Genetic predictors of relapse rate in pediatric MS

Mult Scler. 2016 Oct;22(12):1528-1535. doi: 10.1177/1352458515624269. Epub 2016 Jan 14.


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; ~40% (N = 75) had <50% European ancestry. HLA-DRB1*15 status modified the association of vitamin D status (pixn = 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.

Keywords: Genetics; multiple sclerosis; outcome measurement; relapsing/remitting; vitamin D.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Age of Onset
  • Calcitriol / blood*
  • Child
  • Female
  • Follow-Up Studies
  • Genotyping Techniques
  • HLA-DRB1 Chains / genetics*
  • Humans
  • Male
  • Multiple Sclerosis / blood*
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / physiopathology*
  • Recurrence
  • Sex Factors


  • HLA-DRB1 Chains
  • HLA-DRB1*15 antigen
  • Calcitriol