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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):337-344. Published online January 14, 2008 (doi:10.1001/archneurol.2008.47).

Objective  To identify promising candidate genes linked to interindividual differences in the efficacy of interferon beta therapy. Recombinant interferon beta therapy is widely used to reduce disease activity in multiple sclerosis (MS). However, up to 50% of patients continue to have relapses and worsening disability despite therapy.

Design  We used a genome-wide pharmacogenomic approach to identify single-nucleotide polymorphism (SNP) allelic differences associated with interferon beta therapy response.

Setting  Four collaborating centers in the Mediterranean Basin. Data Coordination Center at the University of California, San Francisco.

Patients  A cohort of 206 patients with relapsing-remitting MS followed up prospectively for 2 years after initiation of treatment.

Intervention  DNA was pooled and hybridized to Affymetrix 100K GeneChips. Pooling schemes were designed to minimize confounding batch effects and increase confidence by technical replication.

Main Outcome Measures  Single-nucleotide polymorphism detection. Comparison of allelic frequencies between good responders and nonresponders to interferon beta therapy.

Results  A multianalytical approach detected significant associations between several SNPs and treatment response, which were validated by individual DNA genotyping on an independent platform. After the validation stage was complete, 81 additional individuals were added to the analysis to increase power. We found that responders and nonresponders had significantly different genotype frequencies for SNPs located in many genes, including glypican 5, collagen type XXV 1, hyaluronan proteoglycan link protein, calpastatin, and neuronal PAS domain protein 3.

Conclusions  The reported results address the question of genetic heterogeneity in MS and the response to immunotherapy by analysis of the correlation between different genotypes and clinical response to interferon beta therapy. Many of the detected differences between responders and nonresponders were genes associated with ion channels and signal transduction pathways. The study also suggests that genetic variants in heparan sulfate proteoglycan genes may be of clinical interest in MS as predictors of the response to therapy. In addition to new insights into the mechanistic biology of interferon beta, these results help define the molecular basis of interferon beta therapy response heterogeneity.

Author Affiliations: Department of Neurology, School of Medicine, University of California, San Francisco (Drs Byun, Baranzini, and Oksenberg and Mss Caillier and Wang); Neuroimmunology Unit, Hospital Vall d’Hebron, Barcelona (Drs Montalban and Comabella), Department of Neurology, University of Navarra, Pamplona (Dr Villoslada), and Institute of Clinical Neurosciences, Hospital Regional Universitario Carlos Haya, Malaga (Dr Fernández), Spain; Department of Neurology and Institut national de la santé et de la recherche médicale (INSERM) U563, University of Toulouse III, Toulouse, France (Dr Brassat); and Division of Epidemiology, School of Public Health, University of California, Berkeley (Dr Barcellos).

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