title: Interferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferonβ therapy in multiple sclerosis.
abstract: Interferon-β (IFNβ) therapy is effective in approximately half of the patients with relapsing-remitting multiple sclerosis (RRMS). Clinical non-responders were characterized by an increased expression of IFN response genes before the start of therapy, and a lack of a pharmacologically induced increase in IFN response gene activity. Because Interferon Regulatory Factor 5 (IRF5) is a master regulator of IFN-activity, we carried out a candidate gene study of IRF5 gene variants in relation to the pharmacological and clinical response upon IFNβ treatment. We found that patients with the IRF5 rs2004640-TT and rs47281420-AA genotype exerted a poor pharmacological response to IFNβ compared with patients carrying the respective G-alleles (P=0.0006 and P=0.0023, respectively). Moreover, patients with the rs2004640-TT genotype developed more magnetic resonance imaging (MRI)-based T2 lesions during IFNβ treatment (P=0.003). Accordingly, an association between MRI-based non-responder status and rs2004640-TT genotype was observed (P=0.010). For the rs4728142-AA genotype a trend of an association with more T2 lesions during IFNβ treatment and MRI-based non-responder status was observed (P=0.103 and P=0.154, respectively). The clinical relevance of the rs2004640-TT genotype was validated in an independent cohort wherein a shorter time to first relapse was found (P=0.037). These findings suggest a role for IRF5 gene variation in the pharmacological and clinical outcome of IFNβ therapy that might have relevance as biomarker to predict the response to IFNβ in multiple sclerosis.
authors.affiliation: VU University Medical Center, Department of Pathology, Amsterdam, The Netherlands. s.vosslamber@vumc.nl
authors.forename: S
authors.initials: S
authors.lastname: Vosslamber
authors.forename: L F
authors.initials: LF
authors.lastname: van der Voort
authors.forename: I J
authors.initials: IJ
authors.lastname: van den Elskamp
authors.forename: R
authors.initials: R
authors.lastname: Heijmans
authors.forename: C
authors.initials: C
authors.lastname: Aubin
authors.forename: B M J
authors.initials: BM
authors.lastname: Uitdehaag
authors.forename: J B A
authors.initials: JB
authors.lastname: Crusius
authors.forename: T C T M
authors.initials: TC
authors.lastname: van der Pouw Kraan
authors.forename: T C T M
authors.initials: TC
authors.lastname: van der PouwKraan
authors.forename: M
authors.initials: M
authors.lastname: Comabella
authors.forename: X
authors.initials: X
authors.lastname: Montalban
authors.forename: D A
authors.initials: DA
authors.lastname: Hafler
authors.forename: P L
authors.initials: PL
authors.lastname: De Jager
authors.forename: J
authors.initials: J
authors.lastname: Killestein
authors.forename: C H
authors.initials: CH
authors.lastname: Polman
authors.forename: C L
authors.initials: CL
authors.lastname: Verweij
mesh_terms: D000328:Adult; D015415:Biomarkers; D015331:Cohort Studies; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D016899:Interferon-beta / Q000494:pharmacology / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D016899:Interferon-beta