Document Detail

Genome-wide scan of 500,000 single-nucleotide polymorphisms among responders and nonresponders to interferon beta therapy in multiple sclerosis.
MedLine Citation:
PMID:  19667218     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Interferon beta is 1 of 2 first-line treatments for relapsing-remitting multiple sclerosis (MS). However, not all patients respond to interferon beta therapy, and to date there is a lack of surrogate markers that reliably correlate with responsiveness to interferon beta therapy in MS.
OBJECTIVE: To identify allelic variants that influence response to interferon beta therapy in patients with MS.
DESIGN: Genome-wide scan.
SETTING: Academic research. Patients Two hundred patients having relapsing-remitting MS treated with interferon beta and having a follow-up period of at least 2 years were classified as responders or nonresponders to treatment based on stringent clinical criteria.
MAIN OUTCOME MEASURES: In the first phase of the study, a pooling-based genome-wide association study of 428 867 single-nucleotide polymorphisms (SNPs) was performed in 53 responders and 53 nonresponders to interferon beta therapy. After applying several selection criteria, 383 SNPs were individually genotyped in an independent validation cohort of 49 responders and 45 nonresponders to interferon beta therapy using a different genotyping platform.
RESULTS: Eighteen SNPs had uncorrected P < .05 associated with interferon beta responder status in the validation cohort. Of these, 7 SNPs were located in genes that code for alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid-type glutamate receptor GRIA3, type 1 interferon-related proteins ADAR and IFNAR2, cell cycle-dependent protein CIT, zinc finger proteins ZFAT and ZFHX4, and guanosine triphosphatase-activating protein STARD13.
CONCLUSIONS: This study supports an underlying polygenic response to interferon beta treatment in MS and highlights the importance of the glutamatergic system in patient response to interferon beta therapy.
Manuel Comabella; David W Craig; Carlos Morcillo-Suárez; Jordi Río; Arcadi Navarro; Marta Fernández; Roland Martin; Xavier Montalban
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Archives of neurology     Volume:  66     ISSN:  1538-3687     ISO Abbreviation:  Arch. Neurol.     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-08-11     Completed Date:  2009-08-20     Revised Date:  2013-02-11    
Medline Journal Info:
Nlm Unique ID:  0372436     Medline TA:  Arch Neurol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  972-8     Citation Subset:  AIM; IM    
Centre d'Esclerosi Múltiple de Catalunya, Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d'Hebron, Edifici Escola d'Infermeria 2 feminine planta, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
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MeSH Terms
Adenosine Deaminase / genetics
Antineoplastic Agents / therapeutic use*
Cohort Studies
DNA Helicases / genetics
Follow-Up Studies
Genome-Wide Association Study*
Interferon-beta / therapeutic use*
Intracellular Signaling Peptides and Proteins
Middle Aged
Multiple Sclerosis, Relapsing-Remitting / drug therapy*,  genetics*
Polymorphism, Single Nucleotide / genetics*
Protein-Serine-Threonine Kinases
Receptor, Interferon alpha-beta / genetics
Receptors, AMPA / genetics
Recombinant Proteins / therapeutic use
Transcription Factors / genetics
Treatment Outcome
Tumor Suppressor Proteins / genetics
Reg. No./Substance:
0/Antineoplastic Agents; 0/IFNAR2 protein, human; 0/Intracellular Signaling Peptides and Proteins; 0/Receptors, AMPA; 0/Recombinant Proteins; 0/STARD13 protein, human; 0/Transcription Factors; 0/Tumor Suppressor Proteins; 0/ZFAT protein, human; 0/glutamate receptor ionotropic, AMPA 3; 156986-95-7/Receptor, Interferon alpha-beta; 77238-31-4/Interferon-beta; EC 2.7.1.-/citron-kinase; EC Kinases; EC 3.5.4.-/dsRNA adenosine deaminase; EC Deaminase; EC 3.6.1.-/DNA Helicases; EC protein, human

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