Cindy Boer

Genetics of Osteoarthritis Consortium GWAS Meta-Analyses | 181 4.1 ed Protein 47) has widespread expression in nervous tissue[72] and demonstrates an altered bone phenotype in mutant mouse lines. RNF144B (Ring Finger Protein 144B) is involved in the protein ubiquitination pathway. IGF1R (Insulin like growth factor 1 receptor) has tyrosine kinase activity and mediates the action of insulin-like growth factor. PFKM (phosphofructokinase) encodes a muscle isozyme that catalyses the phos- phorylation of fructose-6-phosphate during glycolysis. Finally, we identified TRIO And F-Actin Binding Protein ( TRIOBP ) as the likely causal gene for rs12160491, which is as- sociated with total joint replacement, total hip replacement and hip osteoarthritis. This gene has been linked to cardiovascular function[73] and hearing loss[74]. Drug target identification We examined the druggability status[75] of the likely causal genes ( Table 3) using the druggable genome database[8]( Supplementary Table 8 ). From these osteoarthritis likely causal genes 11 reside in tier 1, which incorporates the targets of approved drugs (licensed drugs) and drugs in clinical development ( Supplementary Information, Methods , Table 3 ), and 2 genes reside in tier 2, which includes genes encoding targets with known bioactive drug-like small molecule binding partners and those with ≥50% identity with approved drug targets. Within tier 1, two candidates are already in clinical trials of efficacy for osteo- arthritis. FGF18 encodes fibroblast growth factor 18 that signals through the FGF re- ceptor 3 to promote chondrogenesis. The recombinant FGF18 Sprifermin has recently been shown to increase cartilage thickness in knee osteoarthritis in a phase 2 clinical trial (PMID: 32098758). TNFSF11 encodes receptor activator of nuclear factor kappa-β ligand (RANKL), a pivotal protein in bone remodelling[76], consistent with the con- cept that bone remodelling plays a role in osteoarthritis pathogenesis[77]. The human monoclonal antibody to RANKL, denosumab, is the most potent anti-resorptive agent approved for osteoporosis treatment and is also currently in a phase 2 clinical trial for knee osteoarthritis progression (ISRCTN96920058). The other tier 1 druggable targets of which we have strong supportive evidence as putative effector genes ( Table 3 ): ALDH1A2, IGF1R, TNC, SMO, FGFR3, MAP2K6, CHST3, TGFA, TGFB, all have market authorisation or are in clinical development for other indications. The functional and epidemiological evidence of their role in clinical osteoarthritis presented here provides support for early repurposing investigation.