title: SIRT1 as a potential biomarker of response to treatment with glatiramer acetate in multiple sclerosis.
abstract: SIRT1, a NAD dependent histone and protein deacetylase, is a member of the histone deacetylase class III family. We previously showed that SIRT1 mRNA expression is significantly lower in peripheral blood mononuclear cells (PBMCs) of multiple sclerosis (MS) patients during relapses than in stable patients. We have now investigated SIRT1 as a possible biomarker to predict relapse as well as responsiveness to glatiramer acetate (GA) treatment in relapsing-remitting MS (RRMS) patients. Over the course of 2years, a cohort of 15 GA-treated RRMS patients were clinically monitored using the Expanded Disability Status Scale and assessed for MS relapses. Blood samples collected from MS patients were analyzed for levels of SIRT1 and histone H3 lysine 9 (H3K9) acetylation and dimethylation. During relapses, MS patients had a lower expression of SIRT1 mRNA than did stable MS patients. In addition, there was a significant decrease in H3K9 dimethylation (H3K9me2) during relapses in MS patients when compared to stable patients (p=0.01). Responders to GA treatment had significantly higher SIRT1 mRNA (p=0.01) and H3K9me2 levels than did non-responders (p=0.018). Receiver operating characteristic analysis was used to assess the predictive power of SIRT1 and H3K9me2 as putative biomarkers: for SIRT1 mRNA, the predictive value for responsiveness to GA treatment was 70% (p=0.04) and for H3K9me2 was 71% (p=0.03). Our data suggest that SIRT1 and H3K9me2 could serve as potential biomarkers for evaluating patients' responsiveness to GA therapy in order to help guide treatment decisions in MS.
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hewes
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Tatomir
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Kruszewski
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Rao
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA; Research Service, Veterans Administration Maryland Health Care System, Baltimore, MD, USA.
authors.forename: Cosmin A
authors.initials: CA
authors.lastname: Tegla
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ciriello
authors.affiliation: Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Vingh
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA; Veterans Administration Multiple Sclerosis Center of Excellence, Baltimore, MD, USA.
authors.forename: Walter
authors.initials: W
authors.lastname: Royal
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA; Veterans Administration Multiple Sclerosis Center of Excellence, Baltimore, MD, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bever
authors.affiliation: Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Violeta
authors.initials: V
authors.lastname: Rus
authors.affiliation: Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, USA; Research Service, Veterans Administration Maryland Health Care System, Baltimore, MD, USA; Veterans Administration Multiple Sclerosis Center of Excellence, Baltimore, MD, USA. Electronic address: hrus@umaryland.edu.
authors.forename: Horea
authors.initials: H
authors.lastname: Rus
mesh_terms: D000107:Acetylation; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D000068717:Glatiramer Acetate / Q000627:therapeutic use*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D006657:Histones; D012333:RNA, Messenger; D000068717:Glatiramer Acetate; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Biomarker; Glatiramer acetate; Histone H3; Methylation; Multiple sclerosis; SIRT1