT/CC: 55/38/8 versus C/T: 148/54 versus 73/31 Alleles ‑ Fisher’s exact test; Alleles ‑ 0.330; No association
MMP14/rs8003217 AA/AC/CC ‑ frequencies not A/C ‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ 0.41; IFS ‑ No association
MMP14/rs12893368 CC/CG/GG ‑ frequencies not C/G ‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ 0.53; IFS ‑ No association
MMP16/rs16876790 AA/AT/TT‑ frequencies not A/T ‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ 0.98; IFS ‑ No association
mentioned 0.83; IHS (blacks) ‑ NA
MMP16/rs6469206 GG/GT/TT ‑ frequencies not G/T ‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ 0.03; IFS ‑ No association
MMP16/rs2054415 GG/GT/TT ‑ frequencies not G/T ‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ 0.66; IFS ‑ No significant association
MMP16/rs1551893 AA/AT/TT ‑ frequencies not A/T‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ 0.32; IFS ‑ No significant association
MMP16/rs1382104 CC/CT/TT ‑ frequencies not C/T ‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ 0.30; IFS ‑ No significant association
Contd...

MMP16/rs10089111 GG/GT/TT ‑ frequencies not G/T ‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ 0.18; IFS ‑ No significant association
MMP16/rs2046315 AA/AG/GG ‑ frequencies not A/G ‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ 0.21; IFS ‑ No significant association
GG/AG/AA: 69/30/2 versus A/G: 168/34 versus 83/21 Alleles ‑ Fisher’s exact test; Alleles ‑ 0.283; No association
MMP16/rs10429371 TT/TC/CC ‑ frequencies not T/C ‑ frequencies not mentioned Linear regression analysis IHS (whites) ‑ 0.27; IFS ‑ No association
TT/CT/CC: 51/43/7 versus C/T: 145/57 versus 79/25 Alleles ‑ Fisher’s exact test; Alleles ‑ 0.261; No association
CC/CT/TT: 18/20/10 versus C/T: 49/47 versus 47/47 OR (95% CI): CC versus CT + Genotype P ‑ CC
17/30/0 TT=1.1 (0.5–2.4); CT versus CC versus CT + TT=0.8931;
+ TT=0.4 (0.2–0.9); TT versus CC CT versus CC +
+ CT=25.9 (1.5–456.4); Alleles T TT=0.0320; TT versus
versus C=1.5 (0.8–2.8) CC + CT=0.0262; Alleles
P=0.1645
MMP20/rs1784418 CC/CT/TT: C/T: Caucasians=Caries‑free Chi‑square test and OR (95% Caucasians ‑ 0.087; No association
Caucasians ‑ caries‑free versus versus caries CI) ‑ Caucasians=0.91 (0.27–3.13); Afrodescendants ‑ 0.15
caries experience=7/7/1 experience ‑ 21/9 versus 23/9; Afrodescendants=0.40 (0.09–1.71)
versus 9/5/2; Afrodescendants=Caries‑free
Afrodescendants ‑ caries‑free versus caries experience ‑ 8/8
versus caries experience=3/2/3 versus 20/8
versus 7/6/1
MMP20/rs1784418 CC/CT/TT ‑ frequencies not C/T ‑ frequencies not mentioned Univariate analysis ‑ OR (95% CI): Univariate analysis: No association
mentioned CC=‑; CT=1.25 (0.66–2.37); TT=1.04 CC=‑; CT=0.484;
(0.52–2.05) TT=0.919
CI): CC=‑; CT=1.2 (0.61–2.39); CC=‑; CT=0.598;
TT=1.02 (0.49–2.12) TT=0.947
GG/AG/AA: dmft >1 versus G/A: dmft >1 versus Chi‑square test and OR (95% CI): Genotypes ‑ dmft >1 Associated with WSL
dmft=0‑64/96/38 versus dmft=0‑224/172 versus Alleles ‑ dmft >1 versus dmft=0 versus dmft=0‑0.309;
176/198/83 WSL >1 versus 550/364 WSL >1 versus 1.16 (0.0.91–1.48 WSL >1 versus WSL >1 versus
WSL=0‑72/71/21 versus WSL=0‑215/113 versus 556/408 WSL=0‑0.73 (0.56–0.95); caries WSL=0‑0.050; dmft
167/222/93 caries (WSL + dmft) caries (WSL + dmft) >1 versus (WSL + dmft) >1 versus caries‑free >1 + WSL >1 versus
>1 versus caries‑free caries‑free (WSL + dmft) (WSL + dmft)=0‑0.88 (0.70–1.12) dmft=0 + WSL=0‑0.371;
(WSL + dmft)=0‑97/121/39 =0‑315/199 versus 455/325 alleles ‑ dmft >1 versus
versus 141/173/76 dmft=0‑0.222; WSL >1
versus WSL=0‑0.012;
caries (WSL + dmft) >1
versus caries‑free (WSL +
dmft)=0‑0.290
Contd...

