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 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

Formulating the Review Question

In patients undergoing orthodontic treatment, can genetic polymorphism alter a patient's susceptibility to EARR?

Eligibility Criteria

The inclusion criteria for this review were the following:

• 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

• Studies that did not meet the inclusion criteria

Search Methodology

The electronic MEDLINE, Embase, Cochrane, and PubMed databases were searched. In addition, the bibliography of all relevant articles and textbooks were manually searched. Based on inclusion and exclusion criteria, two reviewers independently selected the relevant articles. There were no disagreements between the two authors.

Data Items and Collection

To answer the clinically relevant question, a four-step 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 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.

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.

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Table 1. Main Characteristics of Included Studies

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Table 1. Extended

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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).

Table 2. Assessment of the Quality of Included Studies

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Table 3. Quality Assessment of Genetic Association Studies

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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 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-κB ligand (RANKL),³⁰ and osteoprotegrin (OPG).³¹ Although these preliminary findings are exciting, most of the current evidence regarding osteoprotegrin, osteoprotegerin ligand, and receptor activator of NF-κB 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 Hardy-Weinberg 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 components for more effective disease prevention and treatment.