Polygenic and Transcriptional Risk Scores Identify Chronic Obstructive Pulmonary Disease Subtypes in the COPDGene and ECLIPSE Cohort Studies

Authors

Matthew Moll, Brigham and Women's Hospital
Julian Hecker, Brigham and Women's Hospital
John Platig, University of Virginia
Jingzhou Zhang, Boston University Medical Center
Auyon J. Ghosh, SUNY Upstate Medical University
Katherine A. Pratte, National Jewish Health
Rui-Sheng Wang, Brigham and Women's Hospital
Davin Hill, Northeastern University
Iain R. Konigsberg, University of Colorado Anschutz Medical Campus
Joe W. Chiles, University Of Alabama At Birmingham
Craig P. Hersh, Brigham and Women's Hospital
Peter J. Castaldi, Brigham and Women's Hospital
Kimberly Glass, Brigham and Women's Hospital
Jennifer G. Dy, Northeastern University
Don D. Sin, St. Paul's Hospital
Ruth Tal-Singer, Global Allergy and Airways Patient Platform
Majd Mouded, Novartis Institute for Biomedical Research
Stephen I. Rennard, University of Nebraska Medical CenterFollow
Gary P. Anderson, University of Melbourne
Gregory L. Kinney, University of Colorado Anschutz Medical Campus
Russell P. Bowler, National Jewish Health
Jeffrey L. Curtis, University of Michigan School of Medicine
Merry-Lynn McDonald, University of Colorado Anschutz Medical Campus
Edwin K. Silverman, Brigham and Women's Hospital
Brian D. Hobbs, Regeneron Pharmaceutical
Michael H. Cho, Brigham and Women's Hospital

Document Type

Article

Journal Title

EBioMedicine

Publication Date

2024

Volume

110

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 FEV

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.

MeSH Headings

Humans, Pulmonary Disease, Chronic Obstructive, Male, Female, Genetic Predisposition to Disease, Aged, Middle Aged, Multifactorial Inheritance, Biomarkers, Risk Factors, Cohort Studies, Protein Interaction Maps, Gene Expression Profiling, Drug Repositioning, Polymorphism, Single Nucleotide

DOI Link

10.1016/j.ebiom.2024.105429

ISSN

2352-3964

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.

Recommended Citation

Moll, Matthew; Hecker, Julian; Platig, John; Zhang, Jingzhou; Ghosh, Auyon J.; Pratte, Katherine A.; Wang, Rui-Sheng; Hill, Davin; Konigsberg, Iain R.; Chiles, Joe W.; Hersh, Craig P.; Castaldi, Peter J.; Glass, Kimberly; Dy, Jennifer G.; Sin, Don D.; Tal-Singer, Ruth; Mouded, Majd; Rennard, Stephen I.; Anderson, Gary P.; Kinney, Gregory L.; Bowler, Russell P.; Curtis, Jeffrey L.; McDonald, Merry-Lynn; Silverman, Edwin K.; Hobbs, Brian D.; and Cho, Michael H., "Polygenic and Transcriptional Risk Scores Identify Chronic Obstructive Pulmonary Disease Subtypes in the COPDGene and ECLIPSE Cohort Studies" (2024). Journal Articles: Pulmonary & Critical Care Med. 18.
https://digitalcommons.unmc.edu/com_pulm_articles/18