title: Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles.
abstract: The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS). We applied data from Norwegian, Swedish and Danish (i.e. Scandinavian) MS patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating to OCB status. GWAS data was compared in 1367 OCB positive and 161 OCB negative Scandinavian MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. HLA-DRB1 genotypes were analyzed in a subset of the OCB positive (n = 2781) and OCB negative (n = 292) MS patients and compared to 890 healthy controls. Results from the genome-wide analyses showed that single nucleotide polymorphisms (SNPs) from the HLA complex and six other loci were associated to OCB status. In SNPs selected for replication, combined analyses showed genome-wide significant association for two SNPs in the HLA complex; rs3129871 (p = 5.7×10(-15)) and rs3817963 (p = 5.7×10(-10)) correlating with the HLA-DRB1*15 and the HLA-DRB1*04 alleles, respectively. We also found suggestive association to one SNP in the Calsyntenin-2 gene (p = 8.83×10(-7)). In HLA-DRB1 analyses HLA-DRB1*15∶01 was a stronger risk factor for OCB positive than OCB negative MS, whereas HLA-DRB1*04∶04 was associated with increased risk of OCB negative MS and reduced risk of OCB positive MS. Protective effects of HLA-DRB1*01∶01 and HLA-DRB1*07∶01 were detected in both groups. The groups were different with regard to age at onset (AAO), MS outcome measures and gender. This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied.
authors.affiliation: Department of Neurology, Oslo University Hospital, Ullevål, and Department of Medical Genetics, University of Oslo, Oslo, Norway.
authors.forename: Inger-Lise
authors.initials: IL
authors.lastname: Mero
authors.forename: Marte W
authors.initials: MW
authors.lastname: Gustavsen
authors.forename: Hanne S
authors.initials: HS
authors.lastname: Sæther
authors.forename: Siri T
authors.initials: ST
authors.lastname: Flåm
authors.forename: Pål
authors.initials: P
authors.lastname: Berg-Hansen
authors.forename: Helle B
authors.initials: HB
authors.lastname: Søndergaard
authors.forename: Poul Erik H
authors.initials: PE
authors.lastname: Jensen
authors.forename: Tone
authors.initials: T
authors.lastname: Berge
authors.forename: Anja
authors.initials: A
authors.lastname: Bjølgerud
authors.forename: Aslaug
authors.initials: A
authors.lastname: Muggerud
authors.forename: Jan H
authors.initials: JH
authors.lastname: Aarseth
authors.forename: Kjell-Morten
authors.initials: KM
authors.lastname: Myhr
authors.forename: Elisabeth G
authors.initials: EG
authors.lastname: Celius
authors.forename: Finn
authors.initials: F
authors.lastname: Sellebjerg
authors.forename: Jan
authors.initials: J
authors.lastname: Hillert
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.forename: Annette Bang
authors.initials: AB
authors.lastname: Oturai
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kockum
authors.forename: Benedicte A
authors.initials: BA
authors.lastname: Lie
authors.forename: Bettina Kulle
authors.initials: BK
authors.lastname: Andreassen
authors.forename: Hanne F
authors.initials: HF
authors.lastname: Harbo
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D003718:Denmark; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000453:epidemiology* / Q000235:genetics*; D009664:Norway; D043025:Oligoclonal Bands / Q000134:cerebrospinal fluid / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013548:Sweden
chemical_list: D059811:HLA-DRB1 Chains; D043025:Oligoclonal Bands