Periodic Reporting for period 1 - PredictCOPD (Understanding the host-environmental interactions across the lifespan determining lung function trajectories and COPD)
Reporting period: 2022-12-01 to 2025-05-31
Chronic Obstructive Pulmonary Disease (COPD) has been traditionally understood as a self-inflicted disease caused by tobacco smoking occurring in old individuals. Over the past few years, however, our group and others have proposed that the pathogenesis of COPD goes beyond smoking, and that there is a range of lung function trajectories through life (trajectome); some of them have roots in early life and can lead to COPD, cardiovascular and metabolic morbidity as well as premature death, while others are associated with healthy ageing. Here I propose that, detrimental gene (G) and environment (E) interactions occurring early in life (T) constitute a ‘first injury hit’ that alters the normal lung developmental program and modify the pace of normal lung aging by reducing the resilience of the lungs to future GxExT interactions. Accordingly, lifelong GxExT interactions determine the individual trajectome and, eventually, the occurrence of COPD and associated multimorbidity. PredictCOPD aims to identify the interactions and mechanisms that determine which individuals will develop COPD and multimorbidty at some point of their life.
The specific aims are: 1) to identify the lifelong environmental and host risk factors associated with the trajectome, COPD and multimorbidity, 2) to use a liquid biopsy method to identify biological factors driving the trajectome, COPD and multimorbidity; 3) to identify clinically relevant preventive and/or early therapeutic targets integrating the results from aims 1 and 2 with novel analytical approaches and 4) to validate findings both in vitro and in other available cohorts.
The project will leverage from several available population and COPD patient studies with available clinical data and biological samples. The results of PredictCOPD have the potential to: 1) promote healthy ageing by preventing and eventually eradicate COPD and associated multimorbidity; and, 2) change COPD treatment from palliative to causal.
The specific aims are: 1) to identify the lifelong environmental and host risk factors associated with the trajectome, COPD and multimorbidity, 2) to use a liquid biopsy method to identify biological factors driving the trajectome, COPD and multimorbidity; 3) to identify clinically relevant preventive and/or early therapeutic targets integrating the results from aims 1 and 2 with novel analytical approaches and 4) to validate findings both in vitro and in other available cohorts.
The project will leverage from several available population and COPD patient studies with available clinical data and biological samples. The results of PredictCOPD have the potential to: 1) promote healthy ageing by preventing and eventually eradicate COPD and associated multimorbidity; and, 2) change COPD treatment from palliative to causal.
During this first period of the grant, the main achivements have been summarized as part of the following publications:
1. Olvera N, Sanchez-Valle J, Nunez-Carpintero I, Rojas-Quintero J, Noell G, Casas-Recasens S, Faiz A, Hansbro P, Guirao A, Lepore R, Cirillo D, Agusti A, Polverino F, Valencia A, Faner R. Lung Tissue Multilayer Network Analysis Uncovers the Molecular Heterogeneity of Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2024; 210: 1219-1229.
2. Casas-Recasens S, Cassim R, Mendoza N, Agusti A, Lodge C, Li S, Bui D, Martino D, Dharmage SC, Faner R. Epigenome-Wide Association Studies of Chronic Obstructive Pulmonary Disease and Lung Function: A Systematic Review. Am J Respir Crit Care Med 2024; 210: 766-778.
3. 5. Olvera N, Casas S, Vonk JM, Garcia T, Boezen HM, van den Berge M, Agusti A, Faner R. Circulating Biomarkers in Young Individuals with Low Peak FEV(1). Am J Respir Crit Care Med 2023; 207: 354-358.
4. Olvera N, Agusti A, Vonk JM, Wang G, Hallberg J, Boezen HM, van den Berge M, Melen E, Faner R. Heterogeneity of reduced FEV(1) in early adulthood: A looking forward, looking backwards analysis. Respirology 2025.
5. Hernandez-Pacheco N, Kilanowski A, Kumar A, Curtin JA, Olvera N, Kress S, Bertels X, Lahousse L, Bhatta L, Granell R, Mari S, Bilbao JR, Sun Y, Tingskov Pedersen CE, Karramass T, Thiering E, Dardani C, Kebede Merid S, Wang G, Hallberg J, Koch S, Garcia-Aymerich J, Esplugues A, Torrent M, Ibarluzea J, Lowe L, Simpson A, Gehring U, Vermeulen RCH, Roberts G, Bergstrom A, Vonk JM, Felix JF, Duijts L, Bonnelykke K, Timpson N, Brusselle G, Brumpton BM, Langhammer A, Turner S, Holloway JW, Arshad SH, Ullah A, Custovic A, Cullinan P, Murray CS, van den Berge M, Kull I, Schikowski T, Wedzicha JA, Koppelman G, Faner R*, Agusti A*, Standl M*, Melen E*, on behalf of the CADSET Clinical Research Collaboration of the European Respiratory Society. Exploring the genetics of airflow limitation in lung function across the lifespan - a polygenic risk score study. EClinicalMedicine 2024; 75: 102731.
Review article:
1. Agusti A, Melen E, DeMeo DL, Breyer-Kohansal R, Faner R. Pathogenesis of chronic obstructive pulmonary disease: understanding the contributions of gene-environment interactions across the lifespan. Lancet Respir Med 2022; 10: 512-524.
1. Olvera N, Sanchez-Valle J, Nunez-Carpintero I, Rojas-Quintero J, Noell G, Casas-Recasens S, Faiz A, Hansbro P, Guirao A, Lepore R, Cirillo D, Agusti A, Polverino F, Valencia A, Faner R. Lung Tissue Multilayer Network Analysis Uncovers the Molecular Heterogeneity of Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2024; 210: 1219-1229.
2. Casas-Recasens S, Cassim R, Mendoza N, Agusti A, Lodge C, Li S, Bui D, Martino D, Dharmage SC, Faner R. Epigenome-Wide Association Studies of Chronic Obstructive Pulmonary Disease and Lung Function: A Systematic Review. Am J Respir Crit Care Med 2024; 210: 766-778.
3. 5. Olvera N, Casas S, Vonk JM, Garcia T, Boezen HM, van den Berge M, Agusti A, Faner R. Circulating Biomarkers in Young Individuals with Low Peak FEV(1). Am J Respir Crit Care Med 2023; 207: 354-358.
4. Olvera N, Agusti A, Vonk JM, Wang G, Hallberg J, Boezen HM, van den Berge M, Melen E, Faner R. Heterogeneity of reduced FEV(1) in early adulthood: A looking forward, looking backwards analysis. Respirology 2025.
5. Hernandez-Pacheco N, Kilanowski A, Kumar A, Curtin JA, Olvera N, Kress S, Bertels X, Lahousse L, Bhatta L, Granell R, Mari S, Bilbao JR, Sun Y, Tingskov Pedersen CE, Karramass T, Thiering E, Dardani C, Kebede Merid S, Wang G, Hallberg J, Koch S, Garcia-Aymerich J, Esplugues A, Torrent M, Ibarluzea J, Lowe L, Simpson A, Gehring U, Vermeulen RCH, Roberts G, Bergstrom A, Vonk JM, Felix JF, Duijts L, Bonnelykke K, Timpson N, Brusselle G, Brumpton BM, Langhammer A, Turner S, Holloway JW, Arshad SH, Ullah A, Custovic A, Cullinan P, Murray CS, van den Berge M, Kull I, Schikowski T, Wedzicha JA, Koppelman G, Faner R*, Agusti A*, Standl M*, Melen E*, on behalf of the CADSET Clinical Research Collaboration of the European Respiratory Society. Exploring the genetics of airflow limitation in lung function across the lifespan - a polygenic risk score study. EClinicalMedicine 2024; 75: 102731.
Review article:
1. Agusti A, Melen E, DeMeo DL, Breyer-Kohansal R, Faner R. Pathogenesis of chronic obstructive pulmonary disease: understanding the contributions of gene-environment interactions across the lifespan. Lancet Respir Med 2022; 10: 512-524.
For the first time we postulated that COPD can instead be understood as the potential end result of the accumulation of gene-environment interactions encountered by an individual over the life course. Integration of a time axis in pathogenic models of COPD is necessary because the biological responses to and clinical consequences of different exposures might vary according to both the age of an individual at which a given gene-environment interaction occurs and the cumulative history of previous gene-environment interactions, to what we refer as the GETomics approach. In the context of this approach, we argue that COPD should be viewed not as a single disease, but as a clinical syndrome characterised by a recognisable pattern of chronic symptoms and structural or functional impairments due to gene-environment interactions across the lifespan that influence normal lung development and ageing. In this setting, in the first two years of this grant, we have moved beyond the state of the art on the following aspects:
• We have shown, that a novel multilayer network analysis is able to identify clinically relevant COPD patient communities, beyond the use of single omic layers. We identified that patients with similarly low FEV1 and emphysema can have molecularly distinct small airways and immune response patterns, indicating that different endotypes can lead to similar clinical presentation. This approach can now be used to different analysis scenarios.
• We have shown that the individuals with low peak lung function present in plasma alterations of the well reported COPD biomarkers such as CC16, sRAGE and CCL19.
• We have shown that a low lung function peak in early adulthood is most often due to impaired FEV1 but not obstruction (PRISm), and results in a significant burden of respiratory symptoms. Only those individuals with airflow limitation, and low or normal FEV1, but not PRISm, associate with a doctor diagnosis of asthma, and FEV1 decline was statistically different in PRISm indicating a need for differentiated clinical approaches. Importantly, these spirometric abnormalities can be already identified in childhood and adolescence.
• Our research in different cohorts across the lifespan provide evidence that a higher genetic risk for COPD is linked to lower lung function from childhood onwards.
• We provided evidence of the lack of methylation genome wide studies across the lifespan and the need of better reporting practices in order to perform proper meta-analysis of the results.
• We have shown, that a novel multilayer network analysis is able to identify clinically relevant COPD patient communities, beyond the use of single omic layers. We identified that patients with similarly low FEV1 and emphysema can have molecularly distinct small airways and immune response patterns, indicating that different endotypes can lead to similar clinical presentation. This approach can now be used to different analysis scenarios.
• We have shown that the individuals with low peak lung function present in plasma alterations of the well reported COPD biomarkers such as CC16, sRAGE and CCL19.
• We have shown that a low lung function peak in early adulthood is most often due to impaired FEV1 but not obstruction (PRISm), and results in a significant burden of respiratory symptoms. Only those individuals with airflow limitation, and low or normal FEV1, but not PRISm, associate with a doctor diagnosis of asthma, and FEV1 decline was statistically different in PRISm indicating a need for differentiated clinical approaches. Importantly, these spirometric abnormalities can be already identified in childhood and adolescence.
• Our research in different cohorts across the lifespan provide evidence that a higher genetic risk for COPD is linked to lower lung function from childhood onwards.
• We provided evidence of the lack of methylation genome wide studies across the lifespan and the need of better reporting practices in order to perform proper meta-analysis of the results.