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

Creators: Castro, Kamilah; Ntranos, Achilles; Amatruda, Mario; Petracca, Maria; Kosa, Peter; Chen, Emily Y.; Morstein, Johannes^{1, 2}; Trauner, Dirk; Watson, Corey T.; Kiebish, Michael A.; Bielekova, Bibiana; Inglese, Matilde; Katz Sand, Ilana; Casaccia, Patrizia

1. New York University
2. California Institute of Technology

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.

Acknowledgement

We are grateful to Yadira Bencosme and all the clinical neurologists and staff at the Corinne Goldsmith Center for Multiple Sclerosis for all the help with Patients' recruitment; to Tamjeed Sikder, Jessica Zheng, Benjamin Inbar and Payal Naik for the isolation of DNA from CD14⁺ cells and plasma separation. We thank Dr. Jimmy Huynh and Dr. Andrew Sharp for initial discussions on DNA methylation.

Funding

This work was supported by funds from the Friedman Brain Institute, NIH, and Multiple Sclerosis Society.

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