Polymorphism of tmprss2 (rs12329760) but not ace2 (rs4240157), tmprss11a (rs353163) and cd147 (rs8259) is associated with the severity of COVID-19 in the Ukrainian population

Main Article Content

Igor Kaidashev https://orcid.org/0000-0002-4708-0859
Olga Izmailova https://orcid.org/0000-0003-4770-3494
Oksana Shlykova https://orcid.org/0000-0002-6764-2767
Alina Kabaliei https://orcid.org/0000-0002-5502-3926
Anastasia Vatsenko https://orcid.org/0000-0002-8763-0974
Dmytro Ivashchenko https://orcid.org/0000-0001-7344-4129
Maksym Dudchenko https://orcid.org/0000-0003-4194-9290
Andrii Volianskyi https://orcid.org/0000-0002-6868-6702
Gennadiy Zelinskyy https://orcid.org/0000-0001-6338-2382
Tetiana Koval https://orcid.org/0000-0003-2685-8665
Ulf Dittmer https://orcid.org/0000-0001-9284-4849


transmembrane serine proteases, cd147, angiotensin-converting enzyme 2, polymorphism, COVID-19, oxygen therapy, TMPRSS2, TMPRSS11A


Background and aim:  Angiotensin-converting enzyme 2 (ACE2), transmembrane serine 2 and serine 11A proteases (TMPRSS2, TMPRSS11A), and a cell surface cluster of differentiation 147 (CD147) might be a gene candidate that exerts the susceptibility to and mortality from coronavirus disease 19 (COVID-19). The aim of this study was to investigate the associations between ace2, tmprss2, tmprss11a, and cd147 polymorphic variants and the severity of COVID-19 in the Ukrainian population. Methods: The study population consisted of the Ukrainian population with COVID-19: patients without oxygen therapy (n=62), with non-invasive (n=92) and invasive (n=35) oxygen therapy, as well as control subjects (n=92). Allelic polymorphisms of ace2 rs4240157, tmprss2 rs12329760, and tmprss11a rs353163 were determined by real-time PCR, and cd147 rs8259 polymorphism was detected by PCR with subsequent restrictase analysis. We compared investigated polymorphisms distribution with other populations by meta-analysis. Results: Our study is the first to obtain data about the distribution of investigated gene polymorphisms in the Ukrainian population: tmprss2 rs12329760 – CC 60.9%, CT 35.9%, TT 3.2%; tmprss11a rs353163 – CC 46.7%, CT 40.2%, TT 13.1%; ace2 rs4240157 – CC 7.6%, C 18.5%, CT 22.8%, TT 19.6%, T 31.5%; cd147 rs8259 – TT 60.9%, AT 32.6%, AA 6.5%. This distribution was similar to the Northern, Western and Southern European populations. There was a statistically significant difference in the frequency of tmprss2 polymorphic genotypes CC 57.1%, CT 28.6%, and TT 14.3% (P<0.05) in COVID-19 patients with invasive oxygen therapy in comparison with non-invasive oxygen therapy. This tmprss2 mutation occurs in the scavenger receptor cysteine-rich (SRCR) domain and might be important for protein-protein interaction in a calcium-dependent manner. Conclusions: Our study indicated the presence of an association between the tmprss2 rs12329760 polymorphism and the severity of COVID-19 in the Ukrainian population.


Download data is not yet available.
Abstract 147 | PDF Downloads 94


1. Mallah SI, Ghorab OK, Al-Salmi S, et al. COVID-19: breaking down a global health crisis. Ann Clin Microbiol Antimicrob. 2021;20(1):35. Published 2021 May 18. doi:10.1186/s12941-021-00438-7.
2. Hou Y, Zhao J, Martin W, et al. New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. BMC Med. 2020;18(1):216. Published 2020 Jul 15. doi:10.1186/s12916-020-01673-z.
3. Giudicessi JR, Roden DM, Wilde AAM, Ackerman MJ. Genetic susceptibility for COVID-19-associated sudden cardiac death in African Americans. Heart Rhythm. 2020;17(9):1487-1492. doi:10.1016/j.hrthm.2020.04.045.