CI): Genotypes ‑ dmft ‑ GG versus dmft ‑ GG versus
AG=1.18 (0.76–1.82); GG versus AG=0.446; GG versus
AA=0.99 (0.56–1.77); WSL ‑ WSL AA=0.994; WSL ‑ WSL
‑ GG versus AG=0.68 (0.45–1.02); ‑ GG versus AG=0.063;
GG versus AA=0.50 (0.28–0.88); GG versus AA=0.018;
dmft + WSL ‑ GG versus AG=0.74 dmft + WSL ‑ GG versus
(0.44–1.25); GG versus AA=0.84 AG=0.712; GG versus
(0.57–1.25) AA=0.274
CC/CT/TT: 20/23/5 versus C/T: 63/33 versus 60/36 OR (95% CI): Genotype ‑ controls OR (95% CI): Genotype No significant association
17/26/5 versus cases ‑ CT=0.8 (0.3–1.7); ‑ controls versus cases
TT=1 (0.3–3.7); allele ‑ controls ‑ CT=0.545; TT=1;
versus cases ‑ T=0.9 (0.5–1.6) allele ‑ controls versus
cases=0.6519
CC/CT/TT: Cases versus C/T: Cases versus OR (95% CI): Cases versus controls P=0.086 No significant association
controls ‑ 16/18/7 versus 1/5/3 controls ‑ 50/32 versus 7/11 ‑ 0.40 (0.14–1.16)
CC/CT/TT: 32/46/23 versus C/T: 110/92 versus 56/48 Fisher’s exact test, Chi‑square test Genotype ‑ 0.993; Allele No association
16/24/12 ‑ 0.507
AA/AG/GG ‑ not mentioned A/G ‑ not mentioned Univariate analysis ‑ OR (95% CI): Univariate analysis: No association
AA=‑; AG=0.532 (0.316–0.897); AG=0.018; GG=0.691
CI): AA=‑; AG=0.606 (0.342–1.074);
GG=1.039 (0.465–2.324)
moderate caries ‑ 0.817; moderate
+ severe caries ‑ 0.848; mild +
moderate + severe caries ‑ 0.829
Contd...

