Genetic Influences on Disease Severity in Rheumatoid Arthritis

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Nikki Lynn

Posted Wednesday, November 04, 2009 6:08 AM

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Association of a Single-Nucleotide Polymorphism in CD40 With the Rate of Joint Destruction in Rheumatoid Arthritis
van der Linden MP, Feitsma AL, le Cessie S, et al
Arthritis Rheum. 2009;60:2242-2247

Summary
Several genetic susceptibility factors for rheumatoid arthritis (RA) have been revealed as a result of genome-wide association studies.[1,2] Twin studies have suggested that, in addition to disease susceptibility, the severity of joint destruction in RA is also significantly influenced by genetic factors.[3] However, apart from the major histocompatibility complex, genetic factors associated with RA severity have not yet been convincingly shown.

In 2008, a multinational team of investigators combined analyses from genome-wide association studies and identified 6 genetic regions for susceptibility to autoantibody-positive RA: CD40, JIF5A/PIP4K2C, CDK6, CCL21, PRKCQ, and MMEL1/TNFRSF14.[4] These 6 susceptibility loci were the focus of the current prospective study by van der Linden and colleagues, which followed 563 patients with RA for a median of 5 years with yearly x-rays. Using the rate of change in Sharp/van der Heijde scores to determine the rate of disease progression,[5] investigators found that CD40 and CDK6 were associated with a higher rate of joint destruction, although only the CD40 association was replicated in an additional patient cohort.

Viewpoint
Disease susceptibility and disease severity are not necessarily related through common genetic factors, but because it can be difficult and costly to assemble cohorts of sufficient size to investigate disease progression on a genome-wide scale, disease susceptibility variants are attractive candidates for investigation into disease progression. At the same time, disease progression variants may prove to be more tractable targets for therapeutic intervention if the pathogenic mechanisms triggered by disease susceptibility variants are firmly entrenched at disease onset.

van der Linden and colleagues appear to have discovered one such disease severity factor for RA. However, as the authors rightly point out, a few inconsistencies will have to be sorted out before their findings can be effectively translated to the clinic. Specifically, the minor allele at CD40 found to be associated with a higher rate of joint destruction was originally identified as protective against the development of RA.[4] The data here would therefore argue that disease susceptibility and severity operate through distinct mechanisms in RA pathogenesis.

Ultimately, if van der Linden's findings are validated, CD40 may prove to be an excellent target for disease-modifying antirheumatic drugs, especially for patients unresponsive to currently available therapy with tumor necrosis factor blockers.

Abstract

http://www.medscape.com/viewarticle/709210

Lynn

Rituxan....In Remission after 8 long years

“Over the last few centuries, a process developed for separating fact from fiction, and it is called science…’the crash testing of ideas.’”

The Microbial Metagenome, Debunking the Marshall protocol

http://whatstheharm.net/homeopathy.html

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