title: Genetic, Immune-Inflammatory, and Oxidative Stress Biomarkers as Predictors for Disability and Disease Progression in Multiple Sclerosis.
abstract: The aim of this study was to evaluate the TNFβ NcoI polymorphism (rs909253) and immune-inflammatory, oxidative, and nitrosative stress (IO&NS) biomarkers as predictors of disease progression in multiple sclerosis (MS). We included 212 MS patients (150 female, 62 male, mean (±standard deviation (SD)) age = 42.7 ± 13.8 years) and 249 healthy controls (177 female, 72 male, 36.8 ± 11 years). The disability was measured the Expanded Disability Status Scale (EDSS) in 2006 and 2011. We determined the TNFβ NcoI polymorphism and serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-4, IL-10, and IL-17, albumin, ferritin, and plasma levels of lipid hydroperoxides (CL-LOOH), carbonyl protein, advanced oxidation protein products (AOPPs), nitric oxide metabolites (NOx), and total radical-trapping antioxidant parameter (TRAP). The mean EDSS (±SD) in 2006 was 1.62 ± 2.01 and in 2011 3.16 ± 2.29, and disease duration was 7.34 ± 7.0 years. IL-10, TNF-α, IFN-γ, AOPP, and NOx levels were significantly higher and IL-4 lower in MS patients with a higher 2011 EDSS scores (≥3) as compared with those with EDSS < 3. The actual increases in EDSS from 2006 to 2011 were positively associated with TNF-α and IFN-γ. Increased IFN-γ values were associated with higher pyramidal symptoms and increased IL-6 with sensitive symptoms. Increased carbonyl protein and IL-10 but lowered albumin levels predicted cerebellar symptoms. The TNFB1/B2 genotype decreased risk towards progression of pyramidal symptoms. Treatments with IFN-β and glatiramer acetate significantly reduced TNF-α but did not affect the other IO&NS biomarkers or disease progression. Taken together, IO&NS biomarkers and NcoI TNFβ genotypes predict high disability in MS and are associated with different aspects of disease progression. New drugs to treat MS should also target oxidative stress pathways.
authors.affiliation: Health Sciences Postgraduate Program, Health Sciences Center, State University of Londrina, Londrina, Paraná, 86.038-440, Brazil.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Kallaur
authors.affiliation: Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, State University of Londrina, Av. Robert Koch, 60, Londrina, Paraná, CEP 86.038-440, Brazil. reiche@sercomtel.com.br.
authors.forename: Edna Maria Vissoci
authors.initials: EMV
authors.lastname: Reiche
authors.affiliation: Health Sciences Postgraduate Program, Health Sciences Center, State University of Londrina, Londrina, Paraná, 86.038-440, Brazil.
authors.forename: Sayonara Rangel
authors.initials: SR
authors.lastname: Oliveira
authors.affiliation: Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, State University of Londrina, Av. Robert Koch, 60, Londrina, Paraná, CEP 86.038-440, Brazil.
authors.forename: Andrea Name Colado
authors.initials: ANC
authors.lastname: Simão
authors.affiliation: Health Sciences Postgraduate Program, Health Sciences Center, State University of Londrina, Londrina, Paraná, 86.038-440, Brazil.|Outpatient Clinic for Demyelinating Diseases, University Hospital, State University of Londrina, Londrina, Paraná, 86061-335, Brazil.
authors.forename: Wildea Lice de Carvalho Jennings
authors.initials: WLCJ
authors.lastname: Pereira
authors.affiliation: Health Sciences Postgraduate Program, Health Sciences Center, State University of Londrina, Londrina, Paraná, 86.038-440, Brazil.
authors.forename: Daniela Frizon
authors.initials: DF
authors.lastname: Alfieri
authors.affiliation: Health Sciences Postgraduate Program, Health Sciences Center, State University of Londrina, Londrina, Paraná, 86.038-440, Brazil.
authors.forename: Tamires
authors.initials: T
authors.lastname: Flauzino
authors.affiliation: Outpatient Clinic for Demyelinating Diseases, University Hospital, State University of Londrina, Londrina, Paraná, 86061-335, Brazil.
authors.forename: Caio de Meleck
authors.initials: CM
authors.lastname: Proença
authors.affiliation: Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, State University of Londrina, Av. Robert Koch, 60, Londrina, Paraná, CEP 86.038-440, Brazil.
authors.forename: Marcell Alysson Batisti
authors.initials: MAB
authors.lastname: Lozovoy
authors.affiliation: Outpatient Clinic for Demyelinating Diseases, University Hospital, State University of Londrina, Londrina, Paraná, 86061-335, Brazil.|Department of Clinical Medicine, Health Sciences Center, State University of Londrina, Londrina, Paraná, 86.038-440, Brazil.
authors.forename: Damacio Ramón
authors.initials: DR
authors.lastname: Kaimen-Maciel
authors.affiliation: Impact Strategic Research Centre, School of Medicine, Deakin University, Geelong, Victoria, Australia.|Department of Psychiatry, King Chulalongkorn Memorial Hospital, Chulalongkorn, Bangkok, Thailand.
authors.forename: Michael
authors.initials: M
authors.lastname: Maes
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D006233:Persons with Disabilities; D018450:Disease Progression; D005260:Female; D005819:Genetic Markers / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D018384:Oxidative Stress / Q000502:physiology*; D011237:Predictive Value of Tests; D012189:Retrospective Studies
chemical_list: D015415:Biomarkers; D005819:Genetic Markers; D018836:Inflammation Mediators
keywords: Cytokines; Disability; Multiple sclerosis; Oxidative stress; Pyramidal symptoms; TNFβ NcoI polymorphism