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Variation within MBP gene predicts disease course in multiple sclerosis
Yuan Zhou1, Steve Simpson1, Jac C Charlesworth1
1Menzies Institute for Medical Research University of Tasmania Hobart TAS Australia.
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.
Insights
Genetic variations in the Myelin Basic Protein (MBP) gene may predict Multiple Sclerosis (MS) progression. A specific MBP variant (rs12959006) was linked to increased relapse risk and disability, and interacted with viral factors.
Area of Science:
- Neuroimmunology
- Genetics of Neurological Disorders
- Myelin Biology
Background:
- Prognosis after a first demyelinating event, indicative of potential Multiple Sclerosis (MS), is challenging to predict.
- Currently, no genetic markers reliably forecast MS progression.
- Myelin Basic Protein (MBP) is crucial for myelin sheath integrity and implicated in demyelinating diseases like MS, yet its genetic role in MS onset remains unclear.
Purpose of the Study:
- To investigate if genetic variations within the Myelin Basic Protein (MBP) gene influence the clinical course of Multiple Sclerosis (MS).
- To determine if MBP gene variations impact conversion to MS, relapse rates, and disability progression.
- To explore potential interactions between MBP gene variants and environmental factors in MS pathogenesis.
Main Methods:
- A prospective longitudinal cohort study followed 127 individuals after their first demyelinating event for up to 5 years.
- Genotyping was performed to analyze variations in the MBP gene.
- Clinical outcomes, including conversion to MS, relapse occurrence, and annualized disability change, were assessed.
Main Results:
- A specific MBP gene variant, rs12959006, was significantly associated with worse clinical outcomes.
- Carriers of the risk genotype (CT + TT) showed a higher hazard of relapse (HR=1.74) and greater annualized disability progression (β=0.18).
- Significant interactions were observed between the risk genotype and baseline anti-HHV6 IgG levels in predicting MS and relapse, suggesting a combined effect with viral factors. Functional analysis indicated the variant is targeted by transcription factors and microRNAs (miR-218, miR-188-3p).
Conclusions:
- Genetic variations in the Myelin Basic Protein (MBP) gene can predict the clinical course of Multiple Sclerosis (MS).
- The identified MBP variant (rs12959006) directly influences MS progression and interacts with environmental factors like HHV6 infection.
- These findings offer new insights into the genetic determinants of MS progression and highlight potential therapeutic targets.