55 research outputs found
Liver injury in non-alcoholic fatty liver disease is associated with urea cycle enzyme dysregulation
The main aim was to evaluate changes in urea cycle enzymes in NAFLD patients and in two preclinical animal models mimicking this entity. Seventeen liver specimens from NAFLD patients were included for immunohistochemistry and gene expression analyses. Three-hundred-and-eighty-two biopsy-proven NAFLD patients were genotyped for rs1047891, a functional variant located in carbamoyl phosphate synthetase-1 (CPS1) gene. Two preclinical models were employed to analyse CPS1 by immunohistochemistry, a choline deficient high-fat diet model (CDA-HFD) and a high fat diet LDLr knockout model (LDLr â/â). A significant downregulation in mRNA was observed in CPS1 and ornithine transcarbamylase (OTC1) in simple steatosis and NASH-fibrosis patients versus controls. Further, age, obesity (BMI > 30Â kg/m2), diabetes mellitus and ALT werefound to be risk factors whereas A-allele from CPS1 was a protective factor from liver fibrosis. CPS1 hepatic expression was diminished in parallel with the increase of fibrosis, and its levels reverted up to normality after changing diet in CDA-HFD mice. In conclusion, liver fibrosis and steatosis were associated with a reduction in both gene and protein expression patterns of mitochondrial urea cycle enzymes. A-allele from a variant on CPS1 may protect from fibrosis development. CPS1 expression is restored in a preclinical model when the main trigger of the liver damage disappears
Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality
AG has received support by NordForsk Nordic Trial Alliance (NTA) grant, by Academy of
Finland Fellow grant N. 323116 and the Academy of Finland for PREDICT consortium N.
340541.
The Richards research group is supported by the Canadian Institutes of Health Research
(CIHR) (365825 and 409511), the Lady Davis Institute of the Jewish General Hospital, the
Canadian Foundation for Innovation (CFI), the NIH Foundation, Cancer Research UK,
Genome Québec, the Public Health Agency of Canada, the McGill Interdisciplinary Initiative in
Infection and Immunity and the Fonds de Recherche Québec Santé (FRQS). TN is supported
by a research fellowship of the Japan Society for the Promotion of Science for Young
Scientists. GBL is supported by a CIHR scholarship and a joint FRQS and Québec Ministry of
Health and Social Services scholarship. JBR is supported by an FRQS Clinical Research
Scholarship. Support from Calcul Québec and Compute Canada is acknowledged. TwinsUK is
funded by the Welcome Trust, the Medical Research Council, the European Union, the
National Institute for Health Research-funded BioResource and the Clinical Research Facility
and Biomedical Research Centre based at Guyâs and St. Thomasâ NHS Foundation Trust in
partnership with Kingâs College London. The Biobanque QuĂ©bec COVID19 is funded by FRQS,
Genome Québec and the Public Health Agency of Canada, the McGill Interdisciplinary
Initiative in Infection and Immunity and the Fonds de Recherche Québec Santé. These funding
agencies had no role in the design, implementation or interpretation of this study.
The COVID19-Host(a)ge study received infrastructure support from the DFG Cluster of
Excellence 2167 âPrecision Medicine in Chronic Inflammation (PMI)â (DFG Grant: âEXC2167â).
The COVID19-Host(a)ge study was supported by the German Federal Ministry of Education
and Research (BMBF) within the framework of the Computational Life Sciences funding
concept (CompLS grant 031L0165). Genotyping in COVID19-Host(a)ge was supported by a
philantropic donation from Stein Erik Hagen.
The COVID GWAs, Premed COVID-19 study (COVID19-Host(a)ge_3) was supported by
"Grupo de Trabajo en Medicina Personalizada contra el COVID-19 de Andalucia"and also by
the Instituto de Salud Carlos III (CIBERehd and CIBERER). Funding comes from
COVID-19-GWAS, COVID-PREMED initiatives. Both of them are supported by "Consejeria de
Salud y Familias" of the Andalusian Government. DMM is currently funded by the the
Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018).
The Columbia University Biobank was supported by Columbia University and the National
Center for Advancing Translational Sciences, NIH, through Grant Number UL1TR001873. The content is solely the responsibility of the authors and does not necessarily represent the official
views of the NIH or Columbia University.
The SPGRX study was supported by the ConsejerĂa de EconomĂa, Conocimiento, Empresas y
Universidad #CV20-10150.
