The Association of GLT6D1 rs1537415 G Allele with Aggressive and Advanced Chronic Periodontitis: A Comprehensive Meta-Analysis

The Association of GLT6D1 rs1537415 G Allele with Aggressive and Advanced Chronic Periodontitis: A Comprehensive Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Association of GLT6D1 rs1537415 G Allele with Aggressive and Advanced Chronic Periodontitis: A Comprehensive Meta-Analysis Theofanis Argyrios Karaoulas, Christoforos Xirouchakis, Chariklia Neophytou, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6953323/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Objective: To evaluate the association of the GLT6D1 rs1537415 G allele with susceptibility to aggressive periodontitis (AgP) and advanced chronic periodontitis (Stage III/IV, Grade B or C) by synthesizing evidence from human genetic association studies. Materials and Methods: Following PRISMA guidelines, a systematic search was conducted in PubMed, Web of Science, and Scopus through December 2024. Eligible studies analyzed the rs1537415 polymorphism in patients with AgP or advanced chronic periodontitis versus healthy controls. Three studies (n = 1,969) were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects models. Heterogeneity and publication bias were evaluated using Chi², I², funnel plots, and Egger’s test. Results: The meta-analysis demonstrated a significant association between the G allele and periodontitis (OR = 1.58; 95% CI: 1.28–1.95; p < 0.0001). Subgroup analysis confirmed consistent effects in European and Sudanese populations, while no significant association was detected in the Brazilian cohort. Functional evidence indicates the G allele impairs GATA-3 transcription factor binding, contributing to immune dysregulation. Conclusions: The GLT6D1 rs1537415 G allele is significantly associated with increased risk of severe periodontitis. It may serve as a useful genetic marker in precision periodontology. Further research in diverse populations is needed to confirm gene-environment interactions and strengthen clinical applicability. GLT6D1 rs1537415 aggressive periodontitis chronic periodontitis genetic susceptibility meta-analysis Figures Figure 1 Figure 2 Figure 3 Introduction Periodontitis is a chronic inflammatory disease that progressively destroys the supporting structures of teeth, including the periodontal ligament and alveolar bone. If untreated, periodontitis can lead to tooth loss and has been linked to systemic health complications such as diabetes and cardiovascular disease ( 1 ). The disease arises from a complex interplay of genetic, microbial, and environmental factors, with genetic predisposition accounting for approximately 50% of individual susceptibility ( 2 ). Advancements in genetic research have highlighted the significant role of single-nucleotide polymorphisms (SNPs) in modulating susceptibility to periodontitis. A systematic review of genome-wide association studies (GWAS) on periodontitis ( 3 ), analyzing 15 high-quality studies, identified 11 SNPs that met genome-wide significance thresholds (P < 5 × 10⁻⁸) and 41 additional SNPs of suggestive significance (P < 5 × 10⁻⁶). However, only three SNPs—rs4284742 [G], rs11084095 [A], and rs12461706 [T]—from the SIGLEC5 gene region were consistently reported across studies, underscoring the heterogeneity in genetics findings. Several other genome-wide significant SNPs have been linked to the etiology of periodontitis. For instance, rs729876 on chromosome 16p13.12 shows trans-eQTL effects on HOXC10 in monocytes, potentially affecting inflammation and fibrinolysis, whereas rs16870060 on chromosome 8q22.3 has tissue-specific effects related to inflammation and immune modulation ( 4 ). Despite these findings, the functional implications of many SNPs remain inadequately understood. Among the prominent genetic loci associated with periodontitis is the glycosyltransferase 6 domain containing 1 (GLT6D1) gene. A European meta-GWAS ( 5 ) on severe periodontitis (stage III/IV grade C, diagnosed at ≤ 35 years) recognized GLT6D1 as a significant genetic locus, alongside others such as FCER1G and HMCN2, which are linked to oral barrier stability and wound healing. Variants in GLT6D1, particularly the rs1537415 SNP, have been connected with immune dysregulation and extracellular matrix instability, which are critical factors in the pathogenesis of periodontitis ( 6 , 7 ). The rs1537415 SNP in GLT6D1 has been strongly associated with susceptibility to aggressive periodontitis (AgP), a severe form of the disease marked by rapid progression in younger individuals. Mechanistic studies indicate that the G allele of rs1537415 reduces the binding affinity of the GATA-3 transcription factor, impairing immune regulation and promoting inflammation ( 8 , 9 ). However, findings regarding the allele's effects have been inconsistent across populations; while some European studies suggest it to be protective, other populations have shown conflicting results ( 10 , 11 ). Genetic research in periodontitis has significantly evolved, shifting from early linkage analysis ( 12 ) and candidate gene studies ( 13 ) to contemporary approaches such as GWAS and next-generation sequencing (NGS). These technologies enable a thorough exploration of the genome, uncovering thousands of genetic variations, especially SNPs, that may be relevant to periodontitis ( 6 , 14 ). Furthermore, bioinformatics tools and databases like the 1000 Genomes Project and HapMap have greatly improved the interpretation and cataloging of genetic variations across diverse populations, enriching our understanding of the genetic factors contributing to diseases ( 15 ). Despite extensive research on AgP, the role of GLT6D1 in other forms of periodontitis, such as chronic periodontitis—a slower-progressing yet more common subtype—remains underexplored. Additionally, population-specific variations and methodological inconsistencies limit the generalizability of existing findings. Therefore, a comprehensive meta-analysis is necessary to clarify the association of the GLT6D1 rs1537415 G allele with periodontitis across diverse populations and to investigate its potential involvement in shared mechanisms underlying periodontitis subtypes. Methods 2.1 Study Design This study was conducted as a systematic review and meta-analysis to assess the association between the GLT6D1 rs1537415 G allele and susceptibility to periodontitis, including both aggressive and advanced chronic forms (Stage III/IV, Grade B or C). The methodology adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines to ensure transparency, reproducibility, and methodological rigor. A predefined protocol was followed for all phases of the review, including literature search, study selection, data extraction, risk of bias assessment, and statistical synthesis. This protocol was not prospectively registered; however, all methodological decisions were made a priori and are reported in full. 2.2 Eligibility Criteria Inclusion Criteria Studies were eligible for inclusion if they met all of the following criteria: Study Design: Human genetic association studies with case-control, cohort, cross-sectional, or GWAS design. Participants: Individuals diagnosed with aggressive periodontitis (AgP) or advanced chronic periodontitis(Stage III/IV, Grade B or C), based on validated diagnostic criteria such as those from the AAP/EFP. Exposure: Analysis of the GLT6D1 rs1537415 polymorphism, reporting genotype or allele frequencies, particularly of the G allele. Comparator: Inclusion of a control group composed of healthy individuals or periodontally unaffected participants. Outcomes: Quantitative data sufficient to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between the G allele and periodontitis. Exclusion Criteria Studies were excluded if they: Lacked genotype frequency data for rs1537415. Did not include a control group. Were reviews, editorials, case reports, or other non-original research articles. Focused on in vitro or animal models. Used combined disease phenotypes without stratified analysis for periodontitis subtypes. 2.3 Information Sources A comprehensive electronic search was conducted in the following databases: PubMed/MEDLINE Web of Science Scopus The final search was completed on December 15, 2024. To ensure completeness, the reference lists of all included full-text articles and relevant systematic reviews were also manually screened for additional eligible studies. 2.4 Search Strategy Database-specific search strategies were developed using a combination of Medical Subject Headings (MeSH) and free-text keywords, customized for each platform. Boolean operators ("AND", "OR") were used to maximize search sensitivity. Core Search Terms Included: "GLT6D1" OR "glycosyltransferase 6 domain containing 1" "rs1537415" OR "G allele" "periodontitis" OR "aggressive periodontitis" OR "chronic periodontitis" OR "stage III" OR "stage IV" OR "grade C" Example Search String (PubMed): ("GLT6D1"[All Fields] OR "rs1537415"[All Fields] OR "G allele"[All Fields]) AND ("periodontitis"[MeSH Terms] OR "aggressive periodontitis"[All Fields] OR "chronic periodontitis"[All Fields]) The full search strategy for each database is presented in Supplementary Appendix 1. 2.5 Data Extraction Two reviewers independently extracted data using a standardized form. The following information was retrieved from each included study: First author and publication year Study design and country of origin Sample size (cases and controls) Diagnostic criteria used for periodontitis Genotype and allele frequencies for rs1537415 Statistical results: ORs, 95% CIs, and p-values Genotyping method used (e.g., GWAS, real-time PCR, MassARRAY) Disagreements were resolved by discussion or consultation with a third reviewer. 