Relationships between bronchodilator responsiveness, a COPD polygenic risk score, and COPD progression

Spyridon Fortis; Alejandro P. Comellas; Russell P. Bowler; Surya P. Bhatt; Craig P. Hersh; Dawn L. Demeo; Gregory Kinney; Edwin K. Silverman; Michael H. Cho; Matthew Moll

doi:10.1016/j.rmed.2026.108636

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Relationships between bronchodilator responsiveness, a COPD polygenic risk score, and COPD progression

Journal article

Peer reviewed

Relationships between bronchodilator responsiveness, a COPD polygenic risk score, and COPD progression

Spyridon Fortis, Alejandro P. Comellas, Russell P. Bowler, Surya P. Bhatt, Craig P. Hersh, Dawn L. Demeo, Gregory Kinney, Edwin K. Silverman, Michael H. Cho and Matthew Moll

Respiratory medicine, Vol.252, 108636

02/2026

DOI: 10.1016/j.rmed.2026.108636

PMCID: PMC12834220

PMID: 41520899

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https://pmc.ncbi.nlm.nih.gov/articles/PMC12834220/View

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Abstract

Bronchodilator responsiveness (BDR) is associated with progression to COPD. Genetic risk for COPD, summarized by polygenic risk scores (PRS), predicts low lung function and COPD. However, it remains unclear whether genetic predisposition to COPD is related to BDR and whether PRS and BDR together influence lung function decline in individuals at risk for the disease. We analyzed data from COPDGene participants with a smoking history and normal spirometry at study enrollment. We cross-sectionally examined the association of a PRS with 2005-BDR-FEV1 % (change relative to pre-bronchodilator) and 2021-BDR-FEV1 % (change relative to predicted). We also examined the association of PRS, 2005-BDR-FEV1 %, and 2021-BDR-FEV1 % with progression to COPD and longitudinal FEV1 decline between enrollment and follow-up adjusted for demographics, smoking history, and FEV1 at enrollment. PRS did not correlate with 2005-BDR-FEV1 % in 1446 African Americans (AA) but PRS correlates with BDR in both unadjusted (rho = 0.01, P < 0.001) and adjusted analysis in 3378 non-Hispanic Whites (NHW). NHW participants with BDR had higher PRS than those without. Models including 2005-BDR-FEV1 % demonstrated better accuracy than those including PRS (Area under the curve: 0.762 vs 0.743 in NHW; 0.693 vs 0.653 in AA). BDR models also outperformed PRS models for longitudinal FEV1 decline. Mediation analysis showed that about one third of the PRS effect on FEV1 decline in NHW was explained through BDR. BDR is more strongly associated with progression to COPD and FEV1 decline than PRS, and part of the PRS effect is mediated through BDR. •Polygenic risk score correlated with bronchodilator responsiveness in non-Hispanic White participants with smoking history and normal spirometry.•Among individuals with smoking history and normal spirometry, bronchodilator responsiveness was more strongly associated with lung function decline than polygenic risk score.•Mediation analysis showed that approximately one third of the effect of polygenic risk score on lug function decline in non-Hispanic White participants was explained through bronchodilator responsiveness.

Bronchodilators responsiveness

COPD

Polygenic risk score

Pulmonary function test

Details

Title: Subtitle: Relationships between bronchodilator responsiveness, a COPD polygenic risk score, and COPD progression
Creators: Spyridon Fortis - Iowa City VA Health Care System
Alejandro P. Comellas - University of Iowa
Russell P. Bowler - National Jewish Health
Surya P. Bhatt - University of Alabama at Birmingham
Craig P. Hersh - Brigham and Women's Hospital
Dawn L. Demeo - Brigham and Women's Hospital
Gregory Kinney - University of Colorado Anschutz Medical Campus
Edwin K. Silverman - Brigham and Women's Hospital
Michael H. Cho - Brigham and Women's Hospital
Matthew Moll - Brigham and Women's Hospital
Resource Type: Journal article
Publication Details: Respiratory medicine, Vol.252, 108636
DOI: 10.1016/j.rmed.2026.108636
PMID: 41520899
PMCID: PMC12834220
NLM abbreviation: Respir Med
ISSN: 0954-6111
eISSN: 1532-3064
Publisher: Elsevier Ltd
Grant note: NIH: U01 HL089897, U01 HL089856 National Heart, Lung, and Blood Institute: 75N92023D00011 COPD FoundationBayer PharmaceuticalsBoehringer-IngelheimGenentechGlaxoSmithKlinePfizerSunovion
The project described was supported by Award Number U01 HL089897, Award Number U01 HL089856, and by NIH contract 75N92023D00011 from the National Heart, Lung, and Blood Institute. 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. 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.
Language: English
Date published: 02/2026
Academic Unit: Pulmonary, Critical Care, and Occupational Medicine; Psychiatry; ICTS; Internal Medicine
Record Identifier: 9985121596802771

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