Genomic analysis points to novel therapeutic targets for osteoarthritis
medwireNews: A genome-wide association study has identified novel genetic variants associated with osteoarthritis (OA) susceptibility, opening the path for the development of new drugs and repositioning of existing therapeutics.
“We anticipate that this advance in basic understanding of osteoarthritis risk factors and mechanisms will stimulate the evaluation of novel drug targets for osteoarthritis,” say Eleftheria Zeggini (Helmholtz Zentrum München, Neuherberg, Germany) and co-authors.
Using data from the UK Biobank and Arthritis Research UK Osteoarthritis Genetics registries on 77,052 patients with knee and/or hip OA and 378,169 controls, they identified 64 loci associated with OA, of which 52 were previously unreported. Of the novel loci, 24 were associated with OA at any site, 15 with hip OA, seven with knee OA, and the remaining six with hip and/or knee OA.
The team then used a raft of data – including fine mapping, expression quantitative trait loci colocalization, and OA tissue expression data – to identify putative effector genes, 10 of which have a therapeutic approved or in clinical trials, “with mechanisms of action that are not inconsistent with potential for efficacy in osteoarthritis,” note the researchers.
Indeed, the drugs targeting four of the genes – namely TGFB1, GDF5, FGF18, and CTSK – are being developed for OA or cartilage regeneration, while the therapeutics targeting interleukin (IL)11 and DPEP1 are approved for unrelated indications, “thus opening the possibility for repositioning,” they say.
Specifically, oprelvekin – a recombinant IL-11 molecule – is approved for the treatment of chemotherapy-induced thrombocytopenia and the DPEP1 inhibitor cilastatin is given in combination with the antibiotic imipenem to prolong its antibacterial effectiveness. The study authors believe that both of these drugs should be investigated in animal models of OA.
Additionally, Zeggini et al found “strong enrichment for genes known to cause monogenic bone development diseases and forms of early-onset osteoarthritis.”
And for eight genes that were “unequivocally” identified as causal OA genes, they highlight that the findings were concordant with those from animal models, such that lower expression or loss-of-function mutations increased the OA risk in humans and animal models.
“These consistent observations in human and animal models provide compelling evidence for a causal role of these genes in osteoarthritis and point to an agonist strategy as the desired mechanism of action for new osteoarthritis drugs targeting these eight genes,” write the investigators in Nature Genetics.
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