Project Summary/Abstract Current therapeutic options for chronic obstructive pulmonary disease (COPD) are limited, and new drug development in COPD has been hampered by the lack of clinically relevant biomarkers to assess likely drug efficacy. We will identify differentially abundant and lung-specific protein biomarkers of COPD in lung tissue and blood (plasma) using comprehensive proteomic analysis. Genetic determinants influence COPD susceptibility, but previously identified COPD genetic determinants account for only a small percentage of COPD heritability. Genetic analysis of protein biomarkers could reveal the network of regulatory factors influencing COPD susceptibility and COPD heterogeneity. Our overall hypothesis is that functional genetic variants lead to abnormal proteomic states that influence the development and heterogeneity of COPD. We will identify potential COPD biomarkers by studying lung-specific proteins that differ in lung tissue and plasma from 100 COPD cases and 50 smoking control subjects. We will then measure the most promising lung- specific plasma proteins in 1950 non-Hispanic White and African American COPDGene subjects with distinct imaging characteristics (airway-predominant COPD, emphysema-predominant COPD, and resistant smokers) to identify protein biomarkers associated with COPD and COPD subtypes. We will also perform genetic association analysis of lung-specific protein levels using whole genome sequencing data in these COPDGene subjects. Genetic determinants of protein biomarker levels will be tested for association with COPD susceptibility and COPD subtypes in multiple COPD populations. We will then determine whether the integrated analysis of the identified protein biomarkers of COPD susceptibility, several previously reported COPD protein biomarkers (CC16, Surfactant Protein D, sRAGE, and PARC), and the genetic determinants of COPD and COPD protein biomarkers enables prediction of disease progression rates in mild-to-moderate COPD subjects. The identification and characterization of novel COPD protein biomarkers may provide insights into COPD pathogenesis and tools for future clinical trials.