Genetic resilience to chronic obstructive pulmonary disease is a clinically distinct subtype in individuals with cigarette smoke exposure.

Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 101090633 Publication Model: Electronic Cited Medium: Internet ISSN: 1465-993X (Electronic) Linking ISSN: 14659921 NLM ISO Abbreviation: Respir Res Subsets: MEDLINE

Publication: 2001- : London : BioMed Central Ltd.
Original Publication: London : Current Science Ltd., c2000-

Pulmonary Disease, Chronic Obstructive*/genetics ; Pulmonary Disease, Chronic Obstructive*/diagnosis ; Pulmonary Disease, Chronic Obstructive*/physiopathology ; Pulmonary Disease, Chronic Obstructive*/epidemiology ; Cigarette Smoking*/genetics ; Cigarette Smoking*/adverse effects ; Cigarette Smoking*/epidemiology ; Genetic Predisposition to Disease*/epidemiology ; Genetic Predisposition to Disease*/genetics ; Smoking*/genetics; Humans ; Male ; Female ; Middle Aged ; Aged ; Longitudinal Studies ; Risk Factors

Competing Interests: Declarations. Ethics approval and consent to participate: Institutional review boards approved the study at all participating centers. The current study was approved by the Mass General Brigham institutional review board (IRB #2007P000554) and SUNY Upstate Medical University institutional review board (IRB #2247707). All participants provided written informed consent. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
Background: There is substantial unexplained variability in the development of disease. A genetic risk score for COPD identifies individuals at markedly elevated risk of COPD; however, many high-genetic risk individuals do not develop disease. We sought to define genetic resilience in COPD by identifying and characterizing individuals who are resistant to their elevated genetic susceptibility.
Methods: We defined resilience to genetic risk (genetic resilience) as absence of airflow obstruction (FEV 1 /FVC ≥ 0.70) in individuals with cigarette smoking exposure with a polygenic risk score for COPD at the 90th percentile or above. We defined clinical resilience according to previously published criteria, including a low symptom burden, limited radiographic disease, and normal lung-function decline despite similar smoking history. Using data from the Genetic Epidemiology of COPD (COPDGene) study, we compared genetically resilient individuals to clinically resilient individuals and genetic risk-matched individuals with COPD on clinical characteristics, radiographic findings, longitudinal outcomes, mortality, biomarkers, and social determinants of health.
Results: We found that, after adjustment for covariates, genetically resilient individuals (n = 144) had better lung function (β = 35.9% predicted, p < 0.001), fewer symptoms, and less radiographic disease compared to genetic risk-matched individuals with COPD (n = 362). Conversely, when compared to clinically resilient individuals (n = 420), genetically resilient individuals had slightly lower lung function and slightly worse radiographic measures of disease. Both clinically and genetically resilient individuals had higher survival compared to genetic-risk matched cases (hazard ratios = 0.34 and 0.41 with p < 0.001 and p = 0.002, respectively). While the majority of genetically resilient individuals remained resilient across the 5-year and 10-year follow-up visits, a higher proportion of clinically resilient individuals remained resilient across the follow-up period. Non-Hispanic white genetically resilient individuals had higher social vulnerability across multiple measures compared to both clinically resilient individuals and genetic risk-matched individuals with COPD.
Discussion: Genetic resilience to COPD represents a unique subtype of smokers that is distinct from clinical resilience and has important disease-related differences from genetic risk-matched individuals with COPD. Future studies are needed to identify the underlying biological contributors to the multiple types of resilience in COPD.
(© 2025. The Author(s).)

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Date Created: 20251029 Date Completed: 20251029 Latest Revision: 20251102

20251102

PMC12560536

10.1186/s12931-025-03380-w

41152839