Autoimmune diseases are caused by multiple factors. Rheumatoid Arthritis (RA) is one of the most common human systemic autoimmune diseases with a prevalence of 0.5%-1% worldwide. It is characterised by inflammation of the synovial tissue and formation of rheumatoid pannus, which erodes adjacent cartilage and bone, causing subsequent joint destruction. RA is believed to result from a combination of genetic and environmental factors. In addition to the well characterised HLA locus, a number of

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... ceptibility genes and loci have been identified by genome-wide association studies (GWAS). However, genetic information alone does not necessarily yield insight into the understanding of the pathogenesis of RA. We previously reported that Peptidylarginine deiminase type 4 (PADI4) is one such RA susceptibility gene. PADI4 catalyses the conversion of peptidylarginine into peptidylcitrulline, and citrulline-containing epitopes are the most specific targets of many RA-specific autoantibodies. We established that SNPs within the coding region of PADI4 are associated with the development of RA and that these RA-associated SNPs produce allelically imbalanced gene expression, which has pathological consequences. However, the individual effects of susceptibility genes are likely to be small, and it is the combination of alleles along with strong effects on the specific pathways affected by these susceptibility genes that are essential for the development of RA. To understand the role of genetics in the pathogenesis of RA, it is therefore important to understand the physiological significance of each susceptibility gene in relation to RA.