title: Complement regulator factor H as a serum biomarker of multiple sclerosis disease state.
abstract: Multiple sclerosis has a variable phenotypic presentation and subsequent disease course that, although unpredictable at disease onset, is of crucial importance in guiding interventions. Effective and accessible biomarkers are required in order to stratify patients and inform treatment. We examined whether the complement regulator factor H and its Tyr402His polymorphism, recently implicated as biomarkers in other chronic inflammatory central nervous system conditions, might identify or predict specific pathological processes and outcomes in multiple sclerosis. Employing novel assays, we measured factor H and its His402 variant in serum from 350 patients with multiple sclerosis classified according to disease course and relapse status. Serum factor H levels were significantly higher in progressive disease (P < 0.001) compared to controls and relapsing patients, after controlling for variables including disease duration, age, gender, disability and treatment. Serum factor H levels were capable of distinguishing secondary progressive from relapsing remitting disease (excluding patients in clinical relapse) with a sensitivity of 89.41%, specificity of 69.47% and a positive predictive value of 72.38%. Acute relapse was also associated with transiently increased factor H levels (P = 0.009) compared to stable relapsing disease. In clinically stable patients, factor H levels remained constant over 1 year (coefficient of variation percentage = 6.8), however, in patients in transition from relapsing to progressive disease, factor H levels significantly increased over a period of 2 years (P = 0.007). Concentration of the His402 variant in heterozytgotes was significantly higher in secondary progressive (P < 0.01) and primary progressive (P < 0.05) disease, suggesting altered expression or consumption of variants when factor H is upregulated. Serum factor H may be an effective indicator of progression and a practical and accessible biomarker and stratifying tool in determining disease course, providing objective evidence to help guide therapeutic decisions.
authors.affiliation: Department of Neurosciences, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: Ingram
authors.forename: Svetlana
authors.initials: S
authors.lastname: Hakobyan
authors.forename: Claire L
authors.initials: CL
authors.lastname: Hirst
authors.forename: Claire L
authors.initials: CL
authors.lastname: Harris
authors.forename: Trevor P
authors.initials: TP
authors.lastname: Pickersgill
authors.forename: Mark D
authors.initials: MD
authors.lastname: Cossburn
authors.forename: Sam
authors.initials: S
authors.lastname: Loveless
authors.forename: Neil P
authors.initials: NP
authors.lastname: Robertson
authors.forename: Bryan Paul
authors.initials: BP
authors.lastname: Morgan
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism; D017242:Complement Factor H / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000097:blood* / Q000175:diagnosis / Q000235:genetics; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood* / Q000175:diagnosis / Q000235:genetics; D011110:Polymorphism, Genetic; D012680:Sensitivity and Specificity; D013997:Time Factors
chemical_list: D015415:Biomarkers; D017242:Complement Factor H