Individual variation of the SARS‐CoV‐2 receptor ACE2 gene expression and regulation
Open accessAbstract
The COVID-19 coronavirus is now spreading worldwide. Its pathogen, SARS-CoV-2, has been shown to use angiotensin-converting enzyme 2 (ACE2) as its host cell receptor, same as the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003. Epidemiology studies found males although only slightly more likely to be infected than females account for the majority of the severely ill and fatality, which also bias for people older than 60 years or with metabolic and cardiovascular diseases. Here by analyzing GTEx and other public data in 30 tissues across thousands of individuals, we found a significantly higher level in Asian females, an age-dependent decrease in all ethnic groups, and a highly significant decrease in type II diabetic patients of ACE2 expression. Consistently, the most significant expression quantitative loci (eQTLs) contributing to high ACE2 expression are close to 100% in East Asians, >30% higher than other ethnic groups. A shockingly common enrichment of viral infection pathways was found among ACE2 anti-expressed genes, and multiple binding sites of virus infection related transcription factors and sex hormone receptors locate at ACE2 regulatory regions. Human and mice data analysis further revealed ACE2 expression is reduced in T2D patients and with inflammatory cytokine treatment and upregulated by estrogen and androgen (both decrease with age). Our findings revealed a negative correlation between ACE2 expression and COVID-19 fatality at both population and molecular levels. These results will be instrumental when designing potential prevention and treatment strategies for ACE2 binding coronaviruses in general.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
ACE2 mRNA is decreased in multiple tissues of elderly humans compared with younger humans.
“one study has shown a decrease in ACE2 mRNA in multiple tissues of elderly humans when compared to their younger counterparts64”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [64]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Clinical characteristics of coronavirus disease 2019 in China
Guan, W.-J., Ni, Z.-Y., Hu, Y., Liang, W.-H., Ou, C.-Q., He, J.-X., Liu, L., Shan, H., Lei, C.-L., Hui, D. S. C., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2002032 · Cited by 30,246 · see citing works
Ruan, Q., Yang, K., Wang, W., Jiang, L., & Song, J. (2020) · Intensive Care Medicine · doi:10.1007/s00134-020-05991-x · Cited by 4,898 · see citing works
A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury
Kuba, K., Imai, Y., Rao, S., Gao, H., Guo, F., Guan, B., Huan, Y., Yang, P., Zhang, Y., Deng, W., et al. (2005) · Nature Medicine · doi:10.1038/nm1267 · Cited by 3,445 · see citing works
Angiotensin-converting enzyme 2 is an essential regulator of heart function
Crackower, M. A., Sarao, R., Oudit, G. Y., Yagil, C., Kozieradzki, I., Scanga, S. E., Oliveira-dos-Santos, A. J., da Costa, J., Zhang, L., Pei, Y., et al. (2002) · Nature · doi:10.1038/nature00786 · Cited by 1,733 · see citing works
Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients
Zhou, Y., Fu, B., Zheng, X., Wang, D., Zhao, C., Qi, Y., Sun, R., Tian, Z., Xu, X., & Wei, H. (2020) · National Science Review · doi:10.1093/nsr/nwaa041 · Cited by 1,295 · see citing works
The role of androgens and estrogens on healthy aging and longevity
Horstman, A. M., Dillon, E. L., Urban, R. J., & Sheffield-Moore, M. (2012) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/gls068 · Cited by 396 · see citing works
Flagged first, then by citations
Research works printed but not linked: 32
