Pharmacogenomics of Interferon-ß Therapy in Multiple Sclerosis: Baseline IFN Signature Determines Pharmacological Differences between Patients

Multiple sclerosis (MS) is a heterogeneous disease. In order to understand the partial responsiveness to IFNbeta in Relapsing Remitting MS (RRMS) we studied the pharmacological effects of IFNbeta therapy. Large scale gene expression profiling was performed on peripheral blood of 16 RRMS patients at baseline and one month after the start of IFNbeta therapy. Differential gene expression was analyzed by Significance Analysis of Microarrays. Subsequent expression analyses on specific genes were performed after three and six months of treatment. Peripheral blood mononuclear cells (PBMC) were isolated and stimulated in vitro with IFNbeta. Genes of interest were measured and validated by quantitative realtime PCR. An independent group of 30 RRMS patients was used for validation. Pharmacogenomics revealed a marked variation in the pharmacological response to IFNbeta between patients. A total of 126 genes were upregulated in a subset of patients whereas in other patients these genes were downregulated or unchanged after one month of IFNbeta therapy. Most interestingly, we observed that the extent of the pharmacological response correlates negatively with the baseline expression of a specific set of 15 IFN response genes (R = -0.7208; p = 0.0016). The negative correlation was maintained after three (R = -0.7363; p = 0.0027) and six (R = -0.8154; p = 0.0004) months of treatment, as determined by gene expression levels of the most significant correlating gene. Similar results were obtained in an independent group of patients (n = 30; R = -0.4719; p = 0.0085). Moreover, the ex vivo results could be confirmed by in vitro stimulation of purified PBMCs at baseline with IFNbeta indicating that differential responsiveness to IFNbeta is an intrinsic feature of peripheral blood cells at baseline. These data imply that the expression levels of IFN response genes in the peripheral blood of MS patients prior to treatment could serve a role as biomarker for the differential clinical response to IFNbet

MicroRNAs regulate human brain endothelial cell-barrier function in inflammation: implications for multiple sclerosis.

Blood-brain barrier (BBB) dysfunction is a major hallmark of many neurological diseases, including multiple sclerosis (MS). Using a genomics approach, we defined a microRNA signature that is diminished at the BBB of MS patients. In particular, miR-125a-5p is a key regulator of brain endothelial tightness and immune cell efflux. Our findings suggest that repair of a disturbed BBB through microRNAs may represent a novel avenue for effective treatment of MS

Validation Study of Existing Gene Expression Signatures for Anti-TNF Treatment in Patients with Rheumatoid Arthritis

So far, there are no means of identifying rheumatoid arthritis (RA) patients who will fail to respond to tumour necrosis factor blocking agents (anti-TNF), prior to treatment. We set out to validate eight previously reported gene expression signatures predicting therapy outcome. Genome-wide expression profiling using Affymetrix GeneChip Exon 1.0 ST arrays was performed on RNA isolated from whole blood of 42 RA patients starting treatment with infliximab or adalimumab. Clinical response according to EULAR criteria was determined at week 14 of therapy. Genes that have been reported to be associated with anti-TNF treatment were extracted from our dataset. K-means partition clustering was performed to assess the predictive value of the gene-sets. We performed a hypothesis-driven analysis of the dataset using eight existing gene sets predictive of anti-TNF treatment outcome. The set that performed best reached a sensitivity of 71% and a specificity of 61%, for classifying the patients in the current study. We successfully validated one of eight previously reported predictive expression profile. This replicated expression signature is a good starting point for developing a prediction model for anti-TNF treatment outcome that can be used in a daily clinical setting. Our results confirm that gene expression profiling prior to treatment is a useful tool to predict anti-TNF (non) response

The gene encoding interleukin-13: a susceptibility locus for asthma and related traits

Asthma is a complex inflammatory disorder controlled by both genetic and environmental influences. Multiple genetic analyses have identified the T helper type 2 (Th2) cytokine gene cluster on chromosome 5q as a susceptibility locus for asthma. Recently, the Th2 cytokine interleukin-13 has been shown to be a critical mediator of the asthma phenotype in murine models. In this commentary we discuss several recent studies that have identified polymorphisms in the gene encoding interleukin-13. The consistent genetic associations of interleukin-13 with asthma and related traits across diverse ethnic populations in these studies provides strong support for the candidacy of this cytokine as a susceptibility locus for asthma and atopy on chromosome 5q31

Use of RNA sequencing to evaluate rheumatic disease patients

Studying the factors that control gene expression is of substantial importance for rheumatic diseases with poorly understood etiopathogenesis. In the past, gene expression microarrays have been used to measure transcript abundance on a genome-wide scale in a particular cell, tissue or organ. Microarray analysis has led to gene signatures that differentiate rheumatic diseases, and stages of a disease, as well as response to treatments. Nowadays, however, with the advent of next-generation sequencing methods, massive parallel sequencing of RNA tends to be the technology of choice for gene expression profiling, due to several advantages over microarrays, as well as for the detection of non-coding transcripts and alternative splicing events. In this review, we describe how RNA sequencing enables unbiased interrogation of the abundance and complexity of the transcriptome, and present a typical experimental workflow and bioinformatics tools that are often used for RNA sequencing analysis. We also discuss different uses of this next-generation sequencing technology to evaluate rheumatic disease patients and investigate the pathogenesis of rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus, juvenile idiopathic arthritis and Sjögren\u27s syndrome

Functional Polymorphisms in IL13 Are Protective against High Schistosoma mansoni Infection Intensity in a Brazilian Population

IL-13 is a signature cytokine of the helper T cell type 2 (TH2) pathway which underlies host defense to helminthic infection and activates production of IgE in both parasitized populations and in urban settings after allergen exposure.Two functional polymorphisms in IL13, rs1800925 (or c.1-1111C>T) and rs20541 (or R130Q) were previously found to be associated with Schistosoma hematobium infection intensity. They have not been thoroughly explored in S. mansoni-endemic populations, however, and were selected along with 5 tagging SNPs for genotyping in 812 individuals in 318 nuclear families from a schistosomiasis-endemic area of Conde, Bahia, in Brazil. Regression models using GEE to account for family membership and family-based quantitative transmission disequilibrium tests (QTDT) were used to evaluate associations with total serum IgE (tIgE) levels and S. mansoni fecal egg counts adjusted for non-genetic covariates. We identified a protective effect for the T allele at rs20541 (P = 0.005) against high S. mansoni egg counts, corroborated by QTDT (P = 0.014). Our findings also suggested evidence for protective effects for the T allele at rs1800925 and A allele at rs2066960 after GEE analysis only (P = 0.050, 0.0002).The two functional variants in IL13 are protective against high S. mansoni egg counts. These markers showed no evidence of association with tIgE levels, unlike tIgE levels previously studied in non-parasitized or atopic study populations

The genetics of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease caused by the interaction of genetic susceptibility and environmental influences. There is increasing evidence that genes link to disease pathogenesis and heterogeneity by causing variation in protease anti-protease systems, defence against oxidative stress and inflammation. The main methods of genomic research for complex disease traits are described, together with the genes implicated in COPD thus far, their roles in disease causation and the future for this area of investigation