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UCSF Team Identifies 18 SNPs Linked to MS Therapy Response

NEW YORK (GenomeWeb News) – Researchers have identified a set of 18 SNPs that may explain why some individuals respond better to a widely used multiple sclerosis treatment than others.
 
Researchers from the University of California, San Francisco, used Affymetrix 100K SNP arrays to identify specific mutations associated with better responses to interferon beta therapy for MS. Their findings appeared yesterday in the online version of Archives of Neurology.
 
According to the National Institute of Neurological Disorders and Stroke, approximately 250,000 to 300,000 Americans suffer from multiple sclerosis, a degenerative disease caused by a progressive loss in the coating surrounding the nerves that leads to muscle weakness and, sometimes, paralysis. To date, there is no cure for MS and around 80 percent of individuals with the disease eventually end up disabled.
 
While treatment with interferon beta has been shown to slow disease progression, the treatment is not effective for all patients — roughly half of those who receive interferon beta therapy relapse or continue deteriorating. In addition, the risk of adverse side effects for the treatment, ranging from flu-like symptoms to depression, is high.
 
“The beneficial outcomes of interferon beta therapy … have been clearly shown. On the other hand, the effect of this treatment is partial, and a substantial amount of patients are not responders,” lead author and UCSF neurologist Esther Byun and her colleagues wrote in the paper. “[I]n the absence of … markers of response, the question remains who and when to treat when adverse effects, inconvenience, and cost of the drug are significant.”
 
In an effort to solve this problem, the researchers followed a group of individuals with the most common form of MS, known as relapsing-remitting MS, as they received interferon beta therapy over two years. They then did large-scale, genomic comparisons between those who responded positively to the treatment and those who did not, in an attempt to get what they called “unbiased detection of DNA variants associated with interferon beta therapy response.”
 
Of the 206 Southern European individuals tested, 99 responded well to the therapy, and 107 didn’t. By pooling and comparing DNA that had been hybridized to Affymetrix 100K GeneChips, the team identified dozens of candidate small nucleotide polymorphisms that were associated with a positive response to the interferon beta treatment.
 
After narrowing down the field to the most likely 35 candidate SNPs, the team added more than 80 individuals to the study, looking patient-by-patient to determine whether those SNPs continued to correspond to better outcomes following interferon beta therapy. The researchers found that 18 of the 35 SNPs were significantly associated with positive interferon beta treatment response.
 
Of these 18 mutations, seven lie within genes and the remainder are in non-coding regions. The researchers found that the top-ranked SNPs that differed between responders and non-responders were related to glutamate and gamma-aminobutyric acid receptors — a “provocative” finding that suggests a link between neuronal excitation and the effect of interferon beta therapy, but one that requires further study, the authors said.
 
While the authors note that additional research needs to be done to further validate the study and understand the functional role of interferon beta, the work has the potential to change the approach to MS treatment from a game of hit-and-miss to a more systematic, personalized plan of attack.
 
“The identification of pharmacogenetic polymorphisms provides important new insights into the mechanism of interferon beta action,” the authors noted, “bringing the paradigms of rational drug design and personalized medicine one step further.”
 

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