2.6 Quality Assessment The methodological quality of the included studies was assessed using the Q-Genie tool, which is specifically designed for genetic association studies. This tool evaluates the following domains: Adequacy of the hypothesis and rationale Definition and classification of outcomes Description and comparability of study groups Disclosure of potential sources of bias Appropriateness of statistical methods and power analysis Each domain was rated as low, moderate, or high quality. Two reviewers independently performed the quality assessments, and discrepancies were resolved by consensus. 2.7 Statistical Analysis Meta-analyses were conducted using Review Manager (RevMan 5.4) software. The Mantel-Haenszel method with a random-effects model was applied to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs) for the association between the rs1537415 G allele and periodontitis. Heterogeneity across studies was assessed using the Chi² test and the I² statistic, with I² >50% indicating substantial heterogeneity. Publication bias was evaluated using Egger’s regression test, conducted in R (meta package). Sensitivity analyses were performed by sequentially removing each study to evaluate the robustness of the results. Results Study Selection A total of 278 articles were identified through database searches. After removing 85 duplicates, 193 articles remained for title and abstract screening. Of these, 162 articles were excluded as they did not meet the inclusion criteria, leaving 31 full-text articles for assessment. Following a detailed review, 28 articles were excluded due to irrelevance to the study criteria or insufficient data. Ultimately, three studies were included in the final analysis (Fig. 1 ): Schaefer et al. (2010): Investigated a European population with AgP ( 9 ). Hashim et al. (2015): Focused on a Middle Eastern population with AgP ( 11 ). Rodrigues et al. (2022): Examined a Brazilian population with advanced periodontitis ( 10 ). Study Characteristics The studies represent diverse populations, genotyping methodologies, and disease subtypes, offering a comprehensive perspective on this genetic association. In the study by Schaefer et al. ( 9 ), German and Dutch populations with AgP were investigated. This GWAS included 438 cases with generalized and localized AgP and 1,320 healthy controls. Cases were diagnosed based on severe clinical and radiographic criteria, characterized by attachment and bone loss typical of AgP. Controls were free of clinical attachment loss and served as a comparison group. High throughput genotyping of rs1537415 was conducted as part of the GWAS, using the Affymetrix GeneChip and TaqMan SNP assays. The study examined the enrichment of the G allele in cases compared to controls, focusing on its statistical significance and ORs. Hashim et al. ( 11 ) study investigated a Sudanese population with AgP. A total of 132 cases and 136 healthy controls were included, and all non-smokers were matched for age and gender. Cases exhibited severe clinical attachment loss and alveolar bone destruction, while controls had no attachment loss or probing depths > 3 mm. DNA was extracted from blood samples, and genotyping of rs1537415 was performed using the Sequenom MassARRAY iPLEX platform. The analysis compared allele and genotype frequencies between cases and controls to evaluate the association of the G allele with AgP. The study by Rodrigues et al. ( 10 ) focused on a Brazilian population with advanced periodontitis. 100 cases were included, all classified as Stage III/IV based on the 2018 periodontal classification, with further stratification into Grade B (52 cases) and Grade C (48 cases). The control group comprised 61 healthy individuals with no clinical attachment loss or probing depths ≥ 3 mm. The controls were matched for age and gender to the cases. DNA was extracted from buccal epithelial cells, and genotyping of the rs1537415 polymorphism in the GLT6D1 gene was performed using real-time quantitative PCR. Cases and controls were compared based on allele and genotype frequencies to assess the association of the G allele with advanced periodontitis. These studies collectively covered distinct populations—Brazilian, German/Dutch, and Sudanese—representing both advanced CP and AgP. They utilized diverse genotyping platforms, including real-time PCR, GWAS, and MassARRAY, and employed rigorous diagnostic criteria for case and control definitions. Together, these methodologies and population characteristics provided a robust foundation for analyzing the association of the rs1537415 polymorphism with periodontitis (Tables 1 , 2 ). Risk Of Bias Assessment The Q-Genie assessment (Table 3 ) highlights the variability in the quality of the included studies. Schaefer et al. ( 9 ) achieved high scores across all domains, demonstrating robust methodology, adequate sample size, and substantial population stratification control, making it the most reliable study. Hashim et al. ( 11 ) showed moderate quality, with strengths in hypothesis framing but constrained by small sample size and inadequate control for population diversity. Rodrigues et al. ( 10 ) exhibited moderate-to-low quality, facing limitations in statistical power and stratification adjustment due to its small sample size. These findings underscore the necessity for extensive, standardized studies to enhance reliability and generalizability. Meta-Analysis Results The meta-analysis included data from three studies comprising a total of 1,969 individuals, with 452 periodontitis cases(aggressive or advanced chronic) and 1,517 healthy controls. The pooled analysis assessed the association of the GLT6D1 rs1537415 G allele with susceptibility to periodontitis. The overall odds ratio (OR) was 1.58 [95% CI: 1.28–1.95], indicating that individuals carrying the G allele have significantly higher odds of developing periodontitis than non-carriers (Z = 4.27, p < 0.0001). A random-effects model was applied, and no significant heterogeneity was observed across studies. Study-Specific Results Schaefer et al. (2009) [9]: Reported a significant association between the G allele and periodontitis (OR = 1.64, 95% CI: 1.30–2.08), contributing the most weight (78.7%) due to its large sample size and GWAS design. Hashim et al. (2015) [11]: Found a non-significant but suggestive association (OR = 1.52, 95% CI: 0.91–2.53), with a moderate contribution (16.8% weight); the wide confidence interval likely reflects limited sample size. Rodrigues et al. (2022) [10]: Did not observe a significant association (OR = 0.93, 95% CI: 0.34–2.51), possibly due to low statistical power and smaller cohort size. Heterogeneity Analysis The pooled data demonstrated no significant heterogeneity, with: I² = 0% Chi² = 1.22, df = 2, p = 0.54 Tau² = 0.00 (calculated using the restricted maximum-likelihood method) Funnel Plot and Publication Bias The funnel plot visually assessed potential publication bias. It displayed a symmetrical distribution of studies around the pooled odds ratio (OR), indicating a low likelihood of publication bias. To confirm this observation, Egger's regression test was conducted, yielding a p-value of 0.233, further supporting the absence of significant small-study effects (Fig. 3 ). Discussion This meta-analysis highlights the association of the GLT6D1 rs1537415 G allele with susceptibility to periodontitis, particularly aggressive forms. The pooled analysis of three studies—including populations from Europe, Africa, and South America—demonstrated a significant overall association between the G allele and increased risk of periodontitis (OR = 1.58, 95% CI: 1.28–1.95, p < 0.0001), suggesting a meaningful genetic contribution to disease susceptibility. The role of rs1537415 has been explored in multiple populations. In European cohorts, Schaefer et al. (2009) [9] first identified the G allele as significantly associated with aggressive periodontitis, reporting an OR of 1.64 (95% CI: 1.30–2.08). This finding was later replicated in a Sudanese population by Hashim et al. (2015) [11], who reported an OR of 1.52 (95% CI: 0.91–2.53). Although the latter did not reach statistical significance, likely due to sample size limitations, the consistency of the effect size supports a shared genetic mechanism across these ethnic groups. In contrast, Rodrigues et al. (2022) [10], studying a Brazilian cohort with advanced chronic periodontitis, found no significant association (OR = 0.93, 95% CI: 0.34–2.51), suggesting population-specific variability or reduced allele penetrance in chronic forms of the disease. The lack of association in the Brazilian study may stem from differences in genetic background, environmental exposures, or diagnostic criteria. While Schaefer and Hashim focused on aggressive periodontitis using stringent clinical criteria, Rodrigues applied the 2018 AAP/EFP classification for advanced chronic periodontitis (Stage III/IV, Grades B/C), which may capture a more heterogeneous phenotype. It is plausible that the rs1537415 G allele exerts a stronger effect in early-onset, rapidly progressing forms of periodontitis (i.e., AgP), whereas chronic forms—with slower progression and greater influence from age, biofilm exposure, and comorbidities—may dilute the genetic effect. Biologically, the GLT6D1 gene encodes a glycosyltransferase involved in immune regulation and extracellular matrix stability. The G allele of rs1537415 is known to reduce the binding affinity of the GATA-3 transcription factor, leading to impaired T-cell differentiation and altered cytokine