Λεπτομέρειες βιβλιογραφικής εγγραφής
| Τίτλος: |
Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes in the COPDGene and ECLIPSE cohort studies |
| Συγγραφείς: |
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 |
| Στοιχεία εκδότη: |
ELSEVIER |
| Έτος έκδοσης: |
2024 |
| Συλλογή: |
The University of Melbourne: Digital Repository |
| Περιγραφή: |
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. |
| Τύπος εγγράφου: |
article in journal/newspaper |
| Γλώσσα: |
English |
| ISSN: |
2352-3964 |
| Relation: |
https://hdl.handle.net/11343/359143 |
| Διαθεσιμότητα: |
https://hdl.handle.net/11343/359143 |
| Rights: |
https://creativecommons.org/licenses/by-nc-nd/4.0 ; CC BY-NC-ND |
| Αριθμός Καταχώρησης: |
edsbas.EC73EA9F |
| Βάση Δεδομένων: |
BASE |