Investigation of pathogenic genes in peri-implantitis from implant clustering failure patients : a whole-exome sequencing study

Abstract

Purpose: Peri-implantitis is a frequently occurring gum disease linked to multi-factorial traits with various environmental and genetic causalities and no known concrete pathogenesis. The varying severity of peri-implantitis among patients with relatively similar lifestyle and environmental traits suggests a genetic aspect which needs to be investigated to understand and regulate the pathogenesis of the disease. The purpose of this study is to find associated pathogenic genes of peri-implantitis from implant clusterization failure patients via WES, GSEA, and network analysis Materials & Methods: Six unrelated individuals with multiple implant clustering failure due to severe peri-implantitis were chosen for this study. These six individuals had relatively healthy lifestyle with no environmental causalities affecting peri-implantitis. ୎ With limitations in mind, genetic study approach was taken to investigate pathogenic genes in peri-implantitis. Whole-exome sequencing (Agilent SureSelect Human All Exon 50 Mb kits) was performed on collected saliva samples via OG-500 (DNAgenoTeK). Common variants with minor allele frequencies (MAF) >= 0.05 from all control datasets were eliminated and the variants having high and moderate impact and loss of function were used for comparison. Gene set enrichment analysis was performed to reveal the functional groups associated with genetic variants. Network analysis was applied to find relationships between functional clusters. Results: 2,022 genes were left after filtering against dbSNP, the 1000 Genomes East Asian population, and healthy Korean randomized subsample data (GSK project). 175 (p-value < 0.05) out of 927 gene sets were obtained via GSEA (DAVID). The top 10 was chosen (p-value < 0.05) from cluster enrichment showing significance of cytoskeleton, cell adhesion, and metal ion binding. Among the functional groups, metal ion binding was located in the center of all clusters, indicating dysfunction of regulation in metal ion concentration might affect cell morphology or cell adhesion, resulting in implant failure. Conclusion: Our results suggest that various genes and gene sets related to factors involved in cell adhesion such as cadherin, fibronectin, EGF domains, and cytoskeletons play critical roles in the osseointegration and pathogenesis of peri-implantitis. Interestingly, these two gene sets are indirectly linked via the metal ion binding protein. One may conclude that dysfunction in cell morphology and cell adhesion by regulatory ୏ imbalance in metal ion concentration and dysregulation of integrins which can have impact on surface adhesion would affect the occurrence of peri-implantitis.