Affiliation:
1. Division of Neuroscience IRCCS San Raffaele Scientific Institute Milan Italy
2. Department of Neurology and MS Center IRCCS Ospedale San Raffaele Milan Italy
3. Università Vita‐Salute San Raffaele Milan Italy
4. Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) University of Toulouse, CNRS, INSERM Toulouse France
5. Neurosciences Department Toulouse University Hospital Toulouse France
6. Department of Immunology Toulouse University Hospitals Toulouse France
Abstract
ObjectiveMultiple sclerosis (MS) has a complex pathobiology, with genetic and environmental factors being crucial players. Understanding the mechanisms underlying heterogeneity in disease activity is crucial for tailored treatment. We explored the impact of DNA methylation, a key mechanism in the genetics‐environment interplay, on disease activity in MS.MethodsPeripheral immune methylome profiling using Illumina Infinium MethylationEPIC BeadChips was conducted on 249 untreated relapsing–remitting MS patients, sampled at the start of disease‐modifying treatment (DMT). A differential methylation analysis compared patients with evidence of disease activity (EDA) to those with no evidence of disease activity (NEDA) over 2 years from DMT start. Utilizing causal inference testing (CIT) and Mendelian randomization (MR), we sought to elucidate the relationships between DNA methylation, gene expression, genetic variation, and disease activity.ResultsFour differentially methylated regions (DMRs) were identified between EDA and NEDA. Examining the influence of single nucleotide polymorphisms (SNPs), 923 variants were found to account for the observed differences in the 4 DMRs. Importantly, 3 out of the 923 SNPs, affecting DNA methylation in a DMR linked to the anti‐Mullerian hormone (AMH) gene, were associated with disease activity risk in an independent cohort of 1,408 MS patients. CIT and MR demonstrated that DNA methylation in AMH acts as a mediator for the genetic risk of disease activity.InterpretationThis study uncovered a novel molecular pathway implicating the interaction between DNA methylation and genetic variation in the risk of disease activity in MS, emphasizing the role of sex hormones, particularly the AMH, in MS pathobiology. ANN NEUROL 2024;96:289–301
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