Blood Transcriptomics Predicts Progression of Pulmonary Fibrosis and Associated Natural Killer Cells
Year: 2021
Type: article
Abstract: Rationale Disease activity in idiopathic pulmonary fibrosis (IPF) remains highly variable, poorly understood, and difficult to predict. Objectives To identify a predictor using short-term longitudinal changes in gene expression that forecasts future FVC decline and to characterize involved pathways and cell types. Methods Seventy-four patients from COMET (Correlating Outcomes with Biochemical Markers to Estimate Time-Progression in IPF) cohort were dichotomized as progressors (≥10% FVC decline) or stable. Blood gene-expression changes within individuals were calculated between baseline and 4 months and regressed with future FVC status, allowing determination of expression variations, sample size, and statistical power. Pathway analyses were conducted to predict downstream effects and identify new targets. An FVC predictor for progression was constructed in COMET and validated using independent cohorts. Peripheral blood mononuclear single-cell RNA-sequencing data from healthy control subjects were used as references to characterize cell type compositions from bulk peripheral blood mononuclear RNA-sequencing data that were associated with FVC decline. Measurements and Main Results The longitudinal model reduced gene-expression variations within stable and progressor groups, resulting in increased statistical power when compared with a cross-sectional model. The FVC predictor for progression anticipated patients with future FVC decline with 78% sensitivity and 86% specificity across independent IPF cohorts. Pattern recognition receptor pathways and mTOR pathways were downregulated and upregulated, respectively. Cellular deconvolution using single-cell RNA-sequencing data identified natural killer cells as significantly correlated with progression. Conclusions Serial transcriptomic change predicts future FVC decline. An analysis of cell types involved in the progressor signature supports the novel involvement of natural killer cells in IPF progression.
Authors: Yong Huang, Justin M. Oldham, Shwu-Fan Ma, Avraham Unterman, Shu-Yi Liao, Andrew J. Barros, Catherine A. Bonham, John S. Kim, Rekha Vij, Ayodeji Adegunsoye, Mary E. Strek, Philip L. Molyneaux, Toby M. Maher, Jose D. Herazo-Maya, Naftali Kaminski, Bethany B. Moore, Fernando J. Martinez, Imre Noth
Institutions: University of Virginia, University of California, Davis, Yale University, National Jewish Health, University of Chicago, Royal Brompton Hospital, Imperial College London, University of Southern California, University of South Florida, Tampa General Hospital, University of Michigan, Cornell University, Weill Cornell Medicine
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Architectural structure and regulation of TOLLIP in IPF, Improving Pulmonary Fibrosis Classification with Genomics Informed Phenotypic Clusters, T cells in idiopathic pulmonary fibrosis, Elucidating the Genomic Determinants of Outcomes in Idiopathic Pulmonary Fibrosis, G3321557982, 1/2 Prospective tReatment EffiCacy in IPF uSlng genOtype for Nac Selection (PRECISIONS) trial and Molecular Endophenotyping in Idiopathic Pulmonary Fibrosis and Interstitial Lung Diseases study, Immunobiology of Lung Injury and Fibrosis, Yale Clinical and Translational Science Award, 1/2 Prospective tReatment EffiCacy in IPF uSlng genOtype for Nac Selection (PRECISIONS) trial and Molecular Endophenotyping in Idiopathic Pulmonary Fibrosis and Interstitial Lung Diseases study
OpenAlex ID: W3135098981