Editors' ChoiceRheumatoid Arthritis

A Powerful (Re)Purpose for Genome-Wide Association Studies

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Science Translational Medicine  08 Jan 2014:
Vol. 6, Issue 218, pp. 218ec9
DOI: 10.1126/scitranslmed.3008136

Drug discovery is an expensive and risky endeavor. Research and discovery pipelines are drying up. The costs of bringing a new pharmaceutical agent to the market are in excess of $3 billion and require nearly a decade of research. Therefore, innovative approaches are required to not only make better use of medications known to target specific diseases but also identify new indications for existing medications. The latter approach is often referred to as drug “repurposing” or “repositioning” and is often described as a more cost-effective route to bringing drugs to the market. Identifying additional uses for existing medications with known safety profiles has the potential to reduce the risk and to accelerate drug discovery.

Rheumatoid arthritis (RA) is a complex and multifactorial disease with several known genetic variants contributing to disease risk. Prior genome-wide association studies (GWASs) have identified ~60 genetic variants associated with RA. To expand the current list of genetic variants, Okada et al. performed a trans-ethnic GWAS using patients with RA from both European and Chinese descent. The authors identified 42 additional variants associated with RA and were able to explain the majority of the known heritability of RA. To identify the genes most likely represented by each of the genetic loci, the authors generated a systematic pipeline that incorporated a variety of publicly available resources. To demonstrate the translational potential of their GWAS findings, the authors then tested to what extent their candidate genes were enriched in known drug-target databases. Not surprisingly, they found that many existing drugs used to treat RA-targeted genes identified by the authors’ GWAS. In addition, the authors identified several additional drugs that target CDK6 and CDK4 and are already approved to treat malignancies. Although these agents have not yet been tested for RA in humans, one—flavopiridol—has effects in animal models of RA, thus demonstrating the validity of their approach.

With more than 1700 published GWASs performed to date, the approach by Okada et al. provides an approach to use existing GWAS data to accelerate drug discovery across a spectrum of disorders. As a consequence, we can expect to shorten the length and to reduce the costs of the drug discovery process.

Y. Okada et al., Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature, published online 25 December 2013 (10.1038/nature12873). [Abstract]

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