The role of the CD[subscript 5]8 locus in multiple sclerosis
Author(s)
De Jager, Philip L.; Baecher-Allan, Clare; Maier, Lisa M.; Arthur, Ariel T.; Ottoboni, Linda; Barcellos, Lisa F.; McCauley, Jacob L.; Sawcer, Stephen; Goris, An; Saarela, Janna; Yelensky, Roman; Price, Alkes; Leppa, Virpi; Patterson, Nick; de Bakker, Paul I. W.; Tran, Dong; Aubin, Cristin; Pobywajlo, Susan; Rossin, Elizabeth; Hu, Xinli; Ashley, Charles W.; Choy, Edwin; Rioux, John D.; Pericak-Vance, Margaret A.; Ivinson, Adrian; Booth, David R.; Stewart, Graeme J.; Palotie, Aarno; Peltonen, Leena; Dubois, Benedicte; Haines, Jonathan L.; Weiner, Howard L.; Compston, Alastair; Hauser, Stephen L.; Daly, Mark J.; Reich, David; Oksenberg, Jorge R.; Hafler, David A.; ... Show more Show less
DownloadDe Jager-2009-The role of the CD58.pdf (701.0Kb)
PUBLISHER_POLICY
Publisher Policy
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Terms of use
Metadata
Show full item recordAbstract
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system associated with demyelination and axonal loss. A whole genome association scan suggested that allelic variants in the CD58 gene region, encoding the costimulatory molecule LFA-3, are associated with risk of developing MS. We now report additional genetic evidence, as well as resequencing and fine mapping of the CD58 locus in patients with MS and control subjects. These efforts identify a CD58 variant that provides further evidence of association with MS (P = 1.1 x 10(-6), OR 0.82) and the single protective effect within the CD58 locus is captured by the rs2300747(G) allele. This protective rs2300747(G) allele is associated with a dose-dependent increase in CD58 mRNA expression in lymphoblastic cell lines (P = 1.1 x 10(-10)) and in peripheral blood mononuclear cells from MS subjects (P = 0.0037). This protective effect of enhanced CD58 expression on circulating mononuclear cells in patients with MS is supported by finding that CD58 mRNA expression is higher in MS subjects during clinical remission. Functional investigations suggest a potential mechanism whereby increases in CD58 expression, mediated by the protective allele, up-regulate the expression of transcription factor FoxP3 through engagement of the CD58 receptor, CD2, leading to the enhanced function of CD4(+)CD25(high) regulatory T cells that are defective in subjects with MS.
Date issued
2009-02Department
Broad Institute of MIT and HarvardJournal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
National Academy of Sciences
Citation
De Jager, Philip L et al. “The role of the CD58 locus in multiple sclerosis.” Proceedings of the National Academy of Sciences 106.13 (2009): 5264-5269.
Version: Final published version
ISSN
0027-8424