production [16, 21]. These effects likely promote the chronic inflammatory responses and connective tissue destruction that characterize periodontitis. Thus, the molecular evidence aligns with the observed epidemiologic associations. These findings support the potential utility of rs1537415 as a genetic risk marker in periodontology. Genetic screening could be incorporated into personalized risk assessment tools, identifying individuals who may benefit from earlier or more intensive preventive interventions. Moreover, understanding the immunogenetic pathways modulated by GLT6D1 may open novel therapeutic avenues targeting T-cell function or glycosylation mechanisms in periodontal disease. Limitations This meta-analysis is subject to several limitations: Only three eligible studies met the inclusion criteria, limiting statistical power and precluding subgroup or meta-regression analyses. There was heterogeneity in diagnostic criteria used to define periodontitis subtypes, particularly between studies on AgP and those using the 2018 classification. The sample sizes were modest, especially in the non-European cohorts, which restricts the generalizability of findings across global populations. Publication bias cannot be fully ruled out, despite visual symmetry of the funnel plot and a non-significant Egger’s test. Future Research Directions To build on these findings, future studies should prioritize the following: Expand multi-ethnic cohorts to validate the association of rs1537415 across diverse populations. Standardize phenotypic definitions and genotyping protocols to reduce inter-study variability. Investigate gene-environment interactions, including smoking, systemic inflammation, and oral hygiene, to understand context-dependent effects of the G allele. Conduct functional studies to elucidate how GLT6D1 polymorphisms affect immune and connective tissue responses in the periodontium. Conclusion This meta-analysis demonstrates a significant association between the GLT6D1 rs1537415 G allele and increased susceptibility to periodontitis, particularly aggressive forms. The pooled data suggest that this polymorphism may serve as a genetic risk marker, supporting the role of host genetics in periodontal disease pathogenesis. Further large-scale, multi-ethnic studies are needed to confirm these findings and explore their clinical utility in personalized periodontal care. Implications for Clinical Practice The findings of this meta-analysis suggest that genetic screening for the GLT6D1 rs1537415 G allele may be beneficial in identifying individuals at increased risk for severe periodontitis, particularly AgP and advanced chronic periodontitis (Stage III/IV, Grade B or C). Early identification of genetically susceptible individuals can facilitate tailored preventive strategies, such as enhanced periodontal monitoring and early intervention protocols. Additionally, this research underscores the potential for precision medicine approaches in periodontology, where genetic profiling could inform individualized treatment planning and risk assessment. Implications for Research Future studies should focus on expanding multi-ethnic cohorts to validate the association of the GLT6D1 rs1537415 G allele with periodontitis across diverse populations. Standardizing diagnostic criteria and genotyping methodologies will be critical to reducing inter-study variability. Additionally, further research should investigate the gene-environment interactions that may modulate this allele’s effects, including factors such as smoking, systemic diseases, and oral microbiome composition. Functional studies exploring the biological mechanisms underlying GLT6D1-mediated immune dysregulation and inflammation could also provide valuable insights for developing targeted therapeutic interventions. Declarations Author Contributions The contributions of all authors are outlined below using the CRediT (Contributor Roles Taxonomy) system: Christoforos Xirouchakis: Conceptualization, Data Curation, Writing – Original Draft Theofanis Argyrios Karaoulas: Methodology, Formal Analysis, Writing – Review & Editing Chariklia Neophytou: Investigation, Visualization, Writing – Review & Editing Ioannis Fragkioudakis: Supervision, Project Administration, Validation All authors have read and approved the final version of the manuscript and agree to be accountable for all aspects of the work, ensuring accuracy and integrity throughout the research and publication process. Compliance with Ethical Standards Conflict of Interest The authors declare that they have no competing interests. Funding This research received no external funding and was entirely self-financed by the authors. Ethical Approval Not applicable. This meta-analysis is based on previously published data and does not involve any new studies with human participants or animals. Informed Consent Not applicable. Clinical trial number: not applicable. Disclosure of Interest The authors report there are no competing interests to declare. This study received no external funding and was entirely self-financed by the authors. The manuscript has not been registered in PROSPERO. The authors recognize the importance of protocol registration and commit to prospective registration for future systematic reviews to enhance methodological transparency. Data Availability Statement All data supporting the findings of this study are included within the manuscript and its supplementary materials. No additional datasets were generated or analyzed during the current study. Further information can be made available by the corresponding author upon reasonable request. References Kinane DF, Stathopoulou PG, Papapanou PN. Periodontal diseases. Nat Rev Dis Primers. 2017 Jun 22;3:17038. Michalowicz BS, Diehl SR, Gunsolley JC, Sparks BS, Brooks CN, Koertge TE, et al. Evidence of a substantial genetic basis for risk of adult periodontitis. J Periodontol. 2000 Nov;71(11):1699–707. Gao C, Iles M, Larvin H, Bishop DT, Bunce D, Ide M, et al. Genome-wide association studies on periodontitis: A systematic review. PLoS One. 2024 Sep 1;19(9). Munz M, Richter GM, Loos BG, Jepsen S, Divaris K, Offenbacher S, et al. Meta-analysis of genome-wide association studies of aggressive and chronic periodontitis identifies two novel risk loci. European Journal of Human Genetics. 2019 Jan 1;27(1):102–13. De Almeida SD, Richter GM, de Coo A, Jepsen S, Kapferer-Seebacher I, Dommisch H, et al. A genome-wide association study meta-analysis in a European sample of stage III/IV grade C periodontitis patients ≤35 years of age identifies new risk loci. J Clin Periodontol. 2024 Apr 1;51(4):431–40. Vaithilingam RD, Safii SH, Baharuddin NA, Ng CC, Cheong SC, Bartold PM, et al. Moving into a new era of periodontal genetic studies: relevance of large case-control samples using severe phenotypes for genome-wide association studies. J Periodontal Res. 2014 Dec;49(6):683–95. Taiete T, Casati MZ, Stolf CS, Corrêa MG, Santamaria MP, Andere NMRB, et al. Validation of reported GLT6D1 (rs1537415), IL10 (rs6667202), and ANRIL (rs1333048) single nucleotide polymorphisms for aggressive periodontitis in a Brazilian population. J Periodontol. 2019 Jan;90(1):44–51. Shimizu S, Momozawa Y, Takahashi A, Nagasawa T, Ashikawa K, Terada Y, et al. A genome-wide association study of periodontitis in a Japanese population. J Dent Res. 2015 Apr;94(4):555–61. Schaefer AS, Richter GM, Nothnagel M, Manke T, Dommisch H, Jacobs G, et al. A genome-wide association study identifies GLT6D1 as a susceptibility locus for periodontitis. Hum Mol Genet. 2010 Feb 1;19(3):553–62. Rodrigues RS, Rêgo R, Caminaga RMS, Goveia JM, Silveira VRS. Analysis of GLT6D1 and CDKN2BAS gene polymorphisms in Brazilian patients with advanced periodontitis. Braz Oral Res. 2022;36:e077. Hashim NT, Linden GJ, Ibrahim ME, Gismalla BG, Lundy FT, Hughes FJ, et al. Replication of the association of GLT6D1 with aggressive periodontitis in a Sudanese population. J Clin Periodontol. 2015 Apr;42(4):319–24. Barrett JH, Teare MD. Linkage analysis. Methods Mol Biol. 2011;760:19–33. Singer JB. Candidate gene association analysis. Methods Mol Biol. 2009;573:223–30. Levy SE, Boone BE. Next-Generation Sequencing Strategies. Cold Spring Harb Perspect Med. 2019 Jul 1;9(7). Magalhães WCS, Rodrigues MR, Silva D, Soares-Souza G, Iannini ML, Cerqueira GC, et al. DIVERGENOME: a bioinformatics platform to assist population genetics and genetic epidemiology studies. Genet Epidemiol. 2012 May;36(4):360–7. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 Mar 29;372:n71. Sohani ZN, Sarma S, Alyass A, De Souza RJ, Robiou-Du-Pont S, Li A, et al. Empirical evaluation of the Q-Genie tool: a protocol for assessment of effectiveness. BMJ Open [Internet]. 2016;6:10403. Available from: http://dx.doi.org/ Sohani ZN, Meyre D, de Souza RJ, Joseph PG, Gandhi M, Dennis BB, et al. Assessing the quality of published genetic association studies in meta-analyses: The quality of genetic studies (Q-Genie) tool. BMC Genet. 2015 May 15;16(1). Sanders AE, Sofer T, Wong Q, Kerr KF, Agler C, Shaffer JR, et al. Chronic Periodontitis Genome-wide Association Study in the Hispanic Community Health Study / Study of Latinos. J Dent Res. 2017 Jan;96(1):64–72. Schaefer AS, Jochens A, Dommisch H, Graetz C, Jockel-Schneider Y, Harks I, et al. A large candidate-gene association study suggests genetic variants at IRF5 and PRDM1 to be associated with aggressive periodontitis. J Clin Periodontol. 