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

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

Get full access to this article

View all access options for this article.

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.

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

0.17 MB