Genetics of multiple sclerosis

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Petr75
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Genetics of multiple sclerosis

Post by Petr75 » Sat Nov 02, 2019 12:12 am

2019 Sep 4
Biology, Athens State University
Breakdown of Multiple Sclerosis Genetics to Identify an Integrated Disease Network and Potential Variant Mechanisms.
https://www.ncbi.nlm.nih.gov/pubmed/31482761

Abstract
Genetics of multiple sclerosis (MS) are highly polygenic with few insights into mechanistic associations with pathology. In this paper, we assessed MS genetics through linkage disequilibrium and missense variant interpretation to yield a MS gene network. This network of 96 genes was taken through pathway analysis, tissue expression profiles, single cell expression segregation, expression quantitative trait loci (eQTLs), genome annotations, transcription factor (TF) binding profiles, structural genome looping, and overlap with additional associated genetic traits. This work revealed immune system dysfunction, nerve cell myelination, energetic control, transcriptional regulation, and variants that overlap multiple autoimmune disorders. Tissue-specific expression and eQTLs of MS genes implicate multiple immune cell types including macrophages, neutrophils, and T-cells, while the genes in neural cell types enrich for oligodendrocyte and myelin sheath biology. There are eQTLs in linkage with lead MS variants in 25 genes including the multi-tissue eQTL, rs9271640, for HLA-DRB1/DRB5. Using multiple functional genomic databases, noncoding variants were identified that disrupt TF binding for GABPA, CTCF, EGR1, YY1, SPI1, CLOCK, ARNTL, BACH1, and GFI1. Overall, this manuscript suggests multiple genetic mechanisms for MS associated variants while highlighting the importance of a systems biology and network approach when elucidating intersections of the immune and nervous system.

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Petr75
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Posts: 548
Joined: Sat Oct 19, 2013 10:17 am
Location: Czech Republic

Re: Genetics of multiple sclerosis

Post by Petr75 » Sat Nov 02, 2019 9:51 am

2019 Sep 4
Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Kelambakkam, India
Gene Regulatory Networks in Peripheral Mononuclear Cells Reveals Critical Regulatory Modules and Regulators of Multiple Sclerosis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726613/

Abstract
Multiple sclerosis (MS) is a complex, demyelinating disease with the involvement of autoimmunity and neurodegeneration. Increasing efforts have been made towards identifying the diagnostic markers to differentiate the classes of MS from other similar neurological conditions. Using a systems biology approach, we constructed four types of gene regulatory networks (GRNs) involved in peripheral blood mononuclear cells (PBMCs). The regulatory strength of each GRN across primary progressive MS (PPMS), relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and control were evaluated by an integrity algorithm. Among the constructed GRNs (referred as TF_gene_miRNA), POU3F2_CDK6_hsa-miR-590-3p, MEIS1_CASC3_hsa-miR-1261, STAT3_OGG1_hsa-miR-298, and TCF4_FMR1_hsa-miR-301b were top-ranked and differentially regulated in all classes of MS compared to control. These GRNs showed potential involvement in regulating various molecular pathways such as interleukin, integrin, glypican, sphingosine phosphate, androgen, and Wnt signaling pathways. For validation, the qPCR analysis of the GRN components (TFs, gene, and miRNAs) in PBMCs of healthy controls (n = 30), RRMS (n = 14), PPMS (n = 13) and SPMS (n = 12) were carried out. Real-time expression analysis of GRNs showed a similar regulatory pattern as derived from our systems biology approach. Also, our study provided several novel GRNs that regulate unique and common molecular mechanisms between MS conditions. Hence, these regulatory components of GRNs will help to understand the disease mechanism across MS classes and further insight may though light towards diagnosis.

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