Peripheral blood epigenetic dysregulation in the onset and progression of knee osteoarthritis

/ Abstract The objective of the proposed research is to better understand peripheral blood epigenetic patterns and peripheral blood inflammatory cell composition are related to the onset and progression of knee osteoarthritis (OA). OA is a leading cause of disability among Veterans and occurs at roughly 5x the rate of civilians. We have previously published data that peripheral blood epigenetic models can predict future rapid progression (both radiographic and pain) several years in advance, and we have generated novel preliminary data that a similar approach can be used to identify healthy individuals who will go on to develop radiographic OA within the subsequent 8 years. However, we have not yet applied these models to a large population methylation dataset to test their predictive capability at the native OA prevalence level, nor have we tested more clinically-relevant progression outcomes (e.g. the need for knee joint replacement). In this project, our first Aim is to leverage the large Million Veterans Program (MVP) DNA methylation dataset to confirm and optimize our peripheral blood DNA methylation models to predict future OA onset (within 8 years) and/or future OA rapid progression (requiring a joint replacement in the next 8 years). We also Aim to translate these optimized models into a clinically- applicable blood test through the use of next-generation DNA methylation sequencing (Bisulfite Short Amplicon Sequencing, BSAS) of the specific methylation sites in the genome most predictive of OA onset and/or progression. In our second Aim, we will develop novel analytical tools to predict the cell-type composition of peripheral blood samples using DNA methylation data by performing genome-wide DNA methylation arrays and high-resolution mass cytometry (CyTOF) in paired samples from our local OA cohort, as well as healthy controls. These models will then be applied to both the MVP methylation dataset and our previously-generated DNA methylation datasets of OA patients and controls. This will allow us to determine, at a large scale, whether differences in cell composition of peripheral blood are present among OA patient subgroup(s) differentiating them from controls, as well as allow us to correct our models from Aim 1 for any cell type discrepancies. The proposed work is important, as we do not have any widely-available predictive biomarkers for OA clinical trial enrichment, nor are there any large-scale data about peripheral blood cellular composition in OA patients. Our work is quite innovative in its focus large-scale OA DNA methylation datasets, machine learning, and cellular composition analysis. Success in our proposal may open new avenues for OA inflammation research and clinical trials. Project Number: 1I01BX007116-01 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Matlock Jeffries | Institution: OKLAHOMA CITY VA MEDICAL CENTER, OKLAHOMA CITY, OK | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 IMMA-G (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11183489