Dataset Information

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.

SUBMITTER: De Jager PL

PROVIDER: S-EPMC2664005 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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The role of the CD58 locus in multiple sclerosis.

De Jager Philip L PL Baecher-Allan Clare C Maier Lisa M LM Arthur Ariel T AT Ottoboni Linda L Barcellos Lisa L McCauley Jacob L JL Sawcer Stephen S Goris An A Saarela Janna J Yelensky Roman R Price Alkes A Leppa Virpi V Patterson Nick N de Bakker Paul I W PI Tran Dong D Aubin Cristin C Pobywajlo Susan S Rossin Elizabeth E Hu Xinli X Ashley Charles W CW Choy Edwin E Rioux John D JD Pericak-Vance Margaret A MA Ivinson Adrian A Booth David R DR Stewart Graeme J GJ Palotie Aarno A Peltonen Leena L Dubois Bénédicte B Haines Jonathan L JL Weiner Howard L HL Compston Alastair A Hauser Stephen L SL Daly Mark J MJ Reich David D Oksenberg Jorge R JR Hafler David A DA

Proceedings of the National Academy of Sciences of the United States of America 20090223 13

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 f ...[more]

PMID: 19237575

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Project description:OBJECTIVE:Multiple sclerosis (MS) is one of the leading neurodegenerative causes of physical disability world-wide. Genetic aberrations of autoimmunity pathway components have been demonstrated to significantly influence MS development. Cluster of Differentiation 58 (CD58) is pertained to a group of genes which had been assayed in several recent association studies. Given the significance of CD58 in modulation of T regulatory cells that control autoimmune responses, the present study was conducted to investigate the frequency of rs12044852 polymorphism and its effect on the outcome of interferon beta (IFN-β) therapy in a subset of Iranian MS patients. MATERIALS AND METHODS:Two hundred MS patients and equal number of healthy controls were recruited to be genotyped in an experimental case-control based study through polymerase chain reaction using specific sequence primers (PCR-SSP). Relapsing remitting multiple sclerosis (RRMS) patients administered IFN-β therapy were followed up with clinical visits every three months up to two years. The mean of multiple sclerosis severity score (MSSS) and expanded disability status scale (EDSS) were measured to monitor the change in severity of MS in response to IFN-β therapy. Pearson's Chi-square and analysis of variance (ANOVA) tests were the main statistical methods used in this study. RESULTS:Strong association was found between the CC genotype and onset of MS (p=0.001, OR=2.22). However, there was no association between rs12044852 and various classifications and severity of MS. Pharmacogenetics-based analysis indicated that carriers of CC genotype had the highest MSSS score compared to others, implying a negative impact of rs12044852 on response to IFN-β therapy. CONCLUSION:Taken together, our findings revealed the critical effect of rs12044852 polymorphism of CD58 on the progression of MS disease. This indicates that genotyping of MS patients may expedite achieving personalized medical management of MS patients.

Dataset Information

The role of the CD58 locus in multiple sclerosis.

Publications

The role of the CD58 locus in multiple sclerosis.

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