title: Pharmacogenetic study of long-term response to interferon-β treatment in multiple sclerosis.
abstract: The aim of the study is the identification of genetic factors that influence the long-term response to interferon-β (IFNβ) (4-year follow-up). We performed a genome-wide association study in 337 IFNβ-treated Italian multiple sclerosis patients at the extreme of treatment response, and we meta-analyzed association effects, integrating results with pathway analysis, gene-expression profiling of IFNβ-stimulated peripheral blood mononuclear cells from 20 healthy controls (HC) and expression quantitative locus (eQTL) analyses. From meta-analysis, 43 markers were associated at P<10-4, and two of them (rs7298096 and rs4726460) pointed to two genes, NINJ2 and TBXAS1, that were significantly downregulated after IFNβ stimulation in HC (P=3.1 × 10-9and 5.6 × 10-10). We also observed an eQTL effect for the allele associated with favorable treatment response (rs4726460A); moreover, TBXAS1 appeared downregulated upon IFNβ administration (β=-0.39; P=0.02). Finally, we found an enrichment of pathways related to inflammatory processes and presynaptic membrane, the latter with involvement of genes related to glutamatergic system (GRM3 and GRIK2), confirming its potential role in the response to IFNβ.
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, CNS Inflammatory Unit, Division of Neuroscience & INSPE, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Clarelli
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, CNS Inflammatory Unit, Division of Neuroscience & INSPE, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Liberatore
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, CNS Inflammatory Unit, Division of Neuroscience & INSPE, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Sorosina
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, CNS Inflammatory Unit, Division of Neuroscience & INSPE, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Osiceanu
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, CNS Inflammatory Unit, Division of Neuroscience & INSPE, San Raffaele Scientific Institute, Milan, Italy.|Department of Neurology and Neurorehabilitation, Division of Neuroscience, INSPE, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Esposito
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, CNS Inflammatory Unit, Division of Neuroscience & INSPE, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Mascia
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, CNS Inflammatory Unit, Division of Neuroscience & INSPE, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Santoro
authors.affiliation: Department of Neurology and Neurorehabilitation, Division of Neuroscience, INSPE, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Pavan
authors.affiliation: Department of Neurology and Neurorehabilitation, Division of Neuroscience, INSPE, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Colombo
authors.affiliation: Department of Neurology and Neurorehabilitation, Division of Neuroscience, INSPE, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Moiola
authors.affiliation: Department of Neurology and Neurorehabilitation, Division of Neuroscience, INSPE, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Martinelli
authors.affiliation: Department of Neurology and Neurorehabilitation, Division of Neuroscience, INSPE, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Comi
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, CNS Inflammatory Unit, Division of Neuroscience & INSPE, San Raffaele Scientific Institute, Milan, Italy.|Department of Neurology and Neurorehabilitation, Division of Neuroscience, INSPE, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Martinelli-Boneschi
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects / Q000627:therapeutic use*; D016899:Interferon-beta / Q000009:adverse effects / Q000627:therapeutic use*; D007558:Italy; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D010597:Pharmacogenetics; D000071185:Pharmacogenomic Testing / Q000379:methods; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D018092:Kainic Acid Receptors / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult; D000097806:GluK2 Kainate Receptor
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D007155:Immunologic Factors; D016899:Interferon-beta; D018092:Kainic Acid Receptors; D018094:Receptors, Metabotropic Glutamate; D000097806:GluK2 Kainate Receptor; C504206:NINJ2 protein, human; C102718:metabotropic glutamate receptor 3