Association between genetic variants in key vitamin-D-pathway genes and external apical root resorption linked to orthodontic treatment.

This study evaluated the association between single-nucleotide polymorphisms (SNPs) in vitamin-D-related genes and the amount of external apical root resorption linked to orthodontic treatment. One hundred and forty-three individuals were assessed. The amount of external apical root resorption of upper central incisors (EARRinc ) and lower first molars (EARRmol ) were evaluated in radiographs. Seven SNPs were genotyped across four genes including the vitamin D receptor [VDR], group-specific component [GC], cytochrome P450 family 27 subfamily B member 1 [CYP27B1], and cytochrome P450 family 24 subfamily A member 1 [CYP24A1]. Linear regressions were implemented to determine allele-effects on external apical root resorption. Individuals carrying the AA genotype in VDR rs2228570 had a 21% higher EARRmol than those having AG and GG genotypes (95% CI: 1.03,1.40). EARRmol in heterozygous rs2228570, was 12% lower than for homozygotes (95%CI: 0.78,0.99). Participants with the CCG haplotype (rs1544410-rs7975232-rs731236) in VDR had an EARRmol 16% lower than those who did not carry this haplotype. Regarding CYP27B1 rs4646536, EARRinc in participants who had at least one G allele was 42% lower than for homozygotes AA (95%CI: 0.37,0.93). Although these results did not remain significant after multiple testing adjustment, potential associations may still be suggested. Further replication studies are needed to confirm or refute these findings.

Risk factors for developmental defects of enamel in children from southeastern Brazil.

INTRODUCTION: Developmental Defects of Enamel (DDEs) comprise qualitative and/or quantitative changes to the enamel during amelogenesis. The aetiology of DDE remains inconclusive. AIM: To determine the association of pre, peri, and postnatal factors with the presence of DDE. DESIGN: Cross-sectional study with 353 children (8 to 11 years-old) in a Brazilian town. METHODS: One calibrated dentist assessed DDE using the Developmental Defects of Enamel Index and a questionnaire collected medical and sociodemographic data. MAIN OUTCOMES: Children with at least one type of DDE were categorized into the DDE group. Subtypes of DDE were also recorded. RESULTS: 63.1% of children had at least one type of DDE. Diffuse opacity was present in 36.7%, demarcated opacity in 14.8%, and hypoplasia in 5.83% of the children. In multivariate analysis, demarcated opacities and hypoplasia were associated with birth weight ⟨ 2500g (OR = 4.82; 95% CI 1.23-1.95). CONCLUSION: Low birth weight predicted DDE.

Association between genetic polymorphisms in the promoter region of the defensin beta 1 gene and persistent apical periodontitis.

AIM: To evaluate the association between the promoter region of defensin beta 1 (DEFB1) genetic polymorphisms and persistent apical periodontitis (PAP) in Brazilian patients. METHODOLOGY: Seventy-three patients with post-treatment PAP (PAP group) and 89 patients with root filled teeth with healed and healthy periradicular tissues (healed group) were included (all teeth had apical periodontitis lesions at the beginning of the treatment). Patients who had undergone at least 1 year of follow-up after root canal treatment were recalled, and their genomic DNA was extracted from saliva. Two single nucleotide polymorphisms (SNPs) in DEFB1 at the g. -52G>A (rs1799946) and g. -20G>A (rs11362) positions were analysed using real-time polymerase chain reaction. The chi-squared test was performed, and the odds ratios were calculated using Epi Info 3.5.2. Logistic regression analysis in the codominant model, using the time of follow-up as a variable, was used to evaluate the SNP-SNP interaction. All tests were performed with an established alpha of 0.05 (P = 0.05). RESULTS: For the rs11362 polymorphism in the codominant and recessive models, patients who carried two copies of the T allele had a significantly lower risk of developing PAP (P = 0.040 and P = 0.031, respectively). For the rs1799946 polymorphism in DEFB1 in the codominant and recessive models, carrying one copy of the T allele significantly increased the risk of developing PAP (P = 0.007 and P = 0.031, respectively). In the logistic regression, both polymorphisms were associated with PAP as well as the SNP-SNP interaction (P < 0.0001). CONCLUSIONS: Polymorphisms in DEFB1 genes were associated with the development of post-treatment persistent apical periodontitis.

MSX1 is differentially expressed in the deepest impacted maxillary third molars.

