Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease
K.A. Serban,
K.A. Pratte,
C. Strange,
R.A. Sandhaus,
A.M. Turner,
T. Beiko,
D.A. Spittle,
L. Maier,
N. Hamzeh,
E.K. Silverman,
B.D. Hobbs,
C.P. Hersh,
D.L. DeMeo,
M.H. Cho,
R.P. Bowler
Affiliations
K.A. Serban
Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, United States; Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, United States; Corresponding authors.
K.A. Pratte
Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, United States
C. Strange
Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC, United States
R.A. Sandhaus
Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, United States
A.M. Turner
Institute for Applied Health Research, University of Birmingham, Birmingham, UK
T. Beiko
Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC, United States
D.A. Spittle
Institute of Inflammation and Aging, University of Birmingham, UK
L. Maier
Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, United States; Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, United States
N. Hamzeh
Pulmonary, Critical Care, Allergy and Sleep Medicine, University of Iowa, Iowa City, IA, United States
E.K. Silverman
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
B.D. Hobbs
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
C.P. Hersh
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
D.L. DeMeo
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
M.H. Cho
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
R.P. Bowler
Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, United States; Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, United States; Corresponding authors.
Summary: Background: Alpha-1 Antitrypsin (AAT) deficiency (AATD), the most common genetic cause of emphysema presents with unexplained phenotypic heterogeneity in affected subjects. Our objectives to identify unique and shared AATD plasma biomarkers with chronic obstructive pulmonary disease (COPD) may explain AATD phenotypic heterogeneity. Methods: The plasma or serum of 5,924 subjects from four AATD and COPD cohorts were analyzed on SomaScan V4.0 platform. Using multivariable linear regression, inverse variance random-effects meta-analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression we tested the association between 4,720 individual proteins or combined in a protein score with emphysema measured by 15th percentile lung density (PD15) or diffusion capacity (DLCO) in distinct AATD genotypes (Pi*ZZ, Pi*SZ, Pi*MZ) and non-AATD, PiMM COPD subjects. AAT SOMAmer accuracy for identifying AATD was tested using receiver operating characteristic curve analysis. Findings: In PiZZ AATD subjects, 2 unique proteins were associated with PD15 and 98 proteins with DLCO. Of those, 68 were also associated with DLCO in COPD also and enriched for three cellular component pathways: insulin-like growth factor, lipid droplet, and myosin complex. PiMZ AATD subjects shared similar proteins associated with DLCO as COPD subjects. Our emphysema protein score included 262 SOMAmers and predicted emphysema in AATD and COPD subjects. SOMAmer AAT level <7.99 relative fluorescence unit (RFU) had 100% sensitivity and specificity for identifying Pi*ZZ, but it was lower for other AATD genotypes. Interpretation: Using SomaScan, we identified unique and shared plasma biomarkers between AATD and COPD subjects and generated a protein score that strongly associates with emphysema in COPD and AATD. Furthermore, we discovered unique biomarkers associated with DLCO and emphysema in PiZZ AATD. Funding: This work was supported by a grant from the Alpha-1 Foundation to RPB. COPDGene was supported by Award U01 HL089897 and U01 HL089856 from the National Heart, Lung, and Blood Institute. Proteomics for COPDGene was supported by NIH 1R01HL137995. GRADS was supported by Award U01HL112707, U01 HL112695 from the National Heart, Lung, and Blood Institute, and UL1TRR002535 to CCTSI; QUANTUM-1 was supported by the National Heart Lung and Blood Institute, the Office of Rare Diseases through the Rare Lung Disease Clinical Research Network (1 U54 RR019498-01, Trapnell PI), and the Alpha-1 Foundation. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion.
