Journal article
Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease
EBioMedicine, Vol.84, pp.104262-104262
10/01/2022
DOI: 10.1016/j.ebiom.2022.104262
PMCID: PMC9507992
PMID: 36155958
Abstract
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 pheno-typic 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 diffu-sion 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: insu-lin-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 eBioMedicine 104262 Published https://doi.org/10.1016/j. ebiom.2022.104262 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 Dis-ease 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.Copyright (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Details
- Title: Subtitle
- Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease
- Creators
- K. A. Serban - National Jewish HealthK. A. Pratte - National Jewish HealthC. Strange - University of South CarolinaR. A. Sandhaus - National Jewish HealthA. M. Turner - University of BirminghamT. Beiko - University of South CarolinaD. A. Spittle - University of BirminghamL. Maier - National Jewish HealthN. Hamzeh - Univ Iowa, Pulm Crit Care Allergy & Sleep Med, Iowa City, IA USAE. K. Silverman - Brigham and Women's HospitalB. D. Hobbs - Brigham and Women's HospitalC. P. Hersh - Brigham and Women's HospitalD. L. DeMeo - Brigham and Women's HospitalM. H. Cho - Brigham and Women's HospitalR. P. Bowler - National Jewish Health
- Resource Type
- Journal article
- Publication Details
- EBioMedicine, Vol.84, pp.104262-104262
- Publisher
- Elsevier
- DOI
- 10.1016/j.ebiom.2022.104262
- PMID
- 36155958
- PMCID
- PMC9507992
- ISSN
- 2352-3964
- eISSN
- 2352-3964
- Number of pages
- 17
- Grant note
- COPD Foundation Alpha-1 Foundation U01 HL089897; U01 HL089856; U01HL112707; U01 HL112695 / National Heart, Lung, and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) 1 U54 RR019498-01 / National Heart Lung and Blood Institute, the Office of Rare Diseases through the Rare Lung Disease Clinical Research Network 1R01HL137995 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 10/01/2022
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Psychiatry; Internal Medicine
- Record Identifier
- 9984359926102771
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