High resolution linkage and association mapping identifies a novel rheumatoid arthritis susceptibility locus homologous to one linked to two rat models of inflammatory arthritis

Rheumatoid arthritis (RA) is an oligogenic autoimmune disease but, to date, linkage and association to major histocompatibility complex (MHC) has been the only consistent finding in genetic studies. However, MHC is estimated to contribute only 30-40% of the total genetic component to disease suscept ibility. Studies in animal models of inflammatory arthritis have identified a number of putative vulnerability loci but the homologous regions in the human genome have not previously been investigated as candidate RA suscepti bility loci. We have investigated linkage to five regions homologous to tho se identified in animal models of inflammatory arthritis in RA affected sib ling pair (ASP) families. Linkage to 17q22 syntenic to a susceptibility loc us common to two experimental rat models was detected in 200 RA ASP familie s and replicated in a further 100 RA ASP families. Linkage to additional ma rkers mapping to the area has refined the extent of linkage to a 4 cM regio n. Association to one of the markers (D17S807) was demonstrated in this coh ort using extensions of the transmission disequilibrium test. Association t o two 2-marker haplotypes including this marker was detected in an independ ent cohort of single-case RA families, thus narrowing the region harbouring the aetiological mutation to similar to1 cM. This is the first time that a n arthritis susceptibility locus mapped in experimental animal models of di sease has been used to identify a novel RA susceptibility locus in humans. The difficult task of identifying a disease mutation from a linkage result should, in this case at least, be facilitated by the combined use of animal and human based investigations.