TY - JOUR
T1 - The Proteomic Profile of Interstitial Lung Abnormalities
AU - Axelsson, Gisli Thor
AU - Gudmundsson, Gunnar
AU - Pratte, Katherine A.
AU - Aspelund, Thor
AU - Putman, Rachel K.
AU - Sanders, Jason L.
AU - Gudmundsson, Elias F.
AU - Hatabu, Hiroto
AU - Gudmundsdottir, Valborg
AU - Gudjonsson, Alexander
AU - Hino, Takuya
AU - Hida, Tomoyuki
AU - Hobbs, Brian D.
AU - Cho, Michael H.
AU - Silverman, Edwin K.
AU - Bowler, Russell P.
AU - Launer, Lenore J.
AU - Jennings, Lori L.
AU - Hunninghake, Gary M.
AU - Emilsson, Valur
AU - Gudnason, Vilmundur
N1 - Funding Information:
Supported by National Institutes of Health grants K08 HL140087 (R.K.P.); K08 HL136928 (B.D.H.); R01 HL135142 and R01 HL137927 (M.H.C.); U01 HL089856, R01 HL113264, R01 137927, R01 133135, and P01 HL114501 (E.K.S.); R01 HL137995 and R01 HL152735 (R.P.B.); R01 HL111024, R01 HL130974, and R01 135142 (G.M.H., H.H.); and R01CA203636 and 5U01CA209414-03 (H.H.). Supported by National Institute on Aging grant 27120120022C (V. Gudnason). Supported by the Icelandic Centre for Research, project grants 141513-051 (G.G., V. Gudnason, and G.M.H.); 195761-051 (V.E.); and 184845-051 and 206692-051 (V. Gudmundsdottir). Supported by Landspítali Háskólasjúkrahús grants A-2019-029, A-2019-030, A-2020-018, and A-2020-017 (G.G.), University of Iceland Research Fund 2021, and the Eimskip University Fund (G.T.A.). The Age, Gene/Environment Susceptibility-Reykjavik Study was supported by National Institutes of Health contracts N01-AG-1-2100 and HHSN27120120022C, the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). COPDGene: The COPDGene study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion. The project described was supported by National Heart, Lung, and Blood Institute grants U01 HL089897, U01 HL089856, R01 HL137995, and R01 HL129937. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. SCCOR: This project was supported by National Heart, Lung, and Blood Institute grants P50HL084948 and R21HL129917 and Pennsylvania Department of Health CURE SAP 4100062224. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute. Funding sources of the study had no role in the collection, analysis, or interpretation of the data, writing of the manuscript, or the decision to submit for publication.
Publisher Copyright:
© 2022 by the American Thoracic Society.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - Rationale: Knowledge on biomarkers of interstitial lung disease is incomplete. Interstitial lung abnormalities (ILAs) are radiologic changes that may present in its early stages. Objectives: To uncover blood proteins associated with ILAs using large-scale proteomics methods. Methods: Data from two prospective cohort studies, the AGES-Reykjavik (Age, Gene/Environment Susceptibility–Reykjavik) study (N = 5,259) for biomarker discovery and the COPDGene (Genetic Epidemiology of COPD) study (N = 4,899) for replication, were used. Blood proteins were measured using DNA aptamers, targeting more than 4,700 protein analytes. The association of proteins with ILAs and ILA progression was assessed with regression modeling, as were associations with genetic risk factors. Adaptive Least Absolute Shrinkage and Selection Operator models were applied to bootstrap data samples to discover sets of proteins predictive of ILAs and their progression. Measurements and Main Results: Of 287 associations, SFTPB (surfactant protein B) (odds ratio [OR], 3.71 [95% confidence interval (CI), 3.20–4.30]; P = 4.28 3 10267), SCGB3A1 (Secretoglobin family 3A member 1) (OR, 2.43 [95% CI, 2.13–2.77]; P = 8.01 3 10240), and WFDC2 (WAP four-disulfide core domain protein 2) (OR, 2.42 [95% CI, 2.11–2.78]; P = 4.01 3 10236) were most significantly associated with ILA in AGES-Reykjavik and were replicated in COPDGene. In AGES-Reykjavik, concentrations of SFTPB were associated with the rs35705950 MUC5B (mucin 5B) promoter polymorphism, and SFTPB and WFDC2 had the strongest associations with ILA progression. Multivariate models of ILAs in AGES-Reykjavik, ILAs in COPDGene, and ILA progression in AGES-Reykjavik had validated areas under the receiver operating characteristic curve of 0.880, 0.826, and 0.824, respectively. Conclusions: Novel, replicated associations of ILA, its progression, and genetic risk factors with numerous blood proteins are demonstrated as well as machine-learning–based models with favorable predictive potential. Several proteins are revealed as potential markers of early fibrotic lung disease.
AB - Rationale: Knowledge on biomarkers of interstitial lung disease is incomplete. Interstitial lung abnormalities (ILAs) are radiologic changes that may present in its early stages. Objectives: To uncover blood proteins associated with ILAs using large-scale proteomics methods. Methods: Data from two prospective cohort studies, the AGES-Reykjavik (Age, Gene/Environment Susceptibility–Reykjavik) study (N = 5,259) for biomarker discovery and the COPDGene (Genetic Epidemiology of COPD) study (N = 4,899) for replication, were used. Blood proteins were measured using DNA aptamers, targeting more than 4,700 protein analytes. The association of proteins with ILAs and ILA progression was assessed with regression modeling, as were associations with genetic risk factors. Adaptive Least Absolute Shrinkage and Selection Operator models were applied to bootstrap data samples to discover sets of proteins predictive of ILAs and their progression. Measurements and Main Results: Of 287 associations, SFTPB (surfactant protein B) (odds ratio [OR], 3.71 [95% confidence interval (CI), 3.20–4.30]; P = 4.28 3 10267), SCGB3A1 (Secretoglobin family 3A member 1) (OR, 2.43 [95% CI, 2.13–2.77]; P = 8.01 3 10240), and WFDC2 (WAP four-disulfide core domain protein 2) (OR, 2.42 [95% CI, 2.11–2.78]; P = 4.01 3 10236) were most significantly associated with ILA in AGES-Reykjavik and were replicated in COPDGene. In AGES-Reykjavik, concentrations of SFTPB were associated with the rs35705950 MUC5B (mucin 5B) promoter polymorphism, and SFTPB and WFDC2 had the strongest associations with ILA progression. Multivariate models of ILAs in AGES-Reykjavik, ILAs in COPDGene, and ILA progression in AGES-Reykjavik had validated areas under the receiver operating characteristic curve of 0.880, 0.826, and 0.824, respectively. Conclusions: Novel, replicated associations of ILA, its progression, and genetic risk factors with numerous blood proteins are demonstrated as well as machine-learning–based models with favorable predictive potential. Several proteins are revealed as potential markers of early fibrotic lung disease.
UR - http://www.scopus.com/inward/record.url?scp=85135405977&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85135405977&partnerID=8YFLogxK
U2 - 10.1164/rccm.202110-2296OC
DO - 10.1164/rccm.202110-2296OC
M3 - Article
C2 - 35438610
AN - SCOPUS:85135405977
SN - 1073-449X
VL - 206
SP - 337
EP - 346
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 3
ER -