Title: The role of the CD58 locus in multiple sclerosis
Authors: De Jager, Philip L ×
Baecher-Allan, Clare
Maier, Lisa M
Arthur, Ariel T
Ottoboni, Linda
Barcellos, Lisa
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, Bénédicte
Haines, Jonathan L
Weiner, Howard L
Compston, Alastair
Hauser, Stephen L
Daly, Mark J
Reich, David
Oksenberg, Jorge R
Hafler, David A #
Issue Date: Mar-2009
Publisher: National Academy of Sciences
Series Title: Proceedings of the National Academy of Sciences of the United States of America vol:106 issue:13 pages:5264-5269
Abstract: 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 rs2300747G 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.
ISSN: 0027-8424
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Research Group Experimental Neurology
Laboratory for Neuroimmunology
× corresponding author
# (joint) last author

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