Rationale:
Emphysema is a
chronic obstructive pulmonary disease phenotype with important prognostic implications. Identifying blood-based
biomarkers of
emphysema will facilitate early diagnosis and development of targeted
therapies. Objectives: To discover blood omics
biomarkers for chest computed tomography-quantified
emphysema 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 sample of 2,370 COPDGene participants with available blood
RNA sequencing, plasma proteomics, and clinical data. Internal validation was conducted in a COPDGene testing sample (n = 1,016), and external validation was done in the ECLIPSE study (n = 526). Because low 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. Elastic net models with bootstrapping were also developed in the training sample sequentially using clinical, blood cell proportions,
RNA-sequencing, and proteomic
biomarkers to predict quantitative
emphysema. Model accuracy was assessed by the area under the receiver operating characteristic curves for subjects stratified into tertiles of
emphysema severity. Measurements and Main Results: Totals of 3,829 genes, 942
isoforms, 260 exons, and 714
proteins were significantly associated with
emphysema (false discovery rate, 5%) and yielded 11 biological pathways. Seventy-four percent of these genes and 62% of these
proteins showed mediation by BMI. Our prediction models demonstrated reasonable predictive performance in both COPDGene and ECLIPSE. The highest-performing model used clinical, blood cell, and
protein data (area under the receiver operating characteristic curve in COPDGene testing, 0.90; 95% confidence interval, 0.85-0.90). Conclusions: Blood transcriptome and
proteome-wide analyses revealed key biological pathways of
emphysema and enhanced the prediction of
emphysema.