IFN-β Pharmacogenomics in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a condition of the CNS marked by inflammation and neurodegeneration. Interferon (IFN)-β was the first, and still is the main, immunomodulatory treatment for MS. Its clinical efficacy is limited, and a proportion of patients, ranging between 20–55%, do not respond to the therapy. Identification and subsequently, implementation in the clinic of biomarkers predictive for individual therapeutic response would facilitate improved patient care in addition to ensuring a more rational provision of this therapy. In this article, we summarize the main findings from studies addressing the pharmacogenomics of clinical response to IFN-β in MS by either whole-genome association scans, candidate gene or transcriptomics studies. Whole-genome DNA association screens have revealed a high representation of brain-specific genes, and have hinted toward both extracellular ligand-gated ion channels and type I IFNs pathway genes as important categories of genetic IFN-β response modifiers. One hit, glypican 5 (GPC5), was recently replicated in an independent study of IFN-β responsiveness. Recent RNA transcriptomics studies have revealed the occurrence of a pre-existing type I IFN gene-expression signature, composed of genes that are predominantly induced by type I IFNs, as a potential contributing feature of poor response to therapy. Thus, while the outlines of a complex polygenic mechanism are gradually being uncovered, the main challenges for the near future will reside in the robust validation of identified response-modifying genes as well as in the decipherment of the mechanistic relationships between these genes and clinical response to IFN-β.

KEYWORDS::

• IFN-β
• multiple sclerosis
• pharmacogenomics
• polymorphic
• transcriptomics
• type I interferon

Financial & competing interest disclosure

Research on the pharmacogenomics of multiple sclerosis treatments in the laboratories of Koen Vandenbroeck and Manuel Comabella is supported with funding from the European Community‘s Seventh Framework Programme (FP7/21007–2012) under grant agreement Nr 212877 (UEPHA*MS; http://www.reem.es/uepha-ms/). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

Research on the pharmacogenomics of multiple sclerosis treatments in the laboratories of Koen Vandenbroeck and Manuel Comabella is supported with funding from the European Community‘s Seventh Framework Programme (FP7/21007–2012) under grant agreement Nr 212877 (UEPHA*MS; http://www.reem.es/uepha-ms/). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.