RESUMEN
Up to 50% of multiple sclerosis (MS) patients do not respond to interferon-beta (IFN-ß) treatment and determination of response requires lengthy clinical follow-up of up to 2 years. Response predictive genetic markers would significantly improve disease management. We aimed to identify IFN-ß treatment response genetic marker(s) by performing a two-stage genome-wide association study (GWAS). The GWAS was carried out using data from 151 Australian MS patients from the ANZgene/WTCCC2 MS susceptibility GWAS (responder (R)=51, intermediate responders=24 and non-responders (NR)=76). Of the single-nucleotide polymorphisms (SNP) that were validated in an independent group of 479 IFN-ß-treated MS patients from Australia, Spain and Italy (R=273 and NR=206), eight showed evidence of association with treatment response. Among the replicated associations, the strongest was observed for FHIT (Fragile Histidine Triad; combined P-value 6.74 × 10-6) and followed by variants in GAPVD1 (GTPase activating protein and VPS9 domains 1; combined P-value 5.83 × 10-5) and near ZNF697 (combined P-value 8.15 × 10-5).
Asunto(s)
Interferón beta/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Adulto , Australia , Femenino , Marcadores Genéticos/genética , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Italia , Masculino , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple/genética , EspañaRESUMEN
Multiple Sclerosis (MS) is a neurological condition driven in part by immune cells from the peripheral circulation, the targets for current successful therapies. The autoimmune and MS risk gene ZMIZ1 is underexpressed in blood in people with MS. We show that, from three independent sets of transcriptomic data, expression of ZMIZ1 is tightly correlated with that of hundreds of other genes. Further we show expression is partially heritable (heritability 0.26), relatively stable over time, predominantly in plasmacytoid dendritic cells and non-classical monocytes, and that levels of ZMIZ1 protein expression are reduced in MS. ZMIZ1 gene expression is increased in response to calcipotriol (1,25 Vitamin D3) (p < 0.0003) and associated with Epstein Barr Virus (EBV) EBNA-1 antibody titre (p < 0.004). MS therapies fingolimod and dimethyl fumarate altered blood ZMIZ1 gene expression compared to untreated MS. The phenotype indicates susceptibility to MS, and may correspond with clinical response and represent a novel clinical target.
Asunto(s)
Autoinmunidad/genética , Esclerosis Múltiple/etiología , Esclerosis Múltiple/metabolismo , Fenotipo , Factores de Transcripción/genética , Vitamina D/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Estudios de Casos y Controles , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Susceptibilidad a Enfermedades , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/inmunología , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Genotipo , Herpesvirus Humano 4/inmunología , Humanos , Patrón de Herencia , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/metabolismo , Esclerosis Múltiple/patología , Polimorfismo de Nucleótido Simple , Estaciones del Año , Factores de Transcripción/metabolismo , Vitamina D/farmacología , Adulto JovenRESUMEN
The data presented in this article are related to the research article entitled "The autoimmune risk gene ZMIZ1 is a vitamin D responsived marker of a molecular phenotype of multiple sclerosis" Fewings et al. (2017) [1]. Here we identify the set of genes correlated with ZMIZ1 in multiple cohorts, provide phenotypic details on those cohorts, and identify the genes negatively correlated with ZMIZ1 and the cells predominantly expressing those genes. We identify the metabolic pathways in which the molecular phenotype genes are over-represented. Finally, we present the flow cytometry gating strategy we have used to identify the immune cells from blood which are producing ZMIZ1 and RPS6.