Table_1_High-resolution DNA methylation screening of the major histocompatibility complex in multiple sclerosis.XLSX

BackgroundThe HLA-DRB1 gene in the major histocompatibility complex (MHC) region in chromosome 6p21 is the strongest genetic factor identified as influencing multiple sclerosis (MS) susceptibility. DNA methylation changes associated with MS have been consistently detected at the MHC region. However, understanding the full scope of epigenetic regulations of the MHC remains incomplete, due in part to the limited coverage of this region by standard whole genome bisulfite sequencing or array-based methods.MethodsWe developed and validated an MHC capture protocol coupled with bisulfite sequencing and conducted a comprehensive analysis of the MHC methylation landscape in blood samples from 147 treatment naïve MS study participants and 129 healthy controls.ResultsWe identified 132 differentially methylated region (DMRs) within MHC region associated with disease status. The DMRs overlapped with established MS risk loci. Integration of the MHC methylome with human leukocyte antigen (HLA) genetic data indicate that the methylation changes are significantly associated with HLA genotypes. Using DNA methylation quantitative trait loci (mQTL) mapping and the causal inference test (CIT), we identified 643 cis-mQTL-DMRs paired associations, including 71 DMRs possibly mediating causal relationships between 55 single nucleotide polymorphisms (SNPs) and MS risk.ResultsThe results describe MS-associated methylation changes in MHC region and highlight the association between HLA genotypes and methylation changes. Results from the mQTL and CIT analyses provide evidence linking MHC region variations, methylation changes, and disease risk for MS.

背景：人类白细胞抗原复合体（MHC）区域中的HLA-DRB1基因位于第6号染色体6p21区，是目前已知的对多发性硬化症（MS）易感性影响最强的遗传因素。与MS相关的DNA甲基化变化在MHC区域已得到持续检测。然而，由于标准全基因组亚硫酸氢盐测序或基于微阵列的方法对此区域的覆盖范围有限，我们对MHC区域表观遗传调控的全貌仍存在认知上的不足。方法：我们开发并验证了一种结合亚硫酸氢盐测序的MHC捕获方案，并对147名未接受治疗的MS研究参与者和129名健康对照者的血液样本中的MHC甲基化景观进行了全面分析。结果：我们在MHC区域内识别了132个与疾病状态相关的差异甲基化区域（DMRs）。这些DMRs与已建立的MS风险位点重叠。将MHC甲基组与人类白细胞抗原（HLA）遗传数据相结合表明，甲基化变化与HLA基因型显著相关。通过DNA甲基化数量性状位点（mQTL）映射和因果推断测试（CIT），我们确定了643对cis-mQTL-DMRs的关联，包括可能与55个单核苷酸多态性（SNPs）和MS风险之间的因果关系介导的71个DMRs。结果：这些结果描述了MHC区域内与MS相关的甲基化变化，并突出了HLA基因型与甲基化变化之间的关联。mQTL和CIT分析的结果为MHC区域变异、甲基化变化与MS疾病风险之间的联系提供了证据。