Abstract：
Genetic variation and epigenetic factors are thought to contribute to the development of hypersensitivity to aspirin. DNA methylation fluctuates dynamically throughout the day. To discover new CpG methylation in lymphocytes associated with aspirin-exacerbated respiratory disease (AERD), we evaluated changes in global CpG methylation profiles from before to after an oral aspirin challenge in patients with AERD and aspirin-tolerant asthma (ATA). Whole-genome CpG methylation levels of peripheral blood mononuclear cells were quantified with an Illumina 860K Infinium Methylation EPIC BeadChip array and then adjusted for inferred lymphocyte fraction (ILF) with GLINT and Tensor Composition Analysis. Among the 866,091 CpGs in the array, differentially methylated CpGs (DMCs) were found in 6 CpGs in samples from all 12 patients with asthma included in the study (AERD, n = 6; ATA, n = 6). DMCs were found in 3 CpGs in the 6 ATA samples and in 615 CpGs in the 6 AERD samples. A total of 663 DMCs in 415 genes and 214 intergenic regions differed significantly in the AERD compared with the ATA. In promoters, 126 CpG loci were predicted to bind to 38 transcription factors (TFs), many of which were factors already known to be involved in the pathogenesis of asthma and immune responses. In conclusion, we identified 615 new CpGs methylated in peripheral blood lymphocytes by oral aspirin challenge in AERD but not in ATA. These findings indicate that oral aspirin challenge induces epigenetic changes in ILFs, specifically in AERD patients, possibly via changes in TF binding, which may have epigenetic effects on the development of AERD.
摘要：
遗传变异和表观遗传因素被认为有助于阿司匹林超敏反应的发展。DNA甲基化全天动态变化。在与阿司匹林加重的呼吸系统疾病（AERD）相关的淋巴细胞中发现新的CpG甲基化，我们评估了AERD和阿司匹林耐受性哮喘(ATA)患者口服阿司匹林激发前后的整体CpG甲基化谱变化.用Illumina860KInfinium甲基化EPICBeadChip阵列定量外周血单核细胞的全基因组CpG甲基化水平，然后用GLINT和张量组成分析调整推断的淋巴细胞分数（ILF）。在阵列中的866,091个CpG中，在研究中纳入的所有12名哮喘患者的6个CpG样本中发现了差异甲基化CpG（DMC）（AERD，n=6；ATA，n=6)。在6个ATA样品中的3个CpG和6个AERD样品中的615个CpG中发现DMC。与ATA相比，AERD中415个基因和214个基因间区域中的663个DMC存在显着差异。在发起人中，预测126个CpG基因座与38个转录因子(TFs)结合，其中许多是已知与哮喘的发病机制和免疫反应有关的因素。总之,我们在AERD中通过口服阿司匹林激发在外周血淋巴细胞中发现了615个新的CpG甲基化,但在ATA中未发现.这些发现表明，口服阿司匹林攻击诱导ILFs的表观遗传变化，特别是在AERD患者中，可能通过TF结合的变化，这可能对AERD的发展有表观遗传影响。
