Aim Our goal was to investigate individual susceptibility to periodontitis by conducting an epigenome-wide association study using peripheral blood. Materials and Methods For 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. Results We identified a region in gene ZFP57 (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 within HOXA4 were significantly hypermethylated in severe periodontal disease compared to no/mild periodontal disease in African American participants. Conclusions Our study highlights epigenetic variations in ZPF57 and HOXA4 that were significantly and reproducibly associated with periodontitis. Future studies should evaluate gene regulatory mechanisms in the candidate regions of these loci. Keywords: Periodontitis, periodontal disease, DNA methylation, Illumina Infinium HumanMethylation450K, epigenome-wide association study (EWAS), peripheral blood.

The authors have declared no competing interest.

The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I,). The Dental ARIC Study was supported by the National Institute of Dental and Craniofacial Research (R01 DE11551). Additional support to complete the analysis was provided by the 2018 American Association for Cancer Research (AACR)-Johnson & Johnson Lung Cancer Innovation Science Award (MPIs: Michaud, Platz, and Kelsey). The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also supported by the Maryland Cigarette Restitution Fund at Johns Hopkins.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study reports analyses conducted solely using de-identified data from the ARIC study. The ARIC study protocol was approved by the Institutional Review Boards at each study site. The ARIC participants gave written informed consent.

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The datasets used in the current study are available from the ARIC study.