Borderline acceleration in blood epigenetic age of unclear biological importance in knee OA progression: Specimens and data from the Osteoarthritis Initiative and Johnston County Osteoarthritis Project.

Objective: Aging is among the strongest risk factors for osteoarthritis (OA). Although epigenetics plays a role in OA, previous studies have not found accelerated peripheral blood epigenetic aging among OA patients overall. The goal of this study was to evaluate peripheral blood epigenetic aging rates among various types of OA progressors and non-progressors (NPs).

Methods: Genome-wide baseline buffy coat DNA methylation data from the Osteoarthritis Initiative (n = 554) and Johnston County Osteoarthritis Project (n = 128) were generated using Illumina MethylationEPICv1 arrays on baseline samples of OA progressors (participants who exhibited radiographic and/or pain progression in 2-5 years) vs. NPs. Epigenetic age was calculated using Horvath, GrimAge, PhenoAge, Horvath-intrinsic epigenetic age acceleration, Hannum, Horvath-SkinBlood, and DunedinPACE calculators and epigenetic age acceleration (EAA) was compared among progressor groups. Age-associated proteins were imputed using GrimAge and generalized logistic models developed to differentiate progressor groups.

Results: Borderline EAA found among radiographic progressors using the SkinBlood calculator (difference in EAA, ΔEAA = 1.5 years, FDR-corrected q = 0.02), dual progressors (pain + radiographic) (ΔEAA = 1.2y, q = 0.05) and any progressor (pain + radiographic + dual) (ΔEAA = 1.1y, q = 0.02), although this was less than the reported error of the calculator (2.5 years). Radiographic progressors also exhibited accelerated epigenetic aging using the PhenoAge calculator (ΔEAA = 2.1y, q = 0.02). Imputed age protein-based models showed marginal performance for radiographic progression (AUC = 0.63) and poor performance for other progressor types (pain AUC = 0.54, dual AUC = 0.52, any AUC = 0.57). Proteins chosen most frequently during modeling had prior links to OA (i.e., growth differentiation factor 8, Matrilin-3, and IL18).

Conclusions: No meaningful difference in epigenetic age was seen among radiographic OA progressors compared to NPs, although not among future pain progressors, using 5 of 7 aging calculators, with minimal and likely not clinically relevant EAA using the SkinBlood and PhenoAge calculators.