Evidence map›Paper›PMID 36194491›Full record

SynthesisThe Journal of clinical investigation2022

Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis.

George Hindy, Daniel J Tyrrell, Alexi Vasbinder, Changli Wei, Feriel Presswalla, Hui Wang, Pennelope Blakely, Ayse Bilge Ozel, Sarah Graham, Grace H Holton and 34 more

Open access · goldFull text readMeta-Analysis
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
57citing papers in PubMed, 2 pooled it
5.2field-weighted citation impact, top 3% 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

57 citing papers in PubMed, 2 syntheses or guidelines pooled it, 64 citations in OpenAlex.

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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

44 authors at 13 institutions in 4 countries.

George HindyDepartment of Clinical Sciences, Lund University, Malmö, Sweden.
Daniel J TyrrellDivision of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Alexi VasbinderDivision of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Changli WeiDepartment of Medicine, Rush University Medical Center, Chicago, Illinois, USA.
Feriel PresswallaDivision of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Hui WangDivision of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Pennelope BlakelyDivision of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Ayse Bilge OzelDepartment of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
Sarah GrahamDepartment of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
Grace H HoltonDivision of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Joseph DowsettDepartment of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark.
Akl C FahedProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Kingsley-Michael AmadiDivision of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Grace K ErneDivision of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Annika TekmullaDivision of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Anis IsmailDivision of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Christopher LauniusDivision of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Nona SotoodehniaCardiovascular Health Research Unit, Division of Cardiology, University of Washington, Seattle, Washington, USA.
James S PankowDivision of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA.
Lise Wegner ThørnerDepartment of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark.
Christian ErikstrupDepartment of Immunology, Aarhus University Hospital, Aarhus, Denmark.
Ole Birger PedersenDepartment of Immunology, Zealand University Hospital, Køge, Denmark.
Karina BanasikNovo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Søren BrunakNovo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Henrik UllumState Serum Institute, Copenhagen, Denmark.
Jesper Eugen-OlsenDepartment of Clinical Research, Copenhagen University Hospital Amager and Hvidovre, Hvidovre, Denmark.
Sisse Rye OstrowskiDepartment of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark.
DBDS Consortium
Mary E HaasRegeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA.
Jonas B NielsenRegeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA.
Luca A LottaRegeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA.
Regeneron Genetics Center
Gunnar EngströmDepartment of Clinical Sciences, Lund University, Malmö, Sweden.
Olle MelanderDepartment of Clinical Sciences, Lund University, Malmö, Sweden.
Marju Orho-MelanderDepartment of Clinical Sciences, Lund University, Malmö, Sweden.
Lili ZhaoDepartment of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
Venkatesh L MurthyDivision of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
David J PinskyDivision of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Cristen J WillerDivision of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Susan R HeckbertDepartment of Epidemiology, University of Washington, Seattle, Washington, USA.
Jochen ReiserDepartment of Medicine, Rush University Medical Center, Chicago, Illinois, USA.
Daniel R GoldsteinDivision of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Karl C DeschDivision of Neonatal-Perinatal Medicine, Department of Pediatrics, Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, USA.
Salim S HayekDivision of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
University of Michigan · USCopenhagen University Hospital · DKLund University · SERegeneron (United States) · USBroad Institute · USRush University Medical Center · USUniversity of Copenhagen · DKUniversity of Washington · USAarhus University Hospital · DKHvidovre Hospital · DKStatens Serum Institut · DKUniversity of Minnesota · USZealand University Hospital Køge · DK

