Role of genetic susceptibility variants in predicting clinical course in multiple sclerosis: a cohort study

Pan, Gongbu, Simpson, Steve, Jr., van der Mei, Ingrid, Charlesworth, Jac C., Lucas, Robyn, Ponsonby, Anne-Louise, Zhou, Yuan, Wu, Feitong, Taylor, Bruce V, Lucas, Robyn M., Dear, Keith, Dwyer, Terry, Blizzard, Leigh, Broadley, Simon, Kilpatrick, Trevor, Williams, David, Lechner-Scott, Jeanette, Shaw, Cameron, Chapman, Caron, Coulthard, Alan and Valery, Patricia (2016) Role of genetic susceptibility variants in predicting clinical course in multiple sclerosis: a cohort study. Journal of Neurology, Neurosurgery and Psychiatry, . doi:10.1136/jnnp-2016-313722

Author Pan, Gongbu
Simpson, Steve, Jr.
van der Mei, Ingrid
Charlesworth, Jac C.
Lucas, Robyn
Ponsonby, Anne-Louise
Zhou, Yuan
Wu, Feitong
Taylor, Bruce V
Lucas, Robyn M.
Dear, Keith
Dwyer, Terry
Blizzard, Leigh
Broadley, Simon
Kilpatrick, Trevor
Williams, David
Lechner-Scott, Jeanette
Shaw, Cameron
Chapman, Caron
Coulthard, Alan
Valery, Patricia
Title Role of genetic susceptibility variants in predicting clinical course in multiple sclerosis: a cohort study
Journal name Journal of Neurology, Neurosurgery and Psychiatry   Check publisher's open access policy
ISSN 1468-330X
Publication date 2016-08-24
Sub-type Article (original research)
DOI 10.1136/jnnp-2016-313722
Open Access Status Not yet assessed
Total pages 9
Place of publication London, United Kingdom
Publisher B M J Group
Language eng
Formatted 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.
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Document type: Journal Article
Sub-type: Article (original research)
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