TY - JOUR
T1 - Variation within MBP gene predicts disease course in multiple sclerosis
AU - Zhou, Yuan
AU - Simpson, Steve
AU - Charlesworth, Jac C.
AU - van der Mei, Ingrid
AU - Lucas, Robyn M.
AU - Ponsonby, Anne Louise
AU - Taylor, Bruce V.
AU - Dear, Keith
AU - Dwyer, Terry
AU - Blizzard, Leigh
AU - Broadley, Simon
AU - Kilpatrick, Trevor
AU - Williams, David
AU - Lechner-Scott, Jeanette
AU - Shaw, Cameron
AU - Chapman, Caron
AU - Coulthard, Alan
AU - Valery, Patricia
N1 - Publisher Copyright:
© 2017 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.
PY - 2017/4
Y1 - 2017/4
N2 - 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.
AB - 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.
KW - clinically definite MS
KW - expanded disability status scale
KW - genetics and single-nucleotide polymorphism
KW - myelin basic protein
KW - relapse
UR - http://www.scopus.com/inward/record.url?scp=85014773996&partnerID=8YFLogxK
U2 - 10.1002/brb3.670
DO - 10.1002/brb3.670
M3 - Article
SN - 2157-9032
VL - 7
JO - Brain and Behavior
JF - Brain and Behavior
IS - 4
M1 - e00670
ER -