Although the etiology of rheumatoid arthritis (RA) is still unknown, it is generally believed that a combination of multiple polymorphic genetic factors and environmental contributions lead to the pathogenic auto-immune reactions characterized by destructive polyarthritis and various extra-articular inflammatory involvements. A genetic approach to identify RA-associated genes from the whole genome is proposed to be one of the promising methodologies to elucidate the etiology of RA. Although multiple genome-wide linkage studies and many association studies to test an individual gene that is functionally relevant to RA have been performed to identify RA-associated nonhuman leukocyte antigen genes, no region or gene has been conclusively shown to be one of the RA-susceptible loci or genes. Therefore, a linkage disequilibrium approach using single nucleotide polymorphisms (SNPs) as genetic markers to identify disease-associated genes was considered a promising alternative method for RA, as well as other common diseases with complex genetic predispositions.
Our RIKEN SNP Research Center has established a high-throughput SNP-genotyping system and has been investigating multiple common diseases using a whole-genome gene-based linkage disequilibrium mapping approach. In 2003, we reported that functional variants of the PADI4 gene were associated with RA. PADI4 is an enzyme that converts arginine residue in proteins to citrulline. The citrullinated proteins are targets of the most specific autoantibodies in RA. We have identified this gene in a whole-genome, hypothesis-free approach. Therefore, this made our methodology strongly reliable in that the RA-associated gene identified by our hypothesis-free approach was functionally strongly relevant to the pathogenesis of RA.
Recently we also found that SLC22A4 and RUNX1 are associated with RA. SLC22A4 is an organic cation transporter with unknown physiologic function, and RUNX1 is a hematologic transcriptional regulator that has been shown to be responsible for acute myelogenic leukemia. It is suggested that the association of RUNX1 with RA is due to its regulation of expression of SLC22A4. Because the physiologic function of SLC22A4 is still unclear, further investigation is needed into how SLC22A4 affects RA susceptibility. Although the association of RUNX1 with RA was identified as a regulatory factor of SLC22A4, it is possible that RUNX1 is a key molecule in autoimmunity, as it has been reported to be associated with systemic lupus erythematosus and psoriasis, two other autoimmune diseases.