The GEN-COVID study was funded by: the MIUR grant âDipartimenti di Eccellenza 2018-2020â
to the Department of Medical Biotechnologies University of Siena, Italy; the âIntesa San Paolo
2020 charity fundâ dedicated to the project NB/2020/0119; and philanthropic donations to the
Department of Medical Biotechnologies, University of Siena for the COVID-19 host genetics
research project (D.L n.18 of March 17, 2020). Part of this research project is also funded by
Tuscany Region âBando Ricerca COVID-19 Toscanaâ grant to the Azienda Ospedaliero
Universitaria Senese (CUP I49C20000280002). Authors are grateful to: the CINECA
consortium for providing computational resources; the Network for Italian Genomes (NIG)
(http://www.nig.cineca.it) for its support; the COVID-19 Host Genetics Initiative
(https://www.covid19hg.org/); the Genetic Biobank of Siena, member of BBMRI-IT, Telethon
Network of Genetic Biobanks (project no. GTB18001), EuroBioBank, and RD-Connect, for
managing specimens.
Genetics against coronavirus (GENIUS), Humanitas University (COVID19-Host(a)ge_4) was
supported by Ricerca Corrente (Italian Ministry of Health), intramural funding (Fondazione
Humanitas per la Ricerca). The generous contribution of Banca Intesa San Paolo and of the
Dolce&Gabbana Fashion Firm is gratefully acknowledged.
Data acquisition and sample processing was supported by COVID-19 Biobank, Fondazione
IRCCS CĂ Granda Milano; LV group was supported by MyFirst Grant AIRC n.16888, Ricerca
Finalizzata Ministero della Salute RF-2016-02364358, Ricerca corrente Fondazione IRCCS
Caâ Granda Ospedale Maggiore Policlinico, the European Union (EU) Programme Horizon
2020 (under grant agreement No. 777377) for the project LITMUS- âLiver Investigation:
Testing Marker Utility in Steatohepatitisâ, Programme âPhotonicsâ under grant agreement
â101016726â for the project âREVEAL: Neuronal microscopy for cell behavioural examination
and manipulationâ, Fondazione Patrimonio Caâ Granda âLiver Bibleâ PR-0361. DP was
supported by Ricerca corrente Fondazione IRCCS Caâ Granda Ospedale Maggiore Policlinico,
CV PREVITAL âStrategie di prevenzione primaria nella popolazione Italianaâ Ministero della
Salute, and Associazione Italiana per la Prevenzione dellâEpatite Virale (COPEV).
Genetic modifiers for COVID-19 related illness (BeLCovid_1) was supported by the "Fonds
Erasme". The Host genetics and immune response in SARS-Cov-2 infection (BelCovid_2)
study was supported by grants from Fondation LĂ©on Fredericq and from Fonds de la
Recherche Scientifique (FNRS).
The INMUNGEN-CoV2 study was funded by the Consejo Superior de Investigaciones
CientĂficas.
KUL is supported by the German Research Foundation (LU 1944/3-1) SweCovid is funded by the SciLifeLab/KAW national COVID-19 research program project
grant to Michael Hultström (KAW 2020.0182) and the Swedish Research Council to Robert
Frithiof (2014-02569 and 2014-07606). HZ is supported by Jeansson Stiftelser, Magnus
Bergvalls Stiftelse.
The COMRI cohort is funded by Technical University of Munich, Munich, Germany.
Genotyping for the COMRI cohort was performed and funded by the Genotyping Laboratory of
Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki,
Helsinki, Finland.
These funding agencies had no role in the design, implementation or interpretation of this
study.Background: There is considerable variability in COVID-19 outcomes amongst younger
adultsâand some of this variation may be due to genetic predisposition. We characterized the
clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent
effect, using individual-level data in a large international multi-centre consortium.
Method: The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by
the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive
patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this
genetic marker with mortality, COVID-19-related complications and laboratory values. We next
examined if the magnitude of these associations varied by age and were independent from
known clinical COVID-19 risk factors.
Findings: We found that rs10490770 risk allele carriers experienced an increased risk of
all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2â1·6) and COVID-19
related mortality (HR 1·5, 95%CI 1·3â1·8). Risk allele carriers had increased odds of several
COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6),
venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI
1·2-2·0). Risk allele carriers †60 years had higher odds of death or severe respiratory failure
(OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction
p-value=0·04). Amongst individuals †60 years who died or experienced severe respiratory
COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers,
compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes.
