Redox-Linked Genetic and Biological Ageing Signals in Rapid Pain Progression of Knee Osteoarthritis: A Hypothesis-Generating Analysis in the Osteoarthritis Initiative

Rapid pain progression in knee osteoarthritis (OA) is heterogeneous and may reflect redox-related mechanisms. We performed an exploratory analysis in Osteoarthritis Initiative (OAI) participants combining nuclear genome-wide association, mitochondrial DNA (mtDNA) haplogroups, and leukocyte telomere length. Rapid pain progression was defined using rescaled Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain (0–100) within 24-month windows. An additive genome-wide association study (GWAS) in 2,946 participants tested 7,762,204 imputed variants, adjusting for age, sex, body mass index (BMI) and three principal components. Haplogroups were analyzed in 3,357 participants, and telomere length (telomere-to-single-copy gene, T/S, ratio) in 301 participants. No variant reached genome-wide significance (p < 5×10−8), but six loci were suggestive (p < 5×10−6) with minimal inflation (λ = 0.995). mtDNA haplogroup H was nominally associated with rapid pain progression (odds ratio, OR = 1.179, p = 0.023). Rapid pain progressors had shorter baseline telomeres (0.825 ± 0.268 vs 0.985 ± 0.375; p < 0.001), and telomere length was inversely associated with progression (OR per 1-unit T/S = 0.260, p = 0.007). These findings are consistent with a redox-linked framework for rapid pain worsening and provide candidates for replication and mechanistic studies.