ABSTRACT
Rationale Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear.
Objectives Define high-risk COPD subtypes using both 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 maximizing 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.
Measurements and Main Results We examined two high-risk omics-defined groups in non-overlapping test sets (n=1,133 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 signaling processes compared to a low-risk (low PRS, low TRS) reference subgroup. “High activity” but not “severe risk” participants had greater prospective FEV1 decline (COPDGene: -51 mL/year; ECLIPSE: - 40 mL/year) and their proteomic profiles were enriched in gene sets perturbed by treatment with 5-lipoxygenase inhibitors and angiotensin-converting enzyme (ACE) inhibitors.
Conclusions 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.
Competing Interest Statement
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. 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 2015-2019 during which he received shares as part of his compensation that he owns.
Funding Statement
MM is supported by K08HL159318.BDH is supported by NIH K08HL136928, U01 HL089856, and an Alpha-1 Foundation Research Grant.JH is supported by P01 HL132825.JHP is supported by NIH K25HL140186.CPH is supported by NIH R01HL157879 and P01HL114501.MHC is supported by NIH R01HL137927, R01HL135142, HL147148, and HL089856.PJC is supported by NIH R01HL124233 and R01HL147326.RPB is supported by NIH R01 HL137995 and R01 HL152735EKS is supported by NIH R01 HL147148, U01 HL089856, R01 HL133135, R01 HL152728, and P01 HL114501.Proteomic data generated for this proposal was supported by R01 HL137995.The COPDGene project was supported by NHLBI grants U01 HL089897 and U01 HL089856 and by NIH contract 75N92023D00011. 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. The ECLIPSE study (NCT00292552; GSK code SCO104960) was funded by GlaxoSmithKline.
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The current study was approved by the Brigham and Women's Hospital Institutional Review Board.
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Footnotes
↵† = Jointly supervised and co-senior authors
This article has an online data supplement.
Data Availability
All data are available through the database of Genotypes and Phenotypes (dbGaP)
