@article{a93c6b7ecb11457f96bc67025f4ea59a,
title = "Body Mass Index in Multiple Sclerosis modulates ceramide-induced DNA methylation and disease course",
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-na{\"i}ve 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. Fund: This work was supported by funds from the Friedman Brain Institute, NIH, and Multiple Sclerosis Society.",
keywords = "Epigenetics, Immunity, Lipids, Neurodegeneration, Obesity",
author = "Kamilah Castro and Achilles Ntranos and Mario Amatruda and Maria Petracca and Peter Kosa and Chen, {Emily Y.} and Johannes Morstein and Dirk Trauner and Watson, {Corey T.} and Kiebish, {Michael A.} and Bibiana Bielekova and Matilde Inglese and {Katz Sand}, Ilana and Patrizia Casaccia",
note = "Funding Information: This work was supported by funds from the Friedman Brain Institute (PC), the National Institute for Neurological Disorders and Stroke , to PC ( R37-NS042925 ) and to KC ( F31-NS098575 ), and the Multiple Sclerosis Society (IK). Funders had no role in study design, data collection, data analysis, interpretation or writing of this manuscript. Funding Information: 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. This work was supported by funds from the Friedman Brain Institute (PC), the National Institute for Neurological Disorders and Stroke, to PC (R37-NS042925) and to KC (F31-NS098575), and the Multiple Sclerosis Society (IK). Funders had no role in study design, data collection, data analysis, interpretation or writing of this manuscript. The authors declare no competing interests. The authors have declared that no conflict of interest exists. KC, PC, IK designed the study. IK was responsible for patients' identification, recruitment and clinical evaluation. PK and BB provided the data on the validation RRMS cohort and healthy control cohort for immunophenotyping and MRI measurements. EC and MAK provided the lipidomic measurements. JM and DT synthesized the NBD-conjugated Ceramide C16. AN and CTW performed analysis of the Illumina 450 K data set and AN analyzed the follow-up clinical data. MA performed the EAE experiments. MI and MP were responsible for MRI data interpretation and measurements in the discovery cohort. KC collected all the data, conducted all the experiments on the THP1 cells, experiments on animal tissue, and conducted the statistical analysis. KC and PC organized the data, prepared the figures and wrote the manuscript. All co-authors critically reviewed the manuscript for content. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = may,
doi = "10.1016/j.ebiom.2019.03.087",
language = "English (US)",
volume = "43",
pages = "392--410",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
}