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DNA Methylation in the Anti-Mullerian Hormone Gene and the Risk of Disease Activity in Multiple Sclerosis
Antonino Giordano1,2,3, Béatrice Pignolet4,5, Elisabetta Mascia1
1Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Objective:
Multiple 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.
Methods:
Peripheral 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.
Results:
Four 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.
Interpretation:
This 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.
Insights
DNA methylation and genetic variations influence multiple sclerosis (MS) disease activity. The anti-Mullerian hormone (AMH) gene
Area of Science:
- Neuroimmunology
- Epigenetics
- Genetics
Background:
- Multiple sclerosis (MS) pathogenesis involves complex genetic and environmental interactions.
- Understanding disease heterogeneity is key for personalized MS treatment strategies.
- DNA methylation is a critical epigenetic mechanism mediating gene-environment interplay.
Purpose of the Study:
- To investigate the role of DNA methylation in multiple sclerosis disease activity.
- To explore the interplay between DNA methylation, gene expression, and genetic variation in MS.
- To identify molecular pathways influencing disease heterogeneity.
Main Methods:
- Peripheral immune cell methylome profiling using Illumina MethylationEPIC arrays in 249 MS patients.
- Differential methylation analysis comparing patients with evidence of disease activity (EDA) versus no evidence of disease activity (NEDA).
- Causal inference testing (CIT) and Mendelian randomization (MR) to assess causal relationships.
Main Results:
- Four differentially methylated regions (DMRs) were identified between EDA and NEDA groups.
- 923 single nucleotide polymorphisms (SNPs) explained methylation differences in the DMRs.
- SNPs in a DMR linked to the anti-Mullerian hormone (AMH) gene were associated with MS disease activity risk in an independent cohort.
Conclusions:
- A novel pathway involving DNA methylation and genetic variation in MS disease activity risk was discovered.
- DNA methylation in the AMH gene mediates genetic risk for disease activity in MS.
- This highlights the role of AMH and sex hormones in MS pathobiology.
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