4. Gemmati D, Bramanti B, Serino ML, Secchiero P, Zauli G, Tisato V. COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2 Genes, Immunity, Inflammation and Coagulation. Might the Double X-chromosome in Females Be Protective against SARS-CoV-2 Compared to the Single X-Chromosome in Males?. Int J Mol Sci. 2020;21(10):3474. Published 2020 May 14. doi:10.3390/ijms21103474.
5. Izmailova O, Shlykova O, Vatsenko A, et al. Allele С (rs5186) of at1r is associated with the severity of COVID-19 in the Ukrainian population. Infect Genet Evol. 2022;98:105227. doi:10.1016/j.meegid.2022.105227.
6. Kaidashev I, Shlykova O, Izmailova O, et al. Host gene variability and SARS-CoV-2 infection: A review article. Heliyon. 2021;7(8):e07863. doi:10.1016/j.heliyon.2021.e07863.
7. Severe Covid-19 GWAS Group, Ellinghaus D, Degenhardt F, et al. Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N Engl J Med. 2020;383(16):1522-1534. doi:10.1056/NEJMoa2020283.
8. Shen Z, Xiao Y, Kang L, et al. Genomic Diversity of Severe Acute Respiratory Syndrome-Coronavirus 2 in Patients With Coronavirus Disease 2019 [published correction appears in Clin Infect Dis. 2021 Dec 16;73(12):2374]. Clin Infect Dis. 2020;71(15):713-720. doi:10.1093/cid/ciaa203.
9. Tabibzadeh A, Zamani F, Laali A, et al. SARS-CoV-2 Molecular and Phylogenetic analysis in COVID-19 patients: A preliminary report from Iran. Infect Genet Evol. 2020;84:104387. doi:10.1016/j.meegid.2020.104387.
10. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-280.e8. doi:10.1016/j.cell.2020.02.052.
11. Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N. TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection. J Virol. 2019;93(6):e01815-18. Published 2019 Mar 5. doi:10.1128/JVI.01815-18.
12. Chen Z, Mi L, Xu J, et al. Function of HAb18G/CD147 in invasion of host cells by severe acute respiratory syndrome coronavirus. J Infect Dis. 2005;191(5):755-760. doi:10.1086/427811.
13. Vilella F, Wang W, Moreno I, Roson B, Quake SR, Simon C. Single-cell RNA sequencing of SARS-CoV-2 cell entry factors in the preconceptional human endometrium. Hum Reprod. 2021;36(10):2709-2719. doi:10.1093/humrep/deab183.
14. Taleghani N, Taghipour F. Diagnosis of COVID-19 for controlling the pandemic: A review of the state-of-the-art. Biosens Bioelectron. 2021;174:112830. doi:10.1016/j.bios.2020.112830.
15. Yan J, Mao Y, Wang C, Wang Z. Association Study between an SNP in CD147 and Its Expression With Acute Coronary Syndrome in a Jiangsu Chinese Population. Medicine (Baltimore). 2015;94(42):e1537. doi:10.1097/MD.0000000000001537.
16. https://www.ensembl.org/Homo_sapiens/Variation/Population?db=core;r=21:41480070-41481070;v=rs12329760;vdb=variation;vf=722896905#ncbialfa_anchor
17. Umar M, Upadhyay R, Kumar S, Ghoshal UC, Mittal B. Modification of risk, but not survival of esophageal cancer patients by esophageal cancer-related gene 1 Arg290Gln polymorphism: a case-control study and meta-analysis. J Gastroenterol Hepatol. 2013;28(11):1717-1724. doi:10.1111/jgh.12335.
18. Akbari MR, Malekzadeh R, Shakeri R, et al. Candidate gene association study of esophageal squamous cell carcinoma in a high-risk region in Iran. Cancer Res. 2009;69(20):7994-8000. doi:10.1158/0008-5472.CAN-09-1149.
19. https://www.ensembl.org/Homo_sapiens/Variation/Population?db=core;r=4:67918556-67919556;v=rs353163;vdb=variation;vf=90470389
20. https://www.ensembl.org/Homo_sapiens/Variation/Population?db=core;r=X:15568341-15569341;v=rs4240157;vdb=variation;vf=93325552
21. Łacina P, Butrym A, Mazur G, Bogunia-Kubik K. BSG and MCT1 Genetic Variants Influence Survival in Multiple Myeloma Patients. Genes (Basel). 2018;9(5):226. Published 2018 Apr 24. doi:10.3390/genes9050226.
