Global methylation correlates with clinical status in multiple sclerosis patients in the first year of IFNbeta treatment

María Jesús Pinto-Medel,Laura Leyva,Óscar Fernández,Pedro Serrano-Castro,Isaac Hurtado-Guerrero,Begoña Oliver-Martos,Jesús Ortega-Pinazo,Patricia Urbaneja-Romero

doi:10.1038/s41598-017-09301-2

Abstract

The alteration of DNA methylation patterns are a key component of disease onset and/or progression. Our objective was to evaluate the differences in Long Interspersed Nuclear Element-1 (LINE-1) methylation levels, as a surrogate marker of global DNA methylation, between multiple sclerosis (MS) patients and healthy controls. In addition, we assessed the association of LINE-1 methylation with clinical disease activity in patients treated with IFNbeta (IFNβ). We found that individuals with high levels of LINE-1 methylation showed 6-fold increased risk of suffering MS. Additionally, treated MS patients who bear high LINE-1 methylation levels had an 11-fold increased risk of clinical activity. Moreover, a negative correlation between treatment duration and percentage of LINE-1 methylation, that was statistically significant exclusively in the group of patients without clinical activity, was observed. Our data suggest that in MS patients, a slight global DNA hypermethylation occurs that may be related to the pathophysiology of the disease. In addition, global DNA methylation levels could play a role as a biomarker for the differential clinical response to IFNβ.

Highlights

IFNbeta (IFNβ) is a first line disease modifying therapy approved for multiple sclerosis (MS) treatment
CpGs can occur in clusters of higher frequency, known as CpG islands, regions of the genome that are thought to be important in gene regulation, especially when they are localized in the promoter region of a gene
We show a relationship between DNA global methylation levels in PBMC and MS

Summary

Introduction

IFNbeta (IFNβ) is a first line disease modifying therapy approved for MS treatment. numerous randomised clinical trails have demonstrated its beneficial therapeutic effects[1], the individual patient’s response to this therapy is highly heterogeneous, and a variable percentage of MS patients are considered as non-responders or suboptimal responders to this therapy. CpG islands demonstrate lower methylation levels (hypomethylation) when associated with active genes and higher methylation levels (hypermethylation) when silencing gene expression[7]. The aberrant gene expression associated with alteration of DNA methylation patterns, is a key component of disease and aging, and has been studied in cancer. An altered balance in the expression of DNA methylation and demethylation enzymes has been reported in relapsing-remitting[20] and secondary progressive MS patients[21]. In this sense, the latter authors support the idea that hypomethylating agents might have therapeutic effects in MS, as they have already achieved an improvement of the clinical course of experimental autoimmune encephalomyelitis[22]. Baranzini et al did not find consistent differences in DNA methylation in a pair of monozygotic twins discordant for MS23

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Methods

Conclusion