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EBioMedicine. 2019 May;43:411-423. doi: 10.1016/j.ebiom.2019.04.042. Epub 2019 Apr 30.

Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression.

Author information

1
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm 17177, Sweden.
2
Unit of Computational Medicine, Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, 17177, Sweden; Science for Life Laboratory, Solna, Sweden.
3
Institute of Computer Science, Foundation for Research and Technology-Hellas, Heraklion, Greece; Computational Medicine Center, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA.
4
Institute of Chemical Biology, Ilia State University, Tbilisi, Georgia; Gnosis Data Analysis PC, Heraklion, Greece.
5
Gnosis Data Analysis PC, Heraklion, Greece; Department of Computer Science, University of Crete, Heraklion, Greece.
6
Unit of Computational Medicine, Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, 17177, Sweden; Biological and Environmental Sciences and Engineering Division, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology, Saudi Arabia; Science for Life Laboratory, Solna, Sweden.
7
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm 17177, Sweden; Center for Neurology, Academic Specialist Clinic, Stockholm Health Services, Stockholm, Sweden.
8
Unit of Computational Medicine, Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, 17177, Sweden; Translational Bioinformatics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain; Centre for Host Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, UK.
9
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm 17177, Sweden. Electronic address: maja.jagodic@ki.se.

Abstract

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. FUND: This work was supported by the Swedish Research Council, Stockholm County Council, AstraZeneca, European Research Council, Karolinska Institutet and Margaretha af Ugglas Foundation.

KEYWORDS:

450 K; DNA methylation; EPIC; Epigenetics; Immune cells; Multiple sclerosis; Relapsing-remitting multiple sclerosis; Secondary progressive multiple sclerosis; omicsNPC

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