22. Li MP, Hu XL, Yang YL, et al. Basigin rs8259 Polymorphism Confers Decreased Risk of Chronic Heart Failure in a Chinese Population. Int J Environ Res Public Health. 2017;14(2):211. Published 2017 Feb 21. doi:10.3390/ijerph14020211.
23. Ni T, Chen M, Yang K, Shao J, Fu Y, Zhou W. Association of CD147 genetic polymorphisms with carotid atherosclerotic plaques in a Han Chinese population with cerebral infarction. Thromb Res. 2017;156:29-35.doi:10.1016/j.thromres.2017.05.027.
24. https://www.ensembl.org/Homo_sapiens/Variation/Population?db=core;r=19:582427-583427;v=rs8259;vdb=variation;vf=201683794.
25. Wulandari L, Hamidah B, Pakpahan C, et al. Initial study on TMPRSS2 p.Val160Met genetic variant in COVID-19 patients. Hum Genomics. 2021;15(1):29. Published 2021 May 17. doi:10.1186/s40246-021-00330-7.
26. Schönfelder K, Breuckmann K, Elsner C, et al. Transmembrane serine protease 2 Polymorphisms and Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Type 2 Infection: A German Case-Control Study. Front Genet. 2021;12:667231. Published 2021 Apr 21. doi:10.3389/fgene.2021.667231.
27. Monticelli M, Hay Mele B, Benetti E, et al. Protective Role of a TMPRSS2 Variant on Severe COVID-19 Outcome in Young Males and Elderly Women. Genes (Basel). 2021;12(4):596. Published 2021 Apr 19. doi:10.3390/genes12040596.
28. Mir MM, Mir R, Alghamdi MAA, et al. Strong Association of Angiotensin Converting Enzyme-2 Gene Insertion/Deletion Polymorphism with Susceptibility to SARS-CoV-2, Hypertension, Coronary Artery Disease and COVID-19 Disease Mortality. J Pers Med. 2021;11(11):1098. Published 2021 Oct 27. doi:10.3390/jpm11111098.
29. Alexandre J, Cracowski JL, Richard V, Bouhanick B; 'Drugs, COVID-19' working group of the French Society of Pharmacology, Therapeutics. Renin-angiotensin-aldosterone system and COVID-19 infection. Ann Endocrinol (Paris). 2020;81(2-3):63-67. doi:10.1016/j.ando.2020.04.005.
30. Asselta R, Paraboschi EM, Mantovani A, Duga S. ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy. Aging (Albany NY). 2020;12(11):10087-10098. doi:10.18632/aging.103415.
31. Das R, Ghate D. Investigating the likely association between genetic ancestry and COVID-19 manifestations. doi: https://doi.org/10.1101/2020.04.05.20054627.
32. Lucas JM, Heinlein C, Kim T, et al. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer Discov. 2014;4(11):1310-1325. doi:10.1158/2159-8290.CD-13-1010.
33. Al-Mulla F, Mohammad A, Al Madhoun A, et al. ACE2 and FURIN variants are potential predictors of SARS-CoV-2 outcome: A time to implement precision medicine against COVID-19. Heliyon. 2021;7(2):e06133. doi:10.1016/j.heliyon.2021.e06133.
34. Latini A, Agolini E, Novelli A, et al. COVID-19 and Genetic Variants of Protein Involved in the SARS-CoV-2 Entry into the Host Cells. Genes (Basel). 2020;11(9):1010. Published 2020 Aug 27. doi:10.3390/genes11091010.
35. Vargas-Alarcón G, Posadas-Sánchez R, Ramírez-Bello J. Variability in genes related to SARS-CoV-2 entry into host cells (ACE2, TMPRSS2, TMPRSS11A, ELANE, and CTSL) and its potential use in association studies. Life Sci. 2020;260:118313. doi:10.1016/j.lfs.2020.118313.
