Eugene R. Bleecker

The University of Arizona | UA · Department of Medicine

Importance: People who smoked cigarettes may experience respiratory symptoms without spirometric airflow obstruction. These individuals are typically excluded from chronic obstructive pulmonary disease (COPD) trials and lack evidence-based therapies. Objective: To define the natural history of persons with tobacco exposure and preserved spiromet...

Rationale: In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILA) is unknown. Objectives: We tested the predictive value of IPF polygenic risk scores...

Telomere length genome-wide association studies (GWAS) have become well-powered to detect novel genes in telomere length regulation. However, no prior work has validated these putative novel genes to confirm the contribution of GWAS loci to telomere length regulation. We conducted a trans-ancestry meta-analysis of 211,369 individuals. Through enric...

Privacy protection is a core principle of genomic but not proteomic research. We identified independent single nucleotide polymorphism (SNP) quantitative trait loci (pQTL) from COPDGene and Jackson Heart Study (JHS), calculated continuous protein level genotype probabilities, and then applied a naïve Bayesian approach to link SomaScan 1.3K proteome...

Background Treatment and preventative advances for chronic obstructive pulmonary disease (COPD) have been slow due, in part, to limited subphenotypes. We tested if unsupervised machine learning on CT images would discover CT emphysema subtypes with distinct characteristics, prognoses and genetic associations. Methods New CT emphysema subtypes were...

Accelerated progression of chronic obstructive pulmonary disease (COPD) is associated with increased risks of hospitalization and death. Prognostic insights into mechanisms and markers of progression could facilitate development of disease-modifying therapies. Although individual biomarkers exhibit some predictive value, performance is modest and t...

Rationale: Bronchiectasis is common among those with heavy smoking histories, but risk factors for bronchiectasis, including α1-antitrypsin deficiency and its implications for COPD severity are uncharacterized in such individuals. Objectives: To characterize the impact of bronchiectasis on COPD and explore α1-antitrypsin as a risk factor for bro...

Background: Abnormal lung volumes representing air trapping identify the subset of smokers with preserved spirometry who develop spirometric COPD and adverse outcomes. However, how lung volumes evolve in early COPD as airflow obstruction develops remains unclear. Methods: To establish how lung volumes change with development of spirometric COPD,...

Objective Genome-wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) in chr11p15.5 region associated with asthma and idiopathic interstitial pneumonias (IIPs). We sought to identify functional genes for asthma by combining SNPs and mRNA expression in bronchial epithelial cells (BEC) in the Severe Asthma Research...

Objective: Subphenotypes of asthma may be determined by age onset and atopic status. We sought to characterize early or late onset atopic asthma with fungal or non-fungal sensitization (AAFS or AANFS) and non-atopic asthma (NAA) in children and adults in the Severe Asthma Research Program (SARP). SARP is an ongoing project involving well-phenotype...

Background: The stability and variability of blood eosinophil counts (BECs) to phenotype patients with severe asthma is not fully understood. Objective: This post hoc, longitudinal, pooled analysis of placebo-arm patients from 2 phase 3 studies evaluated the clinical implications of BEC stability and variability in moderate-to-severe asthma. Me...

Background: T1 inflammation (marked by IFN-γ expression) is now consistently identified in subsets of asthma cohorts, but how it contributes to disease remains unclear. Objective: We sought to understand the role of CCL5 in asthmatic T1 inflammation, and how it interacts with both T1 and T2 inflammation. Methods: CCL5, CXCL9 and CXCL10 mRNA ex...

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic va...

Background: Inhaled corticosteroids (CS) are a backbone of asthma treatment, improving quality of life, exacerbation rates and mortality. Though effective for most, a subset of asthma patients experience CS resistant disease despite receipt of high medication doses. Objective: Our goal was to investigate the transcriptomic response of bronchial...

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries⁵. Here we leveraged global genetic...

Systemic corticosteroids (SCS) are a highly effective treatment for acute exacerbations and long-term symptom control in asthma. Long-term SCS use is highly prevalent across all asthma severities, occurring in over 20% of patients with severe or uncontrolled disease globally. It is now well known that exposure to both long-term and repeated acute c...

Background The Global Initiative for Chronic Obstructive Lung Disease (GOLD) report considers blood eosinophil counts <100 cells/μL (BEC≤100) in individuals with COPD (Chronic Obstructive Pulmonary Disease) to predict poor inhaled corticosteroid (ICS) responsiveness. However, the BEC≤100 phenotype is inadequately characterized, especially in advanc...

