New genes implicated in rheumatoid arthritis

Researchers continue to search for genetic clues into rheumatoid arthritis (RA), a chronic inflammatory joint disease. While its specific cause is not yet known, RA has been linked to an inherited susceptibility. Interestingly, despite its strong genetic component, RA's occurrence among siblings seems to be random.

In the quest to identify disease-specific gene expression profiles in patients with RA, researchers at the University of Michigan Medical Center turned to an ideal population: genetically identical, disease-discordant twins. The July issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis) highlights the results of their state-of-the-art genetic analysis.

Increasing evidence over the past several years indicates that B-lymphocytes play a central role in RA's development. In this study, microarray analysis was applied to lymphoblastoid B cell lines (LCLs) from 11 pairs of monozygotic twins, all with one healthy and one RA-affected twin. A revolutionary DNA technology, microarray can be used to not only compare gene expression in two different tissue samples, but to examine the expression of thousands of genes at once. The researchers extracted complementary DNA from the cells of every twin, labelled samples with fluorescent dye to distinguish RA cells from disease-free cells, and hybridized each on a 20,000-gene chip. Then, using immunohistochemistry and real-time polymerase chain reaction, they confirmed the expression of the most significantly over-expressed genes in synovial tissues. In addition, they compared gene expression in synovial tissue of the RA patients with gene expression in synovial tissue of patients with osteoarthritis (OA).

Between the disease-discordant twins, minor yet measurable differences were detected in the expression of 1,163 transcripts, representing 827 uniquely named genes. Of this total, 3 genes were significantly over-expressed in the cells of RA patients relative to their healthy co-twins. The most significantly over-expressed gene was laeverin, a newly discovered enzyme that works to degrade proteins. The second most significantly over-expressed gene was 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), a steroid pathway enzyme linked to inflammation and bone erosion. This gene was also found over-expressed in the synovial tissue of OA patients. The third most significantly over-expressed gene was cysteine-rich, angiogenic inducer 61 (Cyr61), well-established for its role in the formation of new blood vessels.

“Our findings provide the first evidence that laeverin is abundantly expressed in synovial tissue,” notes the study's leading author, Joseph Holoshitz, M.D. “11ß-HSD2 and Cyr61 have not previously been directly implicated in RA,” he adds. Uncovering 3 new genes with a clear abundance in RA, this study supports the promise of microarray analysis to not only provide further insights into the genetic components of this inflammatory disease, but also to help identify candidates for therapeutic intervention.