- Title
- Role of genetic susceptibility variants in predicting clinical course in multiple sclerosis: a cohort study
- Creator
- Pan, Gongbu; Simpson, Steve; Williams, David; Lechner-Scott, Jeannette; Van Der Mei, Ingrid; Charlesworth, Jac C.; Lucas, Robyn; Ponsonby, Anne-Louise; Zhou, Yuan; Taylor, Bruce V.
- Relation
- NHMRC
- Relation
- Journal of Neurology, Neurosurgery and Psychiatry Vol. 87, Issue 11, p. 1204-1211
- Publisher Link
- http://dx.doi.org/10.1136/jnnp-2016-313722
- Publisher
- BMJ Group
- Resource Type
- journal article
- Date
- 2016
- Description
- 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.
- Subject
- multiple sclerosis; genetic susceptibility variants; clinical course
- Identifier
- http://hdl.handle.net/1959.13/1346455
- Identifier
- uon:29865
- Identifier
- ISSN:0022-3050
- Language
- eng
- Reviewed
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