OR dominant model: mild caries Dominant model: Mild
‑ 1.027; moderate caries ‑ 0.630; caries ‑ 0.951; moderate
severe caries ‑ 0.439; mild + caries ‑ 0.274; severe
moderate caries ‑ 0.804; moderate caries ‑ 0.506; mild +
+ severe caries ‑ 0.574; mild + moderate caries ‑ 0.560;
moderate + severe caries ‑ 0.692 moderate + severe caries
OR recessive model: mild caries ‑ 0.131; mild + moderate
‑ 0.519; moderate caries ‑ 1.022; + severe caries ‑ 0.295
severe caries ‑ 1.188; mild + Recessive model: Mild
moderate caries ‑ 0.741; moderate caries ‑ 0.164; moderate
+ severe caries ‑ 1.107; mild + caries ‑ 0.959; severe
moderate + severe caries ‑ 0.882 caries ‑ 0.678; mild +
moderate caries ‑ 0.433;
moderate + severe caries
‑ 0.783; mild + moderate
MMP20/rs1711437 GG/AG/AA: dmft >1 versus G/A: dmft >1 versus Chi‑square test and OR (95% Genotypes ‑ dmft >1 Associated with WSL
dmft=0‑67/86/24 versus dmft=0‑220/134 versus CI): Alleles ‑ dmft >1 versus versus dmft=0‑0.309;
WSL=0‑74/63/20 versus WSL=0‑211/103 versus versus WSL=0‑0.73 (0.55–0.96); WSL=0‑0.052 dmft
versus 141/173/68 455/309 Multivariate analysis ‑ genotypes dmft=0‑0.878; WSL >1
‑ OR (95% CI): dmft ‑ GG versus versus WSL=0‑0.020;
AG=1.07 (0.70–1.66); GG versus caries (WSL + dmft) >1
AA=0.91 (0.50–1.67); WSL ‑ WSL versus caries‑free (WSL +
‑ GG versus AG=0.65 (0.43–0.97); dmft)=0‑0.052
GG versus AA=0.61 (0.34–1.09); Multivariate analysis:
dmft + WSL ‑ GG versus AG=0.84 Genotypes ‑ dmft ‑ GG
(0.57–1.25); GG versus AA=0.65 versus AG=0.729; GG
(0.38–1.13) versus AA=0.780;
WSL ‑ WSL‑ GG versus
AG=0.038; GG versus
AA=0.096; dmft + WSL
‑ GG versus AG=0.410;
GG versus AA=0.133
CC/CT/TT: 33/44/24 versus C/T: 110/92 versus 55/49 Fisher’s exact test, Chi‑square test Genotype ‑ 0.610; alleles No association
14/27/11 ‑ 0.444
CC/CT/TT: 19/23/6 versus C/T: 61/35 versus 63/31 OR (95% CI): CC versus CT + Genotype P ‑ CC
20/23/4 TT=0.9 (0.4–2.0); CT versus CC + versus CT + TT=0.7686;
TT=1.0 (0.4–2.1); TT versus CC + CT versus CC +
CT=1.5 (0.4–5.8); alleles T versus TT=0.9208; TT versus
C=1.2 (0.6–2.1) CC + CT=0.5287; alleles
P=0.6146
Contd...

