Bibliometric analysis of publications on genetic polymorphism and external apical root resorption research.

OBJECTIVE: This study aimed to analyze the scientific production of genetic polymorphisms and external apical root resorption (EARR) to establish main findings, geographic trends, and research gaps for possible future investigations. METHODS: Unrestricted publications were searched using the Scopus database (March 2023) to include studies that addressed the association between genetic polymorphisms and EARR. Case-control, cohort, cross-sectional, and review studies were considered eligible. The softwares VOS viewer™ and Bibliometrix were used for data analysis. RESULTS: Of the 44 studies analyzed, "Iglesias-Linares A" was the most cited author. The University of Seville (Spain) conducted the most research on this topic. Brazil, Spain, and the USA were the leading countries in terms of citations. The most frequent term in the co-occurrence of keywords was "EARR." The journal American Journal of Orthodontics and Dentofacial Orthopedics presented a great relevance in the area, demonstrating a high number of publications. Several genetic polymorphisms have been investigated, with interleukins being the most studied. CONCLUSION: Endodontics is an area of research that should focus more on root resorption and genetic polymorphisms, as it still underexplored, compared to orthodontics. Polymorphisms have been studied as possible predictors of EARR caused by orthodontic tooth movement. However, the gap in the research indicates a need to search for new genes associated with EARR.

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.

Influence of clinical factors, IL4 and IL6 genes polymorphisms in functional healing in late replantation.

To investigate the genetic association in a sample of replanted teeth, it is necessary to observe the extreme phenotypes, such as, teeth that underwent functional healing and those extracted due to severe external root resorption. Thus, this study aimed to investigate the association of age of the patients, root development, storage media, and polymorphisms in the interleukin 4 (IL4) and interleukin 6 (IL6) genes with teeth that presented extreme outcomes, as functional healing or extraction, in a group whose replantation techniques did not follow the International Association of Dental Traumatology (IADT) 2012 guidelines. Forty-three avulsed and replanted teeth that did not follow IADT 2012 guidelines and underwent functional healing or were extracted were included. Periapical radiographs employed for this study were taken soon after tooth replantation and after 1 year. For genotypic IL4 and IL6 genes analysis, DNA of oral mucosa cells was extracted. Real-time- PCR performed for genotyping polymorphisms in IL4 and IL6 genes. Clinical and genetic variables were analyzed by the Chi-square test and the "Z" test. P values < .05 were considered significant. The results showed that functional healing and extraction were associated with storage media and with the rs2243268 of IL- 4 gene polymorphisms. As conclusion, the C rs2243268 allele of IL4 gene may have a positive relationship with functional healing teeth that were replanted not following the 2012 IADT guidelines. Keeping the tooth dry is associated to a fast loss of avulsed and replanted teeth after 1-year follow-up.

Genetic variation involved in the risk to external apical root resorption in orthodontic patients: a systematic review.

OBJECTIVE: To perform a systematic review/meta-analysis to elucidate the scientific basis for the association between genetic variations and risk of external apical root resorption (EARR) in orthodontic patients. MATERIALS AND METHODS: Four databases (PubMed, Web of Science, Scopus, LILACS) were electronically searched until November 22, 2020, followed by manual and gray literature search. Case-control or cross-sectional studies that evaluated genes involved in the susceptibility of orthodontic patients to EARR were eligible. Two reviewers applied the inclusion and exclusion criteria, extracted qualitative data, as well as assessed methodological quality using instrument proposed for genetic studies. For synthesis results, narrative and quantitative data (meta-analysis) were performed. The certainty of the evidence was tested using the GRADE Working Group approach. RESULTS: Of 201 articles in total, 16 studies were included in the review. Of these, 11 presented moderate and 5 of high methodological quality. In the narrative analysis, from 16 studies, 15 studies (10 genes) showed a significant association with EARR and 9 studies were included in the meta-analysis. Only the polymorphism rs208294 in P2RX7 (dominant model) was associated with EARR (OR = 0.52, 95%CI = 0.29-0.95, p = 0.03) and presented a very low certainty of the evidence. CONCLUSION: Narrative analyses of individual studies demonstrated an association of many genes. The number of studies for each genetic variation was very low, and methodological heterogeneity between the studies was observed. Quantitative analyses (meta-analysis) could only show an involvement for P2RX7 (rs208294) in the risk of orthodontic patients to EARR at a very low certainty of evidence. (CRD42018085411). CLINICAL RELEVANCE: The knowledge regarding the molecular aspects involved in the etiology of EARR will allow orthodontists to use a personalized treatment and early diagnosis of risk patients. This systematic review demonstrates that more studies are necessary to unravel the role of genetic variation for patients' risk to EARR during orthodontic tooth movement.

