DNA methylation signatures of monozygotic twins clinically discordant for multiple sclerosis
ECTRIMS Online Library. Gerdes L. Oct 12, 2018; 232051; 298
Lisa Ann Gerdes
Lisa Ann Gerdes

Abstract: 298

Type: Scientific Session

Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics

Introduction: Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. Although genetic susceptibility is important, a modest concordance rate for MS in monozygotic (MZ) twins suggests that interaction with other risk factors is required to develop clinical symptoms.
Objectives: In this study, we examined whether DNA methylation differences contribute to the discordant clinical manifestation of MS in MZ twins.
Aims: Identification of MS associated methylation changes to gain insight to MS pathogenesis and to study treatment effects on the DNA methylome.
Methods: Genome-wide DNA methylation profiles of peripheral blood mononuclear cells (PBMCs) of 45 MZ twins clinically discordant for MS were generated using the Illumina HumanMethylationEPIC array. Repetitive element methylation and selected differentially methylated positions (DMPs) were validated using targeted deep bisulfite sequencing (TDBS).
Results: Overall, large systematic methylation differences (>5%) were absent in our data, suggesting that previously reported large methylation changes are probably caused by genetic rather than epigenetic differences. In addition, our data does not support the hypothesis that the observed maternal parent-of-origin effect in MS is due to genomic imprinting errors, and no evidence was found that copy number variations explain the discordant phenotype in these MZ twins. Nevertheless, a couple of DMPs associated with the MS phenotype were identified and successfully technically replicated using TDBS, including a differentially methylated region (DMR) in the promoter of the transmembrane protein encoding gene TMEM232. Another MS-associated DMP, located in an enhancer in the gene body of the transcription factor ZBTB16, was also associated with medium-term glucocorticoid treatment history and global hypermethylation in the MS-affected co-twins. Furthermore, several robust epigenetic biomarkers for interferon treatment response were identified.
Conclusion: This epigenome-wide association study (EWAS) in genetically identical twins identified a DMR in the TMEM232 promoter as a candidate loci associated with the clinical manifestation of MS. In addition, our study reveals that not only short-term, but also medium-term treatment effects are detectable in immune cells, which should be taken into account in EWAS design.
Disclosure: Source of funding:
The study was funded by the Gemeinnützige Hertie Foundation. The National Twin cohort receives financial support for travel expenses of the twins (for study visits in Munich) by the German MS Foundation, regional and national division (DMSG Landesverband und Bundesverband Bayern) and the association “Therapieforschung für Multiple Sklerose Kranke”.
Nicole Y.P. Souren: nothing to disclose.
Lisa A. Gerdes has received speaker´s honoraria from Roche Pharma, Sanofi/Aventis-Genzyme and Merck Serono.
Pavlo Lutsik: nothing to disclose.
Gilles Gasparoni: nothing to disclose.
Eduardo Beltran: nothing to disclose.
Abdulrahman Salhab: nothing to disclose.
Tania Kümpfel has received travel expenses and speaker honoraria from Bayer Healthcare, Teva Pharma, Merck, Novartis Pharma, Sanofi-Aventis/Genzyme, CLB Behring, Roche Pharma and Biogen as well as grant support from Bayer-Schering AG, Novartis and Chugai Pharma.
Dieter Weichenhan: nothing to disclose.
Christoph Plass: nothing to disclose.
Reinhard Hohlfeld received research grants and/or speaker honoraria from Actelion, Genzyme-Sanofi, Novartis, Immunic, Roche.
Jörn Walter: nothing to disclose.

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