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

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 (FEV1/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.