Abstract
Introduction: DNA methylation at CpG sites is an epigenetic mechanism that can influence gene expression. Epigenome-wide association studies (EWASs) of immune cells have implicated differential methylation in Multiple Sclerosis MS. Furthermore, differences in global DNA methylation profiles have been demonstrated after treatment with various disease modifying therapies such as interferon beta and dimethyl fumarate. Whether or not these changes can be used to predict response to treatment at baseline is unknown.
Objectives/Aims: The objective of this study was to assess if there are changes in global DNA methylation that can predict response to cladribine tablets in people with MS (pwMS).
Methods: Whole blood DNA was collected from a subset of the prospectively followed cohort from the CLOBAS study which is a phase IV, multicentre, open label, six-year study of cladribine tablets for pwMS. Participants were considered non-responders if they had a clinical relapse or new MRI activity between three- and 30-months post first dose of cladribine tablets. Bisulfite converted DNA was hybridised to Illumina Infinium EPIC v2 arrays and analysed using the ChAMP R package. GLMNet was used to select meaningful features of baseline DNA methylation that could discriminate between responders and non-responders.
Results: Fifteen of 102 participants were considered non-responders after 30 months of cladribine tablet use. The single most significant feature was cg15041948, which maps to the transcription start site of the GPBP1 gene, which codes for the Vasculin protein. This CpG has a good ability to discriminate between responders and non-responders (Area Under the Curve (AUC) = 0.78). Using the top 28 features identified by GLMNet, the ability to discriminate between responders and non-responders was perfect (AUC=1).
Conclusion: We are able to use global DNA methylation profiles to discriminate between responders and non-responders to cladribine treatment. Low numbers mean results should be interpreted with caution, however, the CLOBAS study is a six-year prospective cohort, therefore, longer term follow studies will follow.