Division of Environmental and Occupational Health Sciences, Department of Medicine, and.
Division of Pulmonary and Critical Care Sciences.
Am J Respir Cell Mol Biol. 2022 Dec;67(6):632-640. doi: 10.1165/rcmb.2022-0077OC.
Chronic beryllium disease (CBD) is a Th1 granulomatous lung disease preceded by sensitization to beryllium (BeS). We profiled the methylome, transcriptome, and selected proteins in the lung to identify molecular signatures and networks associated with BeS and CBD. BAL cell DNA and RNA were profiled using microarrays from CBD ( = 30), BeS ( = 30), and control subjects ( = 12). BAL fluid proteins were measured using Olink Immune Response Panel proteins from CBD ( = 22) and BeS ( = 22) subjects. Linear models identified features associated with CBD, adjusting for covariation and batch effects. Multiomic integration methods identified correlated features between datasets. We identified 1,546 differentially expressed genes in CBD versus control subjects and 204 in CBD versus BeS. Of the 101 shared transcripts, 24 have significant cis relationships between gene expression and DNA methylation, assessed using expression quantitative trait methylation analysis, including genes not previously identified in CBD. A multiomic model of top DNA methylation and gene expression features demonstrated that the first component separated CBD from other samples and the second component separated control subjects from remaining samples. The top features on component one were enriched for T-lymphocyte function, and the top features on component two were enriched for innate immune signaling. We identified six differentially abundant proteins in CBD versus BeS, with two (SIT1 and SH2D1A) selected as important RNA features in the multiomic model. Our integrated analysis of DNA methylation, gene expression, and proteins in the lung identified multiomic signatures of CBD that differentiated it from BeS and control subjects.
慢性铍病（CBD）是一种 Th1 肉芽肿性肺病，之前曾对铍（BeS）敏感。我们对甲基组、转录组和肺部的选定蛋白质进行了分析，以确定与 BeS 和 CBD 相关的分子特征和网络。使用来自 CBD（= 30）、BeS（= 30）和对照受试者（= 12）的微阵列对 BAL 细胞 DNA 和 RNA 进行了分析。使用来自 CBD（= 22）和 BeS（= 22）受试者的 Olink 免疫反应面板蛋白测量了 BAL 液中的蛋白质。线性模型确定了与 CBD 相关的特征，同时调整了协变量和批次效应。多组学整合方法确定了数据集之间相关的特征。我们在 CBD 与对照受试者之间鉴定了 1546 个差异表达的基因，在 CBD 与 BeS 之间鉴定了 204 个基因。在 101 个共享转录本中，有 24 个基因的基因表达和 DNA 甲基化之间存在显著的顺式关系，使用表达数量性状甲基化分析进行评估，包括在 CBD 中未先前鉴定的基因。顶级 DNA 甲基化和基因表达特征的多组学模型表明，第一个组件将 CBD 与其他样本分开，第二个组件将对照受试者与其余样本分开。第一组件上的顶级特征富集了 T 淋巴细胞功能，第二组件上的顶级特征富集了先天免疫信号。我们在 CBD 与 BeS 之间鉴定了六个差异丰富的蛋白质，其中两个（SIT1 和 SH2D1A）被选为多组学模型中的重要 RNA 特征。我们对肺部的 DNA 甲基化、基因表达和蛋白质进行的综合分析确定了 CBD 的多组学特征，使其与 BeS 和对照受试者区分开来。
