Journal article
The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis
Human Molecular Genetics, Vol.19(11), pp.2134-2143
2010
Abstract
Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300 000 SNPs for 115 of these samples. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P < 10(-12)) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not associated with clinical course or disability. The ANZgene genome wide association screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory molecule, CD40; the other a region on chromosome 12q13-14. The CD40 haplotype associated with increased MS susceptibility has decreased gene expression in MS (P < 0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequilibrium. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P < 10(-14)). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.
Details
- Title
- The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis
- Authors/Creators
- K.S. Gandhi (Author/Creator) - The University of SydneyF.C. McKay (Author/Creator) - The University of SydneyM. Cox (Author/Creator) - Hunter Medical Research InstituteC. Riveros (Author/Creator) - Hunter Medical Research InstituteN. Armstrong (Author/Creator) - The University of SydneyR.N. Heard (Author/Creator) - The University of SydneyS. Vucic (Author/Creator) - The University of SydneyD.W. Williams (Author/Creator) - Hunter Medical Research InstituteJ. Stankovich (Author/Creator) - Menzies Research InstituteM. Brown (Author/Creator) - The University of QueenslandP. Danoy (Author/Creator) - The University of QueenslandG.J. Stewart (Author/Creator) - The University of SydneyS. Broadley (Author/Creator) - Griffith UniversityP. Moscato (Author/Creator) - Hunter Medical Research InstituteJ. Lechner-Scott (Author/Creator) - Hunter Medical Research InstituteR.J. Scott (Author/Creator) - Hunter Medical Research InstituteD.R. Booth (Author/Creator) - The University of SydneyA.G. Kermode (Author/Creator)
- Publication Details
- Human Molecular Genetics, Vol.19(11), pp.2134-2143
- Publisher
- Oxford University Press
- Identifiers
- 991005542079307891
- Copyright
- © 2010 The Authors.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
- Note
- Appears as a member of the ANZgene Multiple Sclerosis Genetics Consortium
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- Collaboration types
- Domestic collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.203 Neuromuscular Disorders
- 1.203.147 Multiple Sclerosis
- Web Of Science research areas
- Biochemistry & Molecular Biology
- Genetics & Heredity
- ESI research areas
- Molecular Biology & Genetics