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Can Genotypes Predict Response to MS Treatment?
Variability in patient response to interferon beta therapy for multiple sclerosis (MS) may be explained by genetic differences, researchers reported in the January 14 online Archives of Neurology. Esther Byun, MD, and colleagues analyzed single nucleotide polymorphisms (SNPs) among 206 patients with MS who had initiated immunotherapy with one of three interferon beta medications at four hospitals in Spain and found significant genetic differences between responders and nonresponders, particularly in genes associated with ion channels and signal transduction pathways.
SNP DETECTION AND SIGNIFICANCES
Ninety-nine patients were categorized as responders to interferon beta therapy, as they had no relapses and no significant increase in Expanded Disability Status Score (EDSS) during the two-year follow-up; 107 nonresponders had at least two relapses or an increase of 1 point on the EDSS. At baseline, the responders had a lower EDSS and a lower Multiple Sclerosis Severity Score than did nonresponders, noted the authors.
Genome-wide screening identified 35 top-ranked candidate SNPs that differed significantly between responders and nonresponders, and individual genotyping showed genotype differences in 29 of the SNPs. “Altogether, population allele frequency differences detected on SNP microarrays accurately represented differences between responder and nonresponder subjects,” said Dr. Byun, an intern at the University of California Davis Medical Center in Sacramento, and colleagues.
With the addition of 81 participants who were not available for the original screening analysis, “more than half of the SNPs remained significantly different between responders and nonresponders, and the significance of the effect increased in five SNPs,” reported the researchers. The significance of the candidate pharmacogenomic SNPs remained after adjustment for baseline differences in relapse rate and EDSS and did not vary between therapy with interferon beta-1a or beta-1b.
MECHANISMS FOR THERAPY RESPONSE
In the final joint analysis, seven candidate SNPs that remained significantly different between groups were located within genes that may point to “long linkage disequilibrium with annotated genes or polymorphisms in distant cis-regulatory regions,” stated the authors. “The results reflect the pleiotropic action of interferon beta and complex nature of MS.”
The researchers also noted that although the benefits of interferon beta therapy in patients in the relapsing-remitting phase of MS have been established, the adverse effects—which include flulike symptoms and depression—the inconvenience, and the cost are significant enough that patients may discontinue therapy. Although they acknowledge that additional research is needed to know with certainty whether the identified genes can predict a better response to interferon therapy, they concluded, “The identification of pharmacogenetic polymorphisms provides important new insights into the mechanism of interferon beta action, bringing the paradigms of rational drug design and personalized medicine one step further.”
NR
—Jessica Dziedzic
Suggested Reading
Byun E, Caillier SJ, Montalban X, et al. Genome-wide pharmacogenomic analysis of the response to interferon beta therapy in multiple sclerosis. Arch Neurol. 2008 Jan 14; [Epub ahead of print].
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