ROCKVILLE, Md.& ALAMEDA, Calif.—Theonset of rheumatoid arthritis (RA) has grim implications for thepatient—submission to harsh drug regimens that can have severe, evenlife-threatening, side effects or risk worsening of the erosive effects of thedisease. According to Dr. Tom Huizinga, head of the department of rheumatology,Leiden University Medical Centre, and a collaborator and co-author of a newlypublished paper, "Eventually, building on these studies, physicians andpatients should have access to blood tests that can assess each individual'srespective genetic risk of developing this disease, which in turn will enableearlier and more appropriate therapeutic intervention."
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ROCKVILLE, Md.& ALAMEDA, Calif.—Theonset of rheumatoid arthritis (RA) has grim implications for thepatient—submission to harsh drug regimens that can have severe, evenlife-threatening, side effects or risk worsening of the erosive effects of thedisease. According to Dr. Tom Huizinga, head of the department of rheumatology,Leiden University Medical Centre, and a collaborator and co-author of a newlypublished paper, "Eventually, building on these studies, physicians andpatients should have access to blood tests that can assess each individual'srespective genetic risk of developing this disease, which in turn will enableearlier and more appropriate therapeutic intervention."
The paper coauthored by Dr. Huizinga's group at the LeidenUniversity Medical Centre in the Netherlands, the Karolinska Institute inSweden, and Celera (an Applera Corporation business) that was published in theSeptember 2007 edition of the Public Library of Science (Medicine), describesnovel variants in the TRAF1/C5 gene region that predict individualsusceptibility to, and severity of, RA. Carriers of the risk variants (about65-70 percent of the general population) were reported to have an approximate37 percent increased risk for developing RA.
As Dr. John Sninsky, vice president of discovery research atCelera, puts it, "C5 is our contribution and our continuing contribution. C5,which is a complement component, is a genetic variant that Celera hasdetermined is involved in RA and psoriasis. C5 is located next to TNFreceptor-associated factor 1 (TRAF1), an essential effector of the TNFsignaling cascade."
The large study of DNA samples from more than 4,700individuals compared patterns of genetic variation in those with RA to thosewithout the disease. TRAF1/C5 was confirmed as responsible for about 6 percentof the risk for RA. Located on chromosome 9, TRAF1 encodes a protein that is amember of the TRAF protein family, which associates with, and mediates thesignal transduction from, various receptors of the TNF superfamily. C5 encodesa key component of the complement system and activation of that system has beenimplicated in many inflammatory diseases.
Celera first confirmed that this region was associated withRA in 2006, which was preceded by its discovery of PTPN22, now replicated bymultiple laboratories, as a genetic contributor to the etiology of RA. Anothermajor contributor to RA risk is human leukocyte antigen (HLA). "The discoveryof TRAF1/C5 provides a valuable addition to HLA and PTPN22. The aggregation ofrisk levels makes us think there's something very interesting here inexplaining a genetic contribution to RA," Dr. Sninsky states.
"We think this work provides a highly interestingopportunity to develop drugs or pharmacogenomics tests, " Dr. Sninsky observes."TNF blockage therapy has terrible side effects, so although some say thatsegmentation is a problem, the take home message here is that it may actuallyexpedite approval of new therapies."
Huizinga adds, "Currently, we are able to stop jointdestruction and disease progression in most patients with high doses ofimmunosuppressant drugs. However, these regimens have sufficiently large sideeffects that most physicians and their patients decide to start treatment withrelatively mild drugs. The challenge in rheumatology now is the development ofa means to determine those patients at greater risk for this disease and inneed of more intensive treatment strategies. These genetic discoveries aremaking substantial headway in addressing this challenge."
HLAs are thought to account for about 30 percent of theinherited risk for RA, but the identities of non-HLA genes involved in theprocess have been largely unknown. Based on functional data in mice,researchers at Celera and the two European institutions hypothesized that theimmune-related genes complement component 5 (C5) and/or TNF receptor-associatedfactor 1 (TRAF1) represent relevant candidate genes for RA.
