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

Genetic predictors of relapse rate in pediatric MS.

Author information

1
UCSF Pediatric Multiple Sclerosis Center, San Francisco, CA, USA Jennifer.Graves@ucsf.edu.
2
Genetic Epidemiology and Genomics Lab, School of Public Health, and California Institute for Quantitative Biosciences, University of California-Berkeley, Berkeley, CA, USA.
3
Children's Hospital Oakland Research Institute, Oakland, CA, USA.
4
The Multiple Sclerosis Center, Johns Hopkins University, Baltimore, MD, USA.
5
National Pediatric Multiple Sclerosis Center, Stony Brook, NY, USA.
6
Data Coordinating and Analysis Center, University of Utah, Salt Lake City, UT, USA.
7
UCSF Pediatric Multiple Sclerosis Center, San Francisco, CA, USA.

Abstract

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

PMID:
26769066
PMCID:
PMC4945462
DOI:
10.1177/1352458515624269
[Indexed for MEDLINE]
Free PMC Article

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