Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region. Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.

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EudraCT number 2007-001958-99 and ClinicalTrialsGov number NCT01339676.

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SummaryThe frequencies of human T cell lymphotropic virus type 1 (HTLV-1)-speciflc CD8 + precursor cytotoxic T lymphocytes (pCTL) were quantitated from lymphocytes obtained from the peripheral blood and cerebrospinal fluid (CSF) of infected individuals with and without HTLV-l-associated neurological disease. An estimate of the pCTL was obtained by separating CD8 + cells, plating these cells in limiting dilution, and testing weUs for HTLV-1 specific lysis. Targets consisted of autologous lymphoblastoid cell lines (LCL) infected with vaccinia constructs expressing HTLV-1 gene products or LCL pulsed with HTLV-1 synthetic peptides. In patients with HTLV-l-associated myelopathy/tropical spastic paraparesis (HAM/TSP), the frequency of HTLV-1 p40X-specific pCTL was at least 40-280-fold higher than in asymptomatic HTLV-l-infected individuals. All HAM/TSP patients (five of five) predominantly recognized HTLV-1 products encoded within the pX region. Lower pCTL to env were demonstrated in three patients, and only one of five HAM/TSP patients had pCTL to gag. A synthetic peptide corresponding to the tax region of HTLV-1 (peptide 11-19, amino acid sequence LLFGYPVYV) was recognized in association with human histocompatibility leukocyte antigen (HLA)-A2 in two HLA-A2 HAM/TSP patients with a high CD8 + pCTL frequency of 1/325 and 1/265, respectively. A second immunodominant region of HTLV-1 tax (peptide 90-55, amino acid sequence VPYKtLIEEL) was identified to be restricted by HLA-B14 in two HLA-B14 HAM/TSP patients with a CD8 + pCTL frequency of 1/640 and 1/1,125, respectively. Lymphocytes from the CSF of a patient with HAM/TSP also showed a pCTL frequency against p40X of similar magnitude to that demonstrated from peripheral blood lymphocytes (PBL). The HLA-A2-mediated CSF pCTL activity to the immunodominant tax-specific peptide 11-19 was also comparable to pCTL from PBL. These results indicate that an extremely high pCTL frequency to HTLV-1 tax-encoded peptides may be related to pathogenesis of myeloneuropathy associated with HTLV-1.

Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10(-4) were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 x 10(-10), OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.

Background:IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS).Methods:We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case–control cohorts from Spain and Sweden, and a set of MS trio families from Finland.Results:Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel.Conclusion:These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.

Our study of PwMS and HCPs in the MS in the 21st Century initiative has highlighted eight practical actions. These actions identify how differences and gaps in unmet needs, treatment burden, and patient engagement between PwMS and HCPs can be bridged to improve MS disease management. Of particular interest now are patient-centred educational resources that can be used during time-limited consultations to enhance understanding of disease and improve communication. Actively bridging these gaps in a joint approach enables PwMS to take part in shared decision-making; with improved communication and reliable information, patients can make informed decisions with their HCPs, as part of their own personalised disease management.