{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T21:22:48Z","timestamp":1787433768332,"version":"build-2736575974"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005640","name":"Flight Attendant Medical Research Institute","doi-asserted-by":"publisher","award":["CIA190001"],"award-info":[{"award-number":["CIA190001"]}],"id":[{"id":"10.13039\/100005640","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005188","name":"California Tobacco-Related Disease Research Program","doi-asserted-by":"crossref","award":["T29IR0715"],"award-info":[{"award-number":["T29IR0715"]}],"id":[{"id":"10.13039\/100005188","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number","award":["R01HL142503"],"award-info":[{"award-number":["R01HL142503"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Among individuals with a history of smoking but preserved spirometry (tobacco exposed with preserved spirometry, or TEPS), lung volume\u2013based stratification identifies 2 phenotypes at increased risk for chronic obstructive pulmonary disease (pre-COPD): those with a relatively elevated total lung capacity ([TLC]high) and those with a relatively elevated functional residual capacity-to-TLC ratio ([FRC\/TLC]high). These subgroups exhibit distinct respiratory symptoms, radiographic abnormalities, and clinical trajectories.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aimed to determine whether these lung volume\u2013based pre-COPD phenotypes have distinct biological features reflected in their circulating proteomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed peripheral blood proteomic profiles (SomaScan v4.0; 4979 aptamers) from 1959 TEPS participants at the 5-year follow-up visit (visit 2) of the Genetic Epidemiology of COPD study cohort. Participants with [TLC]high and [FRC\/TLC]high (based on computerized tomography scan-derived supine lung volumes) were compared with a low-COPD-risk reference group (without high TLC or high FRC\/TLC). Analyses included covariate-adjusted regression, machine learning, and pathway enrichment modeling, with adjustment for age, sex, height, weight, smoking status and burden, leukocyte and platelet counts, forced expiratory volume in 1\u2009second (percent predicted), and study site (random effect).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Using visit 2 data and visit 3 (10-year) follow-up outcomes, we confirmed the reproducibility and prognostic validity of the lung volume\u2013based phenotypes in 1232 participants with longitudinal data. Over a mean (SD) of 5.3 (1.1)\u2009years, spirometric COPD developed in 17% (133 out of 761) of pre-COPD TEPS vs 8% (37 out of 471) of low-risk TEPS (adjusted odds ratio [aOR],\u20092.51; 95% confidence interval [CI], 1.69-3.75; P\u2009&amp;lt;\u2009.001). Among pre-COPD subgroups, [FRC\/TLC]high TEPS showed greater progression to a Global Initiative for Chronic Obstructive Lung Disease stage 2 or higher (aOR,\u20092.90; 95% CI, 1.62-5.18; P\u2009&amp;lt;\u2009.001) and preserved ratio and impaired spirometry (aOR,\u20093.29; 95% CI, 1.41-7.69; P\u2009=\u2009.005). At baseline (n\u2009=\u20091959), plasma proteomic analysis identified 165 upregulated and 145 downregulated proteins in [TLC]high TEPS compared with low-COPD-risk TEPS, whereas only 22 proteins were differentially expressed in [FRC\/TLC]high TEPS vs low-risk group. Comparison between the 2 pre-COPD phenotypes identified 269 differentially expressed proteins (116 upregulated and 153 downregulated in [FRC\/TLC]high vs [TLC]high), including previously described COPD-related mediators (eg, soluble receptor for advanced glycation end products, insulin-like growth factor-binding protein) and novel candidates (eg, zymogen granule membrane protein 16). Pathway analysis highlighted immune signaling, cellular trafficking, and apoptotic pathways relevant to COPD pathogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Lung volume\u2013based stratification in TEPS identifies biologically distinct subgroups with differing plasma proteomic signature and COPD risk, underscoring the heterogeneity of early disease and revealing potential circulating biomarkers of pre-COPD states.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Registration<\/jats:title>\n                    <jats:p>COPDGene study is registered with ClinicalTrials.gov: ID NCT00608764.<\/jats:p>\n                    <jats:p>Keywords<\/jats:p>\n                    <jats:p>pre-COPD, lung volumes, proteomics, biomarkers, chronic obstructive pulmonary disease.<\/jats:p>\n                  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