Association of genetic polymorphism and external ... - Angle Orthodontist

Systematic Review Article

Association of genetic polymorphism and external apical root resorption Amir Aminoshariaea; Anita Aminoshariaeb; Manish Valiathanc; James C. Kulildd ABSTRACT Objective: To evaluate the relationship between genetic polymorphism and external apical root resorption. Methodology: The protocol was prepared and registered on PROSPERO. Two reviewers independently conducted a comprehensive literature search. The MEDLINE, Embase, Cochrane, and PubMed databases were searched. In addition, the bibliographies of all relevant articles and textbooks were manually searched. Results: Thirteen studies met the inclusion criteria. Four studies were classified as low-quality studies (score ,10), and nine studies were classified as high-quality studies. Discussion: The results of the present review suggest that, although some authors have reported that genetic polymorphism may play a role in external apical root resorption, others have not supported this association. Future studies should be more consistent in their research methodologies to determine with clarity whether an association exists. Conclusion: Future investigations should include larger sample sizes with matching cases/ controls, adjust for confounders, provide power calculation and odds ratios, and report genetic analyses with the Hardy-Weinberg equilibrium. The current investigation suggests guidelines and recommendations for future investigators studying genetic polymorphism in patients undergoing orthodontic treatment. (Angle Orthod. 2016;86:1042–1049) KEY WORDS: Genetic polymorphism; Orthodontics; External root resorption

INTRODUCTION

reported an association between polymorphism and EARR in patients undergoing orthodontic treatment.4–9 However, a meta-analysis investigating whether genetic variants of the interleukin-1b (þ,3954 C.T [rs1143634]) (IL-1b þ3954 C.T) gene polymorphisms were associated with orthodontic EARR reported no association.10 To date, the relationship between genetic polymorphism and EARR in patients undergoing orthodontic treatment remains unknown. Thus, the purpose of this systematic review was to investigate whether currently available evidence supported a relationship between genetic susceptibility and the association with EARR in patients undergoing orthodontic treatment.

A recent systematic review reported an association with increased force levels during orthodontic movement and increased external apical root resorption (EARR).1 The authors did not include genetic polymorphism as a possible risk factor in their investigation. Genetic polymorphism contributing to EARR has been suggested in retrospective studies of familial aggregation2 and in twin studies.3 Recent investigations have a Resident, Department of Orthodontics, Case Western Reserve University, School of Dental Medicine, Cleveland, Ohio. b Associate Professor, Department of Endodontics, Case Western Reserve University, School of Dental Medicine, Cleveland, Ohio. c Associate Professor, Department of Orthodontics, Case Western Reserve University, School of Dental Medicine, Cleveland, Ohio. d Professor Emeritus, Department of Endodontics, University of Missouri-Kansas City, School of Dentistry, Kansas City, Mo. Corresponding author: Dr Anita Aminoshariae, 2123 Abington Road A 280, Cleveland, OH 44106 (e-mail: [email protected])

MATERIALS AND METHODS Protocol and Registration The protocol for this systematic review was developed following established guidelines.11 The protocol was prepared and registered on PROSPERO (registration number CRD42015027367). Also, a well-defined review question was developed by using the

Accepted: March 2016. Submitted: January 2016. Published Online: May 5, 2016 Ó 2016 by The EH Angle Education and Research Foundation, Inc. Angle Orthodontist, Vol 86, No 6, 2016

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DOI: 10.2319/011916-50.1

GENETICS AND ORTHODONTIC ROOT RESORPTION

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Figure 1. PRISMA flow diagram.11 For more information, visit www.prisma-statement.org.

patient population, intervention, comparison, and outcome framework. The AMSTAR checklist, the Oxford Systematic Review Appraisal Sheet, the Critical Appraisal Skills Programme, and the Grading of Recommendations Assessment, Development and Evaluation system for grading evidence were used to ensure the accuracy of the data analysis in this systematic review.11–14 In addition, the STrengthening the Reporting of Genetic Associations (STREGA) statement and checklist were followed to assess the quality of the genetic studies.15,16

Eligibility Criteria The inclusion criteria for this review were the following:

Formulating the Review Question In patients undergoing orthodontic treatment, can genetic polymorphism alter a patient’s susceptibility to EARR?

The following types of studies were considered: clinical trials, case-control studies, cross-sectional studies, or cohort studies published in English-language scientific journals from January 1990 to November 2015 Studies assessing EARR in orthodontically treated teeth as a primary object Sufficient genotype data presented to calculate odds ratios and 95% confidence intervals Studies in which genetic polymorphisms were quantified and the existence of EARR was established Exclusion criteria included the following:

The type of study: cell culture laboratory study or animal study Angle Orthodontist, Vol 86, No 6, 2016

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AMINOSHARIAE, AMINOSHARIAE, VALIATHAN, KULILD

Table 1. Main Characteristics of Included Studies Author, Year

Country

Ethnicity

Sample Size (Case/ Control)

Matching Criteria

Genotype Method

Biological Marker

Sharab et al., 2015

Lexington, KY

White

67/67

Age, gender

Taqman

P2RX7

Pereira et al., 2014

Coimbra, Portugal

White

Not stated

Not described

Taqman

IL1B, RANK, P2RX7, and OPG

Iglesias-Linares et al., 2014

Seville, Spain

White

37/50

PCR-RFLP

Osteopontin gene (rs9138, rs11730582)

Iglesias-Linares et al., 2013

Seville, Spain

White

39/54

Age, gender, ortho classification treatment Age, gender, ortho classification treatment

Taqman

IL-1

Linhartova et al., 2013

Brno, Czech Republic

Czech, White

32/74

Age, gender, ortho classification treatment

PCR-RFLP

IL-1

Iglesias-Linares et al., 2012 (JOE)

Seville, Spain

White

39/154

Taqman

IL-1

Iglesias-Linares et al., 2012 (OD)

Seville, Spain

White

25/29

TaqMan

IL-1

Iglesias-Linares et al., 2012 (IEJ)

Seville, Spain

White

73/73

Taqman

IL-1

Fontana et al., 2012 Sao Paulo, Brazil

Mixed

157 þ 175 (treated)/ 35 (untreated)

Age, gender, ortho classification treatment Age, gender, ortho classification treatment Age, gender, ortho classification treatment Age, gender

TaqI

Vitamin D receptor gene polymorphism

Lages et al., 2007

Sao Paulo, Brazil

White

23/38

Age, gender

TaqI

IL-1B

Gulden et al., 2009

Aachen, Germany

White

96/162

Not stated

TaqI

IL-1

Al-Quawasmin et al., 2003 (JDR)

Indianapolis, IN

Not stated

Not stated

Taql

TNF

Al-Quawasmin et al., 2003

Indianapolis, IN

Not stated

38 families (124 patients, 79 siblings and 45 parents) 35 families (118 persons, 73 siblings and 45 parents)

Not stated

Taql

IL-1

a EARR, external apical root resorption; JOE: J of Endodontics (J Endod); OD: J of Oral Disease (Oral Dis); OPG: Osteoprotegerin (OPG); IEJ: International Endodontic Journal (Int Endod J); JDR: Journal of Dental Research; PCR-RFLP: Polymerase Chain Reaction Restriction Fragment Length Polymorphism; Taql: restriction enzyme https://en.wikipedia.org/wiki/Thermus_aquaticus Thermus aquaticus; Tumor necrosis factor (TNF); Interleukin 1 (IL-1); Interleukin 1A (IL1A); Interleukin 1B (IL-1B).

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Table 1. Extended Outcome P2RX7 a possible factor of susceptibility to EARRa P2RX7 a possible factor of susceptibility to EARR

Variations in the osteopontin gene (rs9138 and rs11730582) are determinants of a genetic predisposition to suffer EARR secondary to orthodontic treatment Variants in a specific allele (allele 1) IL 1 cytokine antagonist gene (rs419598) (or some unknown linked allele) are directly associated (P ¼ .001) with an increased risk of suffering postorthodontic EARR in root-filled teeth No statistical significant differences in the IL1A and IL1B genotype, allele and reconstructed IL1 haplotype frequencies were found, marginally significant differences were observed in the frequencies of IL1RN variant Allele of the interleukin-1 cytokine agonist gene (rs1143634) may predispose to postorthodontic EARR in root-filled teeth

Hardy-Weinberg equilibrium (HWE) No evidence of deviation observed No evidence of deviation observed

No evidence of deviation was observed

Limitations No power calculation. Odds ratio not provided. Correction for type I error not discussed Not clear how many patients were in experimental/ control groups. Not stated if cases and control were matched; no power calculation. Odds ratio not provided Cases and controls not balanced for confounders; no power calculation

No evidence of deviation

Correction for type I error not discussed; no power calculation

It was tested, P , .05

Did not state confounders were adjusted; no power calculation and did not adjust for type I error

Did not state

Did not state confounders were adjusted for the cases/ control. Power calculation not discussed. HWE was not discussed or provided

No association found for IL1A gene; patients who were homozygous (1 1[TT]) for the IL1RN gene were more likely to be affected with EARR

N/A

No statistical association in IL1A, but an association was found in the comparative analysis of subjects homozygous (2/2[TT]) for the IL1B gene, which resulted in a two-times increased risk of suffering postorthodontic EARR in root-filled teeth Clinical factors and vitamin D receptor TaqI polymorphism were associated with external apical root resorption in orthodontic patients