2014 Dec;41(12):1122–31. Rhodin K, Divaris K, North KE, Barros SP, Moss K, Beck JD, et al. Chronic periodontitis genome-wide association studies: gene-centric and gene set enrichment analyses. J Dent Res. 2014 Sep;93(9):882–90. Tables Table 1: General characteristics of the included studies. Study Population Design Sample Size Genotyping Method Schaefer et al. ( 9 ) German/Dutch patients with aggressive periodontitis GWAS Cases: 438 Controls: 1,320 Affymetrix GeneChip and TaqMan SNP Assay Hashim et al. ( 11 ) Sudanese individuals with aggressive periodontitis Case-Control Cases: 132 Controls: 136 Sequenom MassARRAY iPLEX platform Rodrigues et al. ( 10 ) Brazilian patients with advanced periodontitis Case-Control Cases: 100 (Stage III/IV) Controls: 61 Real-time quantitative PCR Table 2: Outcome Table of the included studies. Study SNP (Gene) Outcome G Allele Frequency Odds Ratio (OR) Schaefer et al. ( 9 ) rs1537415 (GLT6D1) Significant association with aggressive periodontitis Cases: 48.4% Controls: 38.8% 1.64 (95% CI: 1.30–2.08) Hashim et al. ( 11 ) rs1537415 (GLT6D1) Significant association with aggressive periodontitis Cases: 37.8% Controls: 28.8% 1.56 (95% CI: 1.15–2.16) Rodrigues et al. ( 10 ) rs1537415 (GLT6D1) No significant association Cases: 66.7% (Group B), 62.8% (Group C) Controls: 62.3% Not significant Table 3: Q-Genie tool for risk of bias assessment. Domain Schaefer et al. (9) Hashim et al. (11) Rodrigues et al. (10) Adequacy of Hypothesis and Rationale High High Moderate Classification and Measurement of Outcomes High Moderate Moderate Description and Comparison of Study Groups High Moderate Moderate Disclosure of Potential Sources of Bias High Moderate Moderate Statistical Methods and Power Analysis High Moderate Low Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6953323","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":488678927,"identity":"84e201d6-81f2-4117-b99c-640ca95e6c58","order_by":0,"name":"Theofanis Argyrios Karaoulas","email":"","orcid":"","institution":"Aristotle University of Thessaloniki","correspondingAuthor":false,"prefix":"","firstName":"Theofanis","middleName":"Argyrios","lastName":"Karaoulas","suffix":""},{"id":488678929,"identity":"d982e806-0980-4da6-a347-aef166c108ee","order_by":1,"name":"Christoforos Xirouchakis","email":"","orcid":"","institution":"Aristotle University of Thessaloniki","correspondingAuthor":false,"prefix":"","firstName":"Christoforos","middleName":"","lastName":"Xirouchakis","suffix":""},{"id":488678931,"identity":"ddb995bb-48c9-48a9-b7fb-38c6935b3589","order_by":2,"name":"Chariklia Neophytou","email":"","orcid":"","institution":"Aristotle University of Thessaloniki","correspondingAuthor":false,"prefix":"","firstName":"Chariklia","middleName":"","lastName":"Neophytou","suffix":""},{"id":488678935,"identity":"fa0f280e-e4fc-4646-8fbe-a31e2d7d368b","order_by":3,"name":"Ioannis Fragkioudakis","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYBACNuYDQPKABAM/iJdQQIwWtgSIFskGkBYDoqwBa2FgMADZxkCMFj423ocfv5yxkDM+vzrxwwMDBnl+sQOEHMZuLC1zQ8LY7MbbzRJAhxnOnJ1AQIt8G4O0xAeJxG03zm4AaUkwuE1ICxsb82+Qls0zzm7+QawWNskPNyQSN/D3biPaFjZrhjMSxhI3eLdZJBhIEPaLfBsb880fx+rk+PvPbr75o8JGnl+agBYQYOYBkRJglRKElYMA4w8QyX+AONWjYBSMglEw8gAADb4/u3Pw1jcAAAAASUVORK5CYII=","orcid":"","institution":"Aristotle University of Thessaloniki","correspondingAuthor":true,"prefix":"","firstName":"Ioannis","middleName":"","lastName":"Fragkioudakis","suffix":""}],"badges":[],"createdAt":"2025-06-23 06:23:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6953323/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6953323/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87663711,"identity":"34fc3cb9-2df6-43b4-9b6d-099ce8c5daea","added_by":"auto","created_at":"2025-07-27 10:54:10","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":78727,"visible":true,"origin":"","legend":"\u003cp\u003eThe PRISMA flow chart of the study selection process.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6953323/v1/6b9aa3a79e1ea8ad8aa4164b.jpg"},{"id":87662551,"identity":"cde1e804-234f-4c82-8bca-1282a4d7e4bc","added_by":"auto","created_at":"2025-07-27 10:46:10","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":48592,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot displaying the meta-analysis of the association between the GLT6D1 rs1537415 G allele and periodontitis risk.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6953323/v1/048c95c2261566c4d866c23a.jpg"},{"id":87662552,"identity":"0606320a-41ce-4a1f-abad-078ceed0dfdd","added_by":"auto","created_at":"2025-07-27 10:46:10","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":29673,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plot assessing publication bias.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6953323/v1/09f64e0a5f664ca4e2886284.jpg"},{"id":87665043,"identity":"f455977e-83b4-4ec9-8329-5121c0f7966a","added_by":"auto","created_at":"2025-07-27 11:02:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":956027,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6953323/v1/6f6f50c5-de5a-4491-84b3-12bcdbc3a9e5.pdf"},{"id":87662549,"identity":"8d4120ff-286d-49df-8369-7d2dac260739","added_by":"auto","created_at":"2025-07-27 10:46:10","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14899,"visible":true,"origin":"","legend":"","description":"","filename":"tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6953323/v1/94e2a8e4ddea9f086cb7f664.docx"},{"id":87662554,"identity":"d335fb8e-b57b-416a-a405-92399afb82ab","added_by":"auto","created_at":"2025-07-27 10:46:10","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":19646,"visible":true,"origin":"","legend":"","description":"","filename":"PRISMA2020ChecklistforSystematicReviews.docx","url":"https://assets-eu.researchsquare.com/files/rs-6953323/v1/06f5e5e89cbb291d8d44e119.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Association of GLT6D1 rs1537415 G Allele with Aggressive and Advanced Chronic Periodontitis: A Comprehensive Meta-Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePeriodontitis is a chronic inflammatory disease that progressively destroys the supporting structures of teeth, including the periodontal ligament and alveolar bone. If untreated, periodontitis can lead to tooth loss and has been linked to systemic health complications such as diabetes and cardiovascular disease (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The disease arises from a complex interplay of genetic, microbial, and environmental factors, with genetic predisposition accounting for approximately 50% of individual susceptibility (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAdvancements in genetic research have highlighted the significant role of single-nucleotide polymorphisms (SNPs) in modulating susceptibility to periodontitis. A systematic review of genome-wide association studies (GWAS) on periodontitis (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), analyzing 15 high-quality studies, identified 11 SNPs that met genome-wide significance thresholds (P \u0026lt; 5 × 10⁻⁸) and 41 additional SNPs of suggestive significance (P \u0026lt; 5 × 10⁻⁶). However, only three SNPs—rs4284742 [G], rs11084095 [A], and rs12461706 [T]—from the SIGLEC5 gene region were consistently reported across studies, underscoring the heterogeneity in genetics findings.\u003c/p\u003e\u003cp\u003eSeveral other genome-wide significant SNPs have been linked to the etiology of periodontitis. For instance, rs729876 on chromosome 16p13.12 shows trans-eQTL effects on HOXC10 in monocytes, potentially affecting inflammation and fibrinolysis, whereas rs16870060 on chromosome 8q22.3 has tissue-specific effects related to inflammation and immune modulation (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Despite these findings, the functional implications of many SNPs remain inadequately understood. Among the prominent genetic loci associated with periodontitis is the glycosyltransferase 6 domain containing 1 (GLT6D1) gene. A European meta-GWAS (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) on severe periodontitis (stage III/IV grade C, diagnosed at ≤ 35 years) recognized GLT6D1 as a significant genetic locus, alongside others such as FCER1G and HMCN2, which are linked to oral barrier stability and wound healing. Variants in GLT6D1, particularly the rs1537415 SNP, have been connected with immune dysregulation and extracellular matrix instability, which are critical factors in the pathogenesis of periodontitis (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe rs1537415 SNP in GLT6D1 has been strongly associated with susceptibility to aggressive periodontitis (AgP), a severe form of the disease marked by rapid progression in younger individuals. Mechanistic studies indicate that the G allele of rs1537415 reduces the binding affinity of the GATA-3 transcription factor, impairing immune regulation and promoting inflammation (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). However, findings regarding the allele's effects have been inconsistent across populations; while some European studies suggest it to be protective, other populations have shown conflicting results (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eGenetic research in periodontitis has significantly evolved, shifting from early linkage analysis (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) and candidate gene studies (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) to contemporary approaches such as GWAS and next-generation sequencing (NGS). These technologies enable a thorough exploration of the genome, uncovering thousands of genetic variations, especially SNPs, that may be relevant to periodontitis (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Furthermore, bioinformatics tools and databases like the 1000 Genomes Project and HapMap have greatly improved the interpretation and cataloging of genetic variations across diverse populations, enriching our understanding of the genetic factors contributing to diseases (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eDespite extensive research on AgP, the role of \u003cem\u003eGLT6D1\u003c/em\u003e in other forms of periodontitis, such as chronic periodontitis—a slower-progressing yet more common subtype—remains underexplored. Additionally, population-specific variations and methodological inconsistencies limit the generalizability of existing findings. Therefore, a comprehensive meta-analysis is necessary to clarify the association of the \u003cem\u003eGLT6D1\u003c/em\u003e rs1537415 G allele with periodontitis across diverse populations and to investigate its potential involvement in shared mechanisms underlying periodontitis subtypes.