. 2024 Dec:110:105429.

doi: 10.1016/j.ebiom.2024.105429. Epub 2024 Nov 6.

Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes in the COPDGene and ECLIPSE cohort studies

Matthew Moll¹, Julian Hecker², John Platig³, Jingzhou Zhang⁴, Auyon J Ghosh⁵, Katherine A Pratte⁶, Rui-Sheng Wang⁷, Davin Hill⁸, Iain R Konigsberg⁹, Joe W Chiles 3rd¹⁰, Craig P Hersh¹¹, Peter J Castaldi¹², Kimberly Glass², Jennifer G Dy⁸, Don D Sin¹³, Ruth Tal-Singer¹⁴, Majd Mouded¹⁵, Stephen I Rennard¹⁶, Gary P Anderson¹⁷, Gregory L Kinney¹⁸, Russell P Bowler¹⁹, Jeffrey L Curtis²⁰, Merry-Lynn McDonald²¹, Edwin K Silverman¹¹, Brian D Hobbs²², Michael H Cho²³

Affiliations

¹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Division of Pulmonary, Critical Care, Sleep and Allergy, Veterans Affairs Boston Healthcare System, West Roxbury, MA, 02123, USA; Harvard Medical School, Boston, MA, 02115, USA.
² Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Harvard Medical School, Boston, MA, 02115, USA.
³ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22903, USA.
⁴ The Pulmonary Center, Boston University Medical Center, Boston, MA 02118, USA.
⁵ Division of Pulmonary, Critical Care, and Sleep Medicine, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
⁶ Department of Biostatistics, National Jewish Health, Denver, CO, 80206, USA.
⁷ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.
⁸ Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, 02115, USA.
⁹ Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
¹⁰ Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
¹¹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Harvard Medical School, Boston, MA, 02115, USA.
¹² Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35233, USA; Division of General Internal Medicine and Primary Care, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Harvard Medical School, Boston, MA, 02115, USA.
¹³ Centre for Heart Lung Innovation, St. Paul's Hospital, and Department of Medicine (Respiratory Division), University of British Columbia, Vancouver, BC, Canada.
¹⁴ Global Allergy and Airways Patient Platform, Vienna, Austria.
¹⁵ Novartis Institute for Biomedical Research, Cambridge, MA, USA.
¹⁶ Division of Pulmonary, Critical Care, and Sleep Medicine, University of Nebraska, Omaha, NE, 68198, USA.
¹⁷ Lung Health Research Centre, Department of Biochemistry and Pharmacology, University of Melbourne, Melbourne, Victoria, Australia.
¹⁸ Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
¹⁹ Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, 80206, USA.
²⁰ Division of Pulmonary and Critical Care Medicine, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA; Medical Service, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, 48109, USA.
²¹ Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA; Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, 701, 19th Street S., LHRB 440, Birmingham, AL, 35233, USA; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
²² Regeneron Pharmaceutical, Tarrytown, NY, USA.
²³ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Harvard Medical School, Boston, MA, 02115, USA. Electronic address: remhc@channing.harvard.edu.

PMID: 39509750
PMCID: PMC11570824
DOI: 10.1016/j.ebiom.2024.105429

Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes in the COPDGene and ECLIPSE cohort studies

Matthew Moll et al. EBioMedicine. 2024 Dec.

. 2024 Dec:110:105429.

doi: 10.1016/j.ebiom.2024.105429. Epub 2024 Nov 6.

Authors

Affiliations

¹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Division of Pulmonary, Critical Care, Sleep and Allergy, Veterans Affairs Boston Healthcare System, West Roxbury, MA, 02123, USA; Harvard Medical School, Boston, MA, 02115, USA.
² Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Harvard Medical School, Boston, MA, 02115, USA.
³ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22903, USA.
⁴ The Pulmonary Center, Boston University Medical Center, Boston, MA 02118, USA.
⁵ Division of Pulmonary, Critical Care, and Sleep Medicine, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
⁶ Department of Biostatistics, National Jewish Health, Denver, CO, 80206, USA.
⁷ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.
⁸ Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, 02115, USA.
⁹ Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
¹⁰ Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
¹¹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Harvard Medical School, Boston, MA, 02115, USA.
¹² Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35233, USA; Division of General Internal Medicine and Primary Care, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Harvard Medical School, Boston, MA, 02115, USA.
¹³ Centre for Heart Lung Innovation, St. Paul's Hospital, and Department of Medicine (Respiratory Division), University of British Columbia, Vancouver, BC, Canada.
¹⁴ Global Allergy and Airways Patient Platform, Vienna, Austria.
¹⁵ Novartis Institute for Biomedical Research, Cambridge, MA, USA.
¹⁶ Division of Pulmonary, Critical Care, and Sleep Medicine, University of Nebraska, Omaha, NE, 68198, USA.
¹⁷ Lung Health Research Centre, Department of Biochemistry and Pharmacology, University of Melbourne, Melbourne, Victoria, Australia.
¹⁸ Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
¹⁹ Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, 80206, USA.
²⁰ Division of Pulmonary and Critical Care Medicine, University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA; Medical Service, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, 48109, USA.
²¹ Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA; Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, 701, 19th Street S., LHRB 440, Birmingham, AL, 35233, USA; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
²² Regeneron Pharmaceutical, Tarrytown, NY, USA.
²³ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Harvard Medical School, Boston, MA, 02115, USA. Electronic address: remhc@channing.harvard.edu.

PMID: 39509750
PMCID: PMC11570824
DOI: 10.1016/j.ebiom.2024.105429

Abstract

Background: Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear. We aimed to define high-risk COPD subtypes using genetics (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) and assess differences in clinical and molecular characteristics.

