title: The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis.
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.
authors.affiliation: Westmead Millennium Institute, University of Sydney, Sydney, Darcy Rd, New South Wales 2145, Australia.
authors.forename: Kaushal S
authors.initials: KS
authors.lastname: Gandhi
authors.forename: Fiona C
authors.initials: FC
authors.lastname: McKay
authors.forename: Mathew
authors.initials: M
authors.lastname: Cox
authors.forename: Carlos
authors.initials: C
authors.lastname: Riveros
authors.forename: Nicola
authors.initials: N
authors.lastname: Armstrong
authors.forename: Robert N
authors.initials: RN
authors.lastname: Heard
authors.forename: Steve
authors.initials: S
authors.lastname: Vucic
authors.forename: David W
authors.initials: DW
authors.lastname: Williams
authors.forename: Jim
authors.initials: J
authors.lastname: Stankovich
authors.forename: Matthew
authors.initials: M
authors.lastname: Brown
authors.forename: Patrick
authors.initials: P
authors.lastname: Danoy
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Stewart
authors.forename: Simon
authors.initials: S
authors.lastname: Broadley
authors.forename: Pablo
authors.initials: P
authors.lastname: Moscato
authors.forename: Jeannette
authors.initials: J
authors.lastname: Lechner-Scott
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
authors.forename: David R
authors.initials: DR
authors.lastname: Booth
mesh_terms: D017951:Antigen Presentation / Q000235:genetics; D019013:CD40 Antigens / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D010085:Oxidative Phosphorylation; D012333:RNA, Messenger / Q000097:blood*; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D019013:CD40 Antigens; D012333:RNA, Messenger