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Abstract

Background:

Many genetic risk variants are now well established in multiple sclerosis (MS), but the impact on clinical phenotypes is unclear.

Objective:

To investigate the impact of established MS genetic risk variants on MS phenotypes, in well-characterized MS cohorts.

Methods:

Norwegian MS patients (n = 639) and healthy controls (n = 530) were successfully genotyped for 61 established MS-associated single nucleotide polymorphisms (SNPs). Data including and excluding Major Histocompatibility Complex (MHC) markers were summed to a MS Genetic Burden (MSGB) score. Study replication was performed in a cohort of white American MS patients (n = 1997) and controls (n = 708).

Results:

The total human leukocyte antigen (HLA) and the non-HLA MSGB scores were significantly higher in MS patients than in controls, in both cohorts (P << 10⁻²²). MS patients, with and without cerebrospinal fluid (CSF) oligoclonal bands (OCBs), had a higher MSGB score than the controls; the OCB-positive patients had a slightly higher MSGB than the OCB-negative patients. An early age at symptom onset (AAO) also correlated with a higher MSGB score, in both cohorts.

Conclusion:

The MSGB score was associated with specific clinical MS characteristics, such as OCBs and AAO. This study underlines the need for well-characterized, large cohorts of MS patients, and the usefulness of summarizing multiple genetic risk factors of modest effect size in genotype-phenotype analyses.

Keywords

Age of onset cerebrospinal fluid genetic association genetic risk genotype multiple sclerosis oligoclonal bands Multiple Sclerosis Genetic Burden

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References

Compston

Coles

. Multiple sclerosis. Lancet 2008; 372: 1502–1517.

Gourraud

Harbo

Hauser

. The genetics of multiple sclerosis: An up-to-date review. Immunol Rev 2012; 248: 87–103.

Sawcer

Hellenthal

Pirinen

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

De Jager

Jia

Wang

. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 2009; 41: 776–782.

Patsopoulos

Esposito

Reischl

. Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. Ann Neurol 2011; 70: 897–912.

Gourraud

Sdika

Khankhanian

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

Gourraud

McElroy

Caillier

. Aggregation of multiple sclerosis genetic risk variants in multiple and single case families. Ann Neurol 2011; 69: 65–74.

Smestad

Sandvik

Holmoy

. Marked differences in prevalence of multiple sclerosis between ethnic groups in Oslo, Norway. J Neurol 2008; 255: 49–55.

Cree

Rioux

McCauley

. A Major Histocompatibility Class I locus contributes to multiple sclerosis susceptibility independently from HLA-DRB1*15:01. PLoS One 2010; 5: e11296.

10.

Lorentzen

Karlsen

Olsson

. Killer immunoglobulin-like receptor ligand HLA-Bw4 protects against multiple sclerosis. Ann Neurol 2009; 65: 658–666.

11.

Polman

Reingold

Banwell

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

12.

Kurtzke

. Rating neurologic impairment in multiple sclerosis: An Expanded Disability Status Scale (EDSS). Neurology 1983; 33: 1444–1452.

13.

Roxburgh

Seaman

Masterman

. Multiple Sclerosis Severity Score: Using disability and disease duration to rate disease severity. Neurology 2005; 64: 1144–1151.

14.

Mero

Gustavsen

Saether

. Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles. PLoS One 2013; 8: e58352.

15.

Andersson

Alvarez-Cermeno

Bernardi

. Cerebrospinal fluid in the diagnosis of multiple sclerosis: A consensus report. J Neurol Neurosurg Psychiatry 1994; 57: 897–902.

16.

Link

Huang

. Oligoclonal bands in multiple sclerosis cerebrospinal fluid: An update on methodology and clinical usefulness. J Neuroimmunol 2006; 180: 17–28.

17.

Lechner-Scott

Spencer

. The frequency of CSF oligoclonal banding in multiple sclerosis increases with latitude. Mult Scler 2012; 18: 974–982.

18.

Rinker

Trinkaus

Naismith

. Higher IgG index found in African Americans versus Caucasians with multiple sclerosis. Neurology 2007; 69: 68–72.

19.

Balnyte

Rastenyte

Uloziene

. The significance of HLA DRB1*1501 and oligoclonal bands in multiple sclerosis: Clinical features and disability. Medicina (Kaunas) 2011; 47: 368–373.

20.

Idiman

Ozakbas

Dogan

. The significance of oligoclonal bands in multiple sclerosis: Relevance of demographic and clinical features, and immunogenetic backgrounds. J Neuroimmunol 2009; 212: 121–124.

21.

Imrell

Landtblom

Hillert

. Multiple sclerosis with and without CSF bands: Clinically indistinguishable but immunogenetically distinct. Neurology 2006; 67: 1062–1064.

22.

Imrell

Greiner

Hillert

. HLA-DRB115 and cerebrospinal fluid-specific oligoclonal immunoglobulin G bands lower age at attainment of important disease milestones in multiple sclerosis. J Neuroimmunol 2009; 210: 128–130.

23.

Joseph

Hirst

Pickersgill

. CSF oligoclonal band status informs prognosis in multiple sclerosis: A case control study of 100 patients. J Neurol Neurosurg Psychiatry 2009; 80: 292–296.

24.

Siritho

Freedman

. The prognostic significance of cerebrospinal fluid in multiple sclerosis. J Neurol Sci 2009; 279: 21–25.

25.

Hensiek

Seaman

Barcellos

. Familial effects on the clinical course of multiple sclerosis. Neurology 2007; 68: 376–383.

26.

Masterman

Ligers

Olsson

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

27.

Smestad

Brynedal

Jonasdottir

. The impact of HLA-A and -DRB1 on age at onset, disease course and severity in Scandinavian multiple sclerosis patients. Eur J Neurol 2007; 14: 835–840.

28.

Celius

Harbo

Egeland

. Sex and age at diagnosis are correlated with the HLA-DR2, DQ6 haplotype in multiple sclerosis. J Neurol Sci 2000; 178: 132–135.

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Oligoclonal bands and age at onset correlate with genetic risk score in multiple sclerosis

Abstract

Background:

Objective:

Methods:

Results:

Conclusion:

Keywords

Get full access to this article

References

Supplementary Material