Identification and functional characterisation of a rheumatoid arthritis susceptibility gene mapping to chromosome 17q24. (360G-Wellcome-069770_Z_02_A)

Background: Based on collaboration with the Karolinska Institute, Sweden, linkage to regions syntenic to those identified in animal models of inflammatory arthritis (IA) have been investigated in rheumatoid arthritis (RA) affected sibling pair (ASP) families previously. Linkage and association to 17q24, syntenic to a region linked to 2 rate models of IA, has been detected and replicated in independent data sets. Objectives: To identify and characterise putative RA disease gene mapping to the region of linkage on chromosome 17q24. Design: Fine mapping studies will be performed using SNP markers with a density of 1 marker per 50Kb across the 5.5Mb region of linkage. Association will be investigated in test and replication data sets of RA affected sibling pair cases and controls in order to define a minimal region of association. Allele and haplotype frequencies will be compared between cases and controls and haplotype analysis will be used to determine the pattern of LD across the region. Expression patterns for genes mapping to an associated block of LD will be examined to determine the RA disease gene mapping to chromosome 17. Systematic examination to determine all SNPs mapping to the gene will be undertaken and the likely functional SNP(s) identified according to knowledge about their position within the gene. Polymorphisms within the disease gene wil be investigated with regard to function to identify the disease variant/s and their role in the aetiology of RA. The functional studies will depend on the disease gene identified and the position of likely variants within the gene but may include techniques such as reporter gene, gel shift and protein binding assays. Material: DNA is available from 400 RA ASP and 500 single-case families, over 1,000 sporadic RA cases and controls. Outcome: Identification and functional characterisation of RA susceptibility genes.