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Plasma angiopoietin-2 as a potential causal marker in sepsis-associated ARDS development: evidence from Mendelian randomization and mediation analysis

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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.

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Acknowledgements

The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the following institutes: National Cancer Institute, National Human Genome Research Institute, National Heart Lung and Blood Institute, National Institue on Drug Abuse, National Institute of Mental Health, and National Institute of Neurological Diseases and Stroke. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 03/31/2018. Further, we acknowledge the patients and families of MESSI cohort who agreed to participate in this research study, and the nurses, physicians, and staff of the Founders 9 Medical Intensive Care Unit at the Hospital of the University of Pennsylvania.

Funding

This work was funded by NIH 137006 (NJM), NIH HL122424 (NJM), NIH HL125723 (JPR), NIH HL110969 and HL140026 (CSC), HL051856 (MAM), HL115354 (JDC), HL101779 (MMW), HL060710 and HL134356 (DCC), the American Thoracic Society Foundation (NJM), and the University of Pennsylvania Research Foundation (NJM). Drs. Christie, Meyer, Calfee, and Matthay also report funding from GlaxoSmithKline. In addition, Dr. Shashaty reports funding from NIH DK097307 and Dr. Cantu from NIH HL116656 and the R.W. Johnson Foundation.

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Authors and Affiliations

  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

    John P. Reilly, Tiffanie K. Jones, Brian J. Anderson, Michael G. S. Shashaty, Thomas G. Dunn, Erik D. Johansson, Thomas R. Riley, Brian Lim, Caroline A. G. Ittner, Jason D. Christie & Nuala J. Meyer

  2. Department of Molecular Cardiology, Cleveland Clinic Lerner Research Institute, Cleveland, USA

    Fan Wang

  3. Pulmonary, Critical Care, Allergy, and Immunologic Medicine, Wake Forest School of Medicine, Winston-Salem, USA

    Jessica A. Palakshappa

  4. Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California San Francisco, San Francisco, USA

    Jason Abbott & Michael A. Matthay

  5. Divison of Cardiothoracic Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA

    Edward Cantu

  6. Harvard University T.H. Chan School of Public Health, Boston, USA

    Xihong Lin & David C. Christiani

  7. Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, USA

    Carmen Mikacenic & Mark M. Wurfel

  8. Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, USA

    David C. Christiani

  9. Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, USA

    Carolyn S. Calfee

  10. Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, USA

    Jason D. Christie & Rui Feng

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  1. John P. Reilly
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Contributions

Dr. Meyer had access to all data and takes responsibility for the integrity of the work. JPR, JDC, RF, and NJM conceived of and designed the study. JPR, JDC, CSC, MAM, RF, DCC, MMW, and NJM obtained funding. JPR, FW, TKJ, JAP, BJA, MGS, TGD, EDJ, TRR, BL, JA, CAI, and NJM acquired data. JPR, FW, JAP, BJA, MGS, EC, XL, IB, CSC, MAM, JDC, RF, XL, IB, and NJM analyzed and interpreted the data. JPR and NJM drafted the manuscript. All authors made significant contributions to the final manuscript and approve its submission.

Corresponding author

Correspondence to Nuala J. Meyer.

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Reilly, J.P., Wang, F., Jones, T.K. et al. Plasma angiopoietin-2 as a potential causal marker in sepsis-associated ARDS development: evidence from Mendelian randomization and mediation analysis. Intensive Care Med 44, 1849–1858 (2018). https://doi.org/10.1007/s00134-018-5328-0

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