Prediction of death or severe respiratory failure among those †60 years improved when
including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770
risk allele was similar to, or better than, most established clinical risk factors.
Interpretation: The major common COVID-19 risk locus on chromosome 3 is associated with
increased risks of morbidity and mortalityâand these are more pronounced amongst individuals
†60 years. The effect on COVID-19 severity was similar to, or larger than most established risk
factors, suggesting potential implications for clinical risk management.Academy of
Finland Fellow grant N. 323116Academy of Finland for PREDICT consortium N.
340541.Canadian Institutes of Health Research
(CIHR) (365825 and 409511)Lady Davis Institute of the Jewish General HospitalCanadian Foundation for Innovation (CFI)NIH FoundationCancer Research UKGenome QuébecPublic Health Agency of CanadaMcGill Interdisciplinary Initiative in
Infection and Immunity and the Fonds de Recherche Québec Santé (FRQS)Japan Society for the Promotion of Science for Young
ScientistsCIHR scholarship and a joint FRQS and Québec Ministry of
Health and Social Services scholarshipFRQS Clinical Research
ScholarshipCalcul QuébecCompute CanadaWelcome TrustMedical Research CouncEuropean UnionNational Institute for Health Research-funded BioResourceClinical Research Facility
and Biomedical Research Centre based at Guyâs and St. Thomasâ NHS Foundation TrustKingâs College LondonGenome QuĂ©becPublic Health Agency of CanadaMcGill Interdisciplinary
Initiative in Infection and ImmunityFonds de Recherche QuĂ©bec SantĂ©(DFG Grant: âEXC2167â)(CompLS grant 031L0165)Stein Erik Hagen"Grupo de Trabajo en Medicina Personalizada contra el COVID-19 de Andalucia"Instituto de Salud Carlos III (CIBERehd and CIBERER)COVID-19-GWASCOVID-PREMED initiatives"Consejeria de
Salud y Familias" of the Andalusian GovernmentAndalusian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018)Columbia UniversityNational
Center for Advancing Translational SciencesNIH Grant Number UL1TR001873ConsejerĂa de EconomĂa, Conocimiento, Empresas y
Universidad #CV20-10150MIUR grant âDipartimenti di Eccellenza 2018-2020ââIntesa San Paolo
2020 charity fundâ dedicated to the project NB/2020/0119Tuscany Region âBando Ricerca COVID-19 ToscanaâCINECA
consortiumNetwork for Italian Genomes (NIG)COVID-19 Host Genetics InitiativeGenetic Biobank of SienaEuroBioBankRD-ConnectRicerca Corrente (Italian Ministry of Health)Fondazione
Humanitas per la RicercaBanca Intesa San PaoloDolce&Gabbana Fashion FirmCOVID-19 BiobankFondazione
IRCCS CĂ Granda MilanoMyFirst Grant AIRC n.16888Ricerca
Finalizzata Ministero della Salute RF-2016-02364358Ricerca corrente Fondazione IRCCS
Caâ Granda Ospedale Maggiore PoliclinicoEuropean Union (EU) Programme Horizon
2020 (under grant agreement No. 777377)âPhotonicsâ â101016726âFondazione Patrimonio Caâ Granda âLiver Bibleâ PR-0361CV PREVITAL âStrategie di prevenzione primaria nella popolazione Italianaâ Ministero della
Salute, and Associazione Italiana per la Prevenzione dellâEpatite Virale (COPEV)"Fonds
Erasme"Fondation LĂ©on FredericqFonds de la
Recherche Scientifique (FNRS)Consejo Superior de Investigaciones
CientĂficasGerman Research Foundation (LU 1944/3-1)SciLifeLab/KAW national COVID-19 research program project (KAW 2020.0182)Swedish Research Council (2014-02569 and 2014-07606)Jeansson Stiftelser, Magnus
Bergvalls StiftelseTechnical University of Munich, Munich, GermanyGenotyping Laboratory of
Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki,
Helsinki, Finlan
Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials
An amendment to this paper has been published and can be accessed via the original article
Detailed stratified GWAS analysis for severe COVID-19 in four European populations
Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12â488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.S.E.H. and C.A.S. partially supported genotyping through a philanthropic donation. A.F. and D.E. were supported by a grant from the German Federal Ministry of Education and COVID-19 grant Research (BMBF; ID:01KI20197); A.F., D.E. and F.D. were supported by the Deutsche Forschungsgemeinschaft Cluster of Excellence âPrecision Medicine in Chronic Inflammationâ (EXC2167). D.E. was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). D.E., K.B. and S.B. acknowledge the Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594). T.L.L., A.T. and O.Ă. were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project numbers 279645989; 433116033; 437857095. M.W. and H.E. are supported by the German Research Foundation (DFG) through the Research Training Group 1743, âGenes, Environment and Inflammationâ. L.V. received funding from: Ricerca Finalizzata Ministero della Salute (RF-2016-02364358), Italian Ministry of Health âCV PREVITALââstrategie di prevenzione primaria cardiovascolare primaria nella popolazione italiana; The European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- and for the project âREVEALâ; Fondazione IRCCS Caâ Granda âRicerca correnteâ, Fondazione Sviluppo Caâ Granda âLiver-BIBLEâ (PR-0391), Fondazione IRCCS Caâ Granda â5permilleâ âCOVID-19 Biobankâ (RC100017A). A.B. was supported by a grant from Fondazione Cariplo to Fondazione Tettamanti: âBio-banking of Covid-19 patient samples to support national and international research (Covid-Bank). This research was partly funded by an MIUR grant to the Department of Medical Sciences, under the program âDipartimenti di Eccellenza 2018â2022â. This study makes use of data generated by the GCAT-Genomes for Life. Cohort study of the Genomes of Catalonia, FundaciĂł IGTP (The Institute for Health Science Research Germans Trias i Pujol) IGTP is part of the CERCA Program/Generalitat de Catalunya. GCAT is supported by AcciĂłn de DinamizaciĂłn del ISCIII-MINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026); the AgĂšncia de GestiĂł dâAjuts Universitaris i de Recerca (AGAUR) (2017-SGR 529). M.M. received research funding from grant PI19/00335 AcciĂłn EstratĂ©gica en Salud, integrated in the Spanish National RDI Plan and financed by ISCIII-SubdirecciĂłn General de EvaluaciĂłn and the Fondo Europeo de Desarrollo Regional (European Regional Development Fund (FEDER)-Una manera de hacer Europaâ). B.C. is supported by national grants PI18/01512. X.F. is supported by the VEIS project (001-P-001647) (co-funded by the European Regional Development Fund (ERDF), âA way to build Europeâ). Additional data included in this study were obtained in part by the COVICAT Study Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, European Institute of Innovation & Technology (EIT), a body of the European Union, COVID-19 Rapid Response activity 73A and SR20-01024 La Caixa Foundation. A.J. and S.M. were supported by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36). A.J. was also supported by national grant PI17/00019 from the AcciĂłn EstratĂ©gica en Salud (ISCIII) and the European Regional Development Fund (FEDER). The Basque Biobank, a hospital-related platform that also involves all Osakidetza health centres, the Basque governmentâs Department of Health and Onkologikoa, is operated by the Basque Foundation for Health Innovation and Research-BIOEF. M.C. received Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal de InvestigaciĂłn (AEI, Spain) and the European Regional Development Fund (FEDER, EU). M.R.G., J.A.H., R.G.D. and D.M.M. are supported by the âSpanish Ministry of Economy, Innovation and Competition, the Instituto de Salud Carlos IIIâ (PI19/01404, PI16/01842, PI19/00589, PI17/00535 and GLD19/00100) and by the Andalussian government (Proyectos EstratĂ©gicos-Fondos Feder PE-0451-2018, COVID-Premed, COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant FI20/00215, PFIS Contratos Predoctorales de FormaciĂłn en InvestigaciĂłn en Salud. Enrique CalderĂłnâs team is supported by CIBER of Epidemiology and Public Health (CIBERESP), âInstituto de Salud Carlos IIIâ. J.C.H. reports grants from Research Council of Norway grant no 312780 during the conduct of the study. E.S. reports grants from Research Council of Norway grant no. 312769. The BioMaterialBank Nord is supported by the German Center for Lung Research (DZL), Airway Research Center North (ARCN). The BioMaterialBank Nord is member of popgen 2.0 network (P2N). P.K. Bergisch Gladbach, Germany and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. He is supported by the German Federal Ministry of Education and Research (BMBF). O.A.C. is supported by the German Federal Ministry of Research and Education and is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germanyâs Excellence StrategyâCECAD, EXC 2030â390661388. