Sage Journals: Discover world-class research

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 (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.

Keywords

Genetics multiple sclerosis relapsing/remitting outcome measurement vitamin D

Get full access to this article

View all access options for this article.

References

Page

Kurtzke

Murphy

. Epidemiology of multiple sclerosis in U.S. veterans. V. Ancestry and the risk of multiple sclerosis. Ann Neurol 1993; 33: 632–639.

Disanto

Magalhaes

Handel

. HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination. Neurology 2011; 76: 781–786.

Patsopoulos

Barcellos

Hintzen

. Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects. PLoS Genet 2013; 9: e1003926.

Oksenberg

Barcellos

Cree

. Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am J Hum Genet 2004; 74: 160–167.

Sawcer

Hellenthal

Pirinen

. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011; 476: 214–219.

International Multiple Sclerosis Genetics Consortium, Beecham

Patsopoulos

. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 2013; 45: 1353–1360.

De Jager

Chibnik

Cui

. Integration of genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility: A weighted genetic risk score. Lancet Neurol 2009; 8: 1111–1119.

Isobe

Damotte

Re V

. Genetic burden in multiple sclerosis families. Genes Immun 2013; 14: 434–440.

Gourraud

Sdika

Khankhanian

. A genome-wide association study of brain lesion distribution in multiple sclerosis. Brain 2013; 136: 1012–1024.

10.

Kalincik

Guttmann

Krasensky

. Multiple sclerosis susceptibility loci do not alter clinical and MRI outcomes in clinically isolated syndrome. Genes Immun 2013; 14: 244–248.

11.

Mowry

Carey

Blasco

. Multiple sclerosis susceptibility genes are associated with relapse severity and recovery. PLoS ONE 2013; 3: e75416.

12.

Mowry

Carey

Blasco

. Association of multiple sclerosis susceptibility variants and early attack location in the CNS. PLoS ONE 2013; 3: e75565.

13.

International Multiple Sclerosis Genetics Consortium. Genome-wide association study of severity in multiple sclerosis. Genes Immun 2011; 12: 615–625.

14.

Goris

Pauwels

Gustavsen

. Genetic variants are major determinants of CSF antibody levels in multiple sclerosis. Brain 2015; 138: 632–643.

15.

Hilven

Patsopoulos

Dubois

. Burden of risk variants correlates with phenotype of multiple sclerosis. Mult Scler 2015; 21: 1670–1680.

16.

Simpson

Jr Taylor

Blizzard

. Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol 2010; 68: 193–203.

17.

Mowry

Krupp

Milazzo

. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol 2010; 67: 618–624.

18.

Lin

Taylor

Simpson

Jr . Association between multiple sclerosis risk-associated SNPs and relapse and disability—A prospective cohort study. Mult Scler 2014; 20: 313–321.

19.

Gorman

Healy

Polgar-Turcsanyi

. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch Neurol 2009; 66: 54–59.

20.

Krupp

Banwell

Tenembaum

Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Neurology 2007; 68: S7–S12.

21.

Walsh

Chokkalingam

Hsu

. Associations between genome-wide Native American ancestry, known risk alleles and B-cell ALL risk in Hispanic children. Leukemia 2013; 27: 2416–2419.

22.

Purcell

Neale

Todd-Brown

. PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

23.

Howie

Donnelly

Marchini

A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 2009; 5: e1000529.

24.

1000 Genomes Project Consortium, Abecasis

Auton

. An integrated map of genetic variation from 1,092 human genomes. Nature 2012; 491: 56–65.

25.

Pritchard

Stephens

Donnelly

Inference of population structure using multilocus genotype data. Genetics 2000; 155: 945–959.

26.

Cann

de Toma

Cazes

. A human genome diversity cell line panel. Science 2002; 296: 261–262.

27.

Ramagopalan

Maugeri

Handunnetthi

. Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet 2009; 5: e1000369.

28.

Nolan

Castley

Tschochner

. Contributions of vitamin D response elements and HLA promoters to multiple sclerosis risk. Neurology 2012; 79: 538–546.

29.

Agliardi

Guerini

Saresella

. Vitamin D receptor (VDR) gene SNPs influence VDR expression and modulate protection from multiple sclerosis in HLA-DRB1*15-positive individuals. Brain Behav Immun 2011; 25: 1460–1467.

30.

Mowry

Waubant

McCulloch

. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol 2012; 72: 234–240.

31.

Kimbrough

Sotirchos

Wilson

. Retinal damage and vision loss in African American multiple sclerosis patients. Ann Neurol 2015; 77: 228–236.

32.

Cree

Khan

Bourdette

. Clinical characteristics of African Americans vs Caucasian Americans with multiple sclerosis. Neurology 2004; 63: 2039–2045.

33.

Nicholas

Kostadima

Hanspal

. MS in South Asians in England: Early disease onset and novel pattern of myelin autoimmunity. BMC Neurol 2015; 15: 72.

34.

Yeh

Chitnis

Krupp

. Pediatric multiple sclerosis. Nat Rev Neurol 2009; 5: 621–631.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.24 MB

Genetic predictors of relapse rate in pediatric MS

Abstract

Background:

Objective:

Methods:

Results:

Conclusion:

Keywords

Get full access to this article

References

Supplementary Material