Researchers compared the DNA of multiple sclerosis (MS) patients whose symptoms were reduced by interferon beta therapy to the DNA of patients whose symptoms were not reduced, patients who continued having relapses. The scientists say they may have identified key genetic differences between the two groups of patients, according to an article published in Archives of Neurology (JAMA/Archives). They say these findings may eventually be used to predict which treatments might help which patients.
MS is a neurological disorder – the patient’s nerve fiber coatings degenerate, leading to muscle weakness, spasms and either partial or complete paralysis. Recombinant interferon beta, a protein, is used to treat MS symptoms. Recombinant interferon beta can sometimes slow down the progression of MS, the authors explain. “Despite interferon beta therapy, up to 50 percent of patients with MS continue to experience relapses and worsening disability. In addition, adverse effects, such as flu-like symptoms and depression, are common, leading many patients to discontinue therapy.”
Esther Byun, M.D., University of California, San Francisco, and team of a multi-center international collaboration monitored 206 Southern European patients; they all had the most common type of MS – relapsing-remitting MS. Patients with relapsing-remitting MS experience spells of symptoms followed by period of symptom-free remission. The patients were monitored for two years after starting to receive interferon beta therapy. Four times each year neurologists analyzed the patients’ levels of disability. During the whole period 107 did not respond positively to interferon beta while 99 did.
The scientists pooled the DNA of individuals in each group and used microarrays to identify, across the genome, genetic markers associated with the response to interferon beta. They identified the top 35 single nucleotide polymorphisms (SNPs), changes in a single base of DNA, that were candidates for further analysis. Then they located these SNPs in each patient to find out whether the mutations apparent in responders were any different from those in the non-responders.
After this analysis was carried out, a further 81 patients with MS (44 responders and 35 non-responders) were included and the DNA of responding patients was once more compared to that of the non-responding ones.
Of the 35 candidate SNPs identified in the initial screen, 18 were found to continue to be significantly associated with treatment response in the combined screen. Seven of the SNPs were located inside genes, while the others were situated in the space between genes. A number of the SNPs were situated in genes previously linked to processes involved with MS, such as the growth and repair of nerve cells.
The researchers said “The beneficial outcomes of interferon beta therapy for patients in the relapsing-remitting phase of MS have been clearly shown. On the other hand, the effect of this treatment is partial, and a substantial amount of patients are not responders. Hence, in the absence of prognostic clinical, neuroradiological and/or immunological markers of response, the question remains who and when to treat when adverse effects, inconvenience and the cost of the drug are significant.”
Being able to identify genetic mutations that have an effect on response to interferon gives us important new information about how the drug works in the body, bringing medicine that bit closer to rational drug design and personalized medicine, the researchers explain.
The authors stressed that further research is needed to be able to fully predict treatment outcomes based on DNA analysis.
“Genome-Wide Pharmacogenomic Analysis of the Response to Interferon Beta Therapy in Multiple Sclerosis”
Esther Byun, MD; Stacy J. Caillier, BSc; Xavier Montalban, MD; Pablo Villoslada, MD, PhD; Oscar Fernández, MD; David Brassat, MD; Manuel Comabella, MD, PhD; Joanne Wang, MPH; Lisa F. Barcellos, PhD; Sergio E. Baranzini, PhD; Jorge R. Oksenberg, PhD
Arch Neurol. 2008;65(3):(doi:10.1001/archneurol.2008.47).
Written by – Christian Nordqvist