Evidence map›Paper›PMID 30343317›Full record

Observational studyIntensive care medicine2018

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

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 and 12 more

Open access · greenAbstract readObservational Study
PubMed Full text at PMC Publisher
In one paragraph

Observational study in Intensive care medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers, 5 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
90citing papers in PubMed, 5 pooled it
9.4field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

90 citing papers in PubMed, 5 syntheses or guidelines pooled it, 126 citations in OpenAlex.

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30 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

22 authors at 6 institutions in 1 country.

John P ReillyPulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania Perelman School of Medicine, 3600 Spruce Street 5039 Gates Building, Philadelphia, PA, 19104, USA.
Fan WangDepartment of Molecular Cardiology, Cleveland Clinic Lerner Research Institute, Cleveland, USA.
Tiffanie K JonesPulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania Perelman School of Medicine, 3600 Spruce Street 5039 Gates Building, Philadelphia, PA, 19104, USA.
Jessica A PalakshappaPulmonary, Critical Care, Allergy, and Immunologic Medicine, Wake Forest School of Medicine, Winston-Salem, USA.
Brian J AndersonPulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania Perelman School of Medicine, 3600 Spruce Street 5039 Gates Building, Philadelphia, PA, 19104, USA.
Michael G S ShashatyPulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania Perelman School of Medicine, 3600 Spruce Street 5039 Gates Building, Philadelphia, PA, 19104, USA.
Thomas G DunnPulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania Perelman School of Medicine, 3600 Spruce Street 5039 Gates Building, Philadelphia, PA, 19104, USA.
Erik D JohanssonPulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania Perelman School of Medicine, 3600 Spruce Street 5039 Gates Building, Philadelphia, PA, 19104, USA.
Thomas R RileyPulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania Perelman School of Medicine, 3600 Spruce Street 5039 Gates Building, Philadelphia, PA, 19104, USA.
Brian LimPulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania Perelman School of Medicine, 3600 Spruce Street 5039 Gates Building, Philadelphia, PA, 19104, USA.
Jason AbbottDepartments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California San Francisco, San Francisco, USA.
Caroline A G IttnerPulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania Perelman School of Medicine, 3600 Spruce Street 5039 Gates Building, Philadelphia, PA, 19104, USA.
Edward CantuDivison of Cardiothoracic Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA.
Xihong LinHarvard University T.H. Chan School of Public Health, Boston, USA.
Carmen MikacenicDivision of Pulmonary and Critical Care Medicine, University of Washington, Seattle, USA.
Mark M WurfelDivision of Pulmonary and Critical Care Medicine, University of Washington, Seattle, USA.
David C ChristianiHarvard University T.H. Chan School of Public Health, Boston, USA.
Carolyn S CalfeeDivision of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, USA.
Michael A MatthayDepartments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California San Francisco, San Francisco, USA.
Jason D ChristiePulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania Perelman School of Medicine, 3600 Spruce Street 5039 Gates Building, Philadelphia, PA, 19104, USA.
Rui FengDepartment of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, USA.
Nuala J MeyerPulmonary, 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.ORCID http://orcid.org/0000-0003-4597-5584
University of Pennsylvania · USUniversity of California, San Francisco · USHarvard University · USUniversity of Washington · USCleveland Clinic Lerner College of Medicine · USWake Forest University · US

Funding

MOLECULAR EPIDEMIOLOGY OF ARDSR01HL060710 · NHLBI · HARVARD UNIVERSITY (SCH OF PUBLIC HLTH) · PI CHRISTIANI, DAVID C · 2000 to 2015
$8.4M
Precision Medicine in the Acute Respiratory Distress SyndromeR35HL140026 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CALFEE, CAROLYN · 2018 to 2024
$6.8M
Genetic risks for ALI in ARDSnet and the iSPAAR ConsortiumRC2HL101779 · NHLBI · UNIVERSITY OF WASHINGTON · PI WURFEL, MARK M · 2009 to 2010
$4.7M
Resolution of Clinical Lung InjuryR37HL051856 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MATTHAY, MICHAEL A. · 2006 to 2015
$3.9M
Targeting Angiopoietin-2 in ARDSR01HL137006 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI MEYER, NUALA JENNINGS · 2017 to 2021
$2.5M
Cigarette Smoke Exposure and Acute Lung Injury After Severe Blunt TraumaR01HL110969 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CALFEE, CAROLYN · 2012 to 2016
$1.9M
EPITHELIAL BARRIER DYSFUNCTION AND MUCOSAL INFLAMMATION IN ASTHMAR01HL122424 · NHLBI · UNIVERSITY OF ROCHESTER · PI GEORAS, STEVE N · 2014 to 2017
$1.9M
RESOLUTION OF CLINICAL LUNG INJURYR01HL051856 · NHLBI · UNIVERSITY OF CALIFORNIA SAN FRANCISCO · PI MATTHAY, MICHAEL A. · 1996 to 2005
$1.7M
Mentored Patient Oriented Research in Lung TransplantationK24HL115354 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI CHRISTIE, JASON D · 2012 to 2021
$1.2M
Neurocognitive Impairment in Acute Respiratory Failure and Shock: Understanding the Role of Neuronal ExcitotoxicityK23HL140482 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI ANDERSON, BRIAN J. · 2018 to 2022
$959k
Lung Transplant donor: prediction, evaluation, and mechanismK23HL116656 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI CANTU, EDWARD · 2013 to 2017
$872k
The Role of ABO Glycosyltransferases in the Acute Respiratory Distress SyndromeK23HL125723 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI REILLY, JOHN PATRICK · 2015 to 2019
$840k
NHLBI NIH HHS 140026NHLBI NIH HHS HL051856NHLBI NIH HHS HL060710NHLBI NIH HHS HL101779NHLBI NIH HHS HL115354NHLBI NIH HHS HL122424NHLBI NIH HHS HL125723NHLBI NIH HHS HL134356NHLBI NIH HHS HL137006NHLBI NIH HHS K23 HL102254NHLBI NIH HHS K23 HL116656NHLBI NIH HHS K23 HL125723NHLBI NIH HHS K23 HL140482NHLBI NIH HHS K24 HL115354NHLBI NIH HHS R01 HL051856NHLBI NIH HHS R01 HL060710NHLBI NIH HHS R01 HL110969NHLBI NIH HHS R01 HL122424NHLBI NIH HHS R01 HL137006NHLBI NIH HHS R35 HL140026NHLBI NIH HHS R37 HL051856NHLBI NIH HHS R56 HL122474NHLBI NIH HHS R56 HL134356NHLBI NIH HHS RC2 HL101779NIDDK NIH HHS K23 DK097307
6 · The paper itself

Abstract

purposeA 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.

methodsWe 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.

resultsPlasma 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.

conclusionsIn 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.

Indexed as

AgedAngiopoietin-2BiomarkersCohort StudiesEthnicityFemaleHumansLogistic ModelsMaleMendelian Randomization AnalysisMiddle AgedRespiratory Distress SyndromeSepsisWhite PeopleAngiopoietin-2ANGPT2 protein, humanBiomarkersAngiopoietin-2Mediation analysisMendelian randomization analysisRespiratory distress syndrome, adult

Identifiers

PMID30343317
PMCPMC6697901
OpenAlexW2884162456

What OpenQuestion holds

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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.