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. This work was supported by grants of the Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland and Lower Saxony. K.U.L. is supported by the German Research Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the Institute of Human Genetics, University Hospital Bonn. F.H. was supported by the Bavarian State Ministry for Science and Arts. Part of the genotyping was supported by a grant to A.R. from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA BioBank, EADB) within the context of the EU Joint ProgrammeâNeurodegenerative Disease Research (JPND). Additional funding was derived from the German Research Foundation (DFG) grant: RA 1971/6-1 to A.R. P.R. is supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH state funds for COVID19 research). F.T. is supported by the Clinician Scientist Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence âPrecision Medicine in Chronic Inflammationâ (EXC2167). C.L. and J.H. are supported by the German Center for Infection Research (DZIF). T.B., M.M.B., O.W. und A.H. are supported by the Stiftung UniversitĂ€tsmedizin Essen. M.A.-H. was supported by Juan de la Cierva Incorporacion program, grant IJC2018-035131-I funded by MCIN/AEI/10.13039/501100011033. E.C.S. is supported by the Deutsche Forschungsgemeinschaft (DFG; SCHU 2419/2-1).Peer reviewe
Detailed stratified GWAS analysis for severe COVID-19 in four European populations
Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic âŒ0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.Andre Franke and David Ellinghaus were supported by a grant from the German
Federal Ministry of Education and Research (01KI20197), Andre Franke, David
Ellinghaus and Frauke Degenhardt were supported by the Deutsche
Forschungsgemeinschaft Cluster of Excellence âPrecision Medicine in Chronic
Inflammationâ (EXC2167). David Ellinghaus was supported by the German Federal
Ministry of Education and Research (BMBF) within the framework of the
Computational Life Sciences funding concept (CompLS grant 031L0165). David
Ellinghaus, Karina Banasik and SĂžren Brunak acknowledge the Novo Nordisk
Foundation (grant NNF14CC0001 and NNF17OC0027594). Tobias L. Lenz, Ana
Teles and Onur Ăzer were funded by the Deutsche Forschungsgemeinschaft (DFG,
German Research Foundation), project numbers 279645989; 433116033; 437857095. Mareike Wendorff and Hesham ElAbd are supported by the German
Research Foundation (DFG) through the Research Training Group 1743, "Genes,
Environment and Inflammation". This project was supported by a Covid-19 grant from
the German Federal Ministry of Education and Research (BMBF; ID: 01KI20197).
Luca Valenti received funding from: Ricerca Finalizzata Ministero della Salute RF2016-02364358, Italian Ministry of Health ""CV PREVITAL â strategie di prevenzione
primaria cardiovascolare primaria nella popolazione italiana; The European Union
(EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project
LITMUS- and for the project ""REVEAL""; Fondazione IRCCS Ca' Granda ""Ricerca
corrente"", Fondazione Sviluppo Ca' Granda ""Liver-BIBLE"" (PR-0391), Fondazione
IRCCS Ca' Granda ""5permille"" ""COVID-19 Biobank"" (RC100017A). Andrea Biondi
was supported by the grant from Fondazione Cariplo to Fondazione Tettamanti: "Biobanking of Covid-19 patient samples to support national and international research
(Covid-Bank). This research was partly funded by a MIUR grant to the Department of
Medical Sciences, under the program "Dipartimenti di Eccellenza 2018â2022". This
study makes use of data generated by the GCAT-Genomes for Life. Cohort study of
the Genomes of Catalonia, FundaciĂł IGTP. IGTP is part of the CERCA Program /
Generalitat de Catalunya. GCAT is supported by AcciĂłn de DinamizaciĂłn del ISCIIIMINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026);
the AgĂšncia de GestiĂł dâAjuts Universitaris i de Recerca (AGAUR) (2017-SGR 529).
Marta Marquié received research funding from ant PI19/00335 Acción Estratégica en
Salud, integrated in the Spanish National RDI Plan and financed by ISCIIISubdirecciĂłn General de EvaluaciĂłn and the Fondo Europeo de Desarrollo Regional
(FEDER-Una manera de hacer Europa").Beatriz Cortes is supported by national
grants PI18/01512. Xavier Farre is supported by VEIS project (001-P-001647) (cofunded by European Regional Development Fund (ERDF), âA way to build Europeâ).
