期刊
EBIOMEDICINE
卷 43, 期 -, 页码 411-423出版社
ELSEVIER
DOI: 10.1016/j.ebiom.2019.04.042
关键词
DNA methylation; Epigenetics; Multiple sclerosis; Immune cells; Secondary progressive multiple sclerosis; Relapsing-remitting multiple sclerosis; 450 K; EPIC; omicsNPC
资金
- Swedish Research Council
- Swedish Association for Persons with Neurological Disabilities
- Swedish Brain Foundation
- Stockholm County Council - ALF project
- AstraZeneca - AstraZeneca-Science for Life Laboratory collaboration
- StratNeuro
- STATEGRA FP7
- European Research Council (FP/2007-2013)/ERC Grant [617393]
- CAUSALPATH
- Karolinska Institute's funds
- Margaretha af Ugglas Foundation
Background: Multiple Sclerosis (MS) is a chronic inflammatory disease and a leading cause of progressive neurological disability among young adults. DNA methylation, which intersects genes and environment to control cellular functions on a molecular level, may provide insights into MS pathogenesis. Methods: We measured DNA methylation in CD4(+)T cells (n = 31), CD8(+) T cells (n = 28), CD14(+ )monocytes (n = 35) and CD19( )(+)B cells (n = 27) from relapsing-remitting (RRMS), secondary progressive (SPMS) patients and healthy controls (HC) using Infinium HumanMethylation450 arrays. Monocyte (n = 25) and whole blood (n = 275) cohorts were used for validations. Findings: B cells from MS patients displayed most significant differentially methylated positions (DMPs), followed by monocytes, while only few DMPs were detected in T cells. We implemented a non-parametric combination framework (omicsNPC) to increase discovery power by combining evidence from all four cell types. Identified shared DMPs co-localized at MS risk loci and clustered into distinct groups. Functional exploration of changes discriminating RRMS and SPMS from HC implicated lymphocyte signaling, T cell activation and migration. SPMS-specific changes, on the other hand, implicated myeloid cell functions and metabolism. Interestingly, neuronal and neurodegenerative genes and pathways were also specifically enriched in the SPMS cluster. Interpretation: We utilized a statistical framework (omicsNPC) that combines multiple layers of evidence to identify DNA methylation changes that provide new insights into MS pathogenesis in general, and disease progression, in particular. (C) 2019 The Authors. Published by Elsevier B.V.
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