title: Roles of the ubiquitin peptidase USP18 in multiple sclerosis and the response to interferon-β treatment.
abstract: OBJECTIVE
  Ubiquitin specific peptidase 18 (USP18) is a deubiquitinating enzyme that functions as a negative regulator of the type I interferon (IFN) signalling pathway and is specifically induced by type I IFNs. In the present study, previous observations by our group were expanded suggesting an implication of USP18 in multiple sclerosis (MS) based on the finding of a deficient expression of the gene in peripheral blood mononuclear cells from MS patients compared with healthy controls.
  
  
  METHODS
  Two polymorphisms, rs2542109 (intronic) and rs9618216 (promoter), were genotyped in a cohort of 691 relapse-onset MS patients and 1028 healthy controls and in 225 MS patients treated with IFNβ and classified into responders and non-responders after 2 years of treatment according to clinical criteria. Correlations between genotypes and expression levels for USP18 and its target ISG15 were performed by real-time polymerase chain reaction.
  
  
  RESULTS
  Two USP18 haplotypes were significantly associated with MS, TG and CG. Additional experiments revealed that CG carriers were characterized by lower USP18 gene expression levels in peripheral blood mononuclear cells and higher clinical disease activity. Finally, AA homozygosis for the intronic polymorphism rs2542109 was associated with the responder phenotype; however, USP18 expression levels induced by IFNβ did not differ amongst MS patients carrying different rs2542109 genotypes.
  
  
  CONCLUSIONS
  Altogether, these results point to a role of USP18 in MS pathogenesis and the therapeutic response to IFNβ.
authors.affiliation: Servei de Neurologia/Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (CEM-Cat), Hospital Universitari Vall d'Hebron (HUVH), Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Malhotra
authors.forename: C
authors.initials: C
authors.lastname: Morcillo-Suárez
authors.forename: R
authors.initials: R
authors.lastname: Nurtdinov
authors.forename: J
authors.initials: J
authors.lastname: Rio
authors.forename: E
authors.initials: E
authors.lastname: Sarro
authors.forename: M
authors.initials: M
authors.lastname: Moreno
authors.forename: J
authors.initials: J
authors.lastname: Castilló
authors.forename: A
authors.initials: A
authors.lastname: Navarro
authors.forename: X
authors.initials: X
authors.lastname: Montalban
authors.forename: M
authors.initials: M
authors.lastname: Comabella
mesh_terms: D000328:Adult; D016207:Cytokines; D004351:Drug Resistance / Q000235:genetics*; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D016899:Interferon-beta / Q000627:therapeutic use*; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome; D016896:Treatment Outcome; D043222:Ubiquitin Thiolesterase; D014452:Ubiquitins
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D014452:Ubiquitins; C074034:ISG15 protein, human; D016899:Interferon-beta; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase
keywords: USP18 polymorphisms; genetic susceptibility; interferon-β; multiple sclerosis; response to treatment