Ariel T Arthur

Publications (3)12.01 Total impact

• Source

  Available from: pnas.org

  Article: 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, [......], 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
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  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.
  Proceedings of the National Academy of Sciences 03/2009; 106(13):5264-9. · 9.68 Impact Factor
• Source

  Available from: Robert Heard

  Article: Genes implicated in multiple sclerosis pathogenesis from consilience of genotyping and expression profiles in relapse and remission.

  Ariel T Arthur, Patricia J Armati, Chris Bye, Robert N S Heard, Graeme J Stewart, John D Pollard, David R Booth
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  ABSTRACT: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Although the pathogenesis of MS remains unknown, it is widely regarded as an autoimmune disease mediated by T-lymphocytes directed against myelin proteins and/or other oligodendrocyte epitopes. In this study we investigated the gene expression profiles of peripheral blood cells from patients with RRMS during the relapse and the remission phases utilizing gene microarray technology. Dysregulated genes encoded in regions associated with MS susceptibility from genomic screens or previous transcriptomic studies were identified. The proximal promoter region polymorphisms of two genes were tested for association with disease and expression level. Distinct sets of dysregulated genes during the relapse and remission phases were identified including genes involved in apoptosis and inflammation. Three of these dysregulated genes have been previously implicated with MS susceptibility in genomic screens: TGFbeta1, CD58 and DBC1. TGFbeta1 has one common SNP in the proximal promoter: -508 T>C (rs1800469). Genotyping two Australian trio sets (total 620 families) found a trend for over-transmission of the T allele in MS in females (p < 0.13). Upregulation of CD58 and DBC1 in remission is consistent with their putative roles in promoting regulatory T cells and reducing cell proliferation, respectively. A fourth gene, ALOX5, is consistently found over-expressed in MS. Two common genetic variants were confirmed in the ALOX5 putative promoter: -557 T>C (rs12762303) and a 6 bp tandem repeat polymorphism (GGGCGG) between position -147 and -176; but no evidence for transmission distortion found. The dysregulation of these genes tags their metabolic pathways for further investigation for potential therapeutic intervention.
  BMC Medical Genetics 01/2008; 9:17. · 2.33 Impact Factor
• Article: The role of the CD[subscript 5]8 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, [......], Leena Peltonen, Benedicte Dubois, Jonathan L Haines, Howard L Weiner, Alastair Compston, Stephen L Hauser, Mark J Daly, David Reich, Jorge R Oksenberg, David A Hafler
  [show abstract] [hide abstract]
  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. National Institutes of Health
  PNAS.