TIMP1/rs4898 CC/CT/TT: dmft >1 versus C/T: dmft >1 versus Chi‑square test and OR (95% Genotypes ‑ dmft >1 No association
dmft=0‑16/62/83 versus dmft=0‑16/62/83 versus CI): Alleles ‑ dmft >1 versus versus dmft=0‑0.775;
45/138/195 WSL >1 versus 45/138/195; WSL >1 versus dmft=0‑1.05 (0.78–1.41); WSL >1 WSL >1 versus
WSL=0‑15/45/66 versus WSL=0‑15/45/66 versus versus WSL=0‑1.01 (0.73–1.39); WSL=0‑0.930; dmft
46/154/211 caries (WSL + dmft) 46/154/211 caries (WSL + dmft) Caries (WSL + dmft) >1 versus >1 + WSL >1 versus
(WSL + dmft)=0‑22/75/112 (WSL + dmft)=0‑22/75/112 (0.85–1.48) alleles ‑ dmft >1 versus
versus 39/125/165 versus 39/125/165 Multivariate analysis ‑ Genotypes dmft=0‑0.751; WSL >1
‑ OR (95% CI): dmft ‑ CC versus versus WSL=0‑0.960;
CT=1.47 (0.68–3.18) CC versus caries (WSL + dmft) >1
TT=1.26 (0.59–2.66); WSL ‑ WSL versus caries‑free (WSL +
‑ CC versus CT=0.87 (0.43–1.74); dmft)=0‑0.405
CC versus TT=0.95 (0.49–1.85); Multivariate analysis:
dmft + WSL ‑ CC versus CT=1.12 Genotypes ‑ dmft ‑ CC
(0.56–2.22); CC versus TT=1.27 versus CT=0.320; CC
(0.65–2.45) versus TT=0.541; WSL
‑ WSL ‑ CC versus
CT=0.699; CC versus
TT=0.894; dmft + WSL ‑
CC versus CT=0.741; CC
versus TT=0.473
TIMP2/rs7501477 GG/GT/TT: Cases ‑ 23/10/4; Not mentioned OR (95% CI), Regression analysis. Values not mentioned No association
controls ‑ 18/10/0 Values not mentioned separately separately for primary
for primary dentition dentition
GG/GT/TT: dmft >1 versus G/T: dmft>1 versus Chi‑square test and OR (95% Genotype ‑ dmft>1 No association
dmft=0‑126/40/3 versus dmft=0‑292/46 versus 633/109 CI): Alleles ‑ dmft>1 versus versus dmft=0‑0.532;
275/83/13 WSL >1 versus WSL >1 versus WSL=0‑251/43 dmft=0‑0.91 (0.62–1.35); WSL >1 WSL >1 versus
WSL=0‑109/33/5 versus versus 673/111 caries versus WSL=0‑1.04 (0.70–1.54); WSL=0‑0.935; dmft>1
292/89/11 caries (WSL+dmft) (WSL+dmft) >1 versus caries‑free Caries (WSL+dmft) >1 versus + WSL>1 versus
>1 versus caries‑free (WSL+dmft)=0‑390/66 versus caries‑free (WSL+dmft)=0‑1.01 dmft=0 + WSL=0‑0.862;
(WSL+dmft)=0‑168/54/6 versus 533/89 (0.71–1.45) alleles ‑ dmft>1 versus
232/69/10 Multivariate analysis ‑ Genotypes dmft=0‑0.638; WSL >1
‑ OR (95% CI): dmft ‑ GG versus versus WSL=0‑0.865;
GT=1.18 (0.71–1.94); GG versus caries (WSL+dmft)
TT=0.42 (0.09–1.80); WSL ‑ GG >1 versus caries‑free
versus GT=1.02 (0.64–1.62); (WSL+dmft)=0‑0.939
GG versus TT=1.22 (0.40–3.67); Multivariate analysis:
dmft+WSL ‑ GG versus GT=1.20 Genotypes ‑ dmft ‑ GG
(0.76–1.90); GG versus TT=0.63 versus GT=0.513; GG
(0.17–2.28) versus TT ‑ 0.243; WSL
‑ WSL ‑ GG versus
GT=0.932; GG versus
TT=0.722; dmft+WSL ‑
GG versus GT‑0.421; GG
versus TT=0.489
IHS=Iowa head start cohort; IFS=Iowa fluoride study cohort; WSL=White‑spot lesions; HWE=Hardy‑Weinberg equilibrium; OR=Odds ratio; CI=Confidence interval; NA=Not available; ECC=Early childhood caries;
S. mutans=Streptococcus mutans; DTV=Downstream variant; SNP=Single‑nucleotide polymorphism; UTV=Upstream variant; MVA=Multi variate analysis, UVA=Uni variate analysis, UTR=Un translated region
Supplementary Table 3: Characteristics of excluded studies
Author/title Reason for exclusion
Duverger O, Carlson JC, Karacz CM, Schwartz ME, Cross MA, Marazita ML, et al. Genetic variants Age not matched (6–12 years)
in pachyonychia congenita‑associated keratins increase susceptibility to tooth decay. PLoS Genet
2018;14:e1007168
Silva MJ, Kilpatrick NM, Craig JM, Manton DJ, Leong P, Burgner DP, et al. Genetic and early‑life No genotyping
environmental influences on dental caries risk: A twin study. Pediatrics 2019;143:e20183499
Morelli T, Agler CS, Divaris K. Genomics of periodontal disease and tooth morbidity. Periodontol Periodontitis‑different study design
2000 2020;82:143‑56
Shungin D, Haworth S, Divaris K, Agler CS, Kamatani Y, Keun Lee M, et al. Genome‑wide analysis of ECC not studied. Traits
dental caries and periodontitis combining clinical and self‑reported data. Nat Commun 2019;10:2773 studied ‑ DMSS, DMFS and
periodontitis ‑ different age group
Kelly AM, Kallistova A, Küchler EC, Romanos HF, Lips A, Costa MC, et al. Measuring the microscopic Age not matched (average age
structures of human dental enamel can predict caries experience. J Pers Med 2020;10:5 10.46 years)
Wang Q, Jia P, Cuenco KT, Zeng Z, Feingold E, Marazita ML, et al. Association signals unveiled by a Different study design.
comprehensive gene set enrichment analysis of dental caries genome‑wide association studies. PLoS Gene ontology study using
One 2013;8:e72653 bio‑informatics on 3–12 year old
patients
Wang Q, Jia P, Cuenco KT, Feingold E, Marazita ML, Wang L, et al. Multi‑dimensional prioritization of Different study design
dental caries candidate genes and its enriched dense network modules. PLoS One 2013;8:e76666
