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

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Title The Multiple Sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis
Author Gandhi, Kaushal S.; McKay, Fiona C.; Cox, Matthew; Riveros, Carlos; Armstrong, Nicola; Heard, Robert N.; Vucic, Steve; Williams, David W.; Stankovich, Jim; Brown, Matthew; Danoy, Patrick; Stewart, Graeme J.; Broadley, Simon; Moscato, Pablo; Lechner-Scott, Jeannette; Scott, Rodney J.; Booth, David R.; al, et
Journal Name Human Molecular Genetics
Editor Kay Davies, Anthony Wynshaw-Boris, Joel Hirschhorn
Year Published 2010
Place of publication United Kingdom
Publisher Oxford University Press
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.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1093/hmg/ddq090
Volume 19
Issue Number 11
Page from 2134
Page to 2143
ISSN 0964-6906
Date Accessioned 2010-07-08
Date Available 2010-09-01T08:07:41Z
Language en_AU
Research Centre Griffith Health Institute; Molecular Basis of Disease
Faculty Griffith Health Faculty
Subject Neurology and Neuromuscular Diseases
URI http://hdl.handle.net/10072/33153
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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