Rheumatoid arthritis (RA) is the commonest inflammatory disease of synovial joints. Approximately 50% of genetic susceptibility to RA is accounted for by the HLA-DRB1 gene together with the PTPN22 gene. A whole genome association (WGA) scan recently carried out by the Wellcome Trust Case Control Consortium (WTCCC) and subsequent validation studies have confirmed that an additional susceptibility locus maps to an inter-genic region of 6q23, near the TNFAIP3 gene. This is a strong candidate RA susceptibility gene as it is induced by TNF, a key inflammatory cytokine in RA. The aim of the project is to characterise the aetiological variant within this region and determine its role in RA susceptibility. The region is being re-sequenced in 80 individuals comprising both cases and controls to include representation of all 3 genotypes. Fine mapping studies will then be undertaken in the original samples included in the WTCCC study to identify the most strongly associated variants in the region. That data should be available by the start of the proposed Fellowship. I will test the most associated variants in an independent validation cohort of 5000 RA samples and 3800 healthy controls from the UK to confirm the most associated variant(s) and characterise the haplotype structure and linkage disequilibrium present in the region. Subsequently, bioinformatic resources will be used to investigate whether the associated variants mapping are associated with expression levels of genes in the region (particularly TNFAIP3) or are predicted to bind transcription factors. Functional studies will then be undertaken to clarify the role of these variants in RA ethiopathogenesis using techniques including luciferase reporter gene assays, electromobility shift assays, expression studies and analysis of protein levels. Experiments will be performed using relevant cell lines and tissues under both basal and TNF-stimulated conditions.
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