IFN-beta pharmacogenomics in multiple sclerosis.
Multiple sclerosis (MS) is a condition of the CNS marked by inflammation and neurodegeneration. Interferon (IFN)-beta 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-beta 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-beta response modifiers. One hit, glypican 5 (GPC5), was recently replicated in an independent study of IFN-beta 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-beta.
Vandenbroeck
Koen
K
Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), Leioa, Spain. k.vandenbroeck@ikerbasque.org
Urcelay
Elena
E
Comabella
Manuel
M
D020869:Gene Expression Profiling; D053673:Glypicans / Q000235:genetics; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000627:therapeutic use*; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins
C106228:GPC5 protein, human; D053673:Glypicans; D007370:Interferon Type I; D011994:Recombinant Proteins