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Genetic Landscape of the ACE2 Coronavirus Receptor.
Yang, Zhijian; Macdonald-Dunlop, Erin; Chen, Jiantao; Zhai, Ranran; Li, Ting; Richmond, Anne; Klaric, Lucija; Pirastu, Nicola; Ning, Zheng; Zheng, Chenqing; Wang, Yipeng; Huang, Tingting; He, Yazhou; Guo, Huiming; Ying, Kejun; Gustafsson, Stefan; Prins, Bram; Ramisch, Anna; Dermitzakis, Emmanouil T; Png, Grace; Eriksson, Niclas; Haessler, Jeffrey; Hu, Xiaowei; Zanetti, Daniela; Boutin, Thibaud; Hwang, Shih-Jen; Wheeler, Eleanor; Pietzner, Maik; Raffield, Laura M; Kalnapenkis, Anette; Peters, James E; Viñuela, Ana; Gilly, Arthur; Elmståhl, Sölve; Dedoussis, George; Petrie, John R; Polasek, Ozren; Folkersen, Lasse; Chen, Yan; Yao, Chen; Võsa, Urmo; Pairo-Castineira, Erola; Clohisey, Sara; Bretherick, Andrew D; Rawlik, Konrad; Esko, Tõnu; Enroth, Stefan; Johansson, Åsa; Gyllensten, Ulf; Langenberg, Claudia.
  • Yang Z; Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China (Z.Y., J.C., R.Z., T.L., Z.N., C.Z., Y.W., X.S.).
  • Macdonald-Dunlop E; Center for Intelligent Medicine Research, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, China (Z.Y., J.C., R.Z., T.L., X.S.).
  • Chen J; Centre for Global Health Research, Usher Institute, University of Edinburgh, UK (E.M.-D., N.P., Y.H., P.K.J., J.F.W., X.S.).
  • Zhai R; Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China (Z.Y., J.C., R.Z., T.L., Z.N., C.Z., Y.W., X.S.).
  • Li T; Center for Intelligent Medicine Research, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, China (Z.Y., J.C., R.Z., T.L., X.S.).
  • Richmond A; Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China (Z.Y., J.C., R.Z., T.L., Z.N., C.Z., Y.W., X.S.).
  • Klaric L; Center for Intelligent Medicine Research, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, China (Z.Y., J.C., R.Z., T.L., X.S.).
  • Pirastu N; Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China (Z.Y., J.C., R.Z., T.L., Z.N., C.Z., Y.W., X.S.).
  • Ning Z; Center for Intelligent Medicine Research, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, China (Z.Y., J.C., R.Z., T.L., X.S.).
  • Zheng C; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, UK (A. Richmond, L.K., T.B., E.P.-C., A.D.B., C.H., J.F.W.).
  • Wang Y; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, UK (A. Richmond, L.K., T.B., E.P.-C., A.D.B., C.H., J.F.W.).
  • Huang T; Centre for Global Health Research, Usher Institute, University of Edinburgh, UK (E.M.-D., N.P., Y.H., P.K.J., J.F.W., X.S.).
  • He Y; Human Technopole Viale Rita Levi-Montalcini, Milan, Italy (N.P.).
  • Guo H; Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China (Z.Y., J.C., R.Z., T.L., Z.N., C.Z., Y.W., X.S.).
  • Ying K; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (Z.N., T.H., Y.C., Y.P., A.M., X.S.).
  • Gustafsson S; Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China (Z.Y., J.C., R.Z., T.L., Z.N., C.Z., Y.W., X.S.).
  • Prins B; Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China (Z.Y., J.C., R.Z., T.L., Z.N., C.Z., Y.W., X.S.).
  • Ramisch A; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (Z.N., T.H., Y.C., Y.P., A.M., X.S.).
  • Dermitzakis ET; Centre for Global Health Research, Usher Institute, University of Edinburgh, UK (E.M.-D., N.P., Y.H., P.K.J., J.F.W., X.S.).
  • Png G; West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu (Y.H.).
  • Eriksson N; Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences, Guangzhou, China (H.G.).
  • Haessler J; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (K.Y.).
  • Hu X; T.H. Chan School of Public Health, Harvard University, Boston, MA (K.Y.).
  • Zanetti D; Department of Medical Sciences, Uppsala University, Sweden (A.S., S.G., L.W., L.L.).
  • Boutin T; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK (B.P., J.E.P., A.S.B.).
  • Hwang SJ; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge (B.P., J.E.P., A.S.B.).
  • Wheeler E; Department of Genetic Medicine and Development, University of Geneva Medical School, Switzerland (A. Ramisch, E.T.D., A.V.).
  • Pietzner M; Department of Genetic Medicine and Development, University of Geneva Medical School, Switzerland (A. Ramisch, E.T.D., A.V.).
  • Raffield LM; Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany (G.P., A.G., E.Z.).
  • Kalnapenkis A; Technical University of Munich (TUM), School of Medicine, Germany (G.P.).
  • Peters JE; Uppsala Clinical Research Center, Sweden (N.E.).
  • Viñuela A; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (J.H., C.K., A.P.R.).
  • Gilly A; Center for Public Health Genomics, University of Virginia, Charlottesville (X.H., A.W.M.).
  • Elmståhl S; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (D.Z., T.L.A.).
  • Dedoussis G; Stanford Cardiovascular Institute, Stanford University, CA (D.Z., T.L.A.).
  • Petrie JR; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, UK (A. Richmond, L.K., T.B., E.P.-C., A.D.B., C.H., J.F.W.).
  • Polasek O; Framingham Heart Study, MA (S.-J.H., C.Y., D.L.).
  • Folkersen L; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (S.-J.H., C.Y., D.L.).
  • Chen Y; MRC Epidemiology Unit, University of Cambridge, UK (E.W., M.P., C.L.).
  • Yao C; MRC Epidemiology Unit, University of Cambridge, UK (E.W., M.P., C.L.).
  • Võsa U; Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin, Germany (M.P., C.L.).
  • Pairo-Castineira E; Department of Genetics, University of North Carolina at Chapel Hill (L.M.R.).
  • Clohisey S; Estonian Genome Centre, Institute of Genomics, University of Tartu, Estonia (A.K., U.V., T.E.).
  • Bretherick AD; Institute of Molecular and Cell Biology, University of Tartu, Estonia (A.K.).
  • Rawlik K; Department of Immunology and Inflammation, Imperial College London, UK (J.E.P.).
  • Esko T; Department of Genetic Medicine and Development, University of Geneva Medical School, Switzerland (A. Ramisch, E.T.D., A.V.).
  • Enroth S; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, UK (A.V.).
  • Johansson Å; Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany (G.P., A.G., E.Z.).
  • Gyllensten U; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK (A.G., E.Z.).
  • Langenberg C; Faculty of Medicine, Lund University, Sweden (S. Elmståhl).
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Angiotensin-Converting Enzyme 2 / COVID-19 Type of study: Experimental Studies / Observational study / Prognostic study / Randomized controlled trials / Reviews / Systematic review/Meta Analysis Topics: Variants Limits: Humans Language: English Journal: Circulation Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Angiotensin-Converting Enzyme 2 / COVID-19 Type of study: Experimental Studies / Observational study / Prognostic study / Randomized controlled trials / Reviews / Systematic review/Meta Analysis Topics: Variants Limits: Humans Language: English Journal: Circulation Year: 2022 Document Type: Article