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Abstract

Background:

Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology.

Objective:

We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS.

Methods:

Cases with onset <18 years (n = 569) and controls (n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases (n = 7588).

Results:

HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR)_meta = 2.95, p < 2.0 × 10⁻¹⁶). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated (p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (OR_avg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (OR_meta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10⁻¹⁶) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02.

Conclusion:

Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.

Keywords

Multiple sclerosis genetics epidemiology pediatrics

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References

Chitnis

Krupp

Yeh

et al . Pediatric multiple sclerosis. Neurol Clin 2011; 29: 481–505.

Yeh

Chitnis

Krupp

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

Waubant

Ponsonby

Pugliatti

et al . Environmental and genetic factors in pediatric inflammatory demyelinating diseases. Neurol 2016; 87(Suppl. 2): S20–S27.

Boiko

Gusev

Sudomoina

et al . Association and linkage of juvenile MS with HLA–DR2(15) in Russians. Neurol 2002; 58(4): 658–660.

Banwell

Bar–Or

Arnold

et al . Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: A prospective national cohort study. Lancet Neurol 2011; 10(5): 426–445.

Beecham

Patsopoulos

Xifara

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

Waubant

Mowry

Krupp

et al . Common viruses associated with lower pediatric multiple sclerosis risk. Neurol 2011; 76: 1989–1995.

Gianfrancesco

Glymour

Walter

et al . Causal effect of genetic variants associated with body mass index on multiple sclerosis susceptibility. Am J Epidemiol 2017; 185(3): 162–171.

Krupp

Tardieu

Amato

et al . International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: Revisions to the 2007 definitions. Mult Scler 2013; 19(10): 1261–1267.

10.

McDonald

Compston

Edan

et al . Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–127.

11.

Polman

Reingold

Banwell

et al . Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69: 292–302.

12.

Nourbakhsh

Graves

Casper

et al . Dietary salt intake and time to relapse in paediatric multiple sclerosis. J Neurol Neurosurg Psychiatry 2016; 87(12): 1350–1353.

13.

Hedstrom

Hillert

Olsson

et al . Smoking and multiple sclerosis susceptibility. Eur J Epidemiol 2013; 28: 867–874.

14.

Zivkovic

Stankovic

Dincic

et al . The tag SNP for HLA-DRB1*1501, rs3135388, is significantly associated with multiple sclerosis susceptibility: Cost-effective high-throughput detection by real-time PCR. Clin Chim Acta 2009; 406: 27–30.

15.

De Jager

Chibnik

Cui

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

16.

Disanto

Magalhaes

Handel

et al . HLA–DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination. Neurol 2011; 76(9): 781–786.

17.

Barcellos

Sawcer

Ramsay

et al . Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis. Hum Mol Genet 2006; 15: 2813–2824.

18.

Patsopoulos

Barcellos

Hintzen

et al . Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects. PLoS Genet 2013; 9(11): e1003926.

19.

Yeo

De Jager

Gregory

et al . A second major histocompatibility complex susceptibility locus for multiple sclerosis. Ann Neurol 2007; 61: 228–236.

20.

Link

Kockum

Lorentzen

et al . Importance of human leukocyte antigen (HLA) class I and II alleles on the risk of multiple sclerosis. PLoS ONE 2012; 7(5): e36779.

21.

Xie

Rowen

Begona

et al . Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse. Genome Res 2003; 13(12): 2621–2636.

22.

Huang

Yoshimura

Isobe

et al . A NOTCH4 missense mutation confers resistance to multiple sclerosis in Japanese. Mult Scler 2013; 19(13): 1696–1703.

23.

McElroy

Isobe

Gourraud

et al . SNP-based analysis of the HLA locus in Japanese multiple sclerosis patients. Genes Immun 2011; 12(7): 523–530.

24.

Duvefelt

Anderson

Fogdell–Hahn

et al . A NOTCH4 association with multiple sclerosis is secondary to HLA-DR*1501. Tissue Antigens 2004; 63(1): 13–20.

25.

Ramagopalan

Knight

Ebers

. Multiple sclerosis and the major histocompatibility complex. Curr Opin Neurol 2009; 22(3): 219–225.

26.

van Pelt

Mescheriakova

Makhani

et al . Risk genes associated with pediatric-onset MS but not with monophasic acquired CNS myelination. Neurol 2013; 81(23): 1996–2001.

27.

Sorosina

Esposito

Guaschino

et al . Inverse correlation of genetic risk score with age at onset in bout-onset and progressive-onset multiple sclerosis. Mult Scler 2015; 21(11): 1463–1467.

28.

Bove

Chua

Xia

et al . Complex relation of HLA-DRB1*1501, age at menarche, and age at multiple sclerosis onset. Neurol Genet 2016; 2(4): e88.

29.

Ramagopalan

Byrnes

Dyment

et al . Parent-of-origin of HLA-DRB1*1501 and age of onset of multiple sclerosis. J Hum Genet 2009; 54: 547–549.

30.

Masterman

Ligers

Olsson

et al . HLA-DR15 is associated with lower age at onset in multiple sclerosis. Ann Neurol 2000; 48: 211–219.

31.

Anagnostouli

Manouseli

Artemiadis

et al . HLA-DRB1* allele frequencies in pediatric, adolescent, and adult-onset multiple sclerosis patients, in a Hellenic sample. Evidence for new and established associations. J Mult Scler 2014; 1: 104.

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Genetic risk factors for pediatric-onset multiple sclerosis

Abstract

Background:

Objective:

Methods:

Results:

Conclusion:

Keywords

Get full access to this article

References

Supplementary Material