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

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.

Figure 1

Receiver operating characteristic (ROC) curves for the multivariate logistic regression analysis for the three risk models. Roc curve analysis was performed with the data of probability predicted by the logistic regression models for each individual of the sample, in each of the models. The area under the ROC curve (AUC) is the discriminating power of the performed model. ROC curve analysis of: (A) Risk of susceptibility to MS. The predictive capacity was increased when LINE-1 methylation levels were included. The model 2, including LINE-1 methylation levels, had a larger AUC and a higher statistical significance than model 1 including age and gender, exclusively. (B) Risk of clinical activity in MS patients undergoing IFNβ therapy. LINE-1 methylation levels had a significant predictive capacity.

Figure 2

Correlations between the percentage of LINE-1 methylation and IFNβ treatment duration. (A) In IFNβ-treated MS patients. (B) In treated patients without clinical activity: there was a significant negative correlation between LINE-1 methylation and treatment duration. (C) In treated patients with clinical activity there was not a significant correlation.