Disanto, G;
Sandve, GK;
Berlanga-Taylor, AJ;
Morahan, JM;
Dobson, R;
Giovannoni, G;
Ramagopalan, SV;
(2012)
Genomic regions associated with multiple sclerosis are active in B cells.
PLoS One
, 7
(3)
, Article e32281. 10.1371/journal.pone.0032281.
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Abstract
More than 50 genomic regions have now been shown to influence the risk of multiple sclerosis (MS). However, the mechanisms of action, and the cell types in which these associated variants act at the molecular level remain largely unknown. This is especially true for associated regions containing no known genes. Given the evidence for a role for B cells in MS, we hypothesized that MS associated genomic regions co-localized with regions which are functionally active in B cells. We used publicly available data on 1) MS associated regions and single nucleotide polymorphisms (SNPs) and 2) chromatin profiling in B cells as well as three additional cell types thought to be unrelated to MS (hepatocytes, fibroblasts and keratinocytes). Genomic intervals and SNPs were tested for overlap using the Genomic Hyperbrowser. We found that MS associated regions are significantly enriched in strong enhancer, active promoter and strong transcribed regions (p = 0.00005) and that this overlap is significantly higher in B cells than control cells. In addition, MS associated SNPs also land in active promoter (p = 0.00005) and enhancer regions more than expected by chance (strong enhancer p = 0.0006; weak enhancer p = 0.00005). These results confirm the important role of the immune system and specifically B cells in MS and suggest that MS risk variants exert a gene regulatory role. Previous studies assessing MS risk variants in T cells may be missing important effects in B cells. Similar analyses in other immunological cell types relevant to MS and functional studies are necessary to fully elucidate how genes contribute to MS pathogenesis.
| Type: | Article |
|---|---|
| Title: | Genomic regions associated with multiple sclerosis are active in B cells. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pone.0032281 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pone.0032281 |
| Language: | English |
| Additional information: | © 2012 Disanto et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMCID: PMC3292555 Dr. Disanto is funded by research fellowship FISM-Fondazione Italiana Sclerosi Multipla-Cod.: 2010/B/5. Dr. Kjetil is supported by EMBIO at the University of Oslo. Dr. Berlanga-Taylor is funded by the National Council for Science and Technology (CONACyT), Mexico, and the Multiple Sclerosis Society of Great Britain and Northern Ireland. Dr. Morahan is funded by the MS Society of Australia and the UK. Dr. Dobson is funded by a joint ABN/Multiple Sclerosis Society of Great Britain Clinical Research Fellowship. Dr. Giovannoni serves on scientific advisory boards for Merck Serono and Biogen Idec and Vertex Pharmaceuticals; has served on the editorial board of Multiple Sclerosis; has received speaker honoraria from Bayer Schering Pharma, Merck Serono, Biogen Idec, Pfizer Inc, Teva Pharmaceutical Industries Ltd.–sanofiaventis, Vertex Pharmaceuticals, Genzyme Corporation, Ironwood, and Novartis; has served as a consultant for Bayer Schering Pharma, Biogen Idec, GlaxoSmithKline, Merck Serono, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd.–sanofiaventis, UCB, Vertex Pharmaceuticals, GW Pharma, Novartis, and FivePrime; serves on the speakers bureau for Merck Serono; and has received research support from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, UCB, Merz Pharmaceuticals, LLC, Teva Pharmaceutical Industries Ltd.–sanofiaventis, GW Pharma, and Ironwood. Dr. Ramagopalan receives research support from the Multiple Sclerosis Society of Canada Scientific Research Foundation and the Multiple Sclerosis Society of Great Britain and Northern Ireland. This work was supported by the Medical Research Council (G0801976), the Wellcome Trust (075491/Z/04), and by a research fellowship FISM Fondazione Italiana Sclerosi Multipla-Cod.: 2010/B/5. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Keywords: | B-Lymphocytes, Cell Line, Cell Line, Tumor, Cells, Cultured, Chromatin, Chromatin Immunoprecipitation, Enhancer Elements, Genetic, Genetic Variation, Genetics, Genomics, Humans, Immune System, Models, Genetic, Monte Carlo Method, Multiple Sclerosis, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Transcription, Genetic |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1344652 |
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