DNA Methylation in the Anti-Mullerian Hormone Gene and the Risk of Disease Activity in Multiple Sclerosis

IF 8.1 1区医学 Q1 CLINICAL NEUROLOGY Annals of Neurology Pub Date : 2024-05-15 DOI:10.1002/ana.26959

Antonino Giordano MD, PhD, Béatrice Pignolet PhD, Elisabetta Mascia PhD, Ferdinando Clarelli MSc, Melissa Sorosina PhD, Kaalindi Misra PhD, Florence Bucciarelli MSc, Laura Ferrè MD, PhD, Lucia Moiola MD, Roland Liblau MD, PhD, Massimo Filippi MD, Federica Esposito MD, PhD

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Abstract

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

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抗苗勒管激素基因的 DNA 甲基化与多发性硬化症的疾病活动风险

目的：多发性硬化症（MS）的病理生物学非常复杂，遗传和环境因素是其中的关键因素。了解疾病活动的异质性的内在机制对于进行有针对性的治疗至关重要。DNA甲基化是遗传与环境相互作用的关键机制，我们探讨了DNA甲基化对多发性硬化症疾病活动性的影响：方法：我们使用 Illumina Infinium MethylationEPIC BeadChips 对 249 名未经治疗的复发缓解型多发性硬化症患者进行了外周免疫甲基组图谱分析，这些患者是在疾病修饰治疗（DMT）开始时采样的。差异甲基化分析比较了有疾病活动证据（EDA）和无疾病活动证据（NEDA）的患者在 DMT 开始后两年内的情况。利用因果推理测试（CIT）和孟德尔随机化（MR），我们试图阐明DNA甲基化、基因表达、遗传变异和疾病活动之间的关系：结果：在 EDA 和 NEDA 之间发现了四个不同的甲基化区域 (DMR)。通过研究单核苷酸多态性（SNPs）的影响，发现923个变异可解释4个DMRs中观察到的差异。重要的是，在这923个SNP中，有3个影响了与抗穆勒氏管激素（AMH）基因相关的DMR中的DNA甲基化，它们与1408名多发性硬化症患者组成的独立队列中的疾病活动风险有关。CIT和MR表明，AMH基因的DNA甲基化是疾病活动性遗传风险的中介：这项研究揭示了DNA甲基化与遗传变异在多发性硬化症疾病活动风险中相互作用的新分子途径，强调了性激素，尤其是AMH在多发性硬化症病理生物学中的作用。ann neurol 2024.

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来源期刊

Annals of Neurology 医学-临床神经学

CiteScore

18.00

自引率

1.80%

发文量

270

审稿时长

3-8 weeks

期刊介绍： Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.