An impacted third molar is one of the most common dental abnormalities. Among the reasons for impaction the most common are: insufficient space, time of eruption, improper position of the tooth bud, and genetic disruptions. To investigate if runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2), and msh homeobox 1 (MSX1) are differently expressed depending on the position of the molar, we studied 32 patients who had been referred for surgical removal. An orthopantomogram was used to separate them according to Winter's, and Pell & Gregory's, classifications. Bone samples were harvested during the operation for gene expression assay. The Kruskal-Wallis, Dunn's post hoc, and Spearman's correlation, tests were used to assess the significance of differences. No correlations were found in expression of the genes, and no differences between expression in maxillary and mandibular third molars, nor were they expressed differently according to Winter's or Pell and Gregory's classifications or in relation to impaction of the mandibular ramus. However, MSX1 was expressed differently when account was taken of the depth of impaction in maxillary third molars (p = 0.029), but there was no difference in expression of RUNX2, BMP2, and MSX1 for the Pell and Gregory classification of depth of impaction (p > 0.05). We conclude that MSX1 is expressed differently depending on the depth of maxillary impaction phenotypes.

Association between facial measurements and polymorphisms in human epidermal growth factor and transforming growth factor ß1.

The aim of the study was to evaluate the association between genetic polymorphisms in human epidermal growth factor (EGF) (rs4444903) and transforming growth factor ß1 - (TGF-ß1) (rs1800470) with facial measurements in patients with dentofacial deformities. A total of 144 adult patients with dentofacial deformities were included. Facial linear and angular measurements were traced in lateral cephalometric radiographs used Dolphin 2D software. Cells from oral mucosa were collected for DNA to be extracted. The polymorphisms were genotyped using real-time polymerase chain reaction (PCR). Probabilites of less than 0.05 were accepted as significant. The rs4444903 heterozygous patients had a decrease in the mandibular length (p=0.043) and the length of the mandibular base (p=0.008), and homozygous A patients also had a reduction in the length of the mandibular base (p=0.013) compared with homozygous G patients. Patients AG had an increase in measurement of the anterior facial height (p=0.032) and in ANS-Me distance (p=0.022) when compared with homozygous A. To the rs1800470, heterozygous patients had an increase in the length of the mandibular base (p=0.043) when compared with homozygous A. Heterozygous AG patients had an increase in angular measurements in TGF-ß1 polymorphism for the upper gonial angle, when compared with the homozygous AA (p=0.032). Genetic polymorphisms in EGF and TGF-ß1 are associated with facial measurements in a Brazilian population of patients with dentofacial deformities.

Measuring the impact of quality of life of children treated for orofacial clefts: a case-control study.

OBJECTIVE: The aim of this study was to assess the quality of life (QoL) of children previously treated for cleft lip and/or palate (CL/P) and compare with non-cleft children. METHOD: A case-control study with 70 children between 5 and 12 years old was carried out. The case group consisted of 35 individuals previously treated for non-syndromic CL/P and presently receiving assessment at a rehabilitation hospital in Brazil. The children had received primary surgical treatment for CL/P reconstruction during early childhood. The control group consisted of 35 healthy children selected to ensure close similarity to the cleft group in age, gender and socioeconomic status. QoL was measured using the AUQEI questionnaire. RESULTS: Cleft lip and palate had no significant influence on the QoL in children (p = 0.44). A higher percentage of the cleft lip and palate group of children reported a lower QoL than the cleft lip or cleft palate groups. Gender had no significant difference on the quality of life in CL/P children (p = 0.2) and in control group (p = 1.0). CONCLUSION: The QoL in children with CL/P was found to be similar to the non-cleft group. Our results confirm that clefts repaired during earlier childhood associated with a health care program, including psychological support, is beneficial for CL/P children.

Candidate gene studies in hypodontia suggest role for FGF3.

INTRODUCTION: The majority of tooth agenesis cases are mild (hypodontia) and typically not associated with the gene mutations linked to oligodontia. From this, we hypothesise that most cases of tooth agenesis fit a polygenic mode of inheritance, where several genes with small effects cause a variety of varying phenotypes. MATERIALS AND METHODS: In this study, we looked at 18 not typically studied genes in this condition, to ascertain their contribution to hypodontia. Our study subjects consisted of 167 patients with hypodontia and their parents from two cohorts (one from Brazil and one from Turkey). An additional 465 DNA samples (93 cases with hypodontia and 372 controls without family history for tooth agenesis or oral clefts) from Brazil were also available for this study. Ninety-three single nucleotide polymorphisms that maximally represent the linkage disequilibrium structure of the genes for the 18 genes were selected and genotyped using Taqman chemistry. Chi square was used to test if genotype distributions were in Hardy-Weinberg equilibrium, and 24 markers that were in Hardy-Weinberg equilibrium and had allele frequencies higher than 5 % in a panel of 50 CEPH samples were further tested. Association between hypodontia and genetic variants was tested with the transmission disequilibrium test within the programme Family-Based Association Test (FBAT) and by using Chi square and Fisher's exact tests. Alpha at a level of 0.05 was used to report results. RESULTS: Results suggest possible associations between several genes and hypodontia in the three populations. In the Turkish cohort (n = 51 parent-affected child trios) the most significant results were as follows: FGF3 rs1893047, p = 0.08; GLI3 rs929387, p = 0.03; GLI3 haplotype rs929387-rs846266, p = 0.002; and PAX9 rs2073242, p = 0.03. In the Brazilian cohort (n = 116 parent-affected child trios), the results were as follows: DLX1 rs788173, p = 0.07; FGF3 rs12574452, p = 0.03; GLI2 rs1992901, p = 0.03; and PITX2 rs2595110, p = 0.01. The second Brazilian cohort also suggested that FGF3 (rs12574452, p = 0.01) is associated with hypodontia and added EDAR (rs17269487, p = 0.04), LHX6 (rs989798, p = 0.02), and MSX1 (rs12532, p = 0.003). CONCLUSION: Our results suggest that several genes are potentially associated with hypodontia and their individual contributions may be modest. Hence, these cases may not be explained by inactivating mutations such as many oligodontia cases segregating in a Mendelian fashion but rather are influenced by one or more susceptibility alleles in multiple small effect genes.