- Boehm, M., & Nabel, E. G. (2002). Angiotensin‐converting enzyme 2 — A new cardiac regulator. New England Journal of Medicine, 347, 1795– 1797. 10.1056/NEJMcibr022472 12456857 · DOI
- Cao, X. (2020). COVID‐19: Immunopathology and its implications for therapy. Nature Reviews Immunology, 20(5), 269– 270. 10.1038/s41577-020-0308-3 PMC7143200 32273594 · DOI · Paper page
- Chai, X. et al. (2020) Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019‐nCoV Infection. bioRxiv, 2020.2002.2003.931766, 10.1101/2020.02.03.931766 · DOI · Paper page
- Channappanavar, R., Fett, C., Mack, M., Ten Eyck, P. P., Meyerholz, D. K., & Perlman, S. (2017). Sex‐based differences in susceptibility to severe acute respiratory syndrome coronavirus infection. The Journal of Immunology, 198, 4046– 4053. 10.4049/jimmunol.1601896 28373583 PMC5450662 · DOI
- Chen, J., Qi, T., Liu, L. I., Ling, Y., Qian, Z., Li, T., … Lu, H. (2020). Clinical progression of patients with COVID‐19 in Shanghai, China. Journal of Infection, 80(5), e1– e6. 10.1016/j.jinf.2020.03.004 PMC7102530 32171869 · DOI
- Chen, N., Zhou, M., Dong, X., Qu, J., Gong, F., Han, Y., … Zhang, L. I. (2020). Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. The Lancet, 395(10223), 507– 513. 10.1016/s0140-6736(20)30211-7 PMC7135076 32007143 · DOI · Paper page
- Chen, T., Wu, D. I., Chen, H., Yan, W., Yang, D., Chen, G., … Ning, Q. (2020). Clinical characteristics of 113 deceased patients with coronavirus disease 2019: Retrospective study. BMJ, 368, m1091 10.1136/bmj.m1091 32217556 PMC7190011 · DOI · Paper page
- Diao, B. et al (2020) Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID‐19). medRxiv, 2020.2002.2018.20024364, 10.1101/2020.02.18.20024364 PMC7205903 32425950 · DOI
- Fan, Z., Wu, G., Yue, M., Ye, J., Chen, Y., Xu, B., … Tan, X. (2019). Hypertension and hypertensive left ventricular hypertrophy are associated with ACE2 genetic polymorphism. Life Sciences, 225, 39– 45. 10.1016/j.lfs.2019.03.059 30917908 · DOI
- Gorbalenya, A. E., Baker, S. C., Baric, R. S., de Groot, R. J., Drosten, C., Gulyaeva, A. A., … Ziebuhr, J. (2020). The species Severe acute respiratory syndrome‐related coronavirus: Classifying 2019‐nCoV and naming it SARS‐CoV‐2. Nature Microbiology, 5, 536– 544. 10.1038/s41564-020-0695-z PMC7095448 32123347 · DOI
- Gralinski, L. E., Sheahan, T. P., Morrison, T. E., Menachery, V. D., Jensen, K., Leist, S. R., … Baric, R. S. (2018). Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis. Mbio, 9, e01753– 18. 10.1128/mBio.01753-18 30301856 PMC6178621 · DOI
- Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y. I., … Cao, B. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet, 395(10223), 497– 506. 10.1016/S0140-6736(20)30183-5 PMC7159299 31986264 · DOI · Paper page
- Huang, F., Guo, J., Zou, Z., Liu, J., Cao, B., Zhang, S., … Li, L. (2014). Angiotensin II plasma levels are linked to disease severity and predict fatal outcomes in H7N9‐infected patients. Nature Communications, 5, 3595 10.1038/ncomms4595 PMC7091598 24800963 · DOI
- Imai, Y., Kuba, K., Rao, S., Huan, Y. I., Guo, F., Guan, B., … Penninger, J. M. (2005). Angiotensin‐converting enzyme 2 protects from severe acute lung failure. Nature, 436, 112– 116. 10.1038/nature03712 16001071 PMC7094998 · DOI · Paper page
- Inciardi, R. M., Lupi, L., Zaccone, G., Italia, L., Raffo, M., Tomasoni, D., … Metra, M. (2020). Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID‐19). JAMA Cardiology, 10.1001/jamacardio.2020.1096. [Epub ahead of print]. PMC7364333 32219357 · DOI
- Karlberg, J., Chong, D. S. Y., & Lai, W. Y. Y. (2004). Do men have a higher case fatality rate of severe acute respiratory syndrome than women do? American Journal of Epidemiology, 159, 229– 231. 10.1093/aje/kwh056 14742282 PMC7110237 · DOI
