Genome-wide scan of 500,000 single-nucleotide polymorphisms among responders and nonresponders to interferon beta therapy in multiple sclerosis.
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.


METHODS
Genome-wide scan.


METHODS
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.


METHODS
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.
Comabella
Manuel
M
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. mcomabel@ir.vhebron.net
Craig
David W
DW
Morcillo-Suárez
Carlos
C
Río
Jordi
J
Navarro
Arcadi
A
Fernández
Marta
M
Martin
Roland
R
Montalban
Xavier
X
D000243:Adenosine Deaminase / Q000235:genetics; D000328:Adult; D000483:Alleles; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015331:Cohort Studies; D004265:DNA Helicases / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D020690:GTPase-Activating Proteins; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D016899:Interferon-beta / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D016601:RNA-Binding Proteins; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D018091:Receptors, AMPA / Q000235:genetics; D011994:Recombinant Proteins / Q000627:therapeutic use; D014157:Transcription Factors / Q000235:genetics; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics
D000970:Antineoplastic Agents; D020690:GTPase-Activating Proteins; C508033:IFNAR2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D016601:RNA-Binding Proteins; D018091:Receptors, AMPA; D011994:Recombinant Proteins; C473607:STARD13 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C529572:ZFAT protein, human; C104723:glutamate receptor ionotropic, AMPA 3; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; C115635:citron-kinase; D017346:Protein Serine-Threonine Kinases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; D004265:DNA Helicases; C115322:CHD3 protein, human