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OBJECTIVE: Prognosis following a first demyelinating event is difficult to predict, with no genetic markers of MS progression currently identified. Myelin basic protein (MBP) is a major component of the myelin sheath of CNS neurons and may play a central role in demyelinating diseases such as MS. However, genetic variation in MBP has not been implicated in MS onset risk in large genome-wide association studies. We hypothesized that genetic variations in MBP may be a determinant of MS clinical course. MATERIALS AND METHODS: We investigated whether variations in the MBP gene altered clinical course (conversion to MS and/or relapse, and annualized change in disability), using a prospectively collected longitudinal cohort study of 127 persons who had had a first demyelinating event, followed up to the 5-year review. RESULTS: We found one variant, rs12959006, predicted worse clinical outcomes. The risk genotype (CT + TT) was significantly associated with hazard of relapse (HR = 1.74, 95% CI = 1.19-2.56, p = .005) and of greater annualized disability progression (β = 0.18, 95% CI = 0.06-0.30, p = .004). We also found a significant interaction between the risk genotype and baseline anti-HHV6 IgG in predicting MS (pinteraction = 0.05) and relapse (pinteraction = 0.02). Functional prediction analysis showed this variant is the target of many transcription factors and the binding sites of miR-218 and miR-188-3p. CONCLUSIONS: Our results provide novel insights into the role of genetic variation within the MBP gene predicting MS clinical course, both directly and by interaction with known environmental MS risk factors.

Original publication

DOI

10.1002/brb3.670

Type

Journal article

Journal

Brain Behav

Volume

7

Keywords

clinically definite MS, expanded disability status scale, genetics and single‐nucleotide polymorphism, myelin basic protein, relapse, Case-Control Studies, Disease Progression, Genetic Predisposition to Disease, Genetic Variation, Genotyping Techniques, Herpesvirus 6, Human, Immunoglobulin G, Kaplan-Meier Estimate, Longitudinal Studies, Multiple Sclerosis, Myelin Basic Protein, Prognosis, Proportional Hazards Models, Prospective Studies, Risk, Severity of Illness Index