Funding

UCLA Clinical Translational Science InstituteUL1TR001881 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARLEEN F. BROWN, ARASH NAEIM · 2016 to 2026
$118.1M
Institute for Clinical and Translational ResearchUL1TR001079 · NCATS · JOHNS HOPKINS UNIVERSITY · PI FORD, DANIEL ERNEST · 2013 to 2017
$60.1M
Michigan Institute for Clinical and Health Research (MICHR)UL1TR002240 · NCATS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI LUMENG, JULIE C, MASHOUR, GEORGE ALEXANDER · 2017 to 2022
$54.9M
Transgenic & Knock-out MouseP30DK063491 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MILES Frome WILKINSON · 2003 to 2026
$40.4M
Wake Forest Clinical and Translational Science AwardUL1TR001420 · NCATS · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI ARD, JAMY D, FOLEY, KRISTIE L · 2015 to 2023
$32.3M
Clinical and Translational Science AwardUL1TR000040 · NCATS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI GINSBERG, HENRY N · 2012 to 2015
$26.2M
Task Area A Core Study Operations.Task Area A shall encompass annual follow-up of cohort members, clinical endpoints ascertainment, study coordination activities, maintenance of the database and biosp75N92020D00001 · NHLBI · UNIVERSITY OF WASHINGTON · PI MCCLELLAND, ROBYN LEAGH · 2020 to 2025
$17.2M
TRAINING IN MOLECULAR AND CELLULAR CARDIOLOGYT32HL007853 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI David J. Pinsky · 1996 to 2026
$11.6M
SNP HEALTH ASSOCIATION RESOURCE (SHARE)N02HL64278 · NHLBI · PI CHIN, SIANG · 2007 to 2007
$9.2M
Using genetics to discover mechanisms of myocardial infarctionR01HL109946 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI YUQING Eugene CHEN, Ida Liisa Surakka · 2011 to 2026
$8.9M
Mechanisms to augment primary immunity in agingR01AG028082 · NIA · YALE UNIVERSITY · PI DENG, JANE C · 2007 to 2023
$6.9M
Task Area A shall encompass annual follow-up of cohort members, clinical events investigations, study operations, and data analysis and manuscript writing. If implemented, Task A.1 will provide fundin75N92020D00005 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI WATSON, KAROL E · 2020 to 2025
$5.1M
Medical Research Council MC_PC_17228NCATS NIH HHS UL1 TR000040NCATS NIH HHS UL1 TR001079NCATS NIH HHS UL1 TR001420NCATS NIH HHS UL1 TR001881NCATS NIH HHS UL1 TR002240NHLBI NIH HHS 75N92020D00001NHLBI NIH HHS 75N92020D00002NHLBI NIH HHS 75N92020D00003NHLBI NIH HHS 75N92020D00004NHLBI NIH HHS 75N92020D00005NHLBI NIH HHS 75N92020D00006NHLBI NIH HHS 75N92020D00007NHLBI NIH HHS HHSN268201500003CNHLBI NIH HHS HHSN268201500003INHLBI NIH HHS K08 HL161448NHLBI NIH HHS N01 HC095159NHLBI NIH HHS N01 HC095160NHLBI NIH HHS N01 HC095161NHLBI NIH HHS N01 HC095162NHLBI NIH HHS N01 HC095163NHLBI NIH HHS N01 HC095164NHLBI NIH HHS N01 HC095165NHLBI NIH HHS N01 HC095166NHLBI NIH HHS N01 HC095167NHLBI NIH HHS N01 HC095168NHLBI NIH HHS N01HC95169NHLBI NIH HHS N02 HL064278NHLBI NIH HHS N02 HL64278NHLBI NIH HHS R01 HL109946NHLBI NIH HHS R01 HL141399NHLBI NIH HHS R01 HL153384NHLBI NIH HHS R35 HL155169NHLBI NIH HHS T32 HL007853NIAID NIH HHS R01 AI138347NIA NIH HHS K99 AG068309NIA NIH HHS R00 AG068309NIA NIH HHS R01 AG028082NIA NIH HHS T32 AG062403NIDDK NIH HHS P30 DK063491NIDDK NIH HHS R01 DK128012
6 · The paper itself

Abstract

People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR's pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin-9 (Pcsk9) transfection in mice overexpressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating suPARTg monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.

Indexed as

AtherosclerosisReceptors, Urokinase Plasminogen ActivatorAnimalsBiomarkersGenome-Wide Association StudyHumansMiceMonocytesProprotein Convertase 9Risk FactorsUrokinase-Type Plasminogen ActivatorBiomarkersPCSK9 protein, humanProprotein Convertase 9Receptors, Urokinase Plasminogen ActivatorUrokinase-Type Plasminogen ActivatorAtherosclerosisCardiologyInnate immunity

Identifiers

PMID36194491
PMCPMC9754000
OpenAlexW4301178755

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Registered trials

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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.