The role of polymorphism of the IL6 gene in tooth replantation.

The absence or presence of root resorption on the root surface of a replanted tooth indicates an immune-inflammatory reaction. Since interleukin-6 (IL-6) is considered an inflammatory marker in bone resorption, this study aimed to investigate the association between clinical variables and polymorphisms in IL6, with the outcome of replanted teeth at 1-year follow-up. Altogether, 127 avulsed teeth that were replanted and had their root canals treated were selected for this study. Periapical radiographs were taken after replantation and after 1 year. Real-time PCR was used to genotype IL6 polymorphisms. Chi-square and 'Z' tests were performed to verify the association between genetic variables and the prognosis of replanted teeth (P < 0.05). An association was observed between the rs2069843 polymorphism of IL6 and the outcome of replanted teeth (P < 0.05). The rs2069843 polymorphism of IL6 may influence the outcome of avulsed and replanted teeth in the first year post-trauma.

Association of clinical variables and polymorphisms in RANKL, RANK, and OPG genes with external apical root resorption.

OBJECTIVES: The aim of this study was to investigate the association of clinical variables and polymorphisms in the RANKL, RANK, and OPG genes with external apical root resorption (EARR). METHODS: The sample was composed of 338 unrelated patients of both sexes, average age 14.9 years (range 8-21) with Class II Division 1 malocclusion, orthodontically treated. Periapical radiographs of the maxillary central incisor with the longer root (reference tooth) were taken before treatment and 6 months after starting treatment. DNA was extracted from buccal epithelial cells with the use of 10 mol/L ammonium acetate and 1 mmol/L EDTA. The analysis of 42 polymorphisms in the RANKL, RANK, and OPG genes was performed by means of real-time polymerase chain reaction. Univariate and multivariate analyzes were performed to verify the association of clinical and genetic variables with EARR (P <0.05). RESULTS: The initial root length and patient age were associated with EARR. Considering the study of polymorphisms of RANKL, no significant association was found of genetic polymorphisms with EARR. For RANK polymorphisms, only rs12455775 was associated with EARR. Regarding OPG polymorphisms, an association of rs3102724, rs2875845, rs1032128, and rs3102728 with EARR was found. After multivariate analysis, the initial root length, rapid maxillary expansion, and rs3102724 of the OPG gene were associated with EARR. CONCLUSIONS: Longer roots of upper central incisors and rapid maxillary expansion, as well as allele A of the rs3102724 polymorphism of the OPG gene, were associated with EARR in the study population.

Analysis of the association of clinical factors and IL4 gene polymorphisms with root resorption in avulsed teeth after 1 year of replantation.

AIM: To investigate the association of clinical variables and polymorphisms (tag SNPs) in the interleukin 4 (IL4) gene, with the prognosis of avulsed and replanted teeth. METHODOLOGY: Ninety-four patients who suffered avulsion and had their teeth replanted and endodontically treated were included. Periapical radiographs were obtained soon after tooth replantation and after 1 year. For genotypic IL4 gene analysis, the DNA from oral mucosa cells was collected, and polymorphisms were investigated by real-time PCR. Univariate and multivariate analyses were performed to verify the association of clinical and genetic variables and the outcome of the replanted teeth (P < 0.05). RESULTS: After multivariate analysis, extra-alveolar time longer than 1 h was significantly associated with external root resorption. No significant association was observed between IL4 gene polymorphisms and root resorption. CONCLUSION: No association between root resorption and IL4 gene polymorphisms was observed. An extra-alveolar time of more than 1 h was associated with a susceptibility for external root resorption. Replanting the tooth in its socket immediately is the most important factor to maintain a healthy root surface.

Tooth resorptions are not hereditary.

Root resorptions caused by orthodontic movement are not supported by consistent scientific evidence that correlate them with heredity, individual predisposition and genetic or familial susceptibility. Current studies are undermined by methodological and interpretative errors, especially regarding the diagnosis and measurements of root resorption from orthopantomographs and cephalograms. Samples are heterogeneous insofar as they comprise different clinical operators, varied types of planning, and in insufficient number, in view of the prevalence of tooth resorptions in the population. Nearly all biological events are coded and managed through genes, but this does not mean tooth resorptions are inherited, which can be demonstrated in heredograms and other methods of family studies. In orthodontic root resorption, one cannot possibly determine percentages of how much would be due to heredity or genetics, environmental factors and unknown factors. There is no need to lay the blame of tooth resorptions on events taking place outside the orthodontic realm since in the vast majority of cases, resorptions are not iatrogenic. In orthodontic practice, when all teeth are analyzed and planned using periapical radiography or computerized tomography, and when considering all predictive factors, tooth resorptions are not iatrogenic in nature and should be considered as one of the clinical events inherent in the treatment applied.

Tooth resorptions are not hereditary

ABSTRACT Root resorptions caused by orthodontic movement are not supported by consistent scientific evidence that correlate them with heredity, individual predisposition and genetic or familial susceptibility. Current studies are undermined by methodological and interpretative errors, especially regarding the diagnosis and measurements of root resorption from orthopantomographs and cephalograms. Samples are heterogeneous insofar as they comprise different clinical operators, varied types of planning, and in insufficient number, in view of the prevalence of tooth resorptions in the population. Nearly all biological events are coded and managed through genes, but this does not mean tooth resorptions are inherited, which can be demonstrated in heredograms and other methods of family studies. In orthodontic root resorption, one cannot possibly determine percentages of how much would be due to heredity or genetics, environmental factors and unknown factors. There is no need to lay the blame of tooth resorptions on events taking place outside the orthodontic realm since in the vast majority of cases, resorptions are not iatrogenic. In orthodontic practice, when all teeth are analyzed and planned using periapical radiography or computerized tomography, and when considering all predictive factors, tooth resorptions are not iatrogenic in nature and should be considered as one of the clinical events inherent in the treatment applied.

RESUMO As reabsorções radiculares decorrentes da movimentação ortodôntica não têm evidência científica consistente que as correlacione com a hereditariedade, predisposição e suscetibilidade genética ou familiar. Os trabalhos sobre esse tema apresentam erros metodológicos e interpretativos, em especial quanto ao diagnóstico e à mensuração das reabsorções radiculares a partir de ortopantomografias e cefalogramas. As amostras são heterogêneas - quanto aos operadores clínicos e tipos de planejamentos aplicados - e em número muito pequeno, considerando-se a prevalência das reabsorções dentárias na população. Quase todos os eventos biológicos são codificados e gerenciados a partir dos genes, mas não por isso as reabsorções dentárias são hereditárias, o que seria demonstrado em heredogramas e outras formas de estudos familiares. Nas reabsorções radiculares em Ortodontia, não é possível determinar percentuais de quanto seria decorrente da hereditariedade ou da genética, de fatores ambientais e de fatores desconhecidos. Não se faz necessário transferir a "culpa" das reabsorções dentárias para eventos externos à Ortodontia pois, na grande maioria dos casos, elas não são iatrogênicas. Na prática ortodôntica, quando se faz a análise de todos os dentes e o planejamento, via radiografia periapical ou tomografia computadorizada, e quando se leva em consideração os fatores preditivos, as reabsorções dentárias não serão de natureza iatrogênica, e devem ser encaradas como uma das intercorrências clínicas do tratamento aplicado.

Polimorfismo (+3954c>T) del gen IL-1B y su asociación con la resorción radicular apical externa post-tratamiento ortodóntico / IL-1B (+3954c>T) gene polymorphism and its association with external root resorption after orthodontic treatment

