Blood-Based Transcriptomic and Proteomic Biomarkers of Emphysema

Abstract

Rationale: Emphysema is a key component of COPD with important prognostic implications. Identifying blood-based biomarkers of emphysema will facilitate early diagnosis and possible development of targeted therapies. Objectives: Discover blood transcriptomic and proteomic biomarkers for chest computed tomography-quantified emphysema in smokers and develop predictive biomarker panels. Methods: Emphysema blood biomarker discovery was performed using differential gene expression, alternative splicing, and protein association analyses in a training set of 2,370 COPDGene participants with available whole blood RNA sequencing, plasma SomaScan proteomics, and clinical data. Validation was conducted in a testing set of 1,016 COPDGene subjects. Since body mass index (BMI) and emphysema often co-occur, we performed a mediation analysis to quantify the effect of BMI on gene and protein associations with emphysema. Predictive models were also developed using elastic net to predict quantitative emphysema from cell blood count, RNA sequencing, and proteomic biomarkers. Model accuracy was assessed by area under the receiver-operator-characteristic-curves (AUROC) for subjects stratified into tertiles of emphysema severity. Measurements and Main Results: 4,913 genes, 1,478 isoforms, 386 exons, and 881 proteins were significantly associated with emphysema (FDR 10%). 75% and 77% of genes and proteins, respectively, were mediated by BMI. The significantly enriched biological pathways were involved in inflammation and cell differentiation, differing between the most and least BMI-mediated genes. The cell blood count plus protein model achieved the highest performance with an AUROC of 0.89. Conclusions: Blood transcriptome and proteome-wide analyses reveal key biological pathways of emphysema and enhance the prediction of emphysema.

Blood-based Transcriptomic and Proteomic Biomarkers of Emphysema

“…We also developed machine learning predictive models for emphysema using transcriptomic and proteomic biomarkers. Some of these results have been previously reported as an abstract (29) and a preprint (30).…”

Blood Biomarkers of Emphysema: What Can They Really Tell Us?

“…In a study reported in this issue of the Journal , Suryadevara and colleagues (pp. 273–287 ) took advantage of available data from the two large COPDGene (Genetic Epidemiology of COPD) and ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points) cohorts ( 5 ). The authors show that a multiomics approach in blood allows the identification of genes, proteins, gene isoforms, and exons relevant to COPD that could not be identified smaller studies using sometimes more relevant tissues.…”

“…Another important aspect of the study by Suryadevara and colleagues ( 5 ) is the focus on emphysema as a continuous trait rather than investigating the heterogeneous group of patients with COPD overall. Thus far, only a few studies have investigated the underlying molecular mechanisms of emphysema using genomewide data, most of them using single-omics approaches with an assessment of the presence of emphysema rather than analyzing the trait as a continuous variable ( 2 , 6 ).…”

“…Suryadevara and colleagues also investigate whether multiomics from the blood can be used to predict the presence of emphysema ( 5 ). Interestingly within their model in COPDGene, the best prediction was with the presence of clinical factors, cellular blood counts, and proteomics.…”

“…In conclusion, blood transcriptomics and proteomics in large cohorts can provide important insight into complex features of disease. Suryadevara and colleagues ( 5 ) have provided one of the largest and most well-powered blood-based signature studies to investigate the associations of biomarkers with degree of emphysema.…”