期刊
GENES AND IMMUNITY
卷 12, 期 6, 页码 466-472出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/gene.2011.18
关键词
multiple sclerosis; pharmacogenetics; MRI; autoimmune diseases; gene expression
资金
- Bayer Schering Pharma
- Biogen Idec
- Merck Serono
- Teva Pharmaceutical Industries Ltd.
- NIH/NINDS [R37 NS024247, P01 NS038037, R01 NS049477]
- NIH [U19 AI070352, P01 AI073748]
- NIH/Rush University [AG030146, JF2138A1, R01 AG015819]
- Bayer Schering
- Teva
- Merck-Serono
- Novartis
- Glaxo SK
- UCB
- Dutch MS Research Foundation [04-549 MS]
Interferon-beta (IFN beta) 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 beta treatment. We found that patients with the IRF5 rs2004640-TT and rs47281420-AA genotype exerted a poor pharmacological response to IFN beta 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 beta 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 beta 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 beta therapy that might have relevance as biomarker to predict the response to IFN beta in multiple sclerosis. Genes and Immunity (2011) 12, 466-472; doi:10.1038/gene.2011.18; published online 7 April 2011
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