Multiomic Signatures of Chronic Beryllium Disease Bronchoalveolar Lavage Cells Relate to T-Cell Function and Innate Immunity

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. Bronchoalveolar lavage (BAL) cell DNA and RNA were profiled using microarrays from CBD (n=30), BeS (n=30), and controls (n=12). BAL fluid (BALF) proteins were measured using Olink Immune Response Panel proteins from CBD (n=22) and BeS (n=22) subjects. Linear models identified features associated with CBD, adjusting for covariation and batch effects. Multi-omic integration methods identifed correlated features between datasets. We identified 1,546 differentially expressed genes in CBD vs controls and 204 in CBD vs BeS. Of the 101 shared transcripts, 24 have significant cis-relationships between gene expression and DNA methylation, assessed using expression quantitative trait methylation (eQTM) analysis, including genes not previously identified in CBD. A multi-omic model of top DNA methylation and gene expression features demonstrated that the first component separated CBD from other samples and the second component separated controls from remaining samples. Top features on component 1 were enriched for T-lymphocyte function and top features on component 2 were enriched for innate immune signaling. We identified six differentially abundant proteins in CBD vs BeS, with two (SIT1 and SH2D1A) selected as important RNA features in the multi-omic model. Our integrated analysis of DNA methylation, gene expression, and proteins in the lung identified multi-omic signatures of CBD that differentiated it from BeS and controls.