Interferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferonβ therapy in multiple sclerosis

• Published in: Genes and immunity Vol. 12; no. 6; pp. 466 - 472
• Main Authors: Vosslamber, S, van der Voort, L F, van den Elskamp, I J, Heijmans, R, Aubin, C, Uitdehaag, B M J, Crusius, J B A, van der PouwKraan, T C T M, Comabella, M, Montalban, X, Hafler, D A, De Jager, P L, Killestein, J, Polman, C H, Verweij, C L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2011; Nature Publishing Group
• Subjects: 631/208/457/649; 631/92/436/434; 692/699/249/1313/1666; 692/700/565/201; Adult; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cohort Studies; Female; Gene Expression; Genetic Variation; Genotype; Genotype & phenotype; Genotypes; Human Genetics; Humans; Immunology; Interferon; Interferon regulatory factor; Interferon Regulatory Factors - genetics; Interferon-beta - pharmacology; Interferon-beta - therapeutic use; Magnetic Resonance Imaging; Male; Multiple sclerosis; Multiple Sclerosis, Relapsing-Remitting - drug therapy; Multiple Sclerosis, Relapsing-Remitting - genetics; original-article; Patients; Polymorphism, Single Nucleotide; Treatment Outcome; β-Interferon; United States; Netherlands; autoimmune diseases; MRI; multiple sclerosis; pharmacogenetics; gene expression
• ISSN: 1466-4879; 1476-5470
• DOI: 10.1038/gene.2011.18

Interferon- β (IFN β ) 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 IFN β treatment. We found that patients with the IRF5 rs2004640-TT and rs47281420-AA genotype exerted a poor pharmacological response to IFN β 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 IFN β 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 IFN β 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 IFN β therapy that might have relevance as biomarker to predict the response to IFN β in multiple sclerosis.