N/A

Did not state confounders were adjusted for the cases/ control. Power calculation not discussed. HWE was not discussed or provided. Correction for type I error not provided Did not state confounders were adjusted for the cases/ control. Power calculation was not discussed. HWE was not discussed or provided. Correction for type I error was not provided

Polymorphism of the IL-1b gene is associated with root resorption

Provided

Allele 1 of the IL-1B polymorphism in patients with sporadic EARR did not contribute to predisposition, but genotype TT of IL-1A polymorphism is associated with EARR TNFRSF11A locus, or another tightly linked gene, is associated with EARR

Allele 1 at the IL-1B gene significantly increased the risk of EARR. IL1A polymorphism not associated

Studies that did not meet the inclusion criteria

Past medical history was not discussed in Methodology section. Not clear if cases/controls were balanced for confounders. HWE was discussed. Power calculation was not provided. Correction for type I error was not discussed Did not state confounders were adjusted. HWE not discussed. Power calculation was not provided. Correction for type I error was not discussed Not clear if cases/controls were matched and adjusted for confounders. HWE discussed. Odds ratio not provided. Correction for false positive (type I) error not provided Not clear if cases/controls were matched and adjusted for confounders. Power calculation not provided. Odds ratio not provided. HWE not provided Not clear if cases/controls were matched and adjusted for confounders. Power calculation not provided. Odds ratio not provided. HWE not provided

bibliography of all relevant articles and textbooks were manually searched. Based on inclusion and exclusion

Search Methodology

criteria, two reviewers independently selected the

The electronic MEDLINE, Embase, Cochrane, and PubMed databases were searched. In addition, the

relevant articles. There were no disagreements between the two authors. Angle Orthodontist, Vol 86, No 6, 2016

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Table 2. Assessment of the Quality of Included Studies Author, Year

Selection

Comparability

Exposure

Study Methodologies

Genetic Analysis

Score

Sharaba et al., 2015 Pereira et al., 2014 Iglesias-Linares et al., 2014 Iglesias-Linares et al., 2013 Linhartova et al., 2013 Iglesias-Linares et al., 2012 Iglesias-Linares et al., 2012 Iglesias-Linares et al., 2012 Fontana et al., 2012 Lages et al., 2009 Gulden et al., 2009 Al-Qawasmi et al., 2003 Al-Qawasmi et al., 2003

****(4) *(1) ****(4) ****(4) ****(4) ****(4) ****(4) ****(4) **(2) ***(3) **(2) *(1) *(1)

**(2) 0 *(1) *(1) *(1) *(1) *(1) *(1) *(1) *(1) 0 0 0

**(2) (0) **(2) **(2) **(2) *(1) *(1) *(1) *(1) **(2) 0 0 0

*(1) *(1) ** (2) **(2) **(2) **(2) **(2) **(2) *(1) *(1) *(1) *(1) *(1)

******(6) ******(6) ******(6) ******(6) ******(6) *****(5) *****(5) *****(5) ******(6) *****(5) *****(5) *****(5) *****(5)

15 8 15 15 15 13 13 13 11 12 8 7 7

* Denotes a positive score.

Data Items and Collection To answer the clinically relevant question, a fourstep method of evidence-based analysis was applied. In step 1, electronic databases and bibliographies of all the relevant articles were both electronically and hand searched for the clinical evidence regarding genetic polymorphism and biological markers. In step 2, the articles were appraised and selected according to study validity and clinical importance, and in step 3, the published evidence was collection and analyzed. Any clinical applicability of the results was determined in step 4. Using the formatted question based on the patient population, intervention, comparison, and outcome framework, methodological MeSH (medical subject heading) terms were generated to make the search strategy more sensitive in the identification of studies. These terms included the following: polymorphism and orthodontics; polymorphism and external apical root resorption; genetic markers and external apical root resorption. Studies that met the previously mentioned inclusion criteria underwent critical analysis. Extracted data included population size; the number of dropouts or withdrawals, if reported; a description of the materials and methods with a detailed assessment of genetic polymorphism; and the outcome variables used to measure any effect of biologic markers on apical periodontitis. Risk of Bias/Quality Assessment in Individual Studies Adherence to guidelines for reporting genetic association studies such as the STREGA statement and the corresponding checklist have improved the quality of genetic studies.15,16 The qualities of the included studies were evaluated according to a modified proposed specific quality assessment scale for genetic association studies.17–19 Angle Orthodontist, Vol 86, No 6, 2016

