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

Gandhi, K. S., McKay, F. C., Cox, M., Riveros, C., Armstrong, N., Heard, R. N., Vucic, S., Williams, D. W., Stankovich, J., Brown, Matthew, Danoy, P., Stewart, G. J., Broadley, S., Moscato, P., Lechner-Scott, J., Scott, R. J., & Booth, D. R. (2010) 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.

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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 tdthomlt; 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.

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ID Code: 89388
Item Type: Journal Article
Refereed: Yes
Keywords: CD40 antigen, cell protein, messenger RNA, protein FAM119B, unclassified drug, adult, aged, antigen presentation, article, chromosome 12q, controlled study, disease course, female, gene expression regulation, gene linkage disequilibrium, genetic association, genetic susceptibility, genetic transcription, genome analysis, genotype, haplotype, human, human cell, immunopathogenesis, leukocyte, major clinical study, male, multiple sclerosis, oxidative phosphorylation, priority journal, signal transduction, single nucleotide polymorphism, synaptic transmission, T lymphocyte, T lymphocyte activation, transcriptomics, translation regulation, blood, chromosome 12, gene expression profiling, genetics, metabolism, pathophysiology, Antigens, CD40, Chromosomes, Human, Pair 12, Haplotypes, Humans, Linkage Disequilibrium, RNA, Messenger, T-Lymphocytes
DOI: 10.1093/hmg/ddq090
ISSN: 0964-6906
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2010 The Authors
Deposited On: 22 Oct 2015 00:41
Last Modified: 19 Aug 2016 04:55

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