- Lehallier, B., Gate, D., Schaum, N., Nanasi, T., Lee, S. E., Yousef, H., … Wyss‐Coray, T.. (2019). Undulating changes in human plasma proteome profiles across the lifespan. Nature Medicine, 25, 1843– 1850. 10.1038/s41591-019-0673-2 PMC7062043 31806903 · DOI · Paper page
- Moore, B. J. B., & June, C. H. (2020). Cytokine release syndrome in severe COVID‐19. Science, 368(6490), 473– 474. 10.1126/science.abb8925 32303591 · DOI · Paper page
- Qin, C., Zhou, L., Hu, Z., Zhang, S., Yang, S., Tao, Y., … Tian, D.‐S. (2020). Dysregulation of immune response in patients with COVID‐19 in Wuhan, China. Clinical Infectious Diseases. ciaa248. 10.1093/cid/ciaa248. [Epub ahead of print]. PMC7108125 32161940 · DOI · Paper page
- Sarzi‐Puttini, P., Giorgi, V., Sirotti, S., Marotto, D., Ardizzone, S., Rizzardini, G., … Galli, M. (2020). COVID‐19, cytokines and immunosuppression: What can we learn from severe acute respiratory syndrome? Clinical and Experimental Rheumatology, 38, 337– 342. 32202240
- Shi, H., Han, X., Jiang, N., Cao, Y., Alwalid, O., Gu, J., … Zheng, C. (2020). Radiological findings from 81 patients with COVID‐19 pneumonia in Wuhan, China: A descriptive study. The Lancet Infectious Diseases, 20, 425– 434. 10.1016/S1473-3099(20)30086-4 32105637 PMC7159053 · DOI · Paper page
- Tchkonia, T., Morbeck, D. E., Von Zglinicki, T., Van Deursen, J., Lustgarten, J., Scrable, H., … Kirkland, J. L. (2010). Fat tissue, aging, and cellular senescence. Aging Cell, 9, 667– 684. 10.1111/j.1474-9726.2010.00608.x 20701600 PMC2941545 · DOI · Paper page
- Team, T. N. C. P. E. R. E. (2020). The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID‐19) in China. Chinese Journal of Epidemiology, 41, 145– 151.32064853
- Totura, A. L., Whitmore, A., Agnihothram, S., Schäfer, A., Katze, M. G., Heise, M. T., & Baric, R. S. (2015). Toll‐like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection. Mbio, 6(3), e00638– 15. 10.1128/mBio.00638-15 26015500 PMC4447251 · DOI
- Wan S., Yi Q., Fan S., Lv J., Zhang X., Guo L., … Gao C. (2020). Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID‐19) infected patients. British Journal of Haematology, 189(3), 428– 437. 10.1111/bjh.16659 32297671 PMC7262036 · DOI
- Wang, D., Hu, B. O., Hu, C., Zhu, F., Liu, X., Zhang, J., … Peng, Z. (2020). Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA, 323(11), 1061 10.1001/jama.2020.1585 PMC7042881 32031570 · DOI · Paper page
- Wang, T., Du, Z., Zhu, F., Cao, Z., An, Y., Gao, Y., & Jiang, B. (2020). Comorbidities and multi‐organ injuries in the treatment of COVID‐19. The Lancet, 395, e52 10.1016/S0140-6736(20)30558-4 PMC7270177 32171074 · DOI
- Yan, Y. W., Liu, Q., Li, N., Du, J. C., Li, X., Li, C., … Jiang, C. Y. (2015). Angiotensin II receptor blocker as a novel therapy in acute lung injury induced by avian influenza A H5N1 virus infection in mouse. Science China Life Sciences, 58, 208– 211. 10.1007/s11427-015-4814-7 25655897 PMC7088914 · DOI
- Yang, P., Gu, H., Zhao, Z., Wang, W., Cao, B., Lai, C., … Wang, X. (2014). Angiotensin‐converting enzyme 2 (ACE2) mediates influenza H7N9 virus‐induced acute lung injury. Scientific Reports, 4, 7027 10.1038/srep07027 25391767 PMC4229671 · DOI · Paper page
- Yang, X., Yu, Y., Xu, J., Shu, H., Xia, J., Liu, H., … Shang, Y.. (2020). Clinical course and outcomes of critically ill patients with SARS‐CoV‐2 pneumonia in Wuhan, China: A single‐centered, retrospective, observational study. The Lancet Respiratory Medicine, 8(5), 475– 481. 10.1016/S2213-2600(20)30079-5 32105632 PMC7102538 · DOI · Paper page