Strömberg N, Esberg A, Sheng N, Mårell L, Löfgren‑Burström A, Danielsson K, et al. Genetic‑ and Age not matched (12 years)
lifestyle‑dependent dental caries defined by the acidic proline‑rich protein genes PRH1 and PRH2.
EBioMedicine 2017;26:38‑46
Pang L, Zhi Q, Zhuang P, Yu L, Tao Y, Lin H. Variation in enamel formation genes influences enamel Age not matched (13–18 years)
demineralization In vitro in a Streptococcus mutans biofilm model. Front Physiol 2017;8:851
Bayram M, Deeley K, Reis MF, Trombetta VM, Ruff TD, Sencak RC, et al. Genetic influences on Age not matched (average age
dental enamel that impact caries differ between the primary and permanent dentitions. Eur J Oral Sci 8.8 ± 2.5 years)
2015;123:327‑34
Eriksson L, Esberg A, Haworth S, Holgerson PL, Johansson I. Allelic variation in taste genes is Age not matched (18–23 years), not
associated with taste and diet preferences and dental caries. Nutrients 2019;11:1491 tested for caries
Ergöz N, Seymen F, Gencay K, Tamay Z, Deeley K, Vinski S, et al. Genetic variation in Ameloblastin is Age not matched (6–12 years)
associated with caries in asthmatic children. Eur Arch Paediatr Dent 2014;15:211‑6
Wang X, Shaffer JR, Weyant RJ, Cuenco KT, DeSensi RS, Crout R, et al. Genes and their effects on dental No SNPs studied
caries may differ between primary and permanent dentitions. Caries Res 2010;44:277‑84
Shaffer JR, Wang X, McNeil DW, Weyant RJ, Crout R, Marazita ML. Genetic susceptibility to dental No genotyping and no SNPs
caries differs between the sexes: A family‑based study. Caries Res 2015;49:133‑40 studied
Dawson DV. New genes are identified that may be associated with childhood caries. J Evid Based Dent Commentary
Pract 2012;12:225‑7
Cavallari T, Tetu Moyses S, Moyses SJ, Iani Werneck R. KLK4 gene and dental decay: Replication in a Age not matched (>12 years)
South Brazilian population. Caries Res 2017;51:240‑3
Izakovicova Holla L, Borilova Linhartova P, Kastovsky J, Bartosova M, Musilova K, Kukla L, Age not matched (13–15 years)
et al. Vitamin D receptor TaqI gene polymorphism and dental caries in Czech children. Caries Res
2017;51:7‑11
Li ZQ, Hu XP, Zhou JY, Xie XD, Zhang JM. Genetic polymorphisms in the carbonic anhydrase VI gene Age not
and dental caries susceptibility. Genet Mol Res 2015;14:5986‑93 matched (51.16 ± 9.48 years)
Halusic AM, Sepich VR, Shirley DC, Granjeiro JM, Costa MC, Küchler EC, et al. Calcium and In‑vitro study
magnesium levels in primary tooth enamel and genetic variation in enamel formation genes. Pediatr
Dent 2014;36:384‑8
Duverger O, Ohara T, Shaffer JR, Donahue D, Zerfas P, Dullnig A, et al. Hair keratin mutations in tooth Age not matched (6–12 years)
enamel increase dental decay risk. J Clin Invest 2014;124:5219‑24
Fine DH, Toruner GA, Velliyagounder K, Sampathkumar V, Godboley D, Furgang D. A lactotransferrin Age not matched (adults 28.8–
single nucleotide polymorphism demonstrates biological activity that can reduce susceptibility to 38.6 years)
caries. Infect Immun 2013;81:1596‑605
Shaffer JR, Wang X, Desensi RS, Wendell S, Weyant RJ, Cuenco KT, et al. Genetic susceptibility to No genotyping done. No SNPs
dental caries on pit and fissure and smooth surfaces. Caries Res 2012;46:38‑46 tested
Werneck RI, Lázaro FP, Cobat A, Grant AV, Xavier MB, Abel L, et al. A major gene effect controls Age not matched (average
resistance to caries. J Dent Res 2011;90:735‑9 age ‑ 30.72 years). No genotyping
done
Ozturk A, Famili P, Vieira AR. The antimicrobial peptide DEFB1 is associated with caries. J Dent Res Age not matched (17–84 years)
2010;89:631‑6
Dawson DV. Genetic factors appear to contribute substantially to dental caries susceptibility, and may Commentary and analysis article
also independently mediate sucrose sweetness preference. J Evid Based Dent Pract 2008;8:37‑9
Contd...
Yu PL, Bixler D, Goodman PA, Azen EA, Karn RC. Human parotid proline‑rich proteins: Correlation of Proteins studied
genetic polymorphisms to dental caries. Genet Epidemiol 1986;3:147‑52
Fatturi AL, Menoncin BL, Reyes MT, Meger M, Scariot R, Brancher JA, et al. The relationship between Age not matched (8 years)
molar incisor hypomineralization, dental caries, socioeconomic factors, and polymorphisms in the
vitamin D receptor gene: A population‑based study. Clin Oral Investig 2020;24:3971‑80
Nicoline N, Partakusuma FB, Joenoes H, Talbot C, Auerkari EI. Association of ENAM c2452t Age not matched (adults)
polymorphism with high rates of caries occurrence in an Indonesian population. Int J App Pharm
2020;12:1
Wang L, Li B, Tie X, Liu T, Zheng S, Liu Y. Association between HLA‑DRB1* allele polymorphism Age not matched (6–12 years)
and caries susceptibility in Han Chinese children and adolescents in the Xinjiang Uygur autonomous
region. J Int Med Res 2020;48:300060519893852

