The role of the CD58 locus in multiple sclerosis

被引：142

作者：

De Jager, Philip L. ^{[1
,2
,3
,4
]}

Baecher-Allan, Clare ^{[1
]}

Maier, Lisa M. ^{[1
,3
,4
]}

Arthur, Ariel T. ^{[5
,6
]}

Ottoboni, Linda ^{[1
,3
,4
]}

Barcellos, Lisa ^{[7
]}

McCauley, Jacob L. ^{[8
]}

Sawcer, Stephen ^{[9
]}

Goris, An ^{[10
]}

Saarela, Janna ^{[11
,12
]}

Yelensky, Roman ^{[3
,4
,13
]}

Price, Alkes ^{[3
,4
,14
]}

Leppa, Virpi ^{[11
,12
]}

Patterson, Nick ^{[3
,4
]}

de Bakker, Paul I. W. ^{[2
,3
,4
]}

Tran, Dong ^{[1
,3
,4
]}

Aubin, Cristin ^{[1
,3
,4
]}

Pobywajlo, Susan ^{[1
]}

Rossin, Elizabeth ^{[1
,3
,4
]}

Hu, Xinli ^{[3
,4
]}

Ashley, Charles W. ^{[1
]}

Choy, Edwin ^{[3
,4
,13
]}

Rioux, John D. ^{[3
,4
,15
,16
]}

Pericak-Vance, Margaret A.

Ivinson, Adrian ^{[17
]}

Booth, David R. ^{[18
]}

Stewart, Graeme J. ^{[18
]}

Palotie, Aarno ^{[3
,4
,10
]}

Peltonen, Leena ^{[3
,4
,10
]}

Dubois, Benedicte ^{[9
]}

Haines, Jonathan L. ^{[19
]}

Weiner, Howard L. ^{[1
]}

Compston, Alastair ^{[9
]}

Hauser, Stephen L. ^{[20
,21
]}

Daly, Mark J. ^{[3
,4
,13
]}

Reich, David ^{[3
,4
]}

Oksenberg, Jorge R. ^{[20
,21
]}

Hafler, David A. ^{[1
,3
,4
]}

机构：

[1] Brigham & Womens Hosp, Ctr Neurol Dis, Div Mol Immunol, Boston, MA 02115 USA

[2] Partners Ctr Personalized Genet Med, Boston, MA 02115 USA

[3] Harvard Univ, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02139 USA

[4] MIT, Cambridge, MA 02139 USA

[5] Univ Sydney, Dept Med, Sydney, NSW 2145, Australia

[6] Univ Sydney, Nerve Res Fdn, Sydney, NSW 2145, Australia

[7] Univ Calif Berkeley, Sch Publ Hlth, Div Epidemiol, Berkeley, CA 94720 USA

[8] Univ Miami, Miller Sch Med, Miami Inst Human Genom, Miami, FL 33136 USA

[9] Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Cambridge CB2 2QQ, England

[10] Univ Louvain, Sect Expt Neurol, B-3000 Louvain, Belgium

[11] Natl Publ Hlth Inst, Dept Mol Med, Helsinki 00290, Finland

[12] Univ Finland, Biomedicum, Program Mol Med, Helsinki 00290, Finland

[13] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[14] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[15] Montreal Heart Inst, Montreal, PQ H3C 3J7, Canada

[16] Univ Montreal, Montreal, PQ H3C 3J7, Canada

[17] Harvard Univ, Sch Med, Harvard Neurodiscovery Ctr, Boston, MA 02115 USA

[18] Westmead Millenium Inst, Inst Immunol & Allergy Res, Sydney, NSW, Australia

[19] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN 37232 USA

[20] Univ Calif San Francisco, Sch Med, Dept Neurol, San Francisco, CA 94143 USA

[21] Univ Calif San Francisco, Sch Med, Inst Human Genet, San Francisco, CA 94143 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 13期

关键词：

genetic; human; RNA; quantitative trait; inflammation; REGULATORY T-CELLS; INTERLEUKIN-7; RECEPTOR; ASSOCIATION; GENES; ALEFACEPT; TRIAL;

D O I：

10.1073/pnas.0813310106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：5264 / 5269

页数：6

共 32 条

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NATURE, 2007, 445 (7129) :766-770

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Zheng, Ye ;

Josefowicz, Steven Z. ;

Kas, Arnold ;

Chu, Tin-Tin ;

Gavin, Marc A. ;

Rudensky, Alexander Y. .

NATURE, 2007, 445 (7130) :936-940

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