Asthma is a heterogenous respiratory disease, usually associated with chronic airway inflammation and hyper-responsiveness, which affects an estimated 339 million people worldwide. Severe asthma affects approximately 5-10% of patients with asthma, approximately 17-34 million people globally, more than half of whom have uncontrolled disease. Severe...

Asthma is an inflammatory disease of the airways characterized by eosinophil recruitment, eosinophil peroxidase release and protein oxidation through bromination, which following tissue remodeling results in excretion of 3-bromotyrosine. Predicting exacerbations and reducing their frequency is critical for the treatment of severe asthma. In this st...

Rationale: CC16 is a protein mainly produced by non-ciliated bronchial epithelial cells (BEC) that participates in host defense. Reduced CC16 protein levels in bronchoalveolar lavage and serum are associated with asthma susceptibility. Objectives: Few studies have investigated the relationship of CC16 and asthma progression, and none has focused...

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this ‘missing heritability’. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,7...

Background Most biologics for severe asthma target only type 2 immunity. Inhibition of interleukin-33 signaling has potential to target type 2 and non-type 2 pathways. Objective This multicenter Phase IIA study evaluated safety and efficacy of GSK3772847, a human monoclonal antibody directed against the interleukin-33 receptor (IL-33R) in subjects...

Introduction Bronchodilator response (BDR) is a measurement of acute bronchodilation in response to short-acting β2-agonists (SABA), with a heritability between 10–40%. Identifying genetic variants associated with BDR may lead to a better understanding of its complex pathophysiology. Methods We performed a genome-wide association study (GWAS) of B...

Rationale: The role of obesity-associated insulin resistance (IR) in airflow limitation in asthma is uncertain. Objectives: Using data in the Severe Asthma Research Program 3 (SARP-3), we evaluated relationships between homeostatic measure of IR (HOMA-IR), lung function (cross sectional and longitudinal analyses) and treatment responses to bronc...

Lung function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry GWAS meta-analysis of lung function to date, comprising 580,869 participants, 1020 independent association signals identified 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. Th...

Rationale: Chronic obstructive pulmonary disease (COPD) is defined by fixed spirometric ratio FEV1/FVC < 0.70 following inhaled bronchodilators. However, the implications of variable obstruction (VO), in which the pre-bronchodilator FEV1/FVC ratio is <0.70 but increases to ≥0.70 following inhaled bronchodilators, have not been determined. Objecti...

Background Clustering key clinical characteristics of participants in the Severe Asthma Research Program (SARP), a large, multicenter prospective observational study of patients with asthma and healthy controls, has led to the identification of novel asthma phenotypes. Purpose To determine whether quantitative CT (qCT) could help distinguish betwee...

Background Heterozygote carriers of potentially pathogenic variants in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene have increased asthma risk. However, the frequency and impact of CFTR variation among individuals with asthma is unknown. Objective To determine whether potentially pathogenic CFTR variants associate with dis...

Background: Heterozygote carriers of potentially pathogenic variants in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene have increased asthma risk. However, the frequency and impact of CFTR variation among individuals with asthma is unknown. Objective: To determine whether potentially pathogenic CFTR variants associate with di...

Introduction Privacy protection is a core principle of genomic research but needs further refinement for high-throughput proteomic platforms. Methods We identified independent single nucleotide polymorphism (SNP) quantitative trait loci (pQTL) from COPDGene and Jackson Heart Study (JHS) and then calculated genotype probabilities by protein level f...

While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived...

Background Regulator of G-Protein Signaling (RGS)-2 terminates bronchoconstrictive Gαq-signaling; murine RGS2 knockout demonstrate airway hyperresponsiveness. While RGS2 promoter variants rs2746071 and rs2746072 associate with a clinical mild asthma phenotype, their impact on human airway smooth muscle (HASM) contractility and asthma severity outco...

Rationale: Cross-sectional analysis of mucus plugs in computed tomography (CT) lung scans in the Severe Asthma Research Program (SARP)-3 showed a high mucus plug phenotype. Objectives: To determine if mucus plugs are a persistent asthma phenotype and if changes in mucus plugs over time associate with changes in lung function. Methods: In a lon...

Background Some individuals have characteristics of both asthma and chronic obstructive pulmonary disease (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. Research Question What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD over...

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omi...

Surfactant protein A (SP-A) is well-known for its protective role in pulmonary immunity. Previous studies from our group have shown that SP-A mediates eosinophil activities, including degranulation and apoptosis. In order to identify potential binding partners on eosinophils for SP-A, eosinophil lysates were subjected to SP-A pull-down and tandem m...

