ObjectivePrognosis 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 MethodsWe 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. ResultsWe 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 (=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 (p(interaction) =0.05) and relapse (p(interaction)=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. ConclusionsOur 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.