Epigenome-wide association study using peripheral blood leukocytes identifies genomic regions associated with periodontal disease and edentulism in the Atherosclerosis Risk in Communities Study

Abstract

ABSTRACTAimOur goal was to investigate individual susceptibility to periodontitis by conducting an epigenome-wide association study using peripheral blood.Materials and MethodsFor this analysis, we included 1077 African American and 457 European American participants of the Atherosclerosis Risk in Communities (ARIC) study who had completed a dental examination or reported being edentulous at visit 4 and had available data on DNA methylation. DNA methylation levels were compared by periodontal disease severity and edentulism to identify differentially methylated regions (DMRs) and evaluate the CpGs belonging to those DMRs using multinominal logistic regression.ResultsWe identified a region in geneZFP57(6p22.1) that was significantly hypomethylated in severe periodontal disease compared to no/mild periodontal disease in European American participants. A separate region in an unknown gene (located in Chr10: 743,992-744,958) demonstrated significant positive association with edentulism compared to no/mild periodontal disease in African American participants. Four CpGs in a region located withinHOXA4were significantly hypermethylated in severe periodontal disease compared to no/mild periodontal disease in African American participants.ConclusionsOur study highlights epigenetic variations inZPF57andHOXA4that were significantly and reproducibly associated with periodontitis. Future studies should evaluate gene regulatory mechanisms in the candidate regions of these loci.CLINICAL RELEVANCEScientific Rationale for StudyWithout altering the DNA sequence, epigenetic effects (e.g., DNA methylation changes) can alter gene activity and influence host response to periodontal infections. Our well-powered study investigates individual susceptibility to periodontitis by conducting a thorough assessment of periodontitis-related DNA methylation levels in blood.Principal FindingsWe identified two gene regions,ZPF57andHOXA4, that are differentially methylated in individuals with compared to those without periodontitis.Practical implicationsStudying differential leukocyte DNA methylation patterns may point to candidate regions and underlying gene regulatory mechanisms that play a key role in the progression and/or susceptibility to periodontitis.