Genetic susceptibility to rheumatoid arthritis and its implications for novel drug discovery.
BACKGROUND
Over 100 susceptibility loci have now been identified for rheumatoid arthritis (RA), several of which are already the targets of approved RA therapies providing proof of concept for the use of genetics in novel drug development for RA. Determining how these loci contribute to disease will be key to elucidating the mechanisms driving disease development, which has the potential for major impact on therapeutic development.


METHODS
Here the authors review the use of genetics in drug discovery, including the use of 'omics' data to prioritise potential drug targets at susceptibility loci using RA as an exemplar. They discuss the current state of RA genetics its impact on stratified medicine, and how the findings from RA genetics studies can be used to inform drug discovery.


CONCLUSIONS
It is anticipated that functional characterisation of disease variants will provide biological validation of a gene as a drug target, providing safer targets, with an increased likelihood of efficacy. In the future, techniques such as genome editing may represent a plausible option for RA therapy. Technologies such as genome-wide chromatin conformation capture Hi-C and CRISPR will be crucial to inform our understanding of how diseases develop and in developing new treatments.
a Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, Manchester Academic Health Science Centre , The University of Manchester , Manchester , UK.
Annie
A
Yarwood
a Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, Manchester Academic Health Science Centre , The University of Manchester , Manchester , UK.
Steve
S
Eyre
a Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, Manchester Academic Health Science Centre , The University of Manchester , Manchester , UK.|b NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust , Manchester Academic Health Science Centre , Manchester , UK.
Jane
J
Worthington
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D058990:Molecular Targeted Therapy
D018501:Antirheumatic Agents
Drug discovery; functional genomics; genetics; rheumatoid arthritis; therapeutic target