\u003c/p\u003e"},{"header":"Methods","content":"\u003ch2\u003e2.1 Study Design\u003c/h2\u003e\u003cp\u003eThis study was conducted as a systematic review and meta-analysis to assess the association between the GLT6D1 rs1537415 G allele and susceptibility to periodontitis, including both aggressive and advanced chronic forms (Stage III/IV, Grade B or C). The methodology adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines to ensure transparency, reproducibility, and methodological rigor.\u003c/p\u003e\u003cp\u003eA predefined protocol was followed for all phases of the review, including literature search, study selection, data extraction, risk of bias assessment, and statistical synthesis. This protocol was not prospectively registered; however, all methodological decisions were made a priori and are reported in full.\u003c/p\u003e\u003ch2\u003e2.2 Eligibility Criteria\u003c/h2\u003e\u003cp\u003e\u003cb\u003eInclusion Criteria\u003c/b\u003e\u003c/p\u003e\u003cp\u003eStudies were eligible for inclusion if they met all of the following criteria:\u003c/p\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eStudy Design: Human genetic association studies with case-control, cohort, cross-sectional, or GWAS design.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eParticipants: Individuals diagnosed with aggressive periodontitis (AgP) or advanced chronic periodontitis(Stage III/IV, Grade B or C), based on validated diagnostic criteria such as those from the AAP/EFP.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eExposure: Analysis of the GLT6D1 rs1537415 polymorphism, reporting genotype or allele frequencies, particularly of the G allele.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eComparator: Inclusion of a control group composed of healthy individuals or periodontally unaffected participants.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eOutcomes: Quantitative data sufficient to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between the G allele and periodontitis.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003cp\u003e\u003cb\u003eExclusion Criteria\u003c/b\u003e\u003c/p\u003e\u003cp\u003eStudies were excluded if they:\u003c/p\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eLacked genotype frequency data for rs1537415.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eDid not include a control group.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eWere reviews, editorials, case reports, or other non-original research articles.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eFocused on in vitro or animal models.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eUsed combined disease phenotypes without stratified analysis for periodontitis subtypes.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003ch2\u003e2.3 Information Sources\u003c/h2\u003e\u003cp\u003eA comprehensive electronic search was conducted in the following databases:\u003c/p\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003ePubMed/MEDLINE\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eWeb of Science\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eScopus\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003cp\u003eThe final search was completed on December 15, 2024. To ensure completeness, the reference lists of all included full-text articles and relevant systematic reviews were also manually screened for additional eligible studies.\u003c/p\u003e\u003ch2\u003e2.4 Search Strategy\u003c/h2\u003e\u003cp\u003eDatabase-specific search strategies were developed using a combination of Medical Subject Headings (MeSH) and free-text keywords, customized for each platform. Boolean operators (\"AND\", \"OR\") were used to maximize search sensitivity.\u003c/p\u003e\u003cp\u003eCore Search Terms Included:\u003c/p\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003e\"GLT6D1\" OR \"glycosyltransferase 6 domain containing 1\"\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\"rs1537415\" OR \"G allele\"\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\"periodontitis\" OR \"aggressive periodontitis\" OR \"chronic periodontitis\" OR \"stage III\" OR \"stage IV\" OR \"grade C\"\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003cp\u003eExample Search String (PubMed):\u003c/p\u003e\u003cp\u003e(\"GLT6D1\"[All Fields] OR \"rs1537415\"[All Fields] OR \"G allele\"[All Fields]) AND (\"periodontitis\"[MeSH Terms] OR \"aggressive periodontitis\"[All Fields] OR \"chronic periodontitis\"[All Fields])\u003c/p\u003e\u003cp\u003eThe full search strategy for each database is presented in Supplementary Appendix 1.\u003c/p\u003e\u003ch2\u003e2.5 Data Extraction\u003c/h2\u003e\u003cp\u003eTwo reviewers independently extracted data using a standardized form. The following information was retrieved from each included study:\u003c/p\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eFirst author and publication year\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eStudy design and country of origin\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eSample size (cases and controls)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eDiagnostic criteria used for periodontitis\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eGenotype and allele frequencies for rs1537415\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eStatistical results: ORs, 95% CIs, and p-values\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eGenotyping method used (e.g., GWAS, real-time PCR, MassARRAY)\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003cp\u003eDisagreements were resolved by discussion or consultation with a third reviewer.\u003c/p\u003e\u003ch2\u003e2.6 Quality Assessment\u003c/h2\u003e\u003cp\u003eThe methodological quality of the included studies was assessed using the Q-Genie tool, which is specifically designed for genetic association studies. This tool evaluates the following domains:\u003c/p\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eAdequacy of the hypothesis and rationale\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eDefinition and classification of outcomes\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eDescription and comparability of study groups\u003c/p\u003e\u003c/li\u003e\u003cll\u003e\u003cp\u003eDisclosure of potential sources of bias\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAppropriateness of statistical methods and power analysis\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003cp\u003eEach domain was rated as low, moderate, or high quality. Two reviewers independently performed the quality assessments, and discrepancies were resolved by consensus.\u003c/p\u003e\u003ch2\u003e2.7 Statistical Analysis\u003c/h2\u003e\u003cp\u003eMeta-analyses were conducted using Review Manager (RevMan 5.4) software. The Mantel-Haenszel method with a random-effects model was applied to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs) for the association between the rs1537415 G allele and periodontitis.\u003c/p\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eHeterogeneity across studies was assessed using the Chi² test and the I² statistic, with I² \u0026gt;50% indicating substantial heterogeneity.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003ePublication bias was evaluated using Egger’s regression test, conducted in R (meta package).\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eSensitivity analyses were performed by sequentially removing each study to evaluate the robustness of the results.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003eStudy Selection\u003c/em\u003e\u003c/p\u003e\u003cp\u003eA total of 278 articles were identified through database searches. After removing 85 duplicates, 193 articles remained for title and abstract screening. Of these, 162 articles were excluded as they did not meet the inclusion criteria, leaving 31 full-text articles for assessment. Following a detailed review, 28 articles were excluded due to irrelevance to the study criteria or insufficient data. Ultimately, three studies were included in the final analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e):\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eSchaefer et al. (2010): Investigated a European population with AgP (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eHashim et al. (2015): Focused on a Middle Eastern population with AgP (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eRodrigues et al. (2022): Examined a Brazilian population with advanced periodontitis (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eStudy Characteristics\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThe studies represent diverse populations, genotyping methodologies, and disease subtypes, offering a comprehensive perspective on this genetic association.