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1.
Circulation ; 145(18): 1398-1411, 2022 05 03.
Article in English | MEDLINE | ID: covidwho-1779500

ABSTRACT

BACKGROUND: SARS-CoV-2, the causal agent of COVID-19, enters human cells using the ACE2 (angiotensin-converting enzyme 2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart and respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biological systems. However, the genetic basis of the ACE2 protein levels is not well understood. METHODS: We have conducted the largest genome-wide association meta-analysis of plasma ACE2 levels in >28 000 individuals of the SCALLOP Consortium (Systematic and Combined Analysis of Olink Proteins). We summarize the cross-sectional epidemiological correlates of circulating ACE2. Using the summary statistics-based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 severity using mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data. RESULTS: We identified 10 loci, including 8 novel, capturing 30% of the heritability of the protein. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis-protein quantitative trait loci-based mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio, 1.63 [95% CI, 1.10-2.42]; P=0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05-2.21]; P=0.03), and infection (odds ratio, 1.60 [95% CI, 1.08-2.37]; P=0.02). Tissue- and cell type-specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells. CONCLUSIONS: Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Cross-Sectional Studies , Genome-Wide Association Study , Humans , Receptors, Coronavirus , SARS-CoV-2
2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329816

ABSTRACT

Pulmonary inflammation drives critical illness in Covid-19, creating a clinically homogeneous extreme phenotype, which we have previously shown to be highly efficient for discovery of genetic associations. Despite the advanced stage of illness, we have found that immunomodulatory therapies have strong beneficial effects in this group. Further genetic discoveries may identify additional therapeutic targets to modulate severe disease. In this new data release from the GenOMICC (Genetics Of Mortality in Critical Care) study we include new microarray genotyping data from additional critically-ill cases in the UK and Brazil, together with cohorts of severe Covid-19 from the ISARIC4C and SCOURGE studies, and meta-analysis with previously-reported data. We find an additional umconvincingnew new genetic associations. Many are in potentially druggable targets, in inflammatory signalling (JAK1, PDE4A), monocyte-macrophage differentiation (CSF2), immunometabolism (SLC2A5, AK5), and host factors required for viral entry and replication (TMPRSS2, RAB2A). As with our previous work, these results provide tractable therapeutic targets for modulation of harmful host-mediated inflammation in Covid-19.

3.
Nature ; 2022 Mar 07.
Article in English | MEDLINE | ID: covidwho-1730298

ABSTRACT

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.

4.
Nature ; 591(7848): 92-98, 2021 03.
Article in English | MEDLINE | ID: covidwho-971937

ABSTRACT

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.


Subject(s)
COVID-19/genetics , COVID-19/physiopathology , Critical Illness , 2',5'-Oligoadenylate Synthetase/genetics , COVID-19/pathology , Chromosomes, Human, Pair 12/genetics , Chromosomes, Human, Pair 19/genetics , Chromosomes, Human, Pair 21/genetics , Critical Care , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics , Drug Repositioning , Female , Genome-Wide Association Study , Humans , Inflammation/genetics , Inflammation/pathology , Inflammation/physiopathology , Lung/pathology , Lung/physiopathology , Lung/virology , Male , Multigene Family/genetics , Receptor, Interferon alpha-beta/genetics , Receptors, CCR2/genetics , TYK2 Kinase/genetics , United Kingdom
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