Journal
MULTIPLE SCLEROSIS JOURNAL
Volume 22, Issue 12, Pages 1528-1535Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1177/1352458515624269
Keywords
Genetics; multiple sclerosis; relapsing/remitting; outcome measurement; vitamin D
Categories
Funding
- National MS Society Sylvia Lawry Award
- Foundation for the Consortium of MS Centers
- NIH BIRCWH program [5K12HD052163]
- Race
- National MS Society [HC 0165]
- NIH [R01AI076544, R01NS049510, R01ES017080, R01NS071463]
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Background: Genetic ancestry, sex, and individual alleles have been associated with multiple sclerosis (MS) susceptibility. Objective: To determine whether established risk factors for disease onset are associated with relapse rate in pediatric MS. Methods: Whole-genome genotyping was performed for 181 MS or high-risk clinically isolated syndrome patients from two pediatric MS centers. Relapses and disease-modifying therapies were recorded as part of continued follow-up. Participants were characterized for 25-hydroxyvitamin D serum status. Ancestral estimates (STRUCTURE v2.3.1), human leukocyte antigen (HLA)-DRB1*15 carrier status (direct sequencing), sex, and a genetic risk score (GRS) of 110 non-HLA susceptibility single-nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate with Cox and negative binomial regression models. Results: Over 622 patient-years, 408 relapses were captured. Girls had greater relapse rate than boys (incident rate ratio (IRR) = 1.40, 95% confidence interval (CI) = 1.04-1.87, p = 0.026). Participants were genetically diverse; similar to 40% (N = 75) had <50% European ancestry. HLA-DRB1*15 status modified the association of vitamin D status (p(ixn) = 0.022) with relapse rate (per 10 ng/mL, in DRB1*15+ hazard ratio (HR) = 0.72, 95% CI = 0.58-0.88, p = 0.002; in DRB1*15-HR = 0.96, 95% CI = 0.83-1.12, p = 0.64). Neither European ancestry nor GRS was associated with relapse rate. Conclusion: We demonstrate that HLA-DRB1*15 modifies the association of vitamin D status with relapse rate. Our findings emphasize the need to pursue disease-modifying effects of MS genes in the context of environmental factors.
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