Common genetic variants in the plasminogen activation pathway are not associated with multiple sclerosis.

Matrix metalloproteinase 9 (MMP9) is involved in multiple sclerosis (MS) aetiology. Previously, we identified differential gene expression of plasminogen activation cascade genes in MS patients. Based on our gene expression results, we wanted to identify whether polymorphisms in the genes associated with the plasminogen pathway could predict MS risk. We genotyped 1153 trio families, 727 MS cases and 604 healthy controls for 17 polymorphisms in MMP9, plasminogen activator urokinase (PLAU), PLAU receptor (PLAUR) and serpin peptidase inhibitor/clade 2/member B2 (SERPINB2) genes. No associations were found between the 17 polymorphisms and MS. Also, gene expression levels were analysed according to genotype: no associations were observed. In conclusion despite the consistent evidence for the role of MMP9 and the plasminogen activation cascade in MS, we found no associations between genotype nor gene expression. This suggested there are other potentially modifiable factors influencing gene expression in MS.

Altered expression of the plasminogen activation pathway in peripheral blood mononuclear cells in multiple sclerosis: possible pathomechanism of matrix metalloproteinase activation.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disorder where a breakdown in the integrity of the blood-brain barrier is thought to allow lymphocytes to enter the central nervous system. OBJECTIVES: The purpose of this study was to examine gene expression profiles between MS patients and healthy controls to identify genes intimately involved in the pathobiology of MS. METHODS: Whole-genome gene expression analysis was performed using peripheral blood mononuclear cells from 39 healthy controls and 37 MS patients, 24 MS patients receiving no disease modifying therapy and 13 MS patients receiving interferon-beta (IFN-beta). Pathway analysis was performed to identify pathways dysregulated in MS. RESULTS: Gene expression profiling of MS identified a signature of predominately immune associated genes. The plasminogen activation pathway contained an over-representation of significantly differentially expressed genes, including matrix metallopeptidase 9 (MMP9). Treatment with IFN-beta ameliorated the over-expression of MMP9, however the expression of two genes, plasminogen activator urokinase (PLAU) and serpin peptidase inhibitor, clade B (ovalbumin), member 2 (SERPINB2), forming part of the plasminogen activation pathway were not affected by IFN-beta therapy. CONCLUSIONS: High expression levels of MMP9 have been associated with MS and the breakdown of the blood-brain barrier, while IFN-beta therapy decreases MMP9 expression. We confirm altered MMP9 expression in MS, and identify dysregulation within the plasminogen activation cascade, a pathway involved in the activation of MMP9.

Potential association of vitamin D receptor polymorphism Taq1 with multiple sclerosis.

BACKGROUND: The environmental influence of sun exposure and vitamin D in particular and its implication with multiple sclerosis (MS) has recently received considerable attention. Current evidence based on genetic and epidemiological studies indicate that vitamin D is implicated in the aetiology of this disease. METHODS: We examined two common variants in the vitamin D receptor (VDR) gene in 1153 trio families and 726 cases and 604 controls. We also examined epistatic interactions between the VDR SNPs rs731236 and rs2228570 with the tagging single nucleotide polymorphism (SNP) rs3135388 for the HLA-DRB*1501 locus containing a highly conserved vitamin D responsive element within its promoter region. RESULTS: We found weak evidence for an association between the rs731236C allele and MS, while there was no direct association with rs2228570. When examining the interaction between the VDR gene variations and the DRB1*1501 tagging SNP a more complex relationship was observed. Although the interaction was not statistically significant, there appeared to be a trend of increasing risk of MS in participants who were homozygous for the HLA-DRB1*1501 allele in association with the more active form of the VDR (Fok1). CONCLUSION: We have identified weak evidence of an association between a common variation within the VDR gene and MS, in the largest study reported to date of this candidate gene. There appears to be a relationship between polymorphisms in the VDR and the risk of MS, which is potentially modified by HLA-DRB1*1501.

MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under-expressed in MS whole blood.

It is well established that Multiple Sclerosis (MS) is an immune mediated disease. Little is known about what drives the differential control of the immune system in MS patients compared to unaffected individuals. MicroRNAs (miRNAs) are small non-coding nucleic acids that are involved in the control of gene expression. Their potential role in T cell activation and neurodegenerative disease has recently been recognised and they are therefore excellent candidates for further studies in MS. We investigated the transcriptome of currently known miRNAs using miRNA microarray analysis in peripheral blood samples of 59 treatment naïve MS patients and 37 controls. Of these 59, 18 had a primary progressive, 17 a secondary progressive and 24 a relapsing remitting disease course. In all MS subtypes miR-17 and miR-20a were significantly under-expressed in MS, confirmed by RT-PCR. We demonstrate that these miRNAs modulate T cell activation genes in a knock-in and knock-down T cell model. The same T cell activation genes are also up-regulated in MS whole blood mRNA, suggesting these miRNAs or their analogues may provide useful targets for new therapeutic approaches.

A transcription factor map as revealed by a genome-wide gene expression analysis of whole-blood mRNA transcriptome in multiple sclerosis.

BACKGROUND: Several lines of evidence suggest that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but complete mapping of the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors that may be involved in one subtype may not be in others. We investigate the possibility that this network could be mapped using microarray technologies and contemporary bioinformatics methods on a dataset derived from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls. METHODOLOGY/PRINCIPAL FINDINGS: We have used two different analytical methodologies: a non-standard differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that are statistically overrepresented in genes that are either differentially expressed (or differentially co-expressed) in cases and controls (e.g., V$KROX_Q6, p-value <3.31E-6; V$CREBP1_Q2, p-value <9.93E-6, V$YY1_02, p-value <1.65E-5). CONCLUSIONS/SIGNIFICANCE: Our analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. The most significant transcription factor motifs were for the Early Growth Response EGR/KROX family, ATF2, YY1 (Yin and Yang 1), E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families. These transcription factors are involved in early T-lymphocyte specification and commitment as well as in oligodendrocyte dedifferentiation and development, both pathways that have significant biological plausibility in MS causation.