title: The role of the CD58 locus in multiple sclerosis.
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 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.
authors.affiliation: Division of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. pdejager@rics.bwh.harvard.edu
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: Clare
authors.initials: C
authors.lastname: Baecher-Allan
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Maier
authors.forename: Ariel T
authors.initials: AT
authors.lastname: Arthur
authors.forename: Linda
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authors.lastname: Ottoboni
authors.forename: Lisa
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authors.lastname: Barcellos
authors.forename: Jacob L
authors.initials: JL
authors.lastname: McCauley
authors.forename: Stephen
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authors.lastname: Sawcer
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authors.forename: Janna
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authors.lastname: Saarela
authors.forename: Roman
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authors.lastname: Yelensky
authors.forename: Alkes
authors.initials: A
authors.lastname: Price
authors.forename: Virpi
authors.initials: V
authors.lastname: Leppa
authors.forename: Nick
authors.initials: N
authors.lastname: Patterson
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Dong
authors.initials: D
authors.lastname: Tran
authors.forename: Cristin
authors.initials: C
authors.lastname: Aubin
authors.forename: Susan
authors.initials: S
authors.lastname: Pobywajlo
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rossin
authors.forename: Xinli
authors.initials: X
authors.lastname: Hu
authors.forename: Charles W
authors.initials: CW
authors.lastname: Ashley
authors.forename: Edwin
authors.initials: E
authors.lastname: Choy
authors.forename: John D
authors.initials: JD
authors.lastname: Rioux
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Adrian
authors.initials: A
authors.lastname: Ivinson
authors.forename: David R
authors.initials: DR
authors.lastname: Booth
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Stewart
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Dubois
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
authors.forename: Alastair
authors.initials: A
authors.lastname: Compston
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: David
authors.initials: D
authors.lastname: Reich
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
mesh_terms: D000483:Alleles; D018801:CD2 Antigens; D018968:CD58 Antigens / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D051858:Forkhead Transcription Factors; D006801:Humans; D007963:Leukocytes, Mononuclear; D009103:Multiple Sclerosis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis*; D012074:Remission Induction; D017421:Sequence Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D015854:Up-Regulation
chemical_list: D018801:CD2 Antigens; D018968:CD58 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger