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A4158 - Genomic Signatures of Type 2 and IL-17 Inflammation Are Associated with Markers of Disease Severity Across Smokers with Preserved Spirometry and Mild/Moderate Airway Obstruction in Spiromics
Author Block: S. Garudadri1, M. K. Han2, E. A. Hoffman3, R. Barr4, E. R. Bleecker5, R. P. Bowler6, A. P. Comellas3, C. B. Cooper7, D. Couper8, G. J. Criner9, M. T. Dransfield10, N. N. Hansel11, R. E. Kanner12, R. Paine12, J. A. Krishnan13, S. P. Peters14, P. Woodruff15, S. Christenson15; 1Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States, 2University of Michigan, Ann Arbor, Ann Arbor, MI, United States, 3University of Iowa, Iowa City, IA, United States, 4Presbyterian Hospital, Columbia University Medical Center, New York, NY, United States, 5University of Arizona, Tucson, AZ, United States, 6Natl Jewish Health, Denver, CO, United States, 7UCLA School of Medicine, Los Angeles, CA, United States, 8University of North Carolina, Chapel Hill, NC, United States, 9Temple University, Philadelphia, PA, United States, 10University of Alabama, Birmingham, Birmingham, AL, United States, 11Johns Hopkins University, Baltimore, MD, United States, 12University of Utah, Salt Lake City, UT, United States, 13University of Illinois, Chicago, IL, United States, 14Wake Forest University, Winston-Salem, NC, United States, 15University of California, San Francisco, San Francisco, CA, United States.
Rationale: There is substantial clinical heterogeneity in COPD, yet the biology underlying this heterogeneity remains poorly understood. Furthermore, we recently demonstrated that the current definition of COPD, which requires an FEV1/FVC ratio ≤ 0.70, may fail to capture the full breadth of smoking-related airway pathology, particularly early disease. We previously developed gene expression signatures of the airway epithelial response to type 2 (T2) and IL-17 driven inflammation in COPD that appear to mark distinct subgroups. Here we explore the association of these adaptive immune responses with smoking-related airway disease. We relate these signatures to clinical markers of disease severity across current and former smokers with preserved spirometry (FEV1/FVC > 0.70) and participants with COPD who have predominantly mild to moderate obstruction. We use airway epithelial RNA sequencing obtained from the well-phenotyped Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) bronchoscopy substudy.
Methods: RNA was isolated and sequenced from epithelial brushes obtained in a subset of SPIROMICS subjects (n=111). We calculated T2 and IL-17 signatures using pre-validated T2 and IL-17 responsive epithelial genes, respectively. We used linear models to assess the association of these gene signatures with disease severity parameters including FEV1, COPD Assessment Test (CAT) score, and CT markers of airway wall thickness, functional small airway disease (PRMfSAD), and emphysema.
Results: Amongst smokers with preserved spirometry (n=58) and participants with COPD (GOLD I=21, GOLD II=27, GOLD III=5), a higher T2 signature was associated with lower FEV1 (p = 0.009), greater airway wall thickness (p=0.01), increased PRMfSAD(p = 0.04), and higher symptom burden (p=0.01) after adjustment for age, gender, smoking status, asthma history, and inhaled corticosteroid use. A higher IL-17 signature was also associated with increased PRMfSAD(p=0.02) in adjusted analyses. However, the T2 and IL-17 signatures were not significantly correlated with each other. In stratified analyses the T2 signature remained associated with airway wall thickness (p=0.004) and CAT score (p=0.02) amongst smokers with preserved spirometry.
Conclusion: Across smokers, enhanced airway epithelial T2 inflammation was associated with objective (lung function and CT-based) and subjective (symptom scores) markers of disease severity, whereas IL-17 related inflammation was associated only with the objective marker of worsening PRMfSAD on CT. Our analyses suggest that T2 and IL-17 related inflammation independently and variably contribute to smoking associated airway disease pathology. T2 inflammation may contribute to symptoms in smokers with preserved spirometry whereas both T2 and IL-17 associated inflammation may contribute to small airway disease.