The quality of each study was assessed by using the following methodological components: (1) selection, (2) comparability, (3) exposure, (4) study methodology/ design, and (5) genetic analyses. Scores ranged from 0 (lowest) to 20 (highest). Studies with scores 10 were classified as high-quality studies, whereas studies with scores ,10 were classified as low-quality studies.18 Outcome Variables and Statistical Analysis Given the heterogeneity among the different studies and data from different inflammatory markers, it was not possible to perform a meta-analysis. RESULTS Study Selection and Characteristics Figure 1 presents a flowchart of the systematic review process according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.11 A total of 13 articles met the inclusion criteria. Table 1 details the characteristics, main results, and limitations of the included studies. Risk of Bias Within Studies Tables 2 and 3 detail the methodological quality assessment as described in a previous article19 and modified from Nibali.17 Four studies were classified as low-quality studies (score ,10), and nine studies were classified as high-quality studies (score .10). DISCUSSION Summary of Evidence This systematic review reported nine of 13 studies with a potentially low risk of bias, and four of 13 studies with a potentially high risk of bias. The results of the present review suggest that although some authors


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Table 3. Quality Assessment of Genetic Association Studies Category Selection

Item Adequate case definition Representativeness of cases Selection of controls Definition of controls

Comparability

Confounders

Exposure

Ascertainment of exposure Same method of ascertainment for cases and controls Nonresponse rate Power calculation Statistics Corrected statistics Odds ratios and confidence intervals Success rate of DNA extraction Success rate of genetic assessment Genotype counts Hardy-Weinberg equilibrium Primer sequence Reproducibility

Study methodology/design

Genetic analyses

Genotyping blind to case-control status Proposed inheritance model

have reported that genetic polymorphism may play a role in EARR,4–9,20–23,24 others have not supported this association.25–26 Published orthodontic investigations in gene studies have seldom adhered to the STREGA or any genetic guidelines. As a result, the study may suffer from methodological inaccuracies, which can introduce bias. Orthodontic treatment has been moving toward a model of evidence-based practice. To that end, the assessment of patient risk to certain orthodontic treatments is an important component of this evidence-based approach. By identifying a patient’s risk of developing certain more significant pathoses, such as EARR, clinicians might be able to intervene by providing a treatment modality that would take into consideration that increased risk to minimize any adverse effects. Gingival crevicular fluid has been reported to serve as a tool to quantify dentin phosphophoryn and dentin sialoprotein of patients experiencing orthodontic-induced root resorption.27 The authors reported that, although this technique might be promising, a longitudinal study to confirm these findings has yet to be published. Other protein biomarkers have been suggested to be salivary secretory IgA,28 osteoprotegerin ligand (OPGL),29 receptor activator of NF-jB ligand (RANKL),30 and osteoprotegrin (OPG).31 Although these preliminary findings are exciting, most of the

Positive Answer (1) Clinical validated diagnosis Consecutive or obviously representative cases selected (no evidence of selection bias) Definition of controls: controls geographically and ethnically matched to the cases Absence of disease and accepted independently defined diagnosis of health adopted Cases and controls balanced (must state confounders were adjusted) Secure record Yes Same for cases and controls Performed a priori Well-described tests of significance for primary outcome Correction for false positive (type I) error Provided Reported good rates Reported good rates Provided in table or text Satisfied Provided or referenced Described genotyping method to allow replication, validated genotyping accuracy Yes Inheritance model-free approach (not exclusively dominant or recessive pattern proposed)

current evidence regarding osteoprotegrin, osteoprotegerin ligand, and receptor activator of NF-jB ligand are based on investigations using rodent models. Based on the current evidence and this systematic review, genetic polymorphism cannot currently be considered a causal factor for EARR, but it might be considered as an additional risk factor placing orthodontic patients at possible risk for EARR. Limitations There were limitations in the current studies, and future studies should be more consistent in their methodologies and reporting. These limitations include the following: not clearly stating and/or not judiciously matching selected case/control groups, balancing or adjusting for confounders, ascertaining case-control groups that had the same exposure and the same method of evaluation, using the HardyWeinberg equilibrium, providing a power calculation for a given sample size, correcting for a false positive (type I) error, and providing odds ratios with confidence intervals. The EARR progression is a multifactorial event. The current findings may, with further research, support that a number of biologic modifiers are closely associated with EARR. Screening and monitoring for systemic disease risk in patients undergoing orthodontic treatment may be valuable Angle Orthodontist, Vol 86, No 6, 2016

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components for more effective disease prevention and treatment. CONCLUSIONS

The results of this review suggest that polymorphism and biological modifiers by which some individuals undergoing orthodontic treatment may manifest a higher incidence of EARR. Future investigations should include larger sample sizes with matching cases/controls, adjust for confounders, provide power calculation and odds ratios, and report genetic analysis with the Hardy-Weinberg equilibrium. The current investigation suggests guidelines and recommendations for future investigators studying genetic polymorphism in patients undergoing orthodontic treatment.

ACKNOWLEDGMENTS The authors report no commercial, proprietary, or financial interest in the products or companies described in this article.

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