Genetic landscape of the ACE2 coronavirus receptor
Peters, James E
Reiner, Alexander P
Wilson, James F
Lippincott, Williams & Wilkins
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Yang, Z., Macdonald-Dunlop, E., Chen, J., Prins, B., Wheeler, E., Pietzner, M., Peters, J. E., et al. (2022). Genetic landscape of the ACE2 coronavirus receptor. Circulation, 145 (18), 1398-1411. https://doi.org/10.1161/CIRCULATIONAHA.121.057888
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, enters human cells using the angiotensin-converting enzyme 2 (ACE2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart, respiratory and gastrointestinal tracts, playing important regulatory roles in the cardio- vascular and other biologic systems. However, the genetic basis of the ACE2 protein levels is not well understood. Methods: We conduct so far the largest genome-wide association meta-analysis of plasma ACE2 levels in over 28,000 individuals of the SCALLOP Consortium. We summarize the cross-sectional epidemiologic 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 disease severity using Mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data. Results: We identified ten loci, including eight novels, capturing 30% of the protein’s heritability. 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-pQTL-based Mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio (OR), 1.63; 95% CI, 1.10 to 2.42; P = 0.01), hospitalization (OR, 1.52; 95% CI, 1.05 to 2.21; P = 0.03), and infection (OR, 1.60; 95% CI, 1.08 to 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.
Cardiovascular diseases, Angiotensin-converting Enzyme 2, Genome-wide Association Study, Covid-19, Sars-cov-2, Humans, Peptidyl-Dipeptidase A, Cross-Sectional Studies, Genome-Wide Association Study, COVID-19, Angiotensin-Converting Enzyme 2, SARS-CoV-2, Receptors, Coronavirus
X.S. was in receipt of a Swedish Research Council Starting Grant (No. 2017-02543). We thank the Edinburgh Compute and Data Facility at the University of Edinburgh for providing high-performance computing resources. J.F.W. and C.H. acknowledge support from the Medical Research Council Hu- man Genetics Unit program grant “Quantitative Traits in Health and Disease” (U. MC_UU_00007/10). The work of L.K. was supported by an RCUK Innovation Fellowship from the National Productivity In- vestment Fund (MR/R026408/1). A.D.B. would like to acknowledge funding from the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z), the Edinburgh Clinical Academic Track (ECAT) programme. A.P.R was supported by grants R01HL146500 and R01HL132947. NSPHS The Northern Swedish Population Health Study (NSPHS) has been funded by the Swedish Medical Research Council (K2007-66X-20270-01-3, 2011-5252, 2012-2884 and 2011-2354), and the Foundation for Strategic Research (SSF). NSPHS as part of European Special Populations Research Network (EUROSPAN) was also supported by the European Commission FP6 STRP (01947, LSHG- CT-2006-01947). Whole-genome sequencing was funded by SciLifeLab. Computations were per- formed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Com- putational Science (UPPMAX) under project sens2016007. DIRECT The DIRECT study has received support from the Innovative Medicines Initiative Joint Un- dertaking under grant agreement No. 115317 (DIRECT), resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EF- PIA companies’ in kind contribution. HELIC MANOLIS & HELIC POMAK This work was funded by the Wellcome Trust (098051) and the European Research Council (ERC-2011-StG 280559-SEPI). EGCUT EGCUT work was supported by the European Regional Development Fund and the programme Mobilitas Pluss (MOBTP108), SP1GI18045T, No.2014-2020.4.01.15-0012 GENTRANSMED and 2014-2020.4.01.16-0125 This study was also funded by EU H2020 grant 692145, Estonian Research Council Grant PUT1660. ARISTOTLE This work was supported by the Swedish Foundation for Strategic Research. The ARIS- TOTLE trial (ClinicalTrials.gov Identifier: NCT00412984) was funded by Bristol-Myers Squibb Co., Princeton, NJ, USA, and Pfizer Inc., New York, NY, USA. The computations were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) partially funded by the Swedish Research Council through grant agreement no. 2018-05973 (project sens2017573). VIS The CROATIA_Vis study was funded by grants from the Medical Research Council (UK), Eu- ropean Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants (108-1080315-0302). WHI The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. FENLAND (The Fenland Study) The Fenland Study (10.22025/2017.10.101.00001) is funded by the Medical Research Council (MC_UU_12015/1). We further acknowledge support for genomics and metabolomics from the Medical Research Council (MC_PC_13046).
External DOI: https://doi.org/10.1161/CIRCULATIONAHA.121.057888
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336928
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/