title: Genetic predictors of relapse rate in pediatric MS.
abstract: Genetic ancestry, sex, and individual alleles have been associated with multiple sclerosis (MS) susceptibility.
  
  
  
  To determine whether established risk factors for disease onset are associated with relapse rate in pediatric MS.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: UCSF Pediatric Multiple Sclerosis Center, San Francisco, CA, USA Jennifer.Graves@ucsf.edu.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Graves
authors.affiliation: Genetic Epidemiology and Genomics Lab, School of Public Health, and California Institute for Quantitative Biosciences, University of California-Berkeley, Berkeley, CA, USA.
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Barcellos
authors.affiliation: Genetic Epidemiology and Genomics Lab, School of Public Health, and California Institute for Quantitative Biosciences, University of California-Berkeley, Berkeley, CA, USA.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Shao
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, USA.
authors.forename: Janelle
authors.initials: J
authors.lastname: Noble
authors.affiliation: The Multiple Sclerosis Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Mowry
authors.affiliation: Genetic Epidemiology and Genomics Lab, School of Public Health, and California Institute for Quantitative Biosciences, University of California-Berkeley, Berkeley, CA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Quach
authors.affiliation: National Pediatric Multiple Sclerosis Center, Stony Brook, NY, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Belman
authors.affiliation: Data Coordinating and Analysis Center, University of Utah, Salt Lake City, UT, USA.
authors.forename: T Charles
authors.initials: TC
authors.lastname: Casper
authors.affiliation: National Pediatric Multiple Sclerosis Center, Stony Brook, NY, USA.
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Krupp
authors.affiliation: UCSF Pediatric Multiple Sclerosis Center, San Francisco, CA, USA.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Waubant
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002117:Calcitriol / Q000097:blood*; D002648:Child; D005260:Female; D005500:Follow-Up Studies; D060005:Genotyping Techniques; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000097:blood* / Q000235:genetics* / Q000503:physiopathology*; D012008:Recurrence; D012737:Sex Factors
chemical_list: D059811:HLA-DRB1 Chains; C507799:HLA-DRB1*15 antigen; D002117:Calcitriol
keywords: Genetics; multiple sclerosis; outcome measurement; relapsing/remitting; vitamin D