Variation within MBP gene predicts disease course in multiple sclerosis

Abstract

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.