通过遗传锚点在哮喘气道上皮中估算DNA甲基化对基因表达的计算机模拟因果效应
2026/04/28
摘要
背景 ：表达数量性状甲基化（eQTM）分析已发现DNA甲基化（DNAm）与基因表达之间存在大量关联，但这些关联背后的因果通路仍不清楚。
方法 ：我们以单核苷酸多态性（SNP）作为遗传锚点，在患有哮喘（219例）和未患哮喘（236例）的青少年的鼻上皮样本中，研究了DNAm与基因表达之间顺式（cis）和反式（trans）关联的潜在因果效应。我们进行了因果中介分析，采用自适应自助法进行联合显著性检验，评估了38,562个eQTM对中DNAm影响基因表达或反之的因果效应。
结果：在73%的eQTM对中，DNAm很可能是基因表达的原因。这些eQTM对中的基因显著富集于免疫通路，并与哮喘表型相关。我们在肺组织的多种细胞类型中复现了表达数量性状位点（eQTL）的发现，并在上呼吸道中复现了eQTL和甲基化数量性状位点（meQTL）的发现。
结论：这些结果表明，DNAm是哮喘预防和治疗的一个有前景的靶点。
Estimating in silico causal effects of DNA methylation on gene expression through genetic anchors in airway epithelium in asthma
Kim S, Caldino Bohn RI, Sriram A, et al.
Abstract
BACKGROUND:Expression quantitative trait methylation (eQTM) analyses have identified numerous associations between DNA methylation (DNAm) and gene expression, but the causal pathways underlying such associations remain poorly understood.
METHODS: Using single-nucleotide polymorphisms (SNPs) as genetic anchors, we examined potential causal effects between DNAm and gene expression in cis and trans associations in nasal epithelial samples from youth with (n = 219) and without (n = 236) asthma. We conducted causal mediation analyses to assess whether DNAm affects gene expression or vice versa by using an adaptive bootstrap for the joint significance test to estimate causal effects for 38,562 eQTM pairs.
RESULTS: DNAm is a plausible cause of gene expression in 73% of pairs. Genes in these eQTM pairs were significantly enriched in immune pathways and associated with asthma phenotypes. We replicated Expression Quantitative Trait Loci (eQTL) findings in various cell types in lung tissue and eQTL and Methylation Quantitative Trait Loci (meQTL) findings in the upper airway.
CONCLUSIONS:These results suggest DNAm as a promising target for asthma prevention and therapy.
背景 ：表达数量性状甲基化（eQTM）分析已发现DNA甲基化（DNAm）与基因表达之间存在大量关联，但这些关联背后的因果通路仍不清楚。
方法 ：我们以单核苷酸多态性（SNP）作为遗传锚点，在患有哮喘（219例）和未患哮喘（236例）的青少年的鼻上皮样本中，研究了DNAm与基因表达之间顺式（cis）和反式（trans）关联的潜在因果效应。我们进行了因果中介分析，采用自适应自助法进行联合显著性检验，评估了38,562个eQTM对中DNAm影响基因表达或反之的因果效应。
结果：在73%的eQTM对中，DNAm很可能是基因表达的原因。这些eQTM对中的基因显著富集于免疫通路，并与哮喘表型相关。我们在肺组织的多种细胞类型中复现了表达数量性状位点（eQTL）的发现，并在上呼吸道中复现了eQTL和甲基化数量性状位点（meQTL）的发现。
结论：这些结果表明，DNAm是哮喘预防和治疗的一个有前景的靶点。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Sci Adv. 2026 Apr 24;12(17):eady3555.DOI: 10.1126/sciadv.ady3555. ）
（Sci Adv. 2026 Apr 24;12(17):eady3555.DOI: 10.1126/sciadv.ady3555. ）
Estimating in silico causal effects of DNA methylation on gene expression through genetic anchors in airway epithelium in asthma
Kim S, Caldino Bohn RI, Sriram A, et al.
Abstract
BACKGROUND:Expression quantitative trait methylation (eQTM) analyses have identified numerous associations between DNA methylation (DNAm) and gene expression, but the causal pathways underlying such associations remain poorly understood.
METHODS: Using single-nucleotide polymorphisms (SNPs) as genetic anchors, we examined potential causal effects between DNAm and gene expression in cis and trans associations in nasal epithelial samples from youth with (n = 219) and without (n = 236) asthma. We conducted causal mediation analyses to assess whether DNAm affects gene expression or vice versa by using an adaptive bootstrap for the joint significance test to estimate causal effects for 38,562 eQTM pairs.
RESULTS: DNAm is a plausible cause of gene expression in 73% of pairs. Genes in these eQTM pairs were significantly enriched in immune pathways and associated with asthma phenotypes. We replicated Expression Quantitative Trait Loci (eQTL) findings in various cell types in lung tissue and eQTL and Methylation Quantitative Trait Loci (meQTL) findings in the upper airway.
CONCLUSIONS:These results suggest DNAm as a promising target for asthma prevention and therapy.
上一篇：
产前暴露于全氟和多氟烷基物质 (PFAS) 与儿童期哮喘和喘息发病率的关系：一项在瑞典罗讷比进行的基于登记的队列研究
下一篇：
血中性粒细胞遗传学揭示中性粒细胞在儿童早期哮喘和病毒性呼吸道疾病中的作用
