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- Fernandes, Sunjay Jude
(författare)
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Exploring the genomic and transcriptomic landscape of immune cells in multiple sclerosis : towards better biomarkers, diagnosis and treatment
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this thesis was to determine the changes in gene regulation taking place in immune cells during the course of Multiple Sclerosis. Over 200 MS-associated SNPs have been identified from GWAS studies. These regions were found to be primarily in the non-coding regions of the genome and point to the vast immune system as the leading cause of MS. Inferring their function therefore has been a challenge. In addition, a complex interaction of genetics and environment has been proposed. This leads to the unresolved question associated with specific changes in the immune system that can lead to disease. In order to resolve the role of the immune system in MS, we applied an array of high-throughput genomic and transcriptomic profiling techniques to identify specific changes in specific immune cells. MS being a complex immune mediated neurological disease, makes inference of regulation dependent changes in gene expression a challenge. By integrating different layers of evidence we are able to propose multiple interactions taking place within and across immune cells. We also find evidence that confirms previous findings in MS related to the increased activity of T and B cells. In addition, we identify multiple new genes, chromatin regions and DNA-methylated regions with differential activity primarily in T and B cells. Collectively the results from these studies highlight the multiple factors leading to the dysregulation of the immune system in MS and the specific cells associated with pathogenesis. These studies also provide a resource for hypothesis building, validation of other studies and application of newer integration methodologies in a complex immune disease such as MS.
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| 2. |
- James, Tojo, et al.
(författare)
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Impact of genetic risk loci for multiple sclerosis on expression of proximal genes in patients
- 2018
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 27:5, s. 912-928
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Tidskriftsartikel (refereegranskat)abstract
- Despite advancements in genetic studies, it is difficult to understand and characterize the functional relevance of disease-associated genetic variants, especially in the context of a complex multifactorial disease such as multiple sclerosis (MS). As a large proportion of expression quantitative trait loci (eQTLs) are context-specific, we performed RNA-Seq in peripheral blood mononuclear cells from MS patients (n = 145) to identify eQTLs in regions centered on 109 MS risk single nucleotide polymorphisms and 7 associated human leukocyte antigen variants. We identified 77 statistically significant eQTL associations, including pseudogenes and non-coding RNAs. Thirty-eight out of 40 testable eQTL effects were colocalized with the disease association signal. As many eQTLs are tissue specific, we aimed to detail their significance in different cell types. Approximately 70% of the eQTLs were replicated and characterized in at least one major peripheral blood mononuclear cell-derived cell type. Furthermore, 40% of eQTLs were found to be more pronounced in MS patients compared with non-inflammatory neurological diseases patients. In addition, we found two single nucleotide polymorphisms to be significantly associated with the proportions of three different cell types. Mapping to enhancer histone marks and predicted transcription factor binding sites added additional functional evidence for eight eQTL regions. As an example, we found that rs71624119, shared with three other autoimmune diseases and located in a primed enhancer (H3K4me1) with potential binding for STAT transcription factors, significantly associates with ANKRD55 expression. This study provides many novel and validated targets for future functional characterization of MS and other diseases.
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