Berlin - June 9, 2004

By LJ Wilcox, PhD

One session, on the opening day of the Annual European Congress of Rheumatology (EULAR 2004), featured 3 presentations of recent research on the genetic control of osteoarthritis (OA) and rheumatoid arthritis (RA). John Loughlin, from Oxford University, began by describing OA as a genetically heterogeneous disease. He stated that OA is perhaps "the most difficult arthritic disease to genetically dissect", but that "breakthroughs are occurring".

The genetic component of OA has only recently been recognized. It is now believed that about 50% of OA in the community occurs due to genetic polymorphisms. In the past, candidate gene approaches identified potential susceptibility genes for OA, including IGF1 (insulin-like growth factor 1), IL1B (interleukin 1 beta), and ESR1 (estrogen receptor alpha 1).

Recently, the research emphasis has shifted to genome-wide linkage scans. Dr Loughlin reported the use of this approach to identify 3 susceptibility loci: Matrilin-3 (MATN3), a structural component of collagen; FRZB, encoding the secreted frizzled-related protein 3; and IL4R, the interleukin 4 receptor. Dr Loughlin emphasized the importance of these findings, stating that these genes "provide us with validated targets"

In the last 2 presentations novel genes associated with RA were discussed. Multiple genes are involved in the predisposition to RA. The HLA locus remains the single largest genetic effect - contributing about 30%-50% of the effect. However, there are multiple non-HLA genes involved and recent studies point to several new candidates.

Peter Gregersen, from the North Shore LIJ Research Institute and the North American Rheumatoid Arthritis Consortium (NARAC), discussed the results of genome-wide linkage and association analysis of RA. The analysis revealed a number of linkage peaks. One peak, on chromosome 18q, was further studied using high-throughput SNP typing. Two regions with evidence of association were identified. Surprisingly, neither region corresponds to the RANK gene on chromosome 18.

The identification of PTPN22 as a susceptibility gene was also discussed. PTPN22 encodes a tyrosine phosphatase present in T cells, and may be involved in T cell signaling. Dr Gregersen concluded his presentation by emphasizing that a variety of approaches are required to identify RA susceptibility genes. Linkage peaks are one of these approaches that can lead to meaningful findings

In the final presentation of the session, Ryo Yamada, from the RIKEN Yokohama Institute in Japan, described a whole-genome survey approach using SNPs by linkage disequilibrium mapping. He reported the identification of the RA associated SNP, SLC22A4. SLC22A4 encodes the solute carrier (family 22, member 4). Previously SLC22A4 was identified as a susceptibility gene for Crohn's disease. Thus, SLC22A4 joins the growing list of genes (eg, HLA, RUNX1) that have been associated with multiple inflammatory, autoimmune diseases. This overlapping association suggests that common underlying processes may be involved in the etiology of these diseases.

Annual European Congress of Rheumatology. www.eular.org