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Genetic variation in the gene LRP2 increases relapse risk in multiple sclerosis
Methods: We conducted a genome-wide association analysis (GWAS) to identify genetic variants that predict MS relapse risk, using a three-stage approach. First, GWAS was conducted using the southern Tasmania MS Longitudinal Study with 141 cases followed prospectively for a mean of 2.3 years. Second, GWAS was conducted using the Ausimmune Longitudinal Study with 127 cases having a classic first demyelinating event followed for 5 years from onset. Third, the top hits with p<5.0×10-6 from the first two stages were combined with a longitudinal US paediatric MS cohort with 181 cases followed for 5 years after onset. Predictors of time to relapse were evaluated by a mixed effects Cox model. An inverse variance fixed effects model was then used to undertake a meta-analysis.
Results: In the pooled results, using these three unique longitudinal MS cohorts, we discovered one novel locus (LRP2; most significant single nucleotide polymorphism rs12988804) that reached genome-wide significance in predicting relapse risk (HR=2.18, p=3.30×10-8). LRP2 is expressed on the surface of many central nervous system cells including neurons and oligodendrocytes and is a critical receptor in axonal guidance.
Conclusions: The finding of a genetic locus that has extensive effects on neuronal development and repair is of interest as a potential modulator of MS disease course.
Publication titleJournal of Neurology, Neurosurgery and Psychiatry
Department/SchoolMenzies Institute for Medical Research
PublisherB M J Publishing Group
Place of publicationBritish Med Assoc House, Tavistock Square, London, England, Wc1H 9Jr
Rights statement© 2017 Article authors