Vasconcelos KR, Arid J, Evangelista S, Oliveira S, Dutra AL, Silva LA, et al. MMP13 contributes to Age not matched (10–12 years)
dental caries associated with developmental defects of enamel. Caries Res 2019;53:441‑6
Olszowski T, Milona M, Janiszewska‑Olszowska J, Safranow K, Skonieczna‑Żydecka K, Walczak A, Age not matched (age >15 years)
et al. The lack of association between FCN2 gene promoter region polymorphisms and dental caries in
polish children. Caries Res 2017;51:79‑84
Karayasheva D, Glushkova M, Boteva E, Mitev V, Kadiyska T. Association study for the role of Age not matched (20–32 years)
Matrix metalloproteinases 2 and 3 gene polymorphisms in dental caries susceptibility. Arch Oral Biol
2016;68:9‑12
Cogulu D, Onay H, Ozdemir Y, Aslan GI, Ozkinay F, Eronat C. The role of vitamin d receptor Age not matched (6–12 years)
polymorphisms on dental caries. J Clin Pediatr Dent 2016;40:211‑4
Hu XP, Li ZQ, Zhou JY, Yu ZH, Zhang JM, Guo ML. Analysis of the association between Age not matched (adults 30–
polymorphisms in the vitamin D receptor (VDR) gene and dental caries in a Chinese population. Genet 67 years)
Mol Res 2015;14:11631‑8
Wendell SK, Wang X, Brown M, Cooper ME, DeSensi RS, Weyant RJ, et al. Genetic Association of Conference proceedings. Podium
Taste Receptor Pathways, Caries and Gender Variations. The 81st Annual Meeting of the American abstract
Association of Physical Anthropologists; 2012;
Vieira AR, Bayram M, Seymen F, Sencak RC, Lippert F, Modesto A. In vitro acid‑mediated initial dental Subjects age not matched. Part of
enamel loss is associated with genetic variants previously linked to caries experience. Front Physiol the study is in vitro
2017;8:104
Sengul F, Kilic M, Gurbuz T, Tasdemir S. Carbonic anhydrase VI gene polymorphism rs2274327 Age not matched (6–16 years)
relationship between salivary parameters and dental‑oral health status in children. Biochem Genet
2016;54:467‑75
Yarat A, Ozturk LK, Ulucan K, Akyuz S, Atala H, Isbir T. Carbonic anhydrase VI exon 2 genetic Age not matched (18–26 years)
polymorphism in Turkish subjects with low caries experience (preliminary study). In vivo 2011;25:941‑4
Pehlivan S, Koturoglu G, Ozkinay F, Alpoz AR, Sipahi M, Pehlivan M. Might there be a link between Age not matched (9.78 years)
mannose‑binding lectin polymorphism and dental caries? Mol Immunol 2005;42:1125‑7
Aribam VG, Aswath N, Ramanathan A. Single‑nucleotide polymorphism in Vitamin D receptor gene Age not matched (6–12 years)
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Akilpprienka B, Malarkodi M, Vivedharani R, Varghese S, Anitha V, Rajamanickam K, et al. Studies Age not mentioned ‑ samples
on the association of, DEFB1 gene polymorphism (rs11362 and rs1799946) and dental caries in South from patients reporting to the
Indian population. J Datta Meghe Inst Med Sci Univ 2019;14:237‑40 department of periodontics
Fine DH. Lactoferrin: A roadmap to the borderland between caries and periodontal disease. J Dent Res Review article
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Ohta M, Ohshima T, Nishimura H, Maeda N, Asada Y. Mapping of a gene influencing initial dental Study design different ‑ animal
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experience in Indian children. J Clin Pediatr Dent 2015;39:458‑61
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Zeng Z, Feingold E, Wang X, Weeks DE, Lee M, Cuenco DT, et al. Genome‑wide association study of Data for children up to 6 years NA
primary dentition pit‑and‑fissure and smooth surface caries. Caries Res 2014;48:330‑8
Shaffer JR, Wang X, Feingold E, Lee M, Begum F, Weeks DE, et al. Genome‑wide association scan for Data for children up to 6 years NA
childhood caries implicates novel genes. J Dent Res 2011;90:1457‑62
Wang X, Willing MC, Marazita ML, Wendell S, Warren JJ, Broffitt B, et al. Genetic and environmental Data for children up to 6 years NA
factors associated with dental caries in children: The Iowa fluoride study. Caries Res 2012;46:177‑84
Devang Divakar D, Alanazi SA, Assiri MY, Mohammed Halawani S, Zaid Alshehri S, Ahmed Saeed Data for children up to 6 years NA
Al‑Amri S, et al. Association between ENAM polymorphisms and dental caries in children. Saudi J Biol
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Kong YY, Zheng JM, Zhang WJ, Jiang QZ, Yang XC, Yu M, et al. The relationship between vitamin Data for children up to 6 years NA
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Alyousef YM, Borgio JF, AbdulAzeez S, Al‑Masoud N, Al‑Ali AA, Al‑Shwaimi E, et al. Association of Data for children up to 6 years NA
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caries susceptibility among cleft lip and/or palate individuals. J Contemp Dent Pract 2014;15:288‑93
Chaussain C, Bouazza N, Gasse B, Laffont AG, Opsahl Vital S, Davit‑Béal T, et al. Dental caries and Data for children up to 6 years NA
enamelin haplotype. J Dent Res 2014;93:360‑5
Krasone K, Lāce B, Akota I, Care R, Deeley K, Küchler EC, et al. Genetic variation in the promoter Data for children up to 6 years NA
