Investigating the Causal Effect of Brain Expression of CCL2, NFKB1, MAPK14, TNFRSF1A, CXCL10 Genes on Multiple Sclerosis:A Two-Sample Mendelian Randomization Approach
| العنوان: | Investigating the Causal Effect of Brain Expression of CCL2, NFKB1, MAPK14, TNFRSF1A, CXCL10 Genes on Multiple Sclerosis:A Two-Sample Mendelian Randomization Approach |
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| المؤلفون: | Teresa Fazia, Andrea Nova, Davide Gentilini, Ashley Beecham, Marialuisa Piras, Valeria Saddi, Anna Ticca, Pierpaolo Bitti, Jacob L. McCauley, Carlo Berzuini, Luisa Bernardinelli |
| المصدر: | Fazia, T, Nova, A, Gentilini, D, Beecham, A, Piras, M, Saddi, V, Ticca, A, Bitti, P, McCauley, J L, Berzuini, C & Bernardinelli, L 2020, ' Investigating the Causal Effect of Brain Expression of CCL2, NFKB1, MAPK14, TNFRSF1A, CXCL10 Genes on Multiple Sclerosis : A Two-Sample Mendelian Randomization Approach ', Frontiers in Bioengineering and Biotechnology, pp. 1-16 . https://doi.org/10.3389/fbioe.2020.00397Test Frontiers in Bioengineering and Biotechnology, Vol 8 (2020) |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Candidate gene, Multiple Sclerosis, Histology, lcsh:Biotechnology, Biomedical Engineering, family data, Hippocampus, Bioengineering, 02 engineering and technology, Biology, White matter, 03 medical and health sciences, lcsh:TP248.13-248.65, Mendelian randomization, medicine, NF-κB signaling pathway, Medulla, Temporal cortex, Putamen, Multiple sclerosis, 021001 nanoscience & nanotechnology, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, gene expression, 0210 nano-technology, Neuroscience, Biotechnology |
| الوصف: | Multiple Sclerosis (MS) exhibits considerable heterogeneity in phenotypic expression, course, prognosis and response to therapy. This suggests this disease involves multiple, as yet poorly understood, causal mechanisms. In this work we assessed the possible causal link between gene expression level of five selected genes related to the pro-inflammatory NF-κB signaling pathway (i.e., CCL2, NFKB1, MAPK14, TNFRSF1A, CXCL10) in ten different brain tissues (i.e., cerebellum, frontal cortex, hippocampus, medulla, occipital cortex, putamen, substantia nigra, thalamus, temporal cortex and intralobular white matter) and MS. We adopted a two-stage Mendelian Randomization (MR) approach for the estimation of the causal effects of interest, based on summary-level data from 20 multiplex Sardinian families and data provided by the United Kingdom Brain Expression Consortium (UKBEC). Through Radial-MR and Cochrane’s Q statistics we identified and removed genetic variants which are most likely to be invalid instruments. To estimate the total causal effect, univariable MR was carried out separately for each gene and brain region. We used Inverse-Variance Weighted estimator (IVW) as main analysis and MR-Egger Regression estimator (MR-ER) and Weighted Median Estimator (WME) as sensitivity analysis. As these genes belong to the same pathway and thus they can be closely related, we also estimated their direct causal effects by applying IVW and MR-ER within a multivariable MR (MVMR) approach using set of genetic instruments specific and common (composite) to each multiple exposures represented by the expression of the candidate genes. Univariate MR analysis showed a significant positive total causal effect for CCL2 and NFKB1 respectively in medulla and cerebellum. MVMR showed a direct positive causal effect for NFKB1 and TNFRSF1A, and a direct negative causal effect for CCL2 in cerebellum; while in medulla we observed a direct positive causal effect for CCL2. Since in general we observed a different magnitude for the gene specific causal effect we hypothesize that in cerebellum and medulla the effect of each gene expression is direct but also mediated by the others. These results confirm the importance of the involvement of NF-κB signaling pathway in brain tissue for the development of the disease and improve our understanding in the pathogenesis of MS. |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b50402b2a0e1c8c00c351241d2112897Test https://www.research.manchester.ac.uk/portal/en/publications/investigating-the-causal-effect-of-brain-expression-of-ccl2-nfkb1-mapk14-tnfrsf1a-cxcl10-genes-on-multiple-sclerosisTest(8f970d91-46b2-43b1-9cf8-8fb5559c8643).html |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b50402b2a0e1c8c00c351241d2112897 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |