Across five studies, we examined genetic determinants of lung function decline, functional capacity, muscle strength, disease burden, COPD endotypes, and outcomes after SARS-CoV-2 infection. We also evaluated a genomic-based prediction model for functional impairment. To achieve these objectives, we used: i) blood-derived genomic data from 24,749 Lifelines participants; ii) saliva-derived data from 639 individuals in the Lab3R-ESSUA cohort (363 COPD, 276 controls); iii) bronchial biopsy gene expression from 56 COPD patients in the GLUCOLD cohort. Findings were validated in five external cohorts.
Genome-wide association studies identified novel variants linked to lung function decline (Chapter 2) and extrapulmonary traits (Chapter 3), underscoring the role of genetics in COPD phenotypes. We also described a new COPD endotype with accelerated decline, high bronchial T-cell infiltration, and poor corticosteroid response (Chapter 4). Furthermore, we found no genetic predisposition for worse COVID-19 outcomes in COPD, suggesting that increased risk is mainly driven by lung damage and systemic inflammation (Chapter 5). Finally, we developed a predictive model using only genomic data to identify COPD patients at risk of functional impairment, highlighting the potential of polygenic risk scores for patient stratification.
These results provide novel insights into COPD biology and support the integration of genetic data into personalised management strategies.
