RESUMEN
BACKGROUND AND PURPOSE: 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 IFNß 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 IFNß 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 IFNß.
Asunto(s)
Resistencia a Medicamentos/genética , Endopeptidasas/genética , Factores Inmunológicos/uso terapéutico , Interferón beta/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/genética , Adulto , Citocinas , Endopeptidasas/metabolismo , Femenino , Expresión Génica/efectos de los fármacos , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Esclerosis Múltiple Recurrente-Remitente/enzimología , Polimorfismo de Nucleótido Simple , Reacción en Cadena en Tiempo Real de la Polimerasa , Transcriptoma , Resultado del Tratamiento , Ubiquitina Tiolesterasa , UbiquitinasRESUMEN
BACKGROUND: Chitinase 3-like 1 (CHI3L1) is upregulated in a wide variety of inflammatory conditions. Recent studies have pointed to a role of CHI3L1 in multiple sclerosis (MS) pathogenesis. OBJECTIVE: The objective of this study was to investigate the role of plasma CHI3L1 in MS clinical course and disease activity and to evaluate the effect of interferon-beta (IFNß) treatment on protein levels. METHODS: Plasma CHI3L1 levels were determined by ELISA in 57 healthy controls (HC), 220 untreated MS patients [66 primary progressive MS patients (PPMS), 30 secondary progressive MS patients (SPMS), and 124 relapsing-remitting MS patients (RRMS), 94 during clinical remission and 30 during relapse], and 32 MS patients receiving IFNß treatment. A polymorphism of the CHI3L1 gene, rs4950928, was genotyped in 3274 MS patients and 3483 HC. RESULTS: Plasma CHI3L1 levels were significantly increased in patients with progressive forms of MS compared with RRMS patients and HC. CHI3L1 levels were similar between RRMS patients in relapse and remission. A trend towards decreased CHI3L1 levels was observed in IFNß-treated patients. Allele C of rs4950928 was significantly associated with PPMS patients and with higher plasma CHI3L1 levels. CONCLUSIONS: These findings point to a role of CHI3L1 in patients with progressive forms of MS, particularly in those with PPMS.
Asunto(s)
Adipoquinas/sangre , Lectinas/sangre , Esclerosis Múltiple Crónica Progresiva/sangre , Adipoquinas/genética , Adulto , Proteína 1 Similar a Quitinasa-3 , Ensayo de Inmunoadsorción Enzimática , Femenino , Genotipo , Humanos , Factores Inmunológicos/uso terapéutico , Interferón beta/uso terapéutico , Lectinas/genética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/genética , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple Crónica Progresiva/genética , Polimorfismo de Nucleótido SimpleRESUMEN
Recent studies have revealed an association between interleukin 28B (IL28B) and response to IFN-alpha treatment in hepatitis C patients. Here we investigated the influence of IL28B polymorphisms in the response to interferon-beta (IFNß) in multiple sclerosis (MS) patients. We genotyped two SNPs of the IL28B gene (rs8099917 and rs12979860) in 588 MS patients classified into responders (n=281) and non-responders (n=307) to IFNß. Combined analysis of the study cohorts showed no significant associations between SNPs rs8099917 and rs12979860 and the response to treatment. These findings do not support a role of IL28B polymorphisms in the response to IFNß in MS patients.
Asunto(s)
Interferón beta/fisiología , Interleucinas/genética , Esclerosis Múltiple/inmunología , Polimorfismo de Nucleótido Simple , Adulto , Estudios de Cohortes , Femenino , Genotipo , Humanos , Interferón beta/uso terapéutico , Interferones , Masculino , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/genéticaRESUMEN
We investigated caspase 8 (CASP8) as a candidate gene for multiple sclerosis (MS) susceptibility. Three SNPs (rs2037815, rs12990906 and rs1035140) were genotyped in 546 MS patients and 547 controls. For SNP rs2037815, GG homozygosity was associated with primary progressive multiple sclerosis (PPMS) when compared with relapse-onset MS and controls. We identified risk (GCA) and protective (ACT) haplotypes associated with PPMS when compared with relapse-onset MS and controls. GG homozygosity for SNP rs2037815 in PPMS patients was associated with a trend towards faster disease progression. These findings point to a role of CASP8 polymorphisms in the MS genetic risk in PPMS patients.
Asunto(s)
Caspasa 8/genética , Predisposición Genética a la Enfermedad/genética , Esclerosis Múltiple Crónica Progresiva/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Frecuencia de los Genes/genética , Marcadores Genéticos/genética , Pruebas Genéticas , Genotipo , Haplotipos/genética , Homocigoto , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/metabolismo , Esclerosis Múltiple Crónica Progresiva/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/genética , Índice de Severidad de la EnfermedadRESUMEN
In the present study, we investigated the B-cell translocation gene 1 (BTG1) as a candidate for multiple sclerosis (MS) susceptibility. BTG1 is a member of a family of genes involved in the apoptotic process. We genotyped two SNPs of the BTG1 gene (rs731652 and rs12694) in 550 MS patients and 548 controls. For SNP rs731652, significant associations with relapse-onset MS were found at the allele and genotype levels when compared with controls. We identified a risk haplotype associated with relapse-onset MS. These findings support the hypothesis that BTG1 polymorphisms may influence genetic predisposition for MS, especially in relapse-onset MS patients.