Association of the Rheumatoid Arthritis Severity Variant rs26232 with the Invasive Activity of Synovial Fibroblasts

Abstract

rs26232, located in intron one of C5orf30, is associated with the susceptibility to and severity of rheumatoid arthritis (RA). Here, we investigate the relationship between this variant and the biological activities of rheumatoid arthritis synovial fibroblasts (RASFs). RASFs were isolated from the knee joints of 33 RA patients. The rs26232 genotype was determined and cellular migration, invasion, and apoptosis were compared using in vitro techniques. The production of adhesion molecules, chemokines, and proteases was measured by ELISA or flow cytometry. Cohort genotypes were CC n = 16; CT n = 14; TT n = 3. In comparison with the RASFs of the CT genotype, the CC genotype showed a 1.48-fold greater invasiveness in vitro (p = 0.02), 1.6-fold higher expression intracellular adhesion molecule (ICAM)-1 (p = 0.001), and 5-fold IFN-γ inducible protein-10 (IP-10) (p = 0.01). There was no association of the rs26232 genotype with the expression levels of either total C5orf30 mRNA or any of the three transcript variants. The rs26232 C allele, which has previously been associated with both the risk and severity of RA, is associated with greater invasive activity of RASFs in vitro, and with higher expression of ICAM-1 and IP-10. In resting RASFs, rs26232 is not a quantitative trait locus for C5orf30 mRNA, indicating a more complex mechanism underlying the genotype‒phenotype relationship.

Genomic Diversity, Population Structure, and Signature of Selection in Five Chinese Native Sheep Breeds Adapted to Extreme Environments

“…Multiples candidate genes were also found to participate in host defense mechanism, resistance diseases, and inflammatory responses, with two most significant genes worth to mention as examples. C5orf30 gene was reported in association with the development of autoimmune disorders in primary biliary cirrhosis as well as the susceptibility and severity of rheumatoid arthritis in humans [55,56]. Another interesting gene is ITCH, which encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases and plays a role in protein trafficking and immune response, and in several signaling pathways that regulate cellular growth and proliferation in multiple processes [57].…”

One year in review 2020: pathogenesis of rheumatoid arthritis

“…Furthermore, a number of genetic variants may contribute to disease susceptibility by affecting the activity of RA synovial fibroblasts (FLS), key cells responsible of tissue remodelling and cartilage damage in the joint of RA patients. For instance, the rs26232 C allele, located in intron one of C5orf30, associated with the susceptibility to and severity of RA, was recently proved to be also associated with RA FLS with more profibrogenic activities and with increased expression of the adhesion molecules ICAM-1 and IP-10 (10). Moreover, different gene variants seem to be associated with specific clinical aspects of the disease, rather than with disease susceptibility.…”