John P Reilly1, Fan Wang2, Tiffanie K Jones1, Jessica A Palakshappa3, Brian J Anderson1, Michael G S Shashaty1, Thomas G Dunn1, Erik D Johansson1, Thomas R Riley1, Brian Lim1, Jason Abbott4, Caroline A G Ittner1, Edward Cantu5, Xihong Lin6, Carmen Mikacenic7, Mark M Wurfel7, David C Christiani6,8, Carolyn S Calfee9, Michael A Matthay4, Jason D Christie1,10, Rui Feng10, Nuala J Meyer11. 1. Pulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania Perelman School of Medicine, 3600 Spruce Street 5039 Gates Building, Philadelphia, PA, 19104, USA. 2. Department of Molecular Cardiology, Cleveland Clinic Lerner Research Institute, Cleveland, USA. 3. Pulmonary, Critical Care, Allergy, and Immunologic Medicine, Wake Forest School of Medicine, Winston-Salem, USA. 4. Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California San Francisco, San Francisco, USA. 5. Divison of Cardiothoracic Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA. 6. Harvard University T.H. Chan School of Public Health, Boston, USA. 7. Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, USA. 8. Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, USA. 9. Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, USA. 10. Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, USA. 11. Pulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania Perelman School of Medicine, 3600 Spruce Street 5039 Gates Building, Philadelphia, PA, 19104, USA. nuala.meyer@uphs.upenn.edu.
Abstract
PURPOSE: A causal biomarker for acute respiratory distress syndrome (ARDS) could fuel precision therapy options. Plasma angiopoietin-2 (ANG2), a vascular permeability marker, is a strong candidate on the basis of experimental and observational evidence. We used genetic causal inference methods-Mendelian randomization and mediation-to infer potential effects of plasma ANG2. METHODS: We genotyped 703 septic subjects, measured ICU admission plasma ANG2, and performed a quantitative trait loci (QTL) analysis to determine variants in the ANGPT2 gene associated with plasma ANG2 (p < 0.005). We then used linear regression and post-estimation analysis to genetically predict plasma ANG2 and tested genetically predicted ANG2 for ARDS association using logistic regression. We estimated the proportion of the genetic effect explained by plasma ANG2 using mediation analysis. RESULTS: Plasma ANG2 was strongly associated with ARDS (OR 1.59 (95% CI 1.35, 1.88) per log). Five ANGPT2 variants were associated with ANG2 in European ancestry subjects (n = 404). Rs2442608C, the most extreme cis QTL (coefficient 0.22, 95% CI 0.09-0.36, p = 0.001), was associated with higher ARDS risk: adjusted OR 1.38 (95% CI 1.01, 1.87), p = 0.042. No significant QTL were identified in African ancestry subjects. Genetically predicted plasma ANG2 was associated with ARDS risk: adjusted OR 2.25 (95% CI 1.06-4.78), p = 0.035. Plasma ANG2 mediated 34% of the rs2442608C-related ARDS risk. CONCLUSIONS: In septic European ancestry subjects, the strongest ANG2-determining ANGPT2 genetic variant is associated with higher ARDS risk. Plasma ANG2 may be a causal factor in ARDS development. Strategies to reduce plasma ANG2 warrant testing to prevent or treat sepsis-associated ARDS.
PURPOSE: A causal biomarker for acute respiratory distress syndrome (ARDS) could fuel precision therapy options. Plasma angiopoietin-2 (ANG2), a vascular permeability marker, is a strong candidate on the basis of experimental and observational evidence. We used genetic causal inference methods-Mendelian randomization and mediation-to infer potential effects of plasma ANG2. METHODS: We genotyped 703 septic subjects, measured ICU admission plasma ANG2, and performed a quantitative trait loci (QTL) analysis to determine variants in the ANGPT2 gene associated with plasma ANG2 (p < 0.005). We then used linear regression and post-estimation analysis to genetically predict plasma ANG2 and tested genetically predicted ANG2 for ARDS association using logistic regression. We estimated the proportion of the genetic effect explained by plasma ANG2 using mediation analysis. RESULTS: Plasma ANG2 was strongly associated with ARDS (OR 1.59 (95% CI 1.35, 1.88) per log). Five ANGPT2 variants were associated with ANG2 in European ancestry subjects (n = 404). Rs2442608C, the most extreme cis QTL (coefficient 0.22, 95% CI 0.09-0.36, p = 0.001), was associated with higher ARDS risk: adjusted OR 1.38 (95% CI 1.01, 1.87), p = 0.042. No significant QTL were identified in African ancestry subjects. Genetically predicted plasma ANG2 was associated with ARDS risk: adjusted OR 2.25 (95% CI 1.06-4.78), p = 0.035. Plasma ANG2 mediated 34% of the rs2442608C-related ARDS risk. CONCLUSIONS: In septic European ancestry subjects, the strongest ANG2-determining ANGPT2 genetic variant is associated with higher ARDS risk. Plasma ANG2 may be a causal factor in ARDS development. Strategies to reduce plasma ANG2 warrant testing to prevent or treat sepsis-associated ARDS.
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