From genome-wide association studies to rational drug target prioritisation in inflammatory arthritis.

Abstract

Early identification of genetically validated drug targets can increase the chances of successful late-stage drug development. 81 high-quality genome-wide association studies (GWAS) in diseases related to inflammatory arthritis have been curated into the GWAS catalogue; however, translation of genetic findings from GWAS into rational drug target discovery has been poor. No human genetic findings have completely driven drug development for inflammatory arthritis; however, genetic associations have partly driven the development of abatacept (CTLA-4-Ig) in rheumatoid arthritis and secukinumab (anti-IL-23R) in ankylosing spondylitis. Roadblocks to progress exist, including little knowledge of the genetic architecture and regulatory mechanisms underlying associations, and the need to identify gene regulatory networks and assess target tractability. New opportunities are arising that could maximise the informativeness of GWAS for drug target validation. Genetic variants can be linked to core genes by using functional genomics and then to peripheral genes interconnected to core genes using network information. Moreover, identification of crosstalk between biological pathways might highlight key points for therapeutic intervention.