\u003c/p\u003e\u003cp\u003eIn the study by Schaefer et al. (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), German and Dutch populations with AgP were investigated. This GWAS included 438 cases with generalized and localized AgP and 1,320 healthy controls. Cases were diagnosed based on severe clinical and radiographic criteria, characterized by attachment and bone loss typical of AgP. Controls were free of clinical attachment loss and served as a comparison group. High throughput genotyping of rs1537415 was conducted as part of the GWAS, using the Affymetrix GeneChip and TaqMan SNP assays. The study examined the enrichment of the G allele in cases compared to controls, focusing on its statistical significance and ORs.\u003c/p\u003e\u003cp\u003eHashim et al. (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) study investigated a Sudanese population with AgP. A total of 132 cases and 136 healthy controls were included, and all non-smokers were matched for age and gender. Cases exhibited severe clinical attachment loss and alveolar bone destruction, while controls had no attachment loss or probing depths\u0026thinsp;\u0026gt;\u0026thinsp;3 mm. DNA was extracted from blood samples, and genotyping of rs1537415 was performed using the Sequenom MassARRAY iPLEX platform. The analysis compared allele and genotype frequencies between cases and controls to evaluate the association of the G allele with AgP.\u003c/p\u003e\u003cp\u003eThe study by Rodrigues et al. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) focused on a Brazilian population with advanced periodontitis. 100 cases were included, all classified as Stage III/IV based on the 2018 periodontal classification, with further stratification into Grade B (52 cases) and Grade C (48 cases). The control group comprised 61 healthy individuals with no clinical attachment loss or probing depths\u0026thinsp;\u0026ge;\u0026thinsp;3 mm. The controls were matched for age and gender to the cases. DNA was extracted from buccal epithelial cells, and genotyping of the rs1537415 polymorphism in the GLT6D1 gene was performed using real-time quantitative PCR. Cases and controls were compared based on allele and genotype frequencies to assess the association of the G allele with advanced periodontitis.\u003c/p\u003e\u003cp\u003eThese studies collectively covered distinct populations\u0026mdash;Brazilian, German/Dutch, and Sudanese\u0026mdash;representing both advanced CP and AgP. They utilized diverse genotyping platforms, including real-time PCR, GWAS, and MassARRAY, and employed rigorous diagnostic criteria for case and control definitions. Together, these methodologies and population characteristics provided a robust foundation for analyzing the association of the rs1537415 polymorphism with periodontitis (Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cem\u003eRisk Of Bias Assessment\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThe Q-Genie assessment (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) highlights the variability in the quality of the included studies. Schaefer et al. (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) achieved high scores across all domains, demonstrating robust methodology, adequate sample size, and substantial population stratification control, making it the most reliable study. Hashim et al. (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) showed moderate quality, with strengths in hypothesis framing but constrained by small sample size and inadequate control for population diversity. Rodrigues et al. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) exhibited moderate-to-low quality, facing limitations in statistical power and stratification adjustment due to its small sample size. These findings underscore the necessity for extensive, standardized studies to enhance reliability and generalizability.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMeta-Analysis Results\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe meta-analysis included data from three studies comprising a total of 1,969 individuals, with 452 periodontitis cases(aggressive or advanced chronic) and 1,517 healthy controls. The pooled analysis assessed the association of the GLT6D1 rs1537415 G allele with susceptibility to periodontitis.\u003c/p\u003e\u003cp\u003eThe overall odds ratio (OR) was 1.58 [95% CI: 1.28\u0026ndash;1.95], indicating that individuals carrying the G allele have significantly higher odds of developing periodontitis than non-carriers (Z\u0026thinsp;=\u0026thinsp;4.27, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). A random-effects model was applied, and no significant heterogeneity was observed across studies.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eStudy-Specific Results\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eSchaefer et al. (2009) [9]: Reported a significant association between the G allele and periodontitis (OR\u0026thinsp;=\u0026thinsp;1.64, 95% CI: 1.30\u0026ndash;2.08), contributing the most weight (78.7%) due to its large sample size and GWAS design.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eHashim et al. (2015) [11]: Found a non-significant but suggestive association (OR\u0026thinsp;=\u0026thinsp;1.52, 95% CI: 0.91\u0026ndash;2.53), with a moderate contribution (16.8% weight); the wide confidence interval likely reflects limited sample size.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eRodrigues et al. (2022) [10]: Did not observe a significant association (OR\u0026thinsp;=\u0026thinsp;0.93, 95% CI: 0.34\u0026ndash;2.51), possibly due to low statistical power and smaller cohort size.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eHeterogeneity Analysis\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eThe pooled data demonstrated no significant heterogeneity, with:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eI\u0026sup2; = 0%\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eChi\u0026sup2; = 1.22, df\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.54\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eTau\u0026sup2; = 0.00 (calculated using the restricted maximum-likelihood method)\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eFunnel Plot and Publication Bias\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThe funnel plot visually assessed potential publication bias. It displayed a symmetrical distribution of studies around the pooled odds ratio (OR), indicating a low likelihood of publication bias. To confirm this observation, Egger's regression test was conducted, yielding a p-value of 0.233, further supporting the absence of significant small-study effects (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis meta-analysis highlights the association of the GLT6D1 rs1537415 G allele with susceptibility to periodontitis, particularly aggressive forms. The pooled analysis of three studies\u0026mdash;including populations from Europe, Africa, and South America\u0026mdash;demonstrated a significant overall association between the G allele and increased risk of periodontitis (OR\u0026thinsp;=\u0026thinsp;1.58, 95% CI: 1.28\u0026ndash;1.95, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), suggesting a meaningful genetic contribution to disease susceptibility.\u003c/p\u003e\u003cp\u003eThe role of rs1537415 has been explored in multiple populations. In European cohorts, Schaefer et al. (2009) [9] first identified the G allele as significantly associated with aggressive periodontitis, reporting an OR of 1.64 (95% CI: 1.30\u0026ndash;2.08). This finding was later replicated in a Sudanese population by Hashim et al. (2015) [11], who reported an OR of 1.52 (95% CI: 0.91\u0026ndash;2.53). Although the latter did not reach statistical significance, likely due to sample size limitations, the consistency of the effect size supports a shared genetic mechanism across these ethnic groups. In contrast, Rodrigues et al. (2022) [10], studying a Brazilian cohort with advanced chronic periodontitis, found no significant association (OR\u0026thinsp;=\u0026thinsp;0.93, 95% CI: 0.34\u0026ndash;2.51), suggesting population-specific variability or reduced allele penetrance in chronic forms of the disease.\u003c/p\u003e\u003cp\u003eThe lack of association in the Brazilian study may stem from differences in genetic background, environmental exposures, or diagnostic criteria. While Schaefer and Hashim focused on aggressive periodontitis using stringent clinical criteria, Rodrigues applied the 2018 AAP/EFP classification for advanced chronic periodontitis (Stage III/IV, Grades B/C), which may capture a more heterogeneous phenotype. It is plausible that the rs1537415 G allele exerts a stronger effect in early-onset, rapidly progressing forms of periodontitis (i.e., AgP), whereas chronic forms\u0026mdash;with slower progression and greater influence from age, biofilm exposure, and comorbidities\u0026mdash;may dilute the genetic effect.\u003c/p\u003e\u003cp\u003eBiologically, the GLT6D1 gene encodes a glycosyltransferase involved in immune regulation and extracellular matrix stability. The G allele of rs1537415 is known to reduce the binding affinity of the GATA-3 transcription factor, leading to impaired T-cell differentiation and altered cytokine production [16, 21]. These effects likely promote the chronic inflammatory responses and connective tissue destruction that characterize periodontitis. Thus, the molecular evidence aligns with the observed epidemiologic associations.