Impact of Genetics on Predisposition and Prognosis of COVID-19

Document Type : Review Article


1 Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

2 Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran


The global pandemic of COVID-19 accounts for more than 3 million deaths globally. COVID-19 is a contagious infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Wide range of clinical manifestations from gastrointestinal (GI) symptoms, loss of smell and taste and mild and severe respiratory infection to death has been reported with COVID-19. However, not much is known about the role of genetics in predisposition and progression of COVID-19. It is assumed that immense diversity of symptoms in infected individuals may be due to differences in host genetic characteristics and that genetic variations may be involved in determining the outcome of disease. However, the exact underlying mechanisms of these variations is unknown to date. Profound understanding of the underlying factors such as host genetics that determine the degree of susceptibility to infection and the disease severity may assist in better prediction of the population with the highest risk of infection along with achieving better medical treatment.
In this review, we focused on the play of genetic variants associated with the susceptibility and severity of COVID-19 disease in the recent pandemic.


1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum in: Lancet. 2020 Jan 30;: PMID: 31986264; PMCID: PMC7159299.
2. Ottaviano G, Carecchio M, Scarpa B, Marchese-Ragona R. Olfactory and rhinological evaluations in SARS-CoV-2 patients complaining of olfactory loss. Rhinology. 2020 Aug 1;58(4):400-401. doi: 10.4193/Rhin20.136. PMID: 32338254.
3. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology. 2020;158(6):1831-1833.e3. doi:10.1053/j.gastro.2020.02.055
4. Ovsyannikova IG, Haralambieva IH, Crooke SN, Poland GA, Kennedy RB. The role of host genetics in the immune response to SARS-CoV-2 and COVID-19 susceptibility and severity. Immunol Rev. 2020 Jul;296(1):205-219. doi: 10.1111/imr.12897. Epub 2020 Jul 13. PMID: 32658335; PMCID: PMC7404857.
5. Elhabyan A, Elyaacoub S, Sanad E, Abukhadra A, Elhabyan A, Dinu V. The role of host genetics in susceptibility to severe viral infections in humans and insights into host genetics of severe COVID-19: A systematic review. Virus Res. 2020 Nov;289:198163. doi: 10.1016/j.virusres.2020.198163. Epub 2020 Sep 9. PMID: 32918943; PMCID: PMC7480444.
6. Shankarkumar U. The human leukocyte antigen (HLA) system. Int J Hum Genet. 2004;4(2):91-103.
7. International HIV Controllers Study, Pereyra F, Jia X, McLaren PJ, Telenti A, de Bakker PI, et al. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science. 2010 Dec 10;330(6010):1551-7. doi: 10.1126/science.1195271. Epub 2010 Nov 4. PMID: 21051598; PMCID: PMC3235490.
8. Zhang Y, Peng Y, Yan H, Xu K, Saito M, Wu H, et al. Multilayered defense in HLA-B51-associated HIV viral control. J Immunol. 2011 Jul 15;187(2):684-91. doi: 10.4049/jimmunol.1100316. Epub 2011 Jun 13. PMID: 21670313; PMCID: PMC3166850.
9. Nguyen A, David JK, Maden SK, et al. Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2. J Virol. 2020;94(13):e00510-20. Published 2020 Jun 16. doi:10.1128/JVI.00510-20
10. Lin M, Tseng HK, Trejaut JA, Lee HL, Loo JH, Chu CC, et al. Association of HLA class I with severe acute respiratory syndrome coronavirus infection. BMC Med Genet. 2003 Sep 12;4:9. doi: 10.1186/1471-2350-4-9. PMID: 12969506; PMCID: PMC212558.
11. Lorente L, Martín MM, Franco A, Barrios Y, Cáceres JJ, Solé-Violán J, et al. HLA genetic polymorphisms and prognosis of patients with COVID-19. Med Intensiva. 2021 Mar;45(2):96-103. doi: 10.1016/j.medin.2020.08.004. Epub 2020 Sep 6. PMID: 32988645; PMCID: PMC7474921.
