RESEARCH - New genes implicated in RA: DNA microarray analysis os disease-discordant identical twins

November 19, 2008

Public release date: 27-Jun-2006

Contact: Amy Molnar

amolnar@...

Wiley-Blackwell

New genes implicated in rheumatoid arthritis

DNA microarray analysis of disease-discordant identical twins uncovers

three disease-relevant genes

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,

ph 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.

http://www.eurekalert.org/pub_releases/2006-06/jws-ngi062006.php

Not an MD

November 19, 2008

, I wish I had known you when I was working on my dissertation! Sure, the

career development of rural adolescents (snore!) might not have been your bag,

but I bet you could have found me killer references!

Kate F

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Sent: Wednesday, November 19, 2008 7:41:28 AM

Subject: [ ] RESEARCH - New genes implicated in RA: DNA microarray

analysis os disease-discordant identical twins