Methods: We defined high-risk groups based on PRS and TRS quantiles by maximising differences in protein biomarkers in a COPDGene training set and identified these groups in COPDGene and ECLIPSE test sets. We tested multivariable associations of subgroups with clinical outcomes and compared protein-protein interaction networks and drug repurposing analyses between high-risk groups.

Findings: We examined two high-risk omics-defined groups in non-overlapping test sets (n = 1133 NHW COPDGene, n = 299 African American (AA) COPDGene, n = 468 ECLIPSE). We defined "high activity" (low PRS, high TRS) and "severe risk" (high PRS, high TRS) subgroups. Participants in both subgroups had lower body-mass index (BMI), lower lung function, and alterations in metabolic, growth, and immune signalling processes compared to a low-risk (low PRS, low TRS) subgroup. "High activity" but not "severe risk" participants had greater prospective FEV₁ decline (COPDGene: -51 mL/year; ECLIPSE: -40 mL/year) and proteomic profiles were enriched in gene sets perturbed by treatment with 5-lipoxygenase inhibitors and angiotensin-converting enzyme (ACE) inhibitors.

Interpretation: Concomitant use of polygenic and transcriptional risk scores identified clinical and molecular heterogeneity amongst high-risk individuals. Proteomic and drug repurposing analysis identified subtype-specific enrichment for therapies and suggest prior drug repurposing failures may be explained by patient selection.

Funding: National Institutes of Health.

Keywords: COPD; Drug repurposing; Endotyping; Polygenic risk scores; Transcriptomics.

Published by Elsevier B.V.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests EKS received grant support from Bayer and Northpond Labs. BDH received grant support from Bayer. MHC has received grant support from Bayer. MM received grant support from Bayer and consulting fees from Sitka, TheaHealth, 2ndMD, and TriNetX. CPH reports grant support from Boehringer-Ingelheim, Novartis, Bayer and Vertex, outside of this study. PJC has received grant support from GlaxoSmithKline and Bayer and consulting fees from GlaxoSmithKline and Novartis. RTS received consulting fees from GSK, AstraZeneca, Roche, Itai and Beyond, Samay Health, Immunomet, ENA Respiratory, Teva, COPD Foundation and Vocalis Health. She is a retiree and shareholder of GSK and holds share options at ENA Respiratory. DDS received honoraria for giving talks on COPD from GSK, Boehringer Ingelheim, and AstraZeneca, is the chair of an NHLBI sponsored clinical trial data safety monitoring board, and deputy editor of European Respiratory Journal. JLC received consulting fees from AstraZeneca PLC, CSL Behring, LLC, and Novartis Corporation. SIR received consulting fees from Verona Pharma, Sanofi, BeyondAir and the Alpha 1 Foundation. He is a founder and president of Great Plains Biometrix. He was an employee of AstraZeneca from 2015 to 2019 during which he received shares as part of his compensation. JHP is supported by NIH K25HL140186. KG is supported by NIH/NHLBI: R01HG011393, R01HL152728, R01HL160008, and R01HL162813.

Figures

**Fig. 1**
Schematic of study design. COPD, chronic obstructive pulmonary disease. COPDGene, Genetic Epidemiology of COPD study. ECLIPSE, Evaluation of COPD to Longitudinally Identify Predictive Surrogate Endpoints study. PRS, polygenic risk score. TRS, transcriptional risk score. STRING, Search Tool for the Retrieval of Interacting Genes/Proteins. MAGMA, Multi-marker Analysis of GenoMic Annotation.

**Fig. 2**
Omics-defined groups or subtypes overlaid on a plot of the polygenic risk score (PRS; *x-axis*) and transcriptional risk score (TRS; *y-axis*) in the COPDGene testing set (n = 1432).

**Fig. 3**
High disease activity (“low PRS, high TRS”) subtype STRING protein–protein interaction networks using differentially expressed proteins in Omics-defined groups (subtypes) in the COPDGene testing set as seed proteins, permitting up to 10 interactors in the first shell and 5 interactors in the second shell. Only high-confidence interactions were included and greater line thickness indicates greater confidence. Differentially expressed proteins were identified by comparing group assignments to the reference group. Colours represent MCL (Markov) clusters.

**Fig. 4**
Severe disease risk (“high PRS, high TRS”) subtype STRING protein–protein interaction networks using differentially expressed proteins in Omics-defined groups (subtypes) in the COPDGene testing set as seed proteins, permitting up to 10 interactors in the first shell and 5 interactors in the second shell. Only high-confidence interactions were included and greater line thickness indicates greater confidence. Differentially expressed proteins were identified by comparing group assignments to the reference group. Colours represent MCL (Markov) clusters.

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Update of

Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes.
Moll M, Hecker J, Platig J, Zhang J, Ghosh AJ, Pratte KA, Wang RS, Hill D, Konigsberg IR, Chiles JW, Hersh CP, Castaldi PJ, Glass K, Dy JG, Sin DD, Tal-Singer R, Mouded M, Rennard SI, Anderson GP, Kinney GL, Bowler RP, Curtis JL, McDonald ML, Silverman EK, Hobbs BD, Cho MH. Moll M, et al. medRxiv [Preprint]. 2024 May 20:2024.05.20.24307621. doi: 10.1101/2024.05.20.24307621. medRxiv. 2024. Update in: EBioMedicine. 2024 Dec;110:105429. doi: 10.1016/j.ebiom.2024.105429. PMID: 38826461 Free PMC article. Updated. Preprint.

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Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes in the COPDGene and ECLIPSE cohort studies

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Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes in the COPDGene and ECLIPSE cohort studies

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