12. Amoroso A, Magistroni P, Vespasiano F, Bella A, Bellino S, Puoti F, et al. HLA and AB0 Polymorphisms May Influence SARS-CoV-2 Infection and COVID-19 Severity. Transplantation. 2021 Jan 1;105(1):193-200. doi: 10.1097/TP.0000000000003507. PMID: 33141807.
13. Li J, Wang X, Chen J, Cai Y, Deng A, Yang M. Association between ABO blood groups and risk of SARS-CoV-2 pneumonia. Br J Haematol. 2020 Jul;190(1):24-27. doi: 10.1111/bjh.16797. Epub 2020 May 26. PMID: 32379894; PMCID: PMC7267665.
14. Zhao J, Yang Y, Huang H, Li D, Gu D, Lu X, et al. Relationship between the ABO Blood Group and the COVID-19 Susceptibility. Clinical Infectious Diseases. 2020;1-4.
15. Zietz M, Zucker J, Tatonetti N. Testing the association between blood type and COVID-19 infection, intubation, and death. medRxiv. Preprint posted online. 2020;10.
16. Guillon P, Clément M, Sébille V, Rivain JG, Chou CF, Ruvoën-Clouet N, et al. Inhibition of the interaction between the SARS-CoV spike protein and its cellular receptor by anti-histo-blood group antibodies. Glycobiology. 2008 Dec;18(12):1085-93. doi: 10.1093/glycob/cwn093. Epub 2008 Sep 25. PMID: 18818423; PMCID: PMC7108609.
17. Gérard C, Maggipinto G, Minon JM. COVID-19 and ABO blood group: another viewpoint. Br J Haematol. 2020;190(2):e93-e94. doi:10.1111/bjh.16884
18. Stussi G, Huggel K, Lutz HU, Schanz U, Rieben R, Seebach JD. Isotype-specific detection of ABO blood group antibodies using a novel flow cytometric method. Br J Haematol. 2005 Sep;130(6):954-63. doi: 10.1111/j.1365-2141.2005.05705.x. PMID: 16156865.
19. Ellinghaus D, Degenhardt F, Bujanda L, Buti M, Albillos A, Invernizzi P, et al. The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis. MedRxiv. 2020;1-23.
20. Ulhaq ZS, Soraya GV. Interleukin-6 as a potential biomarker of COVID-19 progression. Med Mal Infect. 2020 Jun;50(4):382-383. doi: 10.1016/j.medmal.2020.04.002. Epub 2020 Apr 4. PMID: 32259560; PMCID: PMC7129451.
21. Jia R, Xu F, Qian J, Yao Y, Miao C, Zheng YM, et al. Identification of an endocytic signal essential for the antiviral action of IFITM3. Cell Microbiol. 2014 Jul;16(7):1080-93. doi: 10.1111/cmi.12262. Epub 2014 Feb 13. PMID: 24521078; PMCID: PMC4065222.
22. Nikoloudis D, Kountouras D, Hiona A. The frequency of combined IFITM3 haplotype involving the reference alleles of both rs12252
and rs34481144 is in line with COVID-19 standardized mortality ratio of ethnic groups in England. PeerJ. 2020 Nov 12;8:e10402. doi: 10.7717/peerj.10402. PMID: 33240681; PMCID: PMC7666821.
23. Zhang YH, Zhao Y, Li N, Peng YC, Giannoulatou E, Jin RH, Yan HP, Wu H, Liu JH, Liu N, Wang DY, Shu YL, Ho LP, Kellam P, McMichael A, Dong T. Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals. Nat Commun. 2013;4:1418. doi: 10.1038/ncomms2433. PMID: 23361009; PMCID: PMC3562464.
24. Kim YC, Jeong BH. Strong Correlation between the Case Fatality Rate of COVID-19 and the rs6598045 Single Nucleotide Polymorphism (SNP) of the Interferon-Induced Transmembrane Protein 3 (IFITM3) Gene at the Population-Level. Genes (Basel). 2020 Dec 30;12(1):42. doi: 10.3390/genes12010042. PMID: 33396837; PMCID: PMC7824003.
25. Pati A, Padhi S, Suvankar S, Panda AK. Minor Allele of Interferon-Induced Transmembrane Protein 3 Polymorphism (rs12252) Is Covered Against Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Mortality: A Worldwide Epidemiological Investigation. J Infect Dis. 2021 Jan 4;223(1):175-178. doi: 10.1093/infdis/jiaa630. PMID: 33011811; PMCID: PMC7665563.
26. Alghamdi J, Alaamery M, Barhoumi T, Rashid M, Alajmi H, Aljasser N, et al. Interferon-induced transmembrane protein-3 genetic variant rs12252 is associated with