Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes in the COPDGene and ECLIPSE cohort studiesResearch in context
Matthew Moll,
Julian Hecker,
John Platig,
Jingzhou Zhang,
Auyon J. Ghosh,
Katherine A. Pratte,
Rui-Sheng Wang,
Davin Hill,
Iain R. Konigsberg,
Joe W. Chiles, III,
Craig P. Hersh,
Peter J. Castaldi,
Kimberly Glass,
Jennifer G. Dy,
Don D. Sin,
Ruth Tal-Singer,
Majd Mouded,
Stephen I. Rennard,
Gary P. Anderson,
Gregory L. Kinney,
Russell P. Bowler,
Jeffrey L. Curtis,
Merry-Lynn McDonald,
Edwin K. Silverman,
Brian D. Hobbs,
Michael H. Cho
Affiliations
Matthew Moll
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
Julian Hecker
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Harvard Medical School, Boston, MA, 02115, USA
John Platig
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22903, USA
Jingzhou Zhang
The Pulmonary Center, Boston University Medical Center, Boston, MA 02118, USA
Auyon J. Ghosh
Division of Pulmonary, Critical Care, and Sleep Medicine, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
Katherine A. Pratte
Department of Biostatistics, National Jewish Health, Denver, CO, 80206, USA
Rui-Sheng Wang
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
Davin Hill
Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, 02115, USA
Iain R. Konigsberg
Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
Joe W. Chiles, III
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
Craig P. Hersh
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
Peter J. Castaldi
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
Kimberly Glass
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Harvard Medical School, Boston, MA, 02115, USA
Jennifer G. Dy
Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, 02115, USA
Don D. Sin
Centre for Heart Lung Innovation, St. Paul's Hospital, and Department of Medicine (Respiratory Division), University of British Columbia, Vancouver, BC, Canada
Ruth Tal-Singer
Global Allergy and Airways Patient Platform, Vienna, Austria
Majd Mouded
Novartis Institute for Biomedical Research, Cambridge, MA, USA
Stephen I. Rennard
Division of Pulmonary, Critical Care, and Sleep Medicine, University of Nebraska, Omaha, NE, 68198, USA
Gary P. Anderson
Lung Health Research Centre, Department of Biochemistry and Pharmacology, University of Melbourne, Melbourne, Victoria, Australia
Gregory L. Kinney
Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
Russell P. Bowler
Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, 80206, USA
Jeffrey L. Curtis
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
Merry-Lynn McDonald
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
Edwin K. Silverman
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
Brian D. Hobbs
Regeneron Pharmaceutical, Tarrytown, NY, USA
Michael H. Cho
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; Corresponding author. 181 Longwood Avenue, Boston, MA, 02115, USA.
Summary: 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.
