Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
Department of Statistics, Pittsburgh University, Pittsburgh, Pa.
J Allergy Clin Immunol. 2021 Jul;148(1):128-138. doi: 10.1016/j.jaci.2020.12.639. Epub 2021 Jan 10.
Wheeze and allergic sensitization are the strongest early-life predictors of childhood asthma development; the molecular origins of these early-life phenotypes are poorly understood.
We sought to identify metabolites associated with early-life wheeze, allergic sensitization, and childhood asthma.
We conducted a nested case-control study using Environmental influences on Child Health Outcomes Program cohorts for discovery and independent replication. Wheeze and allergic sensitization were defined by number of wheeze episodes and positive specific IgE at age 1 year, respectively. Asthma was defined as physician diagnosis of asthma at age 5 or 6 years. We used untargeted metabolomics, controlling for observed and latent confounding factors, to assess associations between the plasma metabolome and early-life wheeze, allergy, and childhood asthma.
Eighteen plasma metabolites were associated with first-year wheeze in the discovery cohort (n = 338). Z,Z unconjugated bilirubin (UCB) and its related metabolites exhibited a dose-response relationship with wheeze frequency; UCB levels were 13% (β = 0.87; 95% CI, 0.74-1.02) and 22% (β = 0.78; 95% CI, 0.68-0.91) lower in children with 1 to 3 and 4+ wheeze episodes compared with those who never wheezed, respectively. UCB levels were also associated with childhood asthma (β = 0.82; 95% CI, 0.68-0.98). Similar trends were observed in 2 independent cohorts. UCB was significantly negatively correlated with eicosanoid- and oxidative stress-related metabolites. There were no significant associations between metabolites and allergic sensitization.
We identified a novel inverse, dose-dependent association between UCB and recurrent wheeze and childhood asthma. Inflammatory lipid mediators and oxidative stress byproducts inversely correlated with UCB, suggesting that UCB modulates pathways critical to the development of early-life recurrent wheeze and childhood asthma.
喘息和过敏致敏是儿童哮喘发展最强的生命早期预测因子；这些生命早期表型的分子起源知之甚少。
我们旨在确定与生命早期喘息、过敏致敏和儿童哮喘相关的代谢物。
我们使用环境对儿童健康结果计划队列进行了嵌套病例对照研究，用于发现和独立复制。喘息和过敏致敏分别由 1 岁时的喘息发作次数和阳性特异性 IgE 定义。哮喘定义为 5 或 6 岁时医生诊断的哮喘。我们使用非靶向代谢组学，控制观察到的和潜在的混杂因素，评估血浆代谢组与生命早期喘息、过敏和儿童哮喘之间的关联。
在发现队列中，有 18 种血浆代谢物与第一年的喘息有关（n=338）。Z，Z 未结合胆红素（UCB）及其相关代谢物与喘息频率呈剂量反应关系；与从未喘息的儿童相比，有 1 至 3 次和 4+次喘息发作的儿童的 UCB 水平分别低 13%（β=0.87；95%CI，0.74-1.02）和 22%（β=0.78；95%CI，0.68-0.91）。UCB 水平也与儿童哮喘相关（β=0.82；95%CI，0.68-0.98）。在 2 个独立的队列中也观察到了类似的趋势。UCB 与类二十烷酸和氧化应激相关代谢物呈显著负相关。代谢物与过敏致敏之间没有显著关联。
我们发现 UCB 与反复喘息和儿童哮喘之间存在一种新的、负相关的、剂量依赖性的关联。炎症脂质介质和氧化应激副产物与 UCB 呈负相关，这表明 UCB 调节了生命早期反复喘息和儿童哮喘发展的关键途径。