Fine-mapping of 5q12.1-13.3 unveils new genetic contributors to caries.

Caries is a multifactorial disease and little is still known about the host genetic factors influencing susceptibility. Our previous genome-wide linkage scan has identified the interval 5q12.1-5q13.3 as linked to low caries susceptibility in Filipino families. Here we fine-mapped this region in order to identify genetic contributors to caries susceptibility. Four hundred and seventy-seven subjects from 72 pedigrees with similar cultural and behavioral habits and limited access to dental care living in the Philippines were studied. DMFT scores and genotype data of 75 single-nucleotide polymorphisms were evaluated in the Filipino families with the Family-Based Association Test. For replication purposes, a total 1,467 independent subjects from five different populations were analyzed in a case-control format. In the Filipino cohort, statistically significant and borderline associations were found between low caries experience and four genes spanning 13 million base pairs (PART1, ZSWIM6, CCNB1, and BTF3). We were able to replicate these results in some of the populations studied. We detected PART1 and BTF3 expression in whole saliva, and the expression of BTF3 was associated with caries experience. Our results suggest BTF3 may have a functional role in protecting against caries.

Tooth agenesis association with self-reported family history of cancer.

It has been proposed that tooth agenesis and cancer development share common molecular pathways. We performed a cross-sectional study to investigate the epidemiological and molecular association between tooth agenesis and self-reported family history of cancer. Eighty-two individuals with tooth agenesis and 328 individuals with no birth defect were recruited from the same institution. Tooth agenesis was assessed in permanent teeth and was defined based on the age of the participants and when initial tooth formation should be radiographically visible. We also investigated the role of genes involved in dental development that have been implicated in tumorigenesis, and 14 markers in AXIN2, FGF3, FGF10, and FGFR2 were genotyped. Individuals with tooth agenesis had an increased risk of having a family history of cancer (p = 0.00006; OR = 2.7; 95% C.I., 1.6-4.4). There were associations between AXIN2, FGF3, FGF10, and FGFR2 with tooth agenesis [i.e., individuals who carried the polymorphic allele of FGFR2 (rs1219648) presented higher risk for having premolar agenesis (p = 0.02; OR = 1.8; 95% C.I., 1.1-3.0)]. In conclusion, tooth agenesis was associated with positive self-reported family history of cancer and with variants in AXIN2, FGF3, FGF10, and FGFR2. Prospective studies are needed to confirm if tooth agenesis can be used as a risk marker for cancer.

MMP13 polymorphism decreases risk for dental caries.

Recent evidence suggests that genetic studies may contribute to a better understanding of individual susceptibility to caries. Matrix metalloproteinases (MMPs) and their tissue inhibitors have been suggested to be involved in the caries process. The purpose of this study was to determine if polymorphisms in MMP2 (rs243865), MMP9 (rs17576), MMP13 (rs2252070), and TIMP2 (rs7501477) were associated with caries. Eligible unrelated children and adolescents were evaluated using a cross-sectional design. Data on oral health habits was obtained through a questionnaire and caries data was collected by clinical examination. Genotyping of the selected polymorphisms was carried out by real-time PCR. Allele and genotype frequencies were compared between individuals with and without caries experience. Of 505 subjects, 212 were caries-free and most subjects (61.2%) had mixed dentition. Allele frequency of MMP2, MMP13 and TIMP2 was different between caries-affected and caries-free individuals, with significant association for MMP13 (p = 0.004). Mutant allele carriers for MMP13 demonstrated a significantly decreased risk for caries (OR = 0.538, 95% CI 0.313-0.926); this result remained significant after adjustment for candidate genes, type of dentition and dietary factors. Allelic and genotype frequencies of the polymorphism in MMP9 were similar in caries-affected and caries-free individuals. Genetic variations in MMP13 may contribute to individual differences in caries susceptibility. Our findings reinforce that susceptibility to caries results from gene-environment interactions.