Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles

Inger-Lise Mero; Marte W Gustavsen; Hanne S Sæther; Siri T Flåm; Pål Berg-Hansen; Helle B Søndergaard; Poul Erik H. Jensen; Tone Berge; Anja Bjølgerud; Aslaug Muggerud; Jan H Aarseth; Kjell-Morten Myhr; Elisabeth G Celius; Finn Sellebjerg; Jan Hillert; Lars Alfredsson; Tomas Olsson; Annette Bang Oturai; Ingrid Kockum; Benedicte A Lie; Bettina Kulle Andreassen; Hanne F Harbo; International Multiple Sclerosis Genetics Consortium

doi:10.1371/journal.pone.0058352

Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles

Inger-Lise Mero, Marte W Gustavsen, Hanne S Sæther, Siri T Flåm, Pål Berg-Hansen, Helle B Søndergaard, Poul Erik H. Jensen, Tone Berge, Anja Bjølgerud, Aslaug Muggerud, Jan H Aarseth, Kjell-Morten Myhr, Elisabeth G Celius, Finn Sellebjerg, Jan Hillert, Lars Alfredsson, Tomas Olsson, Annette Bang Oturai, Ingrid Kockum, Benedicte A LieBettina Kulle Andreassen, Hanne F Harbo, International Multiple Sclerosis Genetics Consortium

Department of Clinical Medicine

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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.

Original language	English
Article number	e58352
Journal	P L o S One
Volume	8
Issue number	3
Number of pages	9
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0058352
Publication status	Published - 5 Mar 2013

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Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk allelesFinal published version, 195 KB

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Mero, I-L., Gustavsen, M. W., Sæther, H. S., Flåm, S. T., Berg-Hansen, P., Søndergaard, H. B., Jensen, P. E. H., Berge, T., Bjølgerud, A., Muggerud, A., Aarseth, J. H., Myhr, K-M., Celius, E. G., Sellebjerg, F., Hillert, J., Alfredsson, L., Olsson, T., Oturai, A. B., Kockum, I., ... Consortium, I. M. S. G. (2013). Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles. P L o S One, 8(3), [e58352]. https://doi.org/10.1371/journal.pone.0058352

Mero, I-L, Gustavsen, MW, Sæther, HS, Flåm, ST, Berg-Hansen, P, Søndergaard, HB, Jensen, PEH, Berge, T, Bjølgerud, A, Muggerud, A, Aarseth, JH, Myhr, K-M, Celius, EG, Sellebjerg, F, Hillert, J, Alfredsson, L, Olsson, T, Oturai, AB, Kockum, I, Lie, BA, Andreassen, BK, Harbo, HF & Consortium, IMSG 2013, 'Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles', P L o S One, vol. 8, no. 3, e58352. https://doi.org/10.1371/journal.pone.0058352

@article{073c4a0eed1b46459875d51237b80cc5,

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.",

author = "Inger-Lise Mero and Gustavsen, {Marte W} and S{\ae}ther, {Hanne S} and Fl{\aa}m, {Siri T} and P{\aa}l Berg-Hansen and S{\o}ndergaard, {Helle B} and Jensen, {Poul Erik H.} and Tone Berge and Anja Bj{\o}lgerud and Aslaug Muggerud and Aarseth, {Jan H} and Kjell-Morten Myhr and Celius, {Elisabeth G} and Finn Sellebjerg and Jan Hillert and Lars Alfredsson and Tomas Olsson and Oturai, {Annette Bang} and Ingrid Kockum and Lie, {Benedicte A} and Andreassen, {Bettina Kulle} and Harbo, {Hanne F} and Consortium, {International Multiple Sclerosis Genetics}",

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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

AU - Consortium, International Multiple Sclerosis Genetics

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.

U2 - 10.1371/journal.pone.0058352

DO - 10.1371/journal.pone.0058352

M3 - Journal article

C2 - 23472185

SN - 1932-6203

VL - 8

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 3

M1 - e58352

ER -

Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles

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