The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10^-8, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.

中文翻译：

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DNA甲基化作为HLA-DRB1 * 15：01的介质和多发性硬化症的保护性变体。

人类白细胞抗原（HLA）单倍型DRB1 * 15：01是多发性硬化症（MS）的主要危险因素。在这里，我们发现DRB1 * 15：01被低甲基化，并主要在DRB1 * 15：01的载体中的单核细胞中表达。包含HLA-DRB1外显子2的差异甲基化区域（DMR）特别受到影响，并在体外显示出甲基化敏感的调控特性。因果推断和孟德尔随机化提供了证据，表明HLA变体通过修饰HLA-DRB1表达的HLA-DRB1 DMR的改变来介导MS的风险。对14,259例病例和171,347例对照的荟萃分析证实，这些变体具有DRB1 * 15：01的风险，还可以识别保护性变体（rs9267649，p <3.32×10 ^-8，该区域中所有与MS相关的变体经过条件处理后，优势比= 0.86）。rs9267649与HLA-DRB1 DMR处的DNA甲基化增加和HLA-DRB1的表达减少有关，表明对DRB1 * 15：01效应的调节。我们的综合方法提供了对MS易感性分子机制的见解，并提出了针对甲基化介导的主要风险基因调控的假定治疗策略。