36. Hohenester E, Sasaki T, Timpl R. Crystal structure of a scavenger receptor cysteine-rich domain sheds light on an ancient superfamily. Nat Struct Biol. 1999;6(3):228-232. doi:10.1038/6669.
37. Jeon S, Blazyte A, Yoon C, et al. Regional TMPRSS2 V197M Allele Frequencies Are Correlated with COVID-19 Case Fatality Rates. Mol Cells. 2021;44(9):680-687. doi:10.14348/molcells.2021.2249.
38. Zarubin A, Stepanov V, Markov A, et al. Structural Variability, Expression Profile, and Pharmacogenetic Properties of TMPRSS2 Gene as a Potential Target for COVID-19 Therapy. Genes (Basel). 2020;12(1):19. Published 2020 Dec 25. doi:10.3390/genes12010019.
39. de Leeuw AJM, Oude Luttikhuis MAM, Wellen AC, Müller C, Calkhoven CF. Obesity and its impact on COVID-19. J Mol Med (Berl). 2021;99(7):899-915. doi:10.1007/s00109-021-02072-4.
40. Tamara A, Tahapary DL. Obesity as a predictor for a poor prognosis of COVID-19: A systematic review. Diabetes Metab Syndr. 2020;14(4):655-659. doi:10.1016/j.dsx.2020.05.020.
41. Chen Y, Klein SL, Garibaldi BT, et al. Aging in COVID-19: Vulnerability, immunity and intervention. Ageing Res Rev. 2021;65:101205. doi:10.1016/j.arr.2020.101205.
42. Parohan M, Yaghoubi S, Seraji A, Javanbakht MH, Sarraf P, Djalali M. Risk factors for mortality in patients with Coronavirus disease 2019 (COVID-19) infection: a systematic review and meta-analysis of observational studies. Aging Male. 2020;23(5):1416-1424. doi:10.1080/13685538.2020.1774748.
43. Qian W, Kallergi M, Clarke LP, et al. Tree structured wavelet transform segmentation of microcalcifications in digital mammography. Med Phys. 1995;22(8):1247-1254. doi:10.1118/1.597562.
44. Zhang C, Zhang Y, Zhang S, et al. Intracellular autoactivation of TMPRSS11A, an airway epithelial transmembrane serine protease. J Biol Chem. 2020;295(36):12686-12696. doi:10.1074/jbc.RA120.014525.
45. Fernandez C, Burgos A, Morales D, et al. TMPRSS11a is a novel age-altered, tissue specific regulator of migration and wound healing. FASEB J. 2021;35(5):e21597. doi:10.1096/fj.202002253RRR.
46. Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875-879. doi:10.1038/nm1267.
47. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000;275(43):33238-33243. doi:10.1074/jbc.M002615200.
48. Yi L, Gu YH, Wang XL, et al. Association of ACE, ACE2 and UTS2 polymorphisms with essential hypertension in Han and Dongxiang populations from north-western China. J Int Med Res. 2006;34(3):272-283. doi:10.1177/147323000603400306.
49. Patnaik M, Pati P, Swain SN, et al. Association of angiotensin-converting enzyme and angiotensin-converting enzyme-2 gene polymorphisms with essential hypertension in the population of Odisha, India. Ann Hum Biol. 2014;41(2):145-152. doi:10.3109/03014460.2013.837195.
50. Pinheiro DS, Santos RS, Jardim PCBV, et al. The combination of ACE I/D and ACE2 G8790A polymorphisms revels susceptibility to hypertension: A genetic association study in Brazilian patients. PLoS One. 2019;14(8):e0221248. Published 2019 Aug 20. doi:10.1371/journal.pone.0221248.
51. Zheng H, Cao JJ. Angiotensin-Converting Enzyme Gene Polymorphism and Severe Lung Injury in Patients with Coronavirus Disease 2019. Am J Pathol. 2020;190(10):2013-2017. doi:10.1016/j.ajpath.2020.07.009.
52. Yancy CW. COVID-19 and African Americans. JAMA. 2020;323(19):1891-1892. doi:10.1001/jama.2020.6548.
53. Aung AK, Aitken T, Teh BM, et al. Angiotensin converting enzyme genotypes and mortality from COVID-19: An ecological study. J Infect. 2020;81(6):961-965. doi:10.1016/j.jinf.2020.11.012.