\u003c/p\u003e\u003cp\u003eThese findings support the potential utility of rs1537415 as a genetic risk marker in periodontology. Genetic screening could be incorporated into personalized risk assessment tools, identifying individuals who may benefit from earlier or more intensive preventive interventions. Moreover, understanding the immunogenetic pathways modulated by GLT6D1 may open novel therapeutic avenues targeting T-cell function or glycosylation mechanisms in periodontal disease.\u003c/p\u003e\u003cp\u003eLimitations\u003c/p\u003e\u003cp\u003eThis meta-analysis is subject to several limitations:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eOnly three eligible studies met the inclusion criteria, limiting statistical power and precluding subgroup or meta-regression analyses.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eThere was heterogeneity in diagnostic criteria used to define periodontitis subtypes, particularly between studies on AgP and those using the 2018 classification.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eThe sample sizes were modest, especially in the non-European cohorts, which restricts the generalizability of findings across global populations.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003ePublication bias cannot be fully ruled out, despite visual symmetry of the funnel plot and a non-significant Egger\u0026rsquo;s test.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eFuture Research Directions\u003c/p\u003e\u003cp\u003eTo build on these findings, future studies should prioritize the following:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eExpand multi-ethnic cohorts to validate the association of rs1537415 across diverse populations.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eStandardize phenotypic definitions and genotyping protocols to reduce inter-study variability.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eInvestigate gene-environment interactions, including smoking, systemic inflammation, and oral hygiene, to understand context-dependent effects of the G allele.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eConduct functional studies to elucidate how GLT6D1 polymorphisms affect immune and connective tissue responses in the periodontium.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis meta-analysis demonstrates a significant association between the GLT6D1 rs1537415 G allele and increased susceptibility to periodontitis, particularly aggressive forms. The pooled data suggest that this polymorphism may serve as a genetic risk marker, supporting the role of host genetics in periodontal disease pathogenesis. Further large-scale, multi-ethnic studies are needed to confirm these findings and explore their clinical utility in personalized periodontal care.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eImplications for Clinical Practice\u003c/strong\u003e\u003cp\u003eThe findings of this meta-analysis suggest that genetic screening for the GLT6D1 rs1537415 G allele may be beneficial in identifying individuals at increased risk for severe periodontitis, particularly AgP and advanced chronic periodontitis (Stage III/IV, Grade B or C). Early identification of genetically susceptible individuals can facilitate tailored preventive strategies, such as enhanced periodontal monitoring and early intervention protocols. Additionally, this research underscores the potential for precision medicine approaches in periodontology, where genetic profiling could inform individualized treatment planning and risk assessment.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eImplications for Research\u003c/strong\u003e\u003cp\u003eFuture studies should focus on expanding multi-ethnic cohorts to validate the association of the GLT6D1 rs1537415 G allele with periodontitis across diverse populations. Standardizing diagnostic criteria and genotyping methodologies will be critical to reducing inter-study variability. Additionally, further research should investigate the gene-environment interactions that may modulate this allele\u0026rsquo;s effects, including factors such as smoking, systemic diseases, and oral microbiome composition. Functional studies exploring the biological mechanisms underlying GLT6D1-mediated immune dysregulation and inflammation could also provide valuable insights for developing targeted therapeutic interventions.\u003c/p\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe contributions of all authors are outlined below using the CRediT (Contributor Roles Taxonomy) system:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eChristoforos Xirouchakis:\u003c/strong\u003e Conceptualization, Data Curation, Writing – Original Draft\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eTheofanis Argyrios Karaoulas:\u003c/strong\u003e Methodology, Formal Analysis, Writing – Review \u0026amp; Editing\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eChariklia Neophytou:\u003c/strong\u003e Investigation, Visualization, Writing – Review \u0026amp; Editing\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eIoannis Fragkioudakis:\u003c/strong\u003e Supervision, Project Administration, Validation\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eAll authors have read and approved the final version of the manuscript and agree to be accountable for all aspects of the work, ensuring accuracy and integrity throughout the research and publication process.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with Ethical Standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;This research received no external funding and was entirely self-financed by the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Not applicable. This meta-analysis is based on previously published data and does not involve any new studies with human participants or animals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Not applicable.\u003c/p\u003e\n\u003cp\u003eClinical trial number: not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors report there are no competing interests to declare.\u2028This study received no external funding and was entirely self-financed by the authors.\u2028The manuscript has not been registered in PROSPERO. The authors recognize the importance of protocol registration and commit to prospective registration for future systematic reviews to enhance methodological transparency.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data supporting the findings of this study are included within the manuscript and its supplementary materials. No additional datasets were generated or analyzed during the current study. Further information can be made available by the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKinane DF, Stathopoulou PG, Papapanou PN. Periodontal diseases. Nat Rev Dis Primers. 2017 Jun 22;3:17038. \u003c/li\u003e\n\u003cli\u003eMichalowicz BS, Diehl SR, Gunsolley JC, Sparks BS, Brooks CN, Koertge TE, et al. Evidence of a substantial genetic basis for risk of adult periodontitis. J Periodontol. 2000 Nov;71(11):1699\u0026ndash;707. \u003c/li\u003e\n\u003cli\u003eGao C, Iles M, Larvin H, Bishop DT, Bunce D, Ide M, et al. Genome-wide association studies on periodontitis: A systematic review. PLoS One. 2024 Sep 1;19(9). \u003c/li\u003e\n\u003cli\u003eMunz M, Richter GM, Loos BG, Jepsen S, Divaris K, Offenbacher S, et al. Meta-analysis of genome-wide association studies of aggressive and chronic periodontitis identifies two novel risk loci. European Journal of Human Genetics. 2019 Jan 1;27(1):102\u0026ndash;13. \u003c/li\u003e\n\u003cli\u003eDe Almeida SD, Richter GM, de Coo A, Jepsen S, Kapferer-Seebacher I, Dommisch H, et al. A genome-wide association study meta-analysis in a European sample of stage III/IV grade C periodontitis patients \u0026le;35 years of age identifies new risk loci. J Clin Periodontol. 2024 Apr 1;51(4):431\u0026ndash;40. \u003c/li\u003e\n\u003cli\u003eVaithilingam RD, Safii SH, Baharuddin NA, Ng CC, Cheong SC, Bartold PM, et al. Moving into a new era of periodontal genetic studies: relevance of large case-control samples using severe phenotypes for genome-wide association studies. J Periodontal Res. 2014 Dec;49(6):683\u0026ndash;95. \u003c/li\u003e\n\u003cli\u003eTaiete T, Casati MZ, Stolf CS, Corr\u0026ecirc;a MG, Santamaria MP, Andere NMRB, et al. Validation of reported GLT6D1 (rs1537415), IL10 (rs6667202), and ANRIL (rs1333048) single nucleotide polymorphisms for aggressive periodontitis in a Brazilian population. J Periodontol. 2019 Jan;90(1):44\u0026ndash;51. \u003c/li\u003e\n\u003cli\u003eShimizu S, Momozawa Y, Takahashi A, Nagasawa T, Ashikawa K, Terada Y, et al. A genome-wide association study of periodontitis in a Japanese population. J Dent Res. 2015 Apr;94(4):555\u0026ndash;61. \u003c/li\u003e\n\u003cli\u003eSchaefer AS, Richter GM, Nothnagel M, Manke T, Dommisch H, Jacobs G, et al. A genome-wide association study identifies GLT6D1 as a susceptibility locus for periodontitis. Hum Mol Genet. 2010 Feb 1;19(3):553\u0026ndash;62. \u003c/li\u003e\n\u003cli\u003eRodrigues RS, R\u0026ecirc;go R, Caminaga RMS, Goveia JM, Silveira VRS. Analysis of GLT6D1 and CDKN2BAS gene polymorphisms in Brazilian patients with advanced periodontitis. Braz Oral Res. 2022;36:e077. \u003c/li\u003e\n\u003cli\u003eHashim NT, Linden GJ, Ibrahim ME, Gismalla BG, Lundy FT, Hughes FJ, et al. Replication of the association of GLT6D1 with aggressive periodontitis in a Sudanese population. J Clin Periodontol. 2015 Apr;42(4):319\u0026ndash;24. \u003c/li\u003e\n\u003cli\u003eBarrett JH, Teare MD. Linkage analysis. Methods Mol Biol. 2011;760:19\u0026ndash;33. \u003c/li\u003e\n\u003cli\u003eSinger JB. Candidate gene association analysis. Methods Mol Biol. 2009;573:223\u0026ndash;30. \u003c/li\u003e\n\u003cli\u003eLevy SE, Boone BE. Next-Generation Sequencing Strategies. Cold Spring Harb Perspect Med. 2019 Jul 1;9(7). \u003c/li\u003e\n\u003cli\u003eMagalh\u0026atilde;es WCS, Rodrigues MR, Silva D, Soares-Souza G, Iannini ML, Cerqueira GC, et al. DIVERGENOME: a bioinformatics platform to assist population genetics and genetic epidemiology studies. Genet Epidemiol. 