Bingen Jeremy M, Clark Lindsay V, Band Mark R, Munzir Ilyas, Carrithers Michael D
Neurology, University of Illinois College of Medicine, Chicago, IL, United States.
Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL, United States.
Front Genet. 2023 Jan 4;13:1058817. doi: 10.3389/fgene.2022.1058817. eCollection 2022.
Black and Hispanic American patients frequently develop earlier onset of multiple sclerosis (MS) and a more severe disease course that can be resistant to disease modifying treatments. The objectives were to identify differential methylation of genomic DNA (gDNA) associated with disease susceptibility and treatment responses in a cohort of MS patients from underrepresented minority populations. Patients with MS and controls with non-inflammatory neurologic conditions were consented and enrolled under an IRB-approved protocol. Approximately 64% of donors identified as Black or African American and 30% as White, Hispanic-Latino. Infinium MethylationEPIC bead arrays were utilized to measure epigenome-wide gDNA methylation of whole blood. Data were analyzed in the presence and absence of adjustments for unknown covariates in the dataset, some of which corresponded to disease modifying treatments. Global patterns of differential methylation associated with MS were strongest for those probes that showed relative demethylation of loci with lower M values. Pathway analysis revealed unexpected associations with shigellosis and amoebiasis. Enrichment analysis revealed an over-representation of probes in enhancer regions and an under-representation in promoters. In the presence of adjustments for covariates that included disease modifying treatments, analysis revealed 10 differentially methylated regions (DMR's) with an FDR <1E-77. Five of these genes (ARID5B, BAZ2B, RABGAP1, SFRP2, WBP1L) are associated with cancer risk and cellular differentiation and have not been previously identified in MS studies. Hierarchical cluster and multi-dimensional scaling analysis of differential DNA methylation at 147 loci within those DMR's was sufficient to differentiate MS donors from controls. In the absence of corrections for disease modifying treatments, differential methylation in patients treated with dimethyl fumarate was associated with immune regulatory pathways that regulate cytokine and chemokine signaling, axon guidance, and adherens junctions. These results demonstrate possible associations of gastrointestinal pathogens and regulation of cellular differentiation with MS susceptibility in our patient cohort. This work further suggests that analyses can be performed in the presence and absence of corrections for immune therapies. Because of their high representation in our patient cohort, these results may be of specific relevance in the regulation of disease susceptibility and treatment responses in Black and Hispanic Americans.
美国黑人和西班牙裔患者多发性硬化症（MS）的发病往往更早，病程更严重，且可能对疾病修正治疗产生耐药性。研究目的是在一个来自少数族裔人群的MS患者队列中，确定与疾病易感性和治疗反应相关的基因组DNA（gDNA）差异甲基化情况。患有MS的患者和患有非炎性神经系统疾病的对照者按照IRB批准的方案签署知情同意书并入组。约64%的捐赠者为黑人或非裔美国人，30%为白人、西班牙裔拉丁裔。使用Infinium甲基化EPIC微珠阵列来测量全血中全基因组范围的gDNA甲基化。在对数据集中未知协变量进行调整和不进行调整的情况下对数据进行分析，其中一些协变量与疾病修正治疗相对应。与MS相关的差异甲基化全局模式在那些显示较低M值位点相对去甲基化的探针中最为明显。通路分析揭示了与志贺氏菌病和阿米巴病的意外关联。富集分析显示增强子区域的探针过度表达，启动子区域的探针表达不足。在对包括疾病修正治疗在内的协变量进行调整后，分析发现10个差异甲基化区域（DMR），错误发现率（FDR）<1E - 77。其中5个基因（ARID5B、BAZ2B、RABGAP1 SFRP2、WBP1L）与癌症风险和细胞分化相关，此前在MS研究中尚未被发现。对这些DMR内147个位点的差异DNA甲基化进行层次聚类和多维标度分析足以区分MS捐赠者和对照者。在不对疾病修正治疗进行校正的情况下，接受富马酸二甲酯治疗的患者的差异甲基化与调节细胞因子和趋化因子信号传导、轴突导向和黏着连接的免疫调节通路相关。这些结果证明了在我们的患者队列中，胃肠道病原体和细胞分化调节与MS易感性之间可能存在关联。这项工作进一步表明，可以在对免疫疗法进行校正和不进行校正的情况下进行分析。由于他们在我们的患者队列中占比很高，这些结果可能对美国黑人和西班牙裔人群疾病易感性和治疗反应的调节具有特定意义。