54. Pan Y, Wang T, Li Y, et al. Association of ACE2 polymorphisms with susceptibility to essential hypertension and dyslipidemia in Xinjiang, China. Lipids Health Dis. 2018;17(1):241. Published 2018 Oct 20. doi:10.1186/s12944-018-0890-6.
55. Lu N, Yang Y, Wang Y, et al. ACE2 gene polymorphism and essential hypertension: an updated meta-analysis involving 11,051 subjects. Mol Biol Rep. 2012;39(6):6581-6589. doi:10.1007/s11033-012-1487-1.
56. Patel SK, Wai B, Ord M, et al. Association of ACE2 genetic variants with blood pressure, left ventricular mass, and cardiac function in Caucasians with type 2 diabetes. Am J Hypertens. 2012;25(2):216-222. doi:10.1038/ajh.2011.188.
57. Wooster L, Nicholson CJ, Sigurslid HH, Cardenas CLL, Malhotra R. Polymorphisms in the ace2 locus associate with severity of COVID-19 infection [preprint]. MedRxiv. 2020.06.18.20135152; doi: https://doi.org/10.1101/2020.06.18.20135152.
58. Gwinn WM, Damsker JM, Falahati R, et al. Novel approach to inhibit asthma-mediated lung inflammation using anti-CD147 intervention. J Immunol. 2006;177(7):4870-4879. doi:10.4049/jimmunol.177.7.4870.
59. Schulz C, von Brühl ML, Barocke V, et al. EMMPRIN (CD147/basigin) mediates platelet-monocyte interactions in vivo and augments monocyte recruitment to the vascular wall. J Thromb Haemost. 2011;9(5):1007-1019. doi:10.1111/j.1538-7836.2011.04235.x.
60. Venkatesan B, Valente AJ, Prabhu SD, Shanmugam P, Delafontaine P, Chandrasekar B. EMMPRIN activates multiple transcription factors in cardiomyocytes, and induces interleukin-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-kappaB andMKK7/JNK/AP-1 signaling. J Mol Cell Cardiol. 2010;49(4):655-663. doi:10.1016/j.yjmcc.2010.05.007.
61. Arshad AR, Bashir I, Ijaz F, et al. Is COVID-19 Fatality Rate Associated with Malaria Endemicity?. Discoveries (Craiova). 2020;8(4):e120. Published 2020 Dec 11. doi:10.15190/d.2020.17.
62. Wu LS, Li FF, Sun LD, et al. A miRNA-492 binding-site polymorphism in BSG (basigin) confers risk to psoriasis in central south Chinese population. Hum Genet. 2011;130(6):749-757. doi:10.1007/s00439-011-1026-5.
63. Mao Y, Yan J, Wang C, Wang Z, Liu P, Yuan W. Zhonghua Xin Xue Guan Bing Za Zhi. 2014;42(7):566-570.
64. Takeda M. Proteolytic activation of SARS-CoV-2 spike protein. Microbiol Immunol. 2022;66(1):15-23. doi:10.1111/1348-0421.12945.
65. Martínez VG, Moestrup SK, Holmskov U, Mollenhauer J, Lozano F. The conserved scavenger receptor cysteine-rich superfamily in therapy and diagnosis. Pharmacol Rev. 2011;63(4):967-1000. doi:10.1124/pr.111.004523.
66. Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE. Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3 [published correction appears in Genomics 2001 Sep;77(1-2):114]. Genomics. 1997;44(3):309-320. doi:10.1006/geno.1997.4845.
67. Lai AL, Millet JK, Daniel S, Freed JH, Whittaker GR. The SARS-CoV Fusion Peptide Forms an Extended Bipartite Fusion Platform that Perturbs Membrane Order in a Calcium-Dependent Manner. J Mol Biol. 2017;429(24):3875-3892. doi:10.1016/j.jmb.2017.10.017.
68. Cashman DP. Why the lower reported prevalence of asthma in patients diagnosed with COVID-19 validates repurposing EDTA solutions to prevent and manage treat COVID-19 disease. Med Hypotheses. 2020;144:110027. doi:10.1016/j.mehy.2020.110027.

Most read articles by the same author(s)