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

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

Publication date: Apr 30, 2019

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.

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.

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.

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.

Ewing, E., Kular, L., Fernandes, S.J., Karathanasis, N., , Lagani, Ruhrmann, S., , Tsamardinos, Tegner, J., Piehl, F., Gomez-Cabrero, D., and Jagodic, M. Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression. 18017. 2019 EBioMedicine.

Concepts Keywords
AstraZeneca Multiple sclerosis research
Blood Clinical medicine
CD14 Health
CD19 Relapsing–remitting
CD4 Medical specialties
CD8 Spms
Disability Multiple sclerosis
European Council Immune Multiple sclerosis
Karolinska Institutet
Loci
Lymphocyte
Metabolism
Methylated
Methylation
Monocyte
Monocytes
Multiple Sclerosis
Myeloid
Neurodegenerative
Neurological
Pathogenesis
Swedish

Semantics

Type Source Name
disease MESH Secondary progressive multiple sclerosis
disease MESH Relapsing-remitting multiple sclerosis
disease MESH disease progression
disease MESH multiple
pathway BSID Metabolism
disease DOID SPMS
disease DOID RRMS
gene UNIPROT CD19
gene UNIPROT CD14
gene UNIPROT NDUFA2
gene UNIPROT CD8A
gene UNIPROT CD4
disease DOID Multiple Sclerosis
disease MESH Multiple Sclerosis

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