Profiling a new locus for rheumatoid arthritis A European project has continued the work of the Wellcome Trust Case Control Consortium (WTCCC) to find answers to alleviating rheumatoid arthritis (RA). Health © Thinkstock An inflammatory disorder, RA affects up to 1 % of the population worldwide and primarily attacks the flexible synovial joints. As such, RA causes crippling, painful disability as it ultimately results in the destruction of cartilage in the joint. About half of the genetic susceptibility to RA is attributable to two genes. Recently however, a whole genome association (WGA) scan carried out by the WTCCC has confirmed an additional susceptibility gene on the long arm of chromosome 6, 6q. To follow up on WTCCC results, FERAL, an EU-funded project, focused on identifying and characterising this gene mapping to 6q. A possible candidate gene in this region is TNFAIP3, a gene that is induced by tumour necrosis factor (TNF), a key inflammatory cytokine in RA. Fine mapping between the region on 6q between TNFAIP3 and another gene, OLIG3, confirmed the presence of two risk alleles and one protective for RA. FERAL found that the presence of the two risk alleles without the protective version was strongly associated with the development of RA. To investigate the functional role of the three new genes, the project scientists found that the protein coded from TNFAIP3 could be found in the synovial membrane in both RA and osteoarthritis (OA) subjects. Bioinformatic analysis on one single nucleotide polymorphism (SNP) and its seven proxies (alleles) also identified a strong functional marker. Three of the SNPs showed evidence of TNFAIP3 repression. At the close of the project, FERAL researchers were in the process of identifying transcription factors and protein complexes associated with one of the repressor SNPs and mechanisms behind the regulatory effects. Fine mapping of the chromosomal region responsible for causing RA will no doubt discover gene targets for therapeutic purposes. Novel pharmaceutical products for RA could have major implications for chronic disease healthcare agencies. Keywords Rheumatoid arthritis, gene mapping, risk allele, SNP, TNFAIP3, regulatory effect, osteoarthritis
