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. 2013 Jun 13;8(6):e64408.
doi: 10.1371/journal.pone.0064408. Print 2013.

Association of genetic markers with CSF oligoclonal bands in multiple sclerosis patients

Maurizio A Leone  1 , Nadia Barizzone, Federica Esposito, Ausiliatrice Lucenti, Hanne F Harbo, An Goris, Ingrid Kockum, Annette Bang Oturai, Elisabeth Gulowsen Celius, Inger L Mero, Bénédicte Dubois, Tomas Olsson, Helle Bach Søndergaard, Daniele Cusi, Sara Lupoli, Bettina Kulle Andreassen; International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2; Kjell-Morten Myhr, Franca R Guerini; PROGEMUS Group; PROGRESSO Group; Giancarlo Comi, Filippo Martinelli-Boneschi, Sandra D'Alfonso
Affiliations

Association of genetic markers with CSF oligoclonal bands in multiple sclerosis patients

Maurizio A Leone et al. PLoS One. .

Abstract

Objective: to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients.

Methods: We genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed.

Results: HLA-DRB1*15 is associated with OCB+: p = 0.03, Odds Ratio (OR) = 1.6, 95% Confidence Limits (CL) = 1.1-2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09-1.92). The weighted Genetic Risk Score mean was significantly (p = 0.0008) higher in OCB+ (7.668) than in OCB- (7.412) patients. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p = 9.4×10(-7)) outside the HLA region (65 Mb).

Discussion: genetic factors predispose to the development of OCB.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Distribution of the wGRS in MS patients positive (OCB+) or negative (OCB−) for OCB.
wGRS (weighted Genetic Risk Score) has been calculated using the ORs for the 52 non-HLA MS susceptibility variants,6 and three HLA alleles (DRB1*15, DRB1*03 and A*02). The reported p value derived from the comparison of the mean wGRS (Student's t test) in OCB+ vs OCB−.
Figure 2
Figure 2. Results of the GWAS for OCB status and meta-analysis after in silico replication.
(a) Manhattan Plot of the GWAS performed in the Italian OCB+ vs OCB− MS patients, as a discovery dataset. The blue horizontal line indicates the threshold of p values arbitrarily chosen to select the “best associated SNPs” (p-value <10−4, 89 SNPs) to perform in silico replication (Table S1) using data from Scandinavia and Belgium populations. (b) Meta-analysis for the rs9320598 SNP, the strongest signal after the meta-analysis of the combined results of all datasets (Italy, Scandinavia and Belgium). The forest plot summarizes the results obtained for the discovery Italian dataset, for the replication datasets from Scandinavia and Belgium, and the combined analysis calculated using the random and fixed-effect method.
See this image and copyright information in PMC

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