Body Mass Index in Multiple Sclerosis modulates ceramide-induced DNA methylation and disease course

Authors

Kamilah Castro, Icahn School of Medicine at Mount Sinai
Achilles Ntranos, IcahSchool of Medicine at Mount Sinai
Mario Amatruda, CUNY Graduate Center
Maria Petracca, Icahn School of Medicine at Mount Sinai
Peter Kosa, National Institutes of Health
Emily Y. Chen, BERG, LLC.
Johannes Morstein, New York University
Dirk Trauner, New York University
Corey T. Watson, University of Louisville
Michael A. Kiebish, BERG, LLC.
Bibiana Bielekova, National Institutes of Health
Matilde Inglese, Icahn School of Medicine at Mount Sinai
Ilana Katz Sand, Icahn School of Medicine at Mount Sinai
Patricia Casaccia, CUNY Advanced Science Research CenterFollow

Document Type

Article

Publication Date

4-10-2019

Abstract

Background: Multiple Sclerosis (MS) results from genetic predisposition and environmental variables, including elevated Body Mass Index (BMI) in early life. This study addresses the effect of BMI on the epigenome of monocytes and disease course in MS.

Methods: Fifty-four therapy-naive Relapsing Remitting (RR) MS patients with high and normal BMI received clinical and MRI evaluation. Blood samples were immunophenotyped, and processed for unbiased plasma lipidomic profiling and genome-wide DNA methylation analysis of circulating monocytes. The main findings at baseline were validated in an independent cohort of 91 therapy-naïve RRMS patients. Disease course was evaluated by a two-year longitudinal follow up and mechanistic hypotheses tested in human cell cultures and in animal models of MS.

Findings: Higher monocytic counts and plasma ceramides, and hypermethylation of genes involved in negative regulation of cell proliferation were detected in the high BMI group of MS patients compared to normal BMI. Ceramide treatment of monocytic cell cultures increased proliferation in a dose-dependent manner and was prevented by DNA methylation inhibitors. The high BMI group of MS patients showed a negative correlation between monocytic counts and brain volume. Those subjects at a two-year follow-up showed increased T1 lesion load, increased disease activity, and worsened clinical disability. Lastly, the relationship between body weight, monocytic infiltration, DNA methylation and disease course was validated in mouse models of MS.

Interpretation: High BMI negatively impacts disease course in Multiple Sclerosis by modulating monocyte cell number through ceramide-induced DNA methylation of anti-proliferative genes

Comments

This article was originally published in EBioMedicine, available at https://doi.org/10.1016/j.ebiom.2019.03.087

This work is distributed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0).