region of beta‑defensin 1 (DEFB 1) is associated with high caries experience in children born with cleft
lip and palate. Acta Odontol Scand 2014;72:235‑40
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AmelogeninX (AMELX) and dental caries susceptibility. J Dent Res 2013;92:418‑24
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Calvano Küchler E, Maschietto Pucinelli C, Carpio Horta K, Assed Bezerra da Silva R, de Castro Costa Polymorphisms of enamel
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susceptibility in Japanese children. Arch Oral Biol 2015;60:55‑61 formation genes not analyzed
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association between BMP2/DLX3 gene polymorphisms and dental caries in primary and permanent formation genes not analyzed
dentitions. Caries Res 2017;51:590‑5
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caries in primary dentition. J Pak Den ssoc 2014;23:63-9 formation genes not analyzed
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in DEFB1 and miRNA202 are involved in salivary human β‑defensin 1 levels and caries experience in formation genes not analyzed
children. Caries Res 2017;51:209‑15
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and HLA‑DQ between patients with ECC and caries‑free children. J Indian Soc Pedod Prev Dent formation genes not analyzed
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caries experience. Hum Genet 2013;132:1015‑25 formation genes not analyzed
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Polymorphisms and Environmental Factors in Early Childhood Caries in Chinese Children. Biomed formation genes not analyzed
Res Int 2019;2019:4315839
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caries experience in primary teeth. Caries Res 2015;49:425‑33 formation genes not analyzed
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palate and without pathology. Russ J Genet 2019;55:1577‑81
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receptor beta (ESRRB) in DFN35B hearing impairment and dental decay. BMC Med Genet 2014;15:81 formation genes not analyzed
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4q21 near PKD2 and SIBLINGs are associated with dental caries. J Hum Genet 2017;62:491‑6 formation genes not analyzed
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polymorphism might confer protection against dental caries in Polish children. Caries Res 2015;49:390‑3 formation genes not analyzed
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insertion/deletion polymorphism associated with caries in permanent but not primary dentition in formation genes not analyzed
Czech children. Caries Res 2016;50:89‑96
Küchler EC, Deeley K, Ho B, Linkowski S, Meyer C, Noel J, et al. Genetic mapping of high caries Polymorphisms of enamel
experience on human chromosome 13. BMC Med Genet 2013;14:116. formation genes not analyzed
Küchler EC, Feng P, Deeley K, Fitzgerald CA, Meyer C, Gorbunov A, et al. Fine mapping of locus Polymorphisms of enamel
Xq25.1‑27‑2 for a low caries experience phenotype. Arch Oral Biol 2014;59:479‑86 formation genes not analyzed
Abbasoğlu Z, Bussaneli DG, Tanboğa İ, Henn IW, Modesto A, Vieira AR. Fine‑mapping of Xq25.1‑27.2 Polymorphisms of enamel
shows association of early childhood caries with genetic variants depending on dietary habits, formation genes not analyzed
protecting children who drink milk before going to bed. Caries Res 2019;53:333‑8
Shimizu T, Deeley K, Briseño‑Ruiz J, Faraco IM Jr., Poletta FA, Brancher JA, et al. Fine‑mapping of Polymorphisms of enamel
5q12.1‑13.3 unveils new genetic contributors to caries. Caries Res 2013;47:273‑83 formation genes not analyzed
Olatosi OO, Li M, Alade AA, Oyapero A, Busch T, Pape J, et al. Replication of GWAS significant loci in Polymorphisms of enamel
a sub‑Saharan African Cohort with early childhood caries: A pilot study. BMC Oral Health 2021;21:274 formation genes not analyzed
Borgio JF, Alsuwat HS, Alamoudi W, Hegazi FM, Al Otaibi WM, M Ibrahim A, et al. Exome array Polymorphisms of enamel
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NA=Not available; ECC=Early childhood caries; DMSS=Decayed missing filled teeth; DMFS=Decayed missing filled tooth surface
a
b
Supplementry Figure 1: (a and b) Forest plots for CC, CT genotype frequencies of rs3976703 respectively
c
Supplementary Figure 2: (a‑c) Forest plots for CC, CT and TT genotype frequencies of SNPs rs243865
c
Supplementary Figure 3: (a‑c) Forest plots for AA, AG, GG genotype frequencies of rs2252070
a
c
Supplementary Figure 4: (a‑c) Forest plots for CC, CT, TT genotype frequencies of rs1711437
c
Supplementary Figure 5: (a‑c) Forest plots for CC, CT, TT genotype frequencies of rs1784418
a
c
Supplementary Figure 6: (a‑c) Forest Plots for AA, AG, GG genotype frequencies of rs2235091
c
Supplementary Figure 7: (a‑c) Forest plots for GG, GA, AA genotype frequencies of rs17576
a
c
Supplementary Figure 8: (a‑c) Forest plots for GG, GT, TT genotype frequencies of rs7501477
c
Supplementary Figure 9: (a‑c) Forest plots for CC. CT. TT genotype frequencies of rs10429371

Single Nucleotide Polymorphisms of Enamel.2

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Single Nucleotide Polymorphisms of Enamel.2

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Systematic Review and Meta-Analysis

Single nucleotide polymorphisms of enamel formation

gene-based, gene cluster and meta-analysis

Sivakumar Nuvvula8, Selva Arockiam9

ABSTRACT Address for correspondence:

Introduction Reviews (PROSPERO) under protocol CRD42020179922.

and protective factors[3] and is characterized by acidic Eligibility criteria

6 years of age; (2) exposure: SNPs of enamel formation

Registration of protocol and reporting guidelines Data extraction

Table 1: Risk of bias assessment of included studies

Assessment of risk of bias a false detection rate threshold set at 0.05.[24]

Table 2: Gene‑based analysis of enamel formation genes

rs198966 50908754 Intronic 0.041

Table 3: Gene cluster analysis of enamel formation genes

Figure 2: Forest plots for AA genotype of rs12640848

Figure 3: Forest plot for AG genotype of rs12640848

Figure 4: Forest plot for GG genotype of rs12640848

Figure 5: STRING plot showing the clustering of genes into four

Odontogenesis of dentine containing tooth GO:0042475 1.88

Mohammed Halawani S, Zaid Alshehri S, Ahmed Saeed

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region. J Int Med Res 2020;48:300060519893852

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