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https://hdl.handle.net/2440/138787
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Type: | Journal article |
Title: | Role of genetic susceptibility variants in predicting clinical course in multiple sclerosis: A cohort study |
Author: | Pan, G. Simpson, S. van der Mei, I. Charlesworth, J.C. Lucas, R. Ponsonby, A.L. Zhou, Y. Wu, F. Taylor, B.V. Dear, K. Dwyer, T. Blizzard, L. Broadley, S. Kilpatrick, T. Williams, D. Lechner-Scott, J. Shaw, C. Chapman, C. Coulthard, A. Valery, P. |
Citation: | Journal of Neurology, Neurosurgery and Psychiatry, 2016; 87(11):1204-1211 |
Publisher: | BMJ Publishing Group |
Issue Date: | 2016 |
ISSN: | 0022-3050 1468-330X |
Statement of Responsibility: | Gongbu Pan, Steve Simpson Jr, Ingrid van der Mei, Jac C Charlesworth, Robyn Lucas, Anne-Louise Ponsonby, Yuan Zhou, Feitong Wu, AusLong/ Ausimmune Investigator Group, Bruce V Taylor ... Keith Dear ... et al. |
Abstract: | Background: The genetic drivers of multiple sclerosis (MS) clinical course are essentially unknown with limited data arising from severity and clinical phenotype analyses in genome-wide association studies. Methods: Prospective cohort study of 127 first demyelinating events with genotype data, where 116 MS risk-associated single nucleotide polymorphisms (SNPs) were assessed as predictors of conversion to MS, relapse and annualised disability progression (Expanded Disability Status Scale, EDSS) up to 5-year review (ΔEDSS). Survival analysis was used to test for predictors of MS and relapse, and linear regression for disability progression. The top 7 SNPs predicting MS/relapse and disability progression were evaluated as a cumulative genetic risk score (CGRS). Results: We identified 2 non-human leucocyte antigen (HLA; rs12599600 and rs1021156) and 1 HLA (rs9266773) SNP predicting both MS and relapse risk. Additionally, 3 non-HLA SNPs predicted only conversion to MS; 1 HLA and 2 non-HLA SNPs predicted only relapse; and 7 non-HLA SNPs predicted ΔEDSS. The CGRS significantly predicted MS and relapse in a significant, dose-dependent manner: those having ≥5 risk genotypes had a 6-fold greater risk of converting to MS and relapse compared with those with ≤2. The CGRS for ΔEDSS was also significant: those carrying ≥6 risk genotypes progressed at 0.48 EDSS points per year faster compared with those with ≤2, and the CGRS model explained 32% of the variance in disability in this study cohort. Conclusions: These data strongly suggest that MS genetic risk variants significantly influence MS clinical course and that this effect is polygenic. |
Keywords: | Genetic Variation |
Rights: | © Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ |
DOI: | 10.1136/jnnp-2016-313722 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/544922 |
Published version: | http://dx.doi.org/10.1136/jnnp-2016-313722 |
Appears in Collections: | Public Health publications |
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