53 research outputs found
The major genetic risk factor for severe COVID-19 is associated with protection against HIV
There are genetic risk factors that influence the outcome of COVID-19 [COVID-19 Host Genetics Initiative, Nature 600, 472–477 (2021)]. The major genetic risk factor for severe COIVD-19 resides on chromosome 3 and is inherited from Neandertals [H. Zeberg, S. Pääbo, Nature 587, 610–612 (2020)]. The risk-associated DNA segment modulates the expression of several chemokine receptors, among them CCR5, a coreceptor for HIV which is down-regulated in carriers of the COVID-19 risk haplotype. Here I show that carriers of the risk variant have an ∼27% lower risk of HIV infection
Fluorescence-based measurements of membrane-bound angiotensin converting enzyme 2 activity using Xenopus Laevis Oocytes
Functional investigations of enzymes involving cellular expression systems are important for pharmacological studies. The precise control of expression is challenging in transiently transfected mammalian cell lines. Here, we explored the ability of Xenopus laevis oocytes to express a membrane-bound enzyme for functional characterization using standard 96-well plates and a fluorescence-based plate reader assay. We microinjected oocytes with cRNA encoding the angiotensin converting enzyme 2 (ACE2) and measured the enzymatic activity in single oocytes using a commercial fluorescence-based assay. The injected oocytes showed up to a 50-fold increase in fluorescence compared to uninjected oocytes. This fluorescence intensity was dose-dependent on the amount of ACE2 cRNA. These results suggest that Xenopus oocytes can be used for the functional evaluation of membrane-bound enzymes, decreasing the experimental workload
Three-dimensional visualisation of authentic cases in anatomy learning – An educational design study
Many studies have investigated the value of three-dimensional (3D) images in learning anatomy. However, there is a lack of knowledge about students learning processes using technology and 3D images. To understand how to facilitate and support the learning of anatomy, there is a need to know more about the student perspectives on how they can use and benefit from 3D images
Sustained IFN signaling is associated with delayed development of SARS-CoV-2-specific immunity.
Plasma RNAemia, delayed antibody responses and inflammation predict COVID-19 outcomes, but the mechanisms underlying these immunovirological patterns are poorly understood. We profile 782 longitudinal plasma samples from 318 hospitalized patients with COVID-19. Integrated analysis using k-means reveals four patient clusters in a discovery cohort: mechanically ventilated critically-ill cases are subdivided into good prognosis and high-fatality clusters (reproduced in a validation cohort), while non-critical survivors segregate into high and low early antibody responders. Only the high-fatality cluster is enriched for transcriptomic signatures associated with COVID-19 severity, and each cluster has distinct RBD-specific antibody elicitation kinetics. Both critical and non-critical clusters with delayed antibody responses exhibit sustained IFN signatures, which negatively correlate with contemporaneous RBD-specific IgG levels and absolute SARS-CoV-2-specific B and CD4 <sup>+</sup> T cell frequencies. These data suggest that the "Interferon paradox" previously described in murine LCMV models is operative in COVID-19, with excessive IFN signaling delaying development of adaptive virus-specific immunity
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 Guy’s and St. Thomas’ NHS Foundation Trust in
partnership with King’s College London. The Biobanque Québec 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 “Precision Medicine in Chronic Inflammation (PMI)” (DFG Grant: “EXC2167”).
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 Consejería de Economía, Conocimiento, Empresas y
Universidad #CV20-10150.
The GEN-COVID study was funded by: the MIUR grant “Dipartimenti di Eccellenza 2018-2020”
to the Department of Medical Biotechnologies University of Siena, Italy; the “Intesa San Paolo
2020 charity fund” 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 “Bando Ricerca COVID-19 Toscana” 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 Cà Granda Milano; LV group was supported by MyFirst Grant AIRC n.16888, Ricerca
Finalizzata Ministero della Salute RF-2016-02364358, Ricerca corrente Fondazione IRCCS
Ca’ Granda Ospedale Maggiore Policlinico, the European Union (EU) Programme Horizon
2020 (under grant agreement No. 777377) for the project LITMUS- “Liver Investigation:
Testing Marker Utility in Steatohepatitis”, Programme “Photonics” under grant agreement
“101016726” for the project “REVEAL: Neuronal microscopy for cell behavioural examination
and manipulation”, Fondazione Patrimonio Ca’ Granda “Liver Bible” PR-0361. DP was
supported by Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico,
CV PREVITAL “Strategie di prevenzione primaria nella popolazione Italiana” Ministero della
Salute, and Associazione Italiana per la Prevenzione dell’Epatite 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 Léon Fredericq and from Fonds de la
Recherche Scientifique (FNRS).
The INMUNGEN-CoV2 study was funded by the Consejo Superior de Investigaciones
Científicas.
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
adults—and 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] 1·2–1·6) and COVID-19
related mortality (HR 1·5, 95%CI 1·3–1·8). 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 mortality—and 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 Guy’s and St. Thomas’ NHS Foundation TrustKing’s College LondonGenome QuébecPublic Health Agency of CanadaMcGill Interdisciplinary
Initiative in Infection and ImmunityFonds de Recherche Québec Santé(DFG Grant: “EXC2167”)(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 UL1TR001873Consejería de Economía, Conocimiento, Empresas y
Universidad #CV20-10150MIUR grant “Dipartimenti di Eccellenza 2018-2020”“Intesa San Paolo
2020 charity fund” dedicated to the project NB/2020/0119Tuscany Region “Bando Ricerca COVID-19 Toscana”CINECA
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 Cà Granda MilanoMyFirst Grant AIRC n.16888Ricerca
Finalizzata Ministero della Salute RF-2016-02364358Ricerca corrente Fondazione IRCCS
Ca’ Granda Ospedale Maggiore PoliclinicoEuropean Union (EU) Programme Horizon
2020 (under grant agreement No. 777377)“Photonics” “101016726”Fondazione Patrimonio Ca’ Granda “Liver Bible” PR-0361CV PREVITAL “Strategie di prevenzione primaria nella popolazione Italiana” Ministero della
Salute, and Associazione Italiana per la Prevenzione dell’Epatite Virale (COPEV)"Fonds
Erasme"Fondation Léon FredericqFonds de la
Recherche Scientifique (FNRS)Consejo Superior de Investigaciones
CientíficasGerman 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
SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues
Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types
Whole-genome sequencing reveals host factors underlying critical COVID-19
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
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