Additional data included in this study was obtained in part by the COVICAT Study
Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, EIT COVID-19
Rapid Response activity 73A and SR20-01024 La Caixa Foundation. Antonio JuliĂ
and Sara Marsal were supported by the Spanish Ministry of Economy and
Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36).
Antonio JuliĂ was also supported the by national grant PI17/00019 from the AcciĂłn
Estratégica en Salud (ISCIII) and the FEDER. The Basque Biobank is a hospitalrelated platform that also involves all Osakidetza health centres, the Basque government's Department of Health and Onkologikoa, is operated by the Basque
Foundation for Health Innovation and Research-BIOEF. Mario CĂĄceres received
Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal
de InvestigaciĂłn (AEI, Spain) and the European Regional Development Fund
(FEDER, EU). Manuel Romero GĂłmez, Javier Ampuero Herrojo, RocĂo Gallego DurĂĄn
and Douglas Maya Miles are supported by the âSpanish Ministry of Economy,
Innovation and Competition, the Instituto de Salud Carlos IIIâ (PI19/01404,
PI16/01842, PI19/00589, PI17/00535 and GLD19/00100), and by the Andalussian
government (Proyectos Estratégicos-Fondos Feder PE-0451-2018, COVID-Premed,
COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant
FI20/00215, PFIS Contratos Predoctorales de FormaciĂłn en InvestigaciĂłn en Salud.
Enrique CalderĂłn's team is supported by CIBER of Epidemiology and Public Health
(CIBERESP), "Instituto de Salud Carlos III". Jan Cato Holter reports grants from
Research Council of Norway grant no 312780 during the conduct of the study. Dr.
SolligÄrd: reports grants from Research Council of Norway grant no 312769. The
BioMaterialBank Nord is supported by the German Center for Lung Research (DZL),
Airway Research Center North (ARCN). The BioMaterialBank Nord is member of
popgen 2.0 network (P2N). Philipp Koehler has received non-financial scientific grants
from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, and the Cologne
Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases,
University of Cologne, Cologne, Germany. He is supported by the German Federal
Ministry of Education and Research (BMBF).Oliver A. Cornely is supported by the
German Federal Ministry of Research and Education and is funded by the Deutsche
Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's
Excellence Strategy â CECAD, EXC 2030 â 390661388. The COMRI cohort is funded
by Technical University of Munich, Munich, Germany. Genotyping was performed by
the Genotyping laboratory of Institute for Molecular Medicine Finland FIMM
Technology Centre, University of Helsinki. This work was supported by grants of the
Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland
and Lower Saxony. Kerstin U. Ludwig is supported by the German Research
Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the
Institute of Human Genetics, University Hospital Bonn. Frank Hanses was supported
by the Bavarian State Ministry for Science and Arts. Part of the genotyping was
supported by a grant to Alfredo Ramirez from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA
BioBank, EADB) within the context of the EU Joint Programme â Neurodegenerative
Disease Research (JPND). Additional funding was derived from the German Research
Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Philip Rosenstiel is
supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH
state funds for COVID19 research). Florian Tran is supported by the Clinician Scientist
Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence âPrecision
Medicine in Chronic Inflammationâ (EXC2167). Christoph Lange and Jan Heyckendorf
are supported by the German Center for Infection Research (DZIF). Thorsen Brenner,
Marc M Berger, Oliver Witzke und Anke Hinney are supported by the Stiftung
UniversitÀtsmedizin Essen. Marialbert Acosta-Herrera was supported by Juan de la
Cierva Incorporacion program, grant IJC2018-035131-I funded by
MCIN/AEI/10.13039/501100011033. Eva C Schulte is supported by the Deutsche
Forschungsgemeinschaft (DFG; SCHU 2419/2-1).N
Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19
IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.
Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.
DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 nonâcritically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).
INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (nâ=â257), ARB (nâ=â248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; nâ=â10), or no RAS inhibitor (control; nâ=â264) for up to 10 days.
MAIN OUTCOMES AND MEASURES The primary outcome was organ supportâfree days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.
RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ supportâfree days among critically ill patients was 10 (â1 to 16) in the ACE inhibitor group (nâ=â231), 8 (â1 to 17) in the ARB group (nâ=â217), and 12 (0 to 17) in the control group (nâ=â231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ supportâfree days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).
CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570
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