The aetiology of rheumatoid arthritis (RA) is multifactorial involving both genetic and environmental influences. Genome wide association studies have identified more than 100 susceptibility loci including a variant, rs26232, in the 1st intron of C5orf30. We have also described an allele dose association of this variant with severity of x-ray damage of the hands and feet joints. The gene encodes a protein of 206 amino acids that is highly expressed by RA synovial fibroblasts and macrophages. Inhibition of C5orf30 in RA synovial fibroblasts results in increased cellular invasiveness and migration in vitro, furthermore, inhibition in the collagen-induced arthritis model markedly accentuated joint inflammation and damage, with elevated TNF and IL-1 expression. These data confirm C5orf30 to be a previously uncharacterised anti-catabolic and anti-inflammatory mediator in RA. This research project will investigate the mechanisms underlying the genetic link of rs26232 with tissue damage and investigate the interactome of C5orf30 in synovial fibroblasts. Our objectives are to ascertain if rs26232 genotype is; (1) correlated with RASF phenotypic characteristics in vitro including invasiveness, migration and gene expression profiles, (2) differential nuclear protein binding, (3) associated with 3’ untranslated variants of C5orf30 and with differential intracellular localization. We will also identify the interactome of C5orf30 in synovial fibroblasts and determine key interaction domains. These experiments will give important novel information on the biology of C5orf30 in mediating tissue damage in RA.