- Zhou, P., Yang, X.‐L., Wang, X.‐G., Hu, B., Zhang, L., Zhang, W., … Shi, Z.‐L. (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 579, 270– 273. 10.1038/s41586-020-2012-7 32015507 PMC7095418 · DOI · Paper page
- Zou, Z., Yan, Y., Shu, Y., Gao, R., Sun, Y., Li, X., … Jiang, C. (2014). Angiotensin‐converting enzyme 2 protects from lethal avian influenza A H5N1 infections. Nature Communications, 5, 3594 10.1038/ncomms4594 PMC7091848 24800825 · DOI
Cited by
Sorted by citations
Bajaj, V., Gadi, N., Spihlman, A. P., Wu, S. C., Choi, C. H., & Moulton, V. R. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2020.571416 · Cited by 476 · see citing works
SARS-CoV-2, COVID-19 and the aging immune system
Bartleson, J. M., Radenkovic, D., Covarrubias, A. J., Furman, D., Winer, D. A., & Verdin, E. (2021) · Nature Aging · doi:10.1038/s43587-021-00114-7 · Cited by 359 · see citing works
COVID‐19 is an emergent disease of aging
Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., Kerepesi, C., Yim, S. H., Fedichev, P. O., & Gladyshev, V. N. (2020) · Aging Cell · doi:10.1111/acel.13230 · Cited by 172 · see citing works
DNA damage response at telomeres boosts the transcription of SARS‐CoV‐2 receptor ACE2 during aging
Sepe, S., Rossiello, F., Cancila, V., Iannelli, F., Matti, V., Cicio, G., Cabrini, M., Marinelli, E., Alabi, B. R., di Lillo, A., et al. (2022) · The EMBO Reports · doi:10.15252/embr.202153658 · Cited by 42 · see citing works
Arnold, R. H., Tideman, P. A., Devlin, G. P., Carroll, G. E., Elder, A., Lowe, H., Macdonald, P. S., Bannon, P. G., Juergens, C., McGuire, M., et al. (2020) · Heart, Lung and Circulation · doi:10.1016/j.hlc.2020.05.001 · Cited by 38 · see citing works
“Low ACE-2 levels are found in the elderly and may be linked to increased COVID-19 severity [12] [13] [14] .”
Devaux, C. A., & Camoin-Jau, L. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.1042200 · Cited by 20 · see citing works
Chen, H., Peng, J., Wang, T., Wen, J., Chen, S., Huang, Y., & Zhang, Y. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115370 · Cited by 19 · see citing works
Beyond dexamethasone, emerging immuno‐thrombotic therapies for COVID‐19
Jensen, M. P., George, M., Gilroy, D., & Sofat, R. (2021) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.14540 · Cited by 17 · see citing works
- Authors
- Chen, J., Jiang, Q., Xia, X., Liu, K., Yu, Z., Tao, W., Gong, W., & Han, J. J.
- Affiliations
- Peking University (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Han, Jing‐Dong J.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2020-06-19
- Volume
- 19
- Issue
- 7
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC7323071
- OpenAlex
- W3012339747
- Cited by
- 436
- References
- 6
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 25 · 2023: 55 · 2022: 83 · 2021: 123 · 2020: 134 · 2018: 2
- FWCI
- 12.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Aging Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (91749205)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- ACE2 gene expression, SARS-CoV-2, COVID-19 pandemic, sex differences, age-related decline, type 2 diabetes, expression quantitative trait loci, East Asian populations, sex hormone receptors, estrogen, androgens, inflammatory cytokines, COVID-19 mortality, transcription factor binding sites, tissue-specific gene expression
- MeSH terms
- Betacoronavirus, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Female, Gene Expression Regulation, Humans, Peptidyl-Dipeptidase A, Male, Pneumonia, Viral, Receptors, Virus, Testis, Genetic Variation, Coronavirus Infections, Computational Biology, Pandemics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
