Genome-wide pharmacogenomic analysis of the response to interferon beta therapy in multiple sclerosis.
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.


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


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


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


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


METHODS
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 alpha1, 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.
Byun
Esther
E
Department of Neurology, University of California, San Francisco, San Francisco, CA 94143-0435, USA.
Caillier
Stacy J
SJ
Montalban
Xavier
X
Villoslada
Pablo
P
Fernández
Oscar
O
Brassat
David
D
Comabella
Manuel
M
Wang
Joanne
J
Barcellos
Lisa F
LF
Baranzini
Sergio E
SE
Oksenberg
Jorge R
JR
D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins / Q000235:genetics; D015331:Cohort Studies; D024181:Collagen Type XIII / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D016678:Genome; D053673:Glypicans / Q000235:genetics; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D016899:Interferon-beta / Q000627:therapeutic use*; D008297:Male; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D011509:Proteoglycans / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D000099249:Proteoglycan Link Protein
D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D024181:Collagen Type XIII; D016326:Extracellular Matrix Proteins; D053673:Glypicans; D007155:Immunologic Factors; D016899:Interferon-beta; D009419:Nerve Tissue Proteins; D011509:Proteoglycans; D014157:Transcription Factors; D000099249:Proteoglycan Link Protein; C502963:NPAS3 protein, human; C033668:calpastatin