The role of the CD58 locus in multiple sclerosis

Philip L. De Jager; Clare Baecher-Allan; Lisa M. Maier; Ariel T. Arthur; Linda Ottoboni; Lisa Barcellos; Jacob L. McCauley; Stephen Sawcer; An Goris; Janna Saarela; Roman Yelensky; Alkes Price; Virpi Leppa; Nick Patterson; Paul I W De Bakker; Dong Tran; Cristin Aubin; Susan Pobywajlo; Elizabeth Rossin; Xinli Hu; Charles W. Ashley; Edwin Choy; John D. Rioux; Margaret A. Pericak-Vance; Adrian Ivinson; David R. Booth; Graeme J. Stewart; Aarno Palotie; Leena Peltonen; Bénédicte Dubois; Jonathan L. Haines; Howard L. Weiner; Alastair Compston; Stephen L. Hauser; Mark J. Daly; David Reich; Jorge R. Oksenberg; David A. Hafler

doi:10.1073/pnas.0813310106

The role of the CD58 locus in multiple sclerosis

Philip L. De Jager, Clare Baecher-Allan, Lisa M. Maier, Ariel T. Arthur, Linda Ottoboni, Lisa Barcellos, Jacob L. McCauley, Stephen Sawcer, An Goris, Janna Saarela, Roman Yelensky, Alkes Price, Virpi Leppa, Nick Patterson, Paul I W De Bakker, Dong Tran, Cristin Aubin, Susan Pobywajlo, Elizabeth Rossin, Xinli HuCharles W. Ashley, Edwin Choy, John D. Rioux, Margaret A. Pericak-Vance, Adrian Ivinson, David R. Booth, Graeme J. Stewart, Aarno Palotie, Leena Peltonen, Bénédicte Dubois, Jonathan L. Haines, Howard L. Weiner, Alastair Compston, Stephen L. Hauser, Mark J. Daly, David Reich, Jorge R. Oksenberg, David A. Hafler

IRCCS Ospedale San Raffaele

Research output: Contribution to journal › Article › peer-review

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 × 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 × 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 Fo×P3 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.

Original language	English
Pages (from-to)	5264-5269
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	106
Issue number	13
DOIs	https://doi.org/10.1073/pnas.0813310106
Publication status	Published - Mar 31 2009

Keywords

Genetic
Human
Inflammation
Quantitative trait
RNA

ASJC Scopus subject areas

General

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10.1073/pnas.0813310106

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De Jager, P. L., Baecher-Allan, C., Maier, L. M., Arthur, A. T., Ottoboni, L., Barcellos, L., McCauley, J. L., Sawcer, S., Goris, A., Saarela, J., Yelensky, R., Price, A., Leppa, V., Patterson, N., De Bakker, P. I. W., Tran, D., Aubin, C., Pobywajlo, S., Rossin, E., ... Hafler, D. A. (2009). The role of the CD58 locus in multiple sclerosis. Proceedings of the National Academy of Sciences of the United States of America, 106(13), 5264-5269. https://doi.org/10.1073/pnas.0813310106

De Jager, PL, Baecher-Allan, C, Maier, LM, Arthur, AT, Ottoboni, L, Barcellos, L, McCauley, JL, Sawcer, S, Goris, A, Saarela, J, Yelensky, R, Price, A, Leppa, V, Patterson, N, De Bakker, PIW, Tran, D, Aubin, C, Pobywajlo, S, Rossin, E, Hu, X, Ashley, CW, Choy, E, Rioux, JD, Pericak-Vance, MA, Ivinson, A, Booth, DR, Stewart, GJ, Palotie, A, Peltonen, L, Dubois, B, Haines, JL, Weiner, HL, Compston, A, Hauser, SL, Daly, MJ, Reich, D, Oksenberg, JR & Hafler, DA 2009, 'The role of the CD58 locus in multiple sclerosis', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 13, pp. 5264-5269. https://doi.org/10.1073/pnas.0813310106

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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 × 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 × 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 Fo×P3 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.",

keywords = "Genetic, Human, Inflammation, Quantitative trait, RNA",

author = "{De Jager}, {Philip L.} and Clare Baecher-Allan and Maier, {Lisa M.} and Arthur, {Ariel T.} and Linda Ottoboni and Lisa Barcellos and McCauley, {Jacob L.} and Stephen Sawcer and An Goris and Janna Saarela and Roman Yelensky and Alkes Price and Virpi Leppa and Nick Patterson and {De Bakker}, {Paul I W} and Dong Tran and Cristin Aubin and Susan Pobywajlo and Elizabeth Rossin and Xinli Hu and Ashley, {Charles W.} and Edwin Choy and Rioux, {John D.} and Pericak-Vance, {Margaret A.} and Adrian Ivinson and Booth, {David R.} and Stewart, {Graeme J.} and Aarno Palotie and Leena Peltonen and B{\'e}n{\'e}dicte Dubois and Haines, {Jonathan L.} and Weiner, {Howard L.} and Alastair Compston and Hauser, {Stephen L.} and Daly, {Mark J.} and David Reich and Oksenberg, {Jorge R.} and Hafler, {David A.}",

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T1 - The role of the CD58 locus in multiple sclerosis

AU - De Jager, Philip L.

AU - Baecher-Allan, Clare

AU - Maier, Lisa M.

AU - Arthur, Ariel T.

AU - Ottoboni, Linda

AU - Barcellos, Lisa

AU - McCauley, Jacob L.

AU - Sawcer, Stephen

AU - Goris, An

AU - Saarela, Janna

AU - Yelensky, Roman

AU - Price, Alkes

AU - Leppa, Virpi

AU - Patterson, Nick

AU - De Bakker, Paul I W

AU - Tran, Dong

AU - Aubin, Cristin

AU - Pobywajlo, Susan

AU - Rossin, Elizabeth

AU - Hu, Xinli

AU - Ashley, Charles W.

AU - Choy, Edwin

AU - Rioux, John D.

AU - Pericak-Vance, Margaret A.

AU - Ivinson, Adrian

AU - Booth, David R.

AU - Stewart, Graeme J.

AU - Palotie, Aarno

AU - Peltonen, Leena

AU - Dubois, Bénédicte

AU - Haines, Jonathan L.

AU - Weiner, Howard L.

AU - Compston, Alastair

AU - Hauser, Stephen L.

AU - Daly, Mark J.

AU - Reich, David

AU - Oksenberg, Jorge R.

AU - Hafler, David A.

PY - 2009/3/31

Y1 - 2009/3/31

N2 - 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 × 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 × 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 Fo×P3 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.

AB - 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 × 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 × 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 Fo×P3 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.

KW - Genetic

KW - Human

KW - Inflammation

KW - Quantitative trait

KW - RNA

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The role of the CD58 locus in multiple sclerosis

Abstract

Keywords

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