Genetic Landscape of the ACE2 Coronavirus Receptor-Reference-Cited by-同舟云学术

Genetic Landscape of the ACE2 Coronavirus Receptor

Published:2022-05-03 Issue:18 Volume:145 Page:1398-1411
ISSN:0009-7322
Container-title:Circulation
language:en
Short-container-title:Circulation

Author:

Yang Zhijian¹²^ORCID,Macdonald-Dunlop Erin³,Chen Jiantao¹²^ORCID,Zhai Ranran¹²^ORCID,Li Ting¹²,Richmond Anne⁴,Klarić Lucija⁴^ORCID,Pirastu Nicola³⁵^ORCID,Ning Zheng¹⁶^ORCID,Zheng Chenqing¹,Wang Yipeng¹,Huang Tingting⁶^ORCID,He Yazhou³⁷^ORCID,Guo Huiming⁸,Ying Kejun⁹¹⁰^ORCID,Gustafsson Stefan¹¹,Prins Bram¹²¹³,Ramisch Anna¹⁴^ORCID,Dermitzakis Emmanouil T.¹⁴,Png Grace¹⁵¹⁶^ORCID,Eriksson Niclas¹⁷^ORCID,Haessler Jeffrey¹⁸,Hu Xiaowei¹⁹,Zanetti Daniela²⁰²¹^ORCID,Boutin Thibaud⁴,Hwang Shih-Jen²²²³^ORCID,Wheeler Eleanor²⁴,Pietzner Maik²⁴²⁵,Raffield Laura M.²⁶^ORCID,Kalnapenkis Anette²⁷²⁸,Peters James E.²⁹¹²¹³,Viñuela Ana¹⁴³⁰^ORCID,Gilly Arthur¹⁵³¹,Elmståhl Sölve³²,Dedoussis George³³,Petrie John R.³⁴,Polašek Ozren³⁵³⁶,Folkersen Lasse³⁷^ORCID,Chen Yan⁶^ORCID,Yao Chen²²²³,Võsa Urmo²⁷,Pairo-Castineira Erola⁴³⁸,Clohisey Sara³⁸,Bretherick Andrew D.⁴,Rawlik Konrad³⁸,Esko Tõnu²⁷,Enroth Stefan³⁹,Johansson Åsa³⁹,Gyllensten Ulf³⁹,Langenberg Claudia²⁴²⁵^ORCID,Levy Daniel²²²³^ORCID,Hayward Caroline⁴^ORCID,Assimes Themistocles L.²⁰²¹^ORCID,Kooperberg Charles¹⁸^ORCID,Manichaikul Ani W.¹⁹,Siegbahn Agneta¹¹,Wallentin Lars¹¹,Lind Lars¹¹^ORCID,Zeggini Eleftheria¹⁵³¹⁴⁰,Schwenk Jochen M.⁴¹^ORCID,Butterworth Adam S.¹²¹³⁴²⁴³^ORCID,Michaëlsson Karl⁴⁴^ORCID,Pawitan Yudi⁶,Joshi Peter K.³^ORCID,Baillie J. Kenneth³⁸⁴⁵,Mälarstig Anders⁶⁴⁶,Reiner Alexander P.¹⁸^ORCID,Wilson James F.³⁴,Shen Xia¹⁴⁷²³⁶^ORCID, ,

Affiliation:

1. 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.).

2. 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.).

3. 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.).

4. 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.).

5. Human Technopole Viale Rita Levi-Montalcini, Milan, Italy (N.P.).

6. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (Z.N., T.H., Y.C., Y.P., A.M., X.S.).

7. West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu (Y.H.).

8. Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital Guangdong Academy of Medical Sciences, Guangzhou, China (H.G.).

9. Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (K.Y.).

10. T.H. Chan School of Public Health, Harvard University, Boston, MA (K.Y.).

11. Department of Medical Sciences, Uppsala University, Sweden (A.S., S.G., L.W., L.L.).

12. 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.).

13. Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge (B.P., J.E.P., A.S.B.).

14. Department of Genetic Medicine and Development, University of Geneva Medical School, Switzerland (A. Ramisch, E.T.D., A.V.).

15. Institute of Translational Genomics, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany (G.P., A.G., E.Z.).

16. Technical University of Munich (TUM), School of Medicine, Germany (G.P.).

17. Uppsala Clinical Research Center, Sweden (N.E.).

18. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (J.H., C.K., A.P.R.).

19. Center for Public Health Genomics, University of Virginia, Charlottesville (X.H., A.W.M.).

20. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (D.Z., T.L.A.).

21. Stanford Cardiovascular Institute, Stanford University, CA (D.Z., T.L.A.).

22. Framingham Heart Study, MA (S.-J.H., C.Y., D.L.).

23. 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.).

24. MRC Epidemiology Unit, University of Cambridge, UK (E.W., M.P., C.L.).

25. Computational Medicine, Berlin Institute of Health at Charité–Universitätsmedizin, Germany (M.P., C.L.).

26. Department of Genetics, University of North Carolina at Chapel Hill (L.M.R.).

27. Estonian Genome Centre, Institute of Genomics, University of Tartu, Estonia (A.K., U.V., T.E.).

28. Institute of Molecular and Cell Biology, University of Tartu, Estonia (A.K.).

29. Department of Immunology and Inflammation, Imperial College London, UK (J.E.P.).

30. Biosciences Institute, Faculty of Medical Sciences, Newcastle University, UK (A.V.).

31. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK (A.G., E.Z.).

32. Faculty of Medicine, Lund University, Sweden (S. Elmståhl).

33. Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Greece (G.D.).

34. Institute of Cardiovascular & Medical Sciences, University of Glasgow, UK (J. Petrie).

35. University of Split School of Medicine, Croatia (O.P.).

36. Algebra University College, Ilica, Zagreb, Croatia (O.P.).

37. Danish National Genome Center, Copenhagen, Denmark (L.F.).

38. Roslin Institute, University of Edinburgh, Easter Bush, UK (E.P.-C., S.C., K.R., J.K.B.).

39. Department of Immunology, Genetics and Pathology, Uppsala Universitet, Science for Life Laboratory, Sweden (S. Enroth, A.J., U.G.).

40. Technical University of Munich (TUM) and Klinikum Rechts der Isar, TUM School of Medicine, Germany (E.Z.).

41. Affinity Proteomics, Science for Life Laboratory, KTH Royal Institute of Technology, Solna, Sweden (J.M.S.).

42. British Heart Foundation Centre of Research Excellence, University of Cambridge, UK (A.S.B.).

43. National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, UK (A.S.B.).

44. Department of Surgical Sciences, Uppsala University, Sweden (K.M.).

45. Intensive Care Unit, Royal Infirmary of Edinburgh, UK (J.K.B.).

46. Pfizer Worldwide Research, Development and Medical, Stockholm, Sweden (A.M.).

47. State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China (X.S.).

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

Reference58 articles.

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