Background Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we s...

Background: United States population-level data on asthma morbidity and mortality are available primarily through state-level surveys. We hypothesize that significant county-level heterogeneity may be obscured by state-level data, thus impeding focused initiatives to improve asthma outcomes. Objective: To assess heterogeneity in the prevalence o...

Introduction Asthma is a complex disease with heterogeneous expression/severity. There is growing interest in defining asthma endotypes consistently associated with different responses to therapy, focusing on type 2 inflammation (Th2) as a key pathological mechanism. Current asthma endotypes are defined primarily by clinical/laboratory criteria. Ea...

Background: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. Objective: By leveraging data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, the Consortium on Asthma among African-ancestry Pop...

Background We previously described the contributions of increased total airway mucin concentrations to the pathogenesis and diagnosis of the chronic bronchitic component of chronic obstructive pulmonary disease (COPD). Here, we investigated the relative contribution of each of the major airway gel-forming mucins, MUC5AC and MUC5B, to the initiation...

Purpose: Quantitative computed tomography (qCT) imaging-based cluster analysis identified clinically meaningful COPD former-smoker subgroups (clusters) based on cross-sectional data. We aimed to identify progression clusters for former smokers using longitudinal data. Patients and methods: We selected 472 former smokers from SPIROMICS with a bas...

Background Across complex traits, common variants explain only a modest amount of variance, with SNP-heritability consistently below heritability estimates from close relatives. Here, we examined the contribution of rare variant to tobacco use risk in up to 26,000 individuals of European ancestry in the Trans-Omics for Precision Medicine (TOPMed) p...

Background The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-...

Rationale: There is a need to minimize oral corticosteroid (OCS) use in patients with asthma to prevent their costly and burdensome adverse effects. Current guidelines do not provide recommendations for OCS tapering in patients with asthma. Objectives: To develop expert consensus on OCS tapering among international experts. Methods: A modified Delp...

RATIONALE Androgens are potentially beneficial in asthma, but androgen receptor (AR) has not been studied in human airways. OBJECTIVES To measure whether AR and its ligands are associated with human asthma outcomes. METHODS We compared AR expression to lung function, symptom scores and fractional of exhaled nitric oxide (FENO) in adults enrolled in...

Background The purpose of this study was to explore the association between perceived social support and COPD outcomes and to determine whether the associations are mediated by depressive symptoms. Methods Subjects with COPD who were enrolled as part of SPIROMICS were included in this analysis. Questionnaires relating to quality of life, symptom b...

Corticosteroid resistance causes significant morbidity in asthma, and drug repurposing may identify timely and cost-effective adjunctive treatments for corticosteroid resistance. In 95 subjects from the Childhood Asthma Management Program (CAMP) and 19 subjects from the Severe Asthma Research Program (SARP), corticosteroid response was measured by...

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and the traditional variables extracted from computed tomography (CT) images may not be sufficient to describe all the topological features of lung tissues in COPD patients. We employed an unsupervised three-dimensional (3D) convolutional autoencoder (CAE)-feature constructor (...

Severe asthma accounts for almost half of the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Further, the validation and approval of new asthma therapies is a lengthy proc...

BACKGROUND Genetic ancestry plays a role in asthma health disparities. OBJECTIVE To evaluate the impact of ancestry on, and identify genetic variants associated with asthma, serum immunoglobulin E (IgE), and lung function. METHODS 436 Peruvian children (9-19 years) with asthma and 291 without asthma were genotyped using the Illumina Multi-Ethnic...

Rationale: Reports indicate longitudinal variability in sputum differential cell counts while others describe stability. Highly variable sputum eosinophil percents are associated with greater lung function loss than persistently elevated eosinophil percents, but elevated neutrophils are linked to more severe asthma. Objectives: To examine sputum...

Chronic obstructive pulmonary disease (COPD) is heterogeneous in development, progression, and phenotypes. Little is known about the lung microbiome, sampled by bronchoscopy, in milder COPD and its relationships to clinical features that reflect disease heterogeneity (lung function, symptom burden, and functional impairment). Using bronchoalveolar...

Background Adults and adolescents with severe asthma who completed the 48-week SIROCCO and 56-week CALIMA Phase III benralizumab trials entered the safety extension study BORA (NCT02258542). The continued safety and efficacy of benralizumab in the first year of BORA (Year 2 of treatment) have been reported. Objective We report outcomes for adolesc...