1. C5orf30: a novel modulator of tissue damage and inflammation in rheumatoid arthritis
The variant rs26232 was identified as an RA susceptibility variant in a GWAS (Stahl et al., 2010).
In a study of 3 large RA population we reported an allele-dose association of rs26232 with severity of radiological damage (Teare et al., 2013).
This variant lies in the first exon of Chromosome 5 opening reading frame 30 (C5orf30) that encodes a 206 amino acid disordered protein. Single C5orf30 orthologues are only present in vertebrates, where the protein sequences show a high degree of conservation; chimpanzee (99.5%), mice (94%), and chicken (89%) with the most distant orthologue found in bony fish (72% identity to human sequence).
It is predicted to be a disorder protein:
Our studies have also shown (Muthana et al., 2015):
- Highest expression in monocyte/macrophages and RA synovial fibroblasts (RASF)
In the latter cell type:
- Expression reduced by TNF and increased by hypoxia
- Highly expressed in RA synovial tissue
- siRNA-mediated inhibition of C5orf30 in RASF leads to increased invasiveness and migration in vitro
- siRNA-mediated inhibition in CIA model resulted increased arthritis and joint damage with increased IL-1 and TNF and reduced IL-10 expression
Ongoing studies :
- Examination of role of C5orf30 in monocyte/macrophage biology
- Identification of binding partners
- Characterisation of mechanisms linking rs26232 genotype with RA severity
Funded by Arthritis Ireland and Health Research Board
Muthana, M., S. Hawtree, A. Wilshaw, E. Linehan, H. Roberts, S. Khetan, G. Adeleke, F. Wright, M. Akil, U. Fearon, D. Veale, B. Ciani, and A.G. Wilson. 2015. C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis. Proc. Natl. Acad. Sci. U. S. A. 112:11618-11623.
Stahl, E.A., S. Raychaudhuri, E.F. Remmers, G. Xie, S. Eyre, B.P. Thomson, Y. Li, F.A. Kurreeman, A. Zhernakova, A. Hinks, C. Guiducci, R. Chen, L. Alfredsson, C.I. Amos, K.G. Ardlie, A. Barton, J. Bowes, E. Brouwer, N.P. Burtt, J.J. Catanese, J. Coblyn, M.J. Coenen, K.H. Costenbader, L.A. Criswell, J.B. Crusius, J. Cui, P.I. de Bakker, P.L. De Jager, B. Ding, P. Emery, E. Flynn, P. Harrison, L.J. Hocking, T.W. Huizinga, D.L. Kastner, X. Ke, A.T. Lee, X. Liu, P. Martin, A.W. Morgan, L. Padyukov, M.D. Posthumus, T.R. Radstake, D.M. Reid, M. Seielstad, M.F. Seldin, N.A. Shadick, S. Steer, P.P. Tak, W. Thomson, A.H. van der Helm-van Mil, I.E. van der Horst-Bruinsma, C.E. van der Schoot, P.L. van Riel, M.E. Weinblatt, A.G. Wilson, G.J. Wolbink, B.P. Wordsworth, C. Wijmenga, E.W. Karlson, R.E. Toes, N. de Vries, A.B. Begovich, J. Worthington, K.A. Siminovitch, P.K. Gregersen, L. Klareskog, and R.M. Plenge. 2010. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42:508-514.
Teare, M.D., R. Knevel, M.D. Morgan, A. Kleszcz, P. Emery, D.J. Moore, P. Conaghan, T.W. Huizinga, A.W. Morgan, A.H. van der Helm-van Mil, and A.G. Wilson. 2013. Allele-dose association of the C5orf30 rs26232 variant with joint damage in rheumatoid arthritis. Arthritis Rheum. 65:2555-2561.