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The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis

Citation

Gandhi, KS and McKay, FC and Cox, M and Riveros, C and Armstrong, N and Heard, RN and Vucic, S and Williams, DW and Stankovich, J and Brown, M and Danoy, P and Stewart, GJ and Broadley, S and Moscato, P and Lechner-Scott, J and Scott, RJ and Booth, DR and Griffiths, L and Slee, M and Browning, S and Browning, BL and Kilpatrick, T and Rubio, J and Perreau, V and Butzkeuven, H and Tanner, M and Wiley, J and Foote, SJ and Taylor, BVM and Kermode, A and Carroll, B and Bahlo, M, The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis , Human Molecular Genetics, 19, (11) pp. 2134-2143. ISSN 0964-6906 (2010) [Refereed Article]

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The definitive publisher-authenticated version is available online at: www.oxfordjournals.org

Official URL: http://hmg.oxfordjournals.org/content/19/11/2134

DOI: doi:10.1093/hmg/ddq090

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 < 10212) 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 < 10214). 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.

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Clinical sciences
Research Field:Medical genetics (excl. cancer genetics)
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Stankovich, J (Dr Jim Stankovich)
UTAS Author:Foote, SJ (Professor Simon Foote)
UTAS Author:Taylor, BVM (Professor Bruce Taylor)
ID Code:65296
Year Published:2010
Web of Science® Times Cited:84
Deposited By:Menzies Institute for Medical Research
Deposited On:2010-10-27
Last Modified:2011-06-15
Downloads:0

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