http://nova.newcastle.edu.au/vital/access/services/Feed ${session.getAttribute("locale")} 5 http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:9594 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. 2011-12-05T23:30:03.749Z ]]> http://nova.newcastle.edu.au/vital/access/manager/Repository/uon:7518 To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13–14 (rs703842, P = 5.4 times 10⁻¹¹; rs10876994, P = 2.7 times 10⁻¹⁰; rs12368653, P = 1.0 times 10⁻⁷) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 times 10⁻⁷; rs1569723, P = 2.9 times 10⁻⁷). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 times 10⁻¹⁸⁴; CD58, P = 9.6 times 10⁻⁸; EVI5-RPL5, P = 2.5 times 10⁻⁶; IL2RA, P = 7.4 times 10⁻⁶; CLEC16A, P = 1.1 times 10⁻⁴; IL7R, P = 1.3 times 10⁻³; TYK2, P = 3.5 times 10⁻³) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001). 2011-04-07T02:50:06.341Z ]]>