A genomics-based systems approach towards drug repositioning for rheumatoid arthritis

Rong Xu, QuanQiu Wang

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of synovial joints. RA affects up to 1 % of the population worldwide. Currently, there are no drugs that can cure RA or achieve sustained remission. The unknown cause of the disease represents a significant challenge in the drug development. In this study, we address this challenge by proposing an alternative drug discovery approach that integrates and reasons over genetic interrelationships between RA and other genetic diseases as well as a large amount of higher-level drug treatment data. We first constructed a genetic disease network using disease genetics data from Genome-Wide Association Studies (GWAS). We developed a network-based ranking algorithm to prioritize diseases genetically-related to RA (RA-related diseases). We then developed a drug prioritization algorithm to reposition drugs from RA-related diseases to treat RA. Our algorithm found 74 of the 80 FDA-approved RA drugs and ranked them highly (recall: 0.925, median ranking: 8.93 %), demonstrating the validity of our strategy. When compared to a study that used GWAS data to directly connect RA-associated genes to drug targets ("direct genetics-based" approach), our algorithm ("indirect genetics-based") achieved a comparable overall performance, but complementary precision and recall in retrospective validation (precision: 0.22, recall: 0.36; F1: 0.27 vs. precision: 0.74, recall: 0.16; F1: 0.28). Our approach performed significantly better in novel predictions when evaluated using 165 not-yet-FDA-approved RA drugs (precision: 0.46, recall: 0.50; F1: 0.47 vs. precision: 0.40, recall: 0.006; F1: 0.01). In summary, although the fundamental pathophysiological mechanisms remain uncharacterized, our proposed computation-based drug discovery approach to analyzing genetic and treatment interrelationships among thousands of diseases and drugs can facilitate the discovery of innovative drugs for treating RA.