Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
Genetics and Molecular Biology Program, Emory University, Atlanta, GA 30322, USA.
G3 (Bethesda). 2022 Apr 4;12(4). doi: 10.1093/g3journal/jkac041.
Recently, we identified 1,189 CpG sites whose DNA methylation level in blood associated with Crohn's disease. Here, we examined associations between DNA methylation and genetic variants to identify methylation quantitative trait loci across disease states in (1) 402 blood samples from 164 newly diagnosed pediatric Crohn's disease patients taken at 2 time points (diagnosis and follow-up), and 74 non-inflammatory bowel disease controls, (2) 780 blood samples from a non-Crohn's disease adult population, and (3) 40 ileal biopsies (17 Crohn's disease cases and 23 non-inflammatory bowel disease controls) from group (1). Genome-wide DNAm profiling and genotyping were performed using the Illumina MethylationEPIC and Illumina Multi-Ethnic arrays. SNP-CpG associations were identified via linear models adjusted for age, sex, disease status, disease subtype, estimated cell proportions, and genotype-based principal components. In total, we observed 535,448 SNP-CpG associations between 287,881 SNPs and 12,843 CpG sites (P < 8.21 × 10-14). Associations were highly consistent across different ages, races, disease states, and tissue types, suggesting that the majority of these methylation quantitative trait loci participate in common gene regulation. However, genes near CpGs associated with inflammatory bowel disease SNPs were enriched for 18 KEGG pathways relevant to inflammatory bowel disease-linked immune function and inflammatory responses. We observed suggestive evidence for a small number of tissue-specific associations and disease-specific associations in ileum, though larger studies will be needed to confirm these results. Our study concludes that the vast majority of blood-derived methylation quantitative trait loci are common across individuals, though a subset may be involved in processes related to Crohn's disease. Independent cohort studies will be required to validate these findings.
最近，我们确定了 1189 个 CpG 位点，这些位点在血液中的 DNA 甲基化水平与克罗恩病相关。在这里，我们研究了 DNA 甲基化与遗传变异之间的关联，以确定在（1）164 名新诊断的儿科克罗恩病患者的 402 个血液样本（在诊断和随访时采集）和 74 名非炎症性肠病对照者中，在疾病状态下的全基因组甲基化数量性状位点；（2）780 名非克罗恩病成年人群的血液样本；和（3）来自组（1）的 40 个回肠活检样本（17 例克罗恩病病例和 23 例非炎症性肠病对照者）中。使用 Illumina MethylationEPIC 和 Illumina Multi-Ethnic 阵列进行全基因组 DNAm 谱分析和基因分型。通过线性模型调整年龄、性别、疾病状态、疾病亚型、估计的细胞比例和基于基因型的主成分，识别 SNP-CpG 关联。总共，我们在 287881 个 SNP 和 12843 个 CpG 位点之间观察到 535448 个 SNP-CpG 关联（P<8.21×10-14）。在不同的年龄、种族、疾病状态和组织类型中，关联高度一致，表明这些甲基化数量性状位点的大多数都参与了常见的基因调控。然而，与炎症性肠病 SNP 相关的 CpG 附近的基因富集了与炎症性肠病相关的免疫功能和炎症反应相关的 18 个 KEGG 途径。我们观察到在回肠中存在少量组织特异性和疾病特异性关联的提示性证据，尽管需要更大的研究来证实这些结果。我们的研究得出结论，绝大多数来自血液的甲基化数量性状位点在个体之间是常见的，尽管有一部分可能与克罗恩病有关。需要独立的队列研究来验证这些发现。
