Clinical Features of Genetic Resilience in Chronic Obstructive Pulmonary Disease

Introduction In the personalized risk quantification of chronic obstructive pulmonary disease (COPD), genome-wide association studies and polygenic risk scores (PRS) complement traditional risk factors, such as age and cigarette smoking. However, despite being at considerable levels of risk, some individuals do not develop COPD. Research on COPD resilience remains largely unexplored. Methods We applied the previously published COPD PRS to whole genome sequencing data from non-Hispanic white and African American individuals in the COPDGene study. We defined genetic resilience as individuals unaffected by COPD with a polygenic risk score above the 90th percentile. We defined risk-matched case individuals as those with COPD (i.e., FEV1/FVC < 0.70) and a PRS above the 90th percentile. We defined low risk individuals without COPD (i.e., FEV1/FVC > 0.70) as a polygenic risk score below the 10th percentile. We compared genetically resilient individuals to risk-matched individuals with COPD and low risk individuals by demographics, lung function, respiratory symptoms, co-morbidities, and chest CT scan measurements. We also performed survival analyses, differential expression analysis, and matching for sensitivity analyses. Results We identified 211 resilient individuals without COPD, 605 genetic risk-matched individuals with COPD, and 527 low-risk individuals without COPD. Resilient individuals had higher FEV1 % predicted and lower percent emphysema. In contrast, resilient individuals had higher airway wall thickness compared to low-risk unaffected individuals. While there was no difference in survival between low-risk and resilient individuals, resilient individuals had higher survival compared to risk matched cases. We also identified two genes that were differentially expressed between low-risk unaffected individuals and resilient individuals. Conclusion Genetically resilient individuals had a reduced burden of COPD disease-related measures compared to risk-matched cases but had subtly increased measures compared to low-risk unaffected individuals. Further genetic studies will be needed to illuminate the underlying pathobiology of our observations. ### Competing Interest Statement AJG received consulting fees from TDA Research. MM received grant support from Bayer. EKS received grant support from GlaxoSmithKline and Bayer. CPH reports grant support from Boehringer-Ingelheim, Novartis, Bayer and Vertex. MHC has received grant support from GlaxoSmithKline and Bayer, consulting fees from Genentech and AstraZeneca, and speaking fees from Illumina. None of the funding was allocated toward this specific work. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The IRB of Brigham and Women's Hospital gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors