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21.10.2018 | Original

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

verfasst von: John P. Reilly, Fan Wang, Tiffanie K. Jones, Jessica A. Palakshappa, Brian J. Anderson, Michael G. S. Shashaty, Thomas G. Dunn, Erik D. Johansson, Thomas R. Riley, Brian Lim, Jason Abbott, Caroline A. G. Ittner, Edward Cantu, Xihong Lin, Carmen Mikacenic, Mark M. Wurfel, David C. Christiani, Carolyn S. Calfee, Michael A. Matthay, Jason D. Christie, Rui Feng, Nuala J. Meyer

Erschienen in: Intensive Care Medicine | Ausgabe 11/2018

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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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Titel: Plasma angiopoietin-2 as a potential causal marker in sepsis-associated ARDS development: evidence from Mendelian randomization and mediation analysis
verfasst von: John P. Reilly
Fan Wang
Tiffanie K. Jones
Jessica A. Palakshappa
Brian J. Anderson
Michael G. S. Shashaty
Thomas G. Dunn
Erik D. Johansson
Thomas R. Riley
Brian Lim
Jason Abbott
Caroline A. G. Ittner
Edward Cantu
Xihong Lin
Carmen Mikacenic
Mark M. Wurfel
David C. Christiani
Carolyn S. Calfee
Michael A. Matthay
Jason D. Christie
Rui Feng
Nuala J. Meyer
Publikationsdatum: 21.10.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Intensive Care Medicine / Ausgabe 11/2018
Print ISSN: 0342-4642
Elektronische ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-018-5328-0

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

Abstract

Purpose

Methods

Results

Conclusions

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Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

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Abstract

Purpose

Methods

Results

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