Departments of Human Genetics, The University of Chicago, Chicago, Ill.
Departments of Statistics, The University of Chicago, Chicago, Ill.
J Allergy Clin Immunol. 2020 Dec;146(6):1358-1366. doi: 10.1016/j.jaci.2020.07.005. Epub 2020 Jul 18.
The upper airways present a barrier to inhaled allergens and microbes, which alter immune responses and subsequent risk for diseases, such as allergic rhinitis (AR).
We tested the hypothesis that early-life microbial exposures leave a lasting signature in DNA methylation that ultimately influences the development of AR in children.
We studied upper airway microbiota at 1 week, 1 month, and 3 months of life, and measured DNA methylation and gene expression profiles in upper airway mucosal cells and assessed AR at age 6 years in children in the Copenhagen Prospective Studies on Asthma in Childhood birth cohort.
We identified 956 AR-associated differentially methylated CpGs in upper airway mucosal cells at age 6 years, 792 of which formed 3 modules of correlated differentially methylated CpGs. The eigenvector of 1 module was correlated with the expression of genes enriched for lysosome and bacterial invasion of epithelial cell pathways. Early-life microbial diversity was lower at 1 week (richness P = .0079) in children with AR at age 6 years, and reduced diversity at 1 week was also correlated with the same module's eigenvector (ρ = -0.25; P = 3.3 × 10). We show that the effect of microbiota richness at 1 week on risk for AR at age 6 years was mediated in part by the epigenetic signature of this module.
Our results suggest that upper airway microbial composition in infancy contributes to the development of AR during childhood, and this trajectory is mediated, at least in part, through altered DNA methylation patterns in upper airway mucosal cells.
上呼吸道是吸入过敏原和微生物的屏障，这些物质会改变免疫反应，进而增加患过敏性鼻炎（AR）等疾病的风险。
我们检验了这样一个假设，即生命早期的微生物暴露会在 DNA 甲基化中留下持久的印记，最终影响儿童 AR 的发生。
我们研究了生命 1 周、1 个月和 3 个月时的上呼吸道微生物群，并测量了上呼吸道黏膜细胞中的 DNA 甲基化和基因表达谱，并在哥本哈根儿童哮喘前瞻性研究出生队列中评估了儿童 6 岁时的 AR。
我们在儿童 6 岁时的上呼吸道黏膜细胞中鉴定出 956 个与 AR 相关的差异甲基化 CpG，其中 792 个形成了 3 个相关差异甲基化 CpG 模块。1 个模块的本征向量与富含溶酶体和细菌入侵上皮细胞途径的基因表达相关。6 岁时有 AR 的儿童在生命 1 周时的上呼吸道微生物多样性较低（丰富度 P =.0079），1 周时的多样性降低与该模块的本征向量也呈负相关（ρ = -0.25；P = 3.3×10）。我们表明，1 周时微生物丰富度对 6 岁时 AR 风险的影响部分是由该模块的表观遗传特征介导的。
我们的结果表明，婴儿期上呼吸道微生物组成有助于儿童期 AR 的发生，而这一轨迹至少部分是通过上呼吸道黏膜细胞中改变的 DNA 甲基化模式介导的。
