Observational transcriptomic analysis identifies genes associated with knee osteoarthritis severity in older adults.

Objectives. The association between skeletal muscle gene expression and knee osteoarthritis (OA) was examined among older adult participants of the Study of Muscle, Mobility and Aging (SOMMA). Methods. Inclusion criteria included knee radiographs and bulk RNA sequencing (RNAseq) in vastus lateralis muscle, resulting in 523 participants (56% female). Radiographic knee OA was determined by Kellgren-Lawrence (KL) grades. Differential gene expression was analyzed using a control group (KL [≤] 1, n = 326) and two nested case groups: (a) KL [≥] 2 (n = 197), (b) KL [≥] 3 (n = 112). Results. Compared with controls, there were 27 and 41 genes associated (FDR [≤] 0.05) with KL [≥] 2 and KL [≥] 3, respectively, and 16 genes significantly associated in both contrasts. For 15 of the 16 genes, the association magnitude was larger with more severe OA (KL [≥] 3). Genes associated in both contrasts included brain-derived neurotrophic factor (BDNF) and interferon regulatory factor-2 (IRF2). Gene sets enriched in KL [≥] 2 and KL [≥] 3 contrasts included DNA repair and branched chain amino acid (BCAA) catabolism. Conclusions. Our results in older adult SOMMA participants indicate that knee OA is associated with genes and pathways expressed in skeletal muscle that are involved in pain sensitization, BCAA catabolism, muscle function preservation, calcium transport and storage, inflammation, and extracellular matrix remodeling. Additional longitudinal studies will be needed to determine how these genes could affect the progression of knee OA.