2012 May;36(4):360\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 Mar 29;372:n71. \u003c/li\u003e\n\u003cli\u003eSohani ZN, Sarma S, Alyass A, De Souza RJ, Robiou-Du-Pont S, Li A, et al. Empirical evaluation of the Q-Genie tool: a protocol for assessment of effectiveness. BMJ Open [Internet]. 2016;6:10403. Available from: http://dx.doi.org/\u003c/li\u003e\n\u003cli\u003eSohani ZN, Meyre D, de Souza RJ, Joseph PG, Gandhi M, Dennis BB, et al. Assessing the quality of published genetic association studies in meta-analyses: The quality of genetic studies (Q-Genie) tool. BMC Genet. 2015 May 15;16(1). \u003c/li\u003e\n\u003cli\u003eSanders AE, Sofer T, Wong Q, Kerr KF, Agler C, Shaffer JR, et al. Chronic Periodontitis Genome-wide Association Study in the Hispanic Community Health Study / Study of Latinos. J Dent Res. 2017 Jan;96(1):64\u0026ndash;72. \u003c/li\u003e\n\u003cli\u003eSchaefer AS, Jochens A, Dommisch H, Graetz C, Jockel-Schneider Y, Harks I, et al. A large candidate-gene association study suggests genetic variants at IRF5 and PRDM1 to be associated with aggressive periodontitis. J Clin Periodontol. 2014 Dec;41(12):1122\u0026ndash;31. \u003c/li\u003e\n\u003cli\u003eRhodin K, Divaris K, North KE, Barros SP, Moss K, Beck JD, et al. Chronic periodontitis genome-wide association studies: gene-centric and gene set enrichment analyses. J Dent Res. 2014 Sep;93(9):882\u0026ndash;90. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1: General characteristics of the included studies.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePopulation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDesign\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample Size\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGenotyping Method\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSchaefer et al. (\u003c/strong\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGerman/Dutch patients with aggressive periodontitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGWAS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCases: 438\u003cbr\u003e\u0026nbsp;Controls: 1,320\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAffymetrix GeneChip and TaqMan SNP Assay\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHashim et al. (\u003c/strong\u003e\u003cstrong\u003e11\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSudanese individuals with aggressive periodontitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCase-Control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCases: 132\u003cbr\u003e\u0026nbsp;Controls: 136\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSequenom MassARRAY iPLEX platform\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRodrigues et al. (\u003c/strong\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBrazilian patients with advanced periodontitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCase-Control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCases: 100 (Stage III/IV)\u003cbr\u003e\u0026nbsp;Controls: 61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eReal-time quantitative PCR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 2: \u003cstrong\u003eOutcome Table of the included studies.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSNP (Gene)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eG Allele Frequency\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOdds Ratio (OR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSchaefer et al. (\u003c/strong\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ers1537415 (GLT6D1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSignificant association with aggressive periodontitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCases: 48.4%\u003cbr\u003e\u0026nbsp;Controls: 38.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.64 \u0026nbsp;(95% CI: 1.30\u0026ndash;2.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHashim et al. (\u003c/strong\u003e\u003cstrong\u003e11\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ers1537415 (GLT6D1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSignificant association with aggressive periodontitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCases: 37.8%\u003cbr\u003e\u0026nbsp;Controls: 28.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.56 (95% CI: 1.15\u0026ndash;2.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRodrigues et al. (\u003c/strong\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ers1537415 (GLT6D1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo significant association\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCases: 66.7% (Group B), 62.8% (Group C)\u003cbr\u003e\u0026nbsp;Controls: 62.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNot significant\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 3: Q-Genie tool for risk of bias assessment.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"596\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDomain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSchaefer et al.\u0026nbsp;(9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHashim et al. (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRodrigues et al. (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAdequacy of Hypothesis and Rationale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eClassification and Measurement of Outcomes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDescription and Comparison of Study Groups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDisclosure of Potential Sources of Bias\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eStatistical Methods and Power Analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"GLT6D1, rs1537415, aggressive periodontitis, chronic periodontitis, genetic susceptibility, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-6953323/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6953323/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eObjective:\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo evaluate the association of the GLT6D1 rs1537415 G allele with susceptibility to aggressive periodontitis (AgP) and advanced chronic periodontitis (Stage III/IV, Grade B or C) by synthesizing evidence from human genetic association studies.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMaterials and Methods:\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFollowing PRISMA guidelines, a systematic search was conducted in PubMed, Web of Science, and Scopus through December 2024. Eligible studies analyzed the rs1537415 polymorphism in patients with AgP or advanced chronic periodontitis versus healthy controls. Three studies (n\u0026thinsp;=\u0026thinsp;1,969) were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects models. Heterogeneity and publication bias were evaluated using Chi\u0026sup2;, I\u0026sup2;, funnel plots, and Egger\u0026rsquo;s test.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults:\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe meta-analysis demonstrated a significant association between the G allele and periodontitis (OR\u0026thinsp;=\u0026thinsp;1.58; 95% CI: 1.28\u0026ndash;1.95; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Subgroup analysis confirmed consistent effects in European and Sudanese populations, while no significant association was detected in the Brazilian cohort. Functional evidence indicates the G allele impairs GATA-3 transcription factor binding, contributing to immune dysregulation.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions:\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe GLT6D1 rs1537415 G allele is significantly associated with increased risk of severe periodontitis. It may serve as a useful genetic marker in precision periodontology. Further research in diverse populations is needed to confirm gene-environment interactions and strengthen clinical applicability.\u003c/p\u003e","manuscriptTitle":"The Association of GLT6D1 rs1537415 G Allele with Aggressive and Advanced Chronic Periodontitis: A Comprehensive Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-27 10:46:05","doi":"10.21203/rs.3.rs-6953323/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-08T05:39:26+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-29T23:47:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-21T15:22:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"99746318508379291840576125869636302845","date":"2025-07-21T13:29:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"214863737275394787048857282860022960096","date":"2025-07-18T23:49:44+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-18T17:21:33+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-07-11T11:44:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-09T02:01:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-09T01:59:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Oral Health","date":"2025-06-23T06:18:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cf651f09-4136-4b83-989a-0a56758eaea0","owner":[],"postedDate":"July 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-10-30T06:23:30+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-27 10:46:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6953323","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6953323","identity":"rs-6953323","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}