El objetivo fue determinar la presencia del polimorfismo rs1143634 (+3954C>T) del gen Interleuquina 1 Beta (IL-1B) y su asociación con la resorción radicular apical externa (RRE) post-tratamiento ortodóntico. Se realizó un estudio piloto de individuos tratados con aparatología ortodontica, 13 (casos) presentaron RRE posterior al tratamiento ortodóntico y 22 (controles) estaban clínicamente sanos. A partir de muestras de células epiteliales de mucosa bucal se extrajo ADN y se genotipificó el polimorfismo rs1143634 (+3954C>T) del gen IL-1B mediante la reacción en cadena de la polimerasa y digestión del producto con la enzima de restricción TaqI. Se estimaron las frecuencias alélicas y genotípicas del rs1143634; además, se evaluó la desviación del equilibrio de Hardy-Weinberg. Las frecuencias alélicas y genotípicas se compararon mediante la prueba de c2 con razón deverosimilitud (p <0,05). El promedio de edad de los participantes fue 28,1 (DE=11,5) años y el 68,6 % era mujeres. Al comparar la distribución de los genotipos del polimorfismo IL-1B (+3954C>T) entre grupos no se encontró una diferencia estadísticamente significativa (p=0,0926). Sin embargo, se observó una diferencia significativa en la distribución de alelos (p= 0,035), siendo el alelo T (alelo 2) más prevalente en el grupo control. El polimorfismo IL-1B (+3954C>T) se encontró presente en la población de estudio. Aunque no existieron diferencias en la distribución de los genotipos que apoyara una asociación entre este polimorfismo y la RRE, si hubo una diferencia en la distribución de los alelos, sugiriendo que el alelo T posiblemente actúa como factor protector contra el desarrollo de la RRE.

The objective of this study was to determine the presence of Interleukin 1 beta (IL-1B) rs1143634 (+3954C>T) gene polymorphism and its association with external apical root resorption (ERR) after orthodontic treatment. We conducted a pilot study of individuals treated with orthodontic treatment, 13 (cases) had ERR after orthodontic treatment and 22 (controls) were clinically healthy. DNA was extracted from samples of epithelial cells from the oral cavity and IL-1B rs1143634 (+3954C>T) gene polymorphism was genotyped by polymerase chain reaction and digestion product through the TaqI restriction enzyme. Genotype and allele frequencies of rs1143634 were estimated; in addition, the deviation from Hardy-Weinberg equilibrium was assessed. Allele and genotype frequencies were compared using the c2 test with likelihood ratio (p <0.05). The mean age of participants was 28.6 (SD= 11.5) years and 68.6 % were females. No statistically significant association was found between the genotypes distribution of IL-1B (+3954C>T) polymorphism with ERR (p= 0.0926). However, a significant difference in the alleles distribution (p= 0.035) was observed, where the allele T (allele 2) was more prevalent in the control group. IL-1B (+3954C>T) polymorphism was present in the study population. Although there were no differences in the genotypes distribution to support an association between this polymorphism with ERR, there was a difference in the alleles distribution, suggesting that the allele T possibly acts as a protective factor against the development of ERR.

A study of the interleukin-1 gene cluster polymorphisms and inflammatory external root resorption in replanted permanent teeth.

AIM: To investigate whether single nucleotide polymorphisms (SNPs) within the interleukin-1 gene cluster (IL1) are associated with the occurrence and severity of inflammatory external root resorption (IERR) after replantation of avulsed permanent teeth. METHODOLOGY: Indexes of IERR were radiographically assessed in 182 mature replanted permanent teeth from 146 patients at the onset of endodontic therapy. DNA was extracted from buccal mucosa cells and genotyped using TaqMan probes-based assays for the SNPs IL1A -889C/T (rs 180058), IL1B +3954C/T (rs1143634) and IL1RN +2018C/T (rs419598). Teeth were grouped into two categories: IERR absent to mild (indexes ≤ 4) and moderate to severe IERR (indexes > 4). Genetic variations in the IL1 gene cluster were tested for their effect on the occurrence and extension of IERR using the GEE model (generalized estimation equation). Patient's age at the moment of injury, timing of pulpectomy, extra-alveolar period and storage condition of the avulsed teeth was included as possible confounders. RESULTS: No association was found between SNPs IL1A -889C/T, IL1B +3954C/T (rs1143634) and IL1RN +2018C/T (rs419598) and IERR indexes. Timing of pulpectomy (OR 3.5 IC 95% 2.0-6.2 P < 0.001) and patient's age at the moment of trauma (OR 0.29 IC 95% 0.12-0.67 P = 0.004) significantly affected the risk of developing severe IERR. CONCLUSIONS: While timing of pulpectomy and patient's age at the moment of trauma were confirmed as important risk factors, SNPs within the IL1 gene cluster did not affect the susceptibility for IERR after replantation of permanent teeth.

Interleukin-1ß +3954 polymorphisms and risk of external apical root resorption in orthodontic treatment: a meta-analysis.

The purpose of this meta-analysis was to determine whether genetic variants of the interleukin-1ß[+3954 C>T (rs1143634)] (IL-1ß +3954 C>T) gene polymorphisms were associated with orthodontic external apical root resorption (EARR). A meta-analysis was carried out using data entered into the PubMed and Embase electronic databases before October 5, 2012. A total of 7 studies were identified for meta-analysis. The strength of the relationship between IL-1ß +3954 C>T polymorphism and the risk of EARR was assessed using odds ratio (OR). The studies provided overall OR estimates for EARR. Overall, the variant genotypes (CC and CT) of the IL-1ß +3954 C>T polymorphism were unassociated with EARR risk compared with the TT homozygote [CC vs TT, OR = 1.28, 95% confidence interval (95%CI) = 0.27-6.08; CT vs TT, OR = 0.74, 95%CI = 0.11-5.02]. Similarly, no associations were found in the dominant and recessive models (dominant model, OR = 1.08, 95%CI = 0.24-4.86; recessive model, OR = 1.85, 95%CI = 0.87-3.93). No publication bias was found, and no association was apparent between the IL-1ß +3954 C>T polymorphism and risk of EARR in orthodontic treatment patients. Further multicenter and better-controlled studies are required to confirm these findings.

Association analysis of clinical aspects and vitamin D receptor gene polymorphism with external apical root resorption in orthodontic patients.

INTRODUCTION: Vitamin D is responsible for the regulation of certain genes at the transcription level, via interaction with the vitamin D receptor, and influences host immune responses and aspects of bone development, growth, and homeostasis. Our aim was to investigate the association of TaqI vitamin D receptor gene polymorphism with external apical root resorption during orthodontic treatment. METHODS: Our subjects were 377 patients with Class II Division 1 malocclusion, divided into 3 groups: (1) 160 with external apical root resorption ≤1.43 mm, (2) 179 with external apical root resorption >1.43 mm), and (3) 38 untreated subjects. External apical root resorption of the maxillary incisors was evaluated on periapical radiographs taken before and after 6 months of treatment. After DNA collection and purification, vitamin D receptor TaqI polymorphism analysis was performed by polymerase chain reaction-restriction fragment length polymorphism. Univariate and multivariate analyses were performed to verify the association of clinical and genetic variables with external apical root resorption (P <0.05). RESULTS: There was a higher proportion of external apical root resorption in orthodontically treated patients compared with the untreated subjects. In patients orthodontically treated, age higher than 14 years old, initial size of the maxillary incisor root superior to 30 mm, and premolar extraction were associated with increased external apical root resorption. Genotypes containing the C allele were weakly associated with protection against external apical root resorption (CC + CT × TT [odds ratio, 0.29; 95% confidence interval, 0.07-1.23; P = 0.091]) when treated orthodontic patients were compared to untreated individuals. CONCLUSIONS: Clinical factors and vitamin D receptor TaqI polymorphism were associated with external apical root resorption in orthodontic patients.

Association of functional gene polymorphism IL-1beta in patients with external apical root resorption.

INTRODUCTION: External apical root resorption (EARR) is a frequent complication of orthodontic treatment. Interleukin 1beta (IL-1beta) is a potent stimulus for bone resorption and osteoclastic cell recruitment during orthodontic tooth movement. The purpose of this study was to assess the association between a polymorphism in the IL-1beta genes and EARR during orthodontic treatment. METHODS: The sample included 61 Brazilian orthodontic patients, divided into 2 groups according to the presence (affected group, n = 23) or absence (control group, n = 38) of EARR in the central and lateral maxillary incisors in the posttreatment period. DNA was obtained from buccal swab cells. The polymorphism was analyzed by the polymerase chain reaction followed by digestion with restriction enzyme. The polymerase chain reaction products were analyzed in 10% polyacrylamide gel and stained with silver. RESULTS: There were significant statistical differences (P <0.05) among the frequencies of the alleles and genotypes of the IL-1beta gene polymorphism between the affected and unaffected groups, suggesting that allele 1 predisposed the subjects to EARR (odds ratio = 4.0). CONCLUSIONS: The polymorphism of the IL-1beta gene is associated with root resorption in the studied population.