Interferon response genes and the therapeutic response to interferons

“The following study may be hard to understand if you don’t have a biology background. What these investigators are doing is simply studying variants in a gene that are affected by intereferon beta. Interferon beta is injected into your body and binds to a receptor on white blood cells causing it to change the way it functions. To do this interferon beta affects the way certain genes function, by switching some genes on and other off. The level of ON and OFF varies like a dimmer switch and depending on what variation you have in your genes the affects differ from one person to the next. This study found that if you have a particular variant of the gene IRF5 you were less likely to respond compared to someone with another variant.”

Vosslamber et al. Interferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferonβ therapy in multiple sclerosis. Genes Immun. 2011 Sep;12(6):466-72. doi: 10.1038/gene.2011.18.

Background: Interferon-β (IFNβ) therapy is effective in approximately half of the MSers with 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, the investigators carried out a candidate gene study of IRF5 gene variants in relation to the pharmacological and clinical response upon IFNβ treatment. 

ResultsThey found that MSers with the IRF5 rs2004640-TT and rs47281420-AA genotype exerted a poor pharmacological response to IFNβ compared with MSers carrying the respective G-alleles (P=0.0006 and P=0.0023, respectively). Moreover, MSers 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). 

Conclusions: 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.
“This is now the third group that have found that genes linked to an interferon signature in the peripheral blood is a poor response marker for interferon beta in MS. This suggest that a test may be developed to use in clinical practice to predict interferon responses. Before this happens this data will need to be reproduced in a larger number of MSers on treatment. Fortunately, a lot of data has already been collected in other clinical trials making this a relatively easy task to do; assuming the Pharma companies who have this data agree to do the analysis.”

“The implications of this work are large and may result in a segmentation of the DMT market based on biomarkers. At last some data to truly personalise treatments! I wonder if NICE and the payers will accept this data?”

2 thoughts on “Interferon response genes and the therapeutic response to interferons”

  1. Unfortunately I don't think this would result in non-responders being allowed to have early aggressive treatments- more likely they would be offered glatimer acetate instead, and possibly RRMSers would get even less choice initially. The makers of Copaxone would be rubbing their hands with glee.

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