TY - JOUR
T1 - Oligoclonal Band Status in Scandinavian Multiple Sclerosis Patients Is Associated with Specific Genetic Risk Alleles
AU - Mero, Inger Lise
AU - Gustavsen, Marte W.
AU - Sæther, Hanne S.
AU - Flåm, Siri T.
AU - Berg-Hansen, Pål
AU - Søndergaard, Helle B.
AU - Jensen, Poul Erik H.
AU - Berge, Tone
AU - Bjølgerud, Anja
AU - Muggerud, Aslaug
AU - Aarseth, Jan H.
AU - Myhr, Kjell Morten
AU - Celius, Elisabeth G.
AU - Sellebjerg, Finn
AU - Hillert, Jan
AU - Alfredsson, Lars
AU - Olsson, Tomas
AU - Oturai, Annette Bang
AU - Kockum, Ingrid
AU - Lie, Benedicte A.
AU - Andreassen, Bettina Kulle
AU - Harbo, Hanne F.
N1 - Funding Information:
We thank all patients and healthy controls for their participation. The International Multiple Sclerosis Genetics Consortium and the Wellcome Trust Case Control Consortium2 provided the genotypes used in the screening phase of this study. We acknowledge the collaboration and principal funding for the genome-wide study provided by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium2 project (085475/B/08/Z and 085475/Z/08/Z). We thank all contributors to the collection of samples and clinical data in the Norwegian MS Registry and Biobank. The Norwegian Bone Marrow Donor Registry, Rikshospitalet, Oslo University Hospital are acknowledged for providing Norwegian controls. The Centre for Integrative Genetics; CIGENE, Norwegian University of Life Sciences (UMB) Aas is thanked for performing Sequenom analyses.
PY - 2013/3/5
Y1 - 2013/3/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84874604770&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0058352
DO - 10.1371/journal.pone.0058352
M3 - Article
SN - 1932-6203
VL - 8
JO - PLoS ONE
JF - PLoS ONE
IS - 3
M1 - e58352
ER -