Redox-Related 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 the rescaled Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for pain (0-100) within 24-month windows. An additive genome-wide association study (GWAS) in 2946 participants tested 7,762,204 imputed variants, adjusting for age, sex, body mass index (BMI) and three principal components. Haplogroups were analysed in 3357 participants, and telomere length (telomere-to-single-copy gene, T/S, ratio) was analysed in 301 participants. No variant reached genome-wide significance (<i>p</i> < 5 × 10^-8), but six loci were suggestive (<i>p</i> < 5 × 10^-6), with minimal inflation (λ = 0.995). mtDNA haplogroup H was nominally associated with rapid pain progression (odds ratio, OR = 1.179, <i>p</i> = 0.023). Rapid pain progressors had shorter baseline telomeres (0.825 ± 0.268 vs. 0.985 ± 0.375; <i>p</i> < 0.001), and telomere length was inversely associated with progression (OR per 1-unit T/S = 0.260, <i>p</i> = 0.007). These preliminary, hypothesis-generating findings are compatible with a redox-related interpretation of rapid pain progression and require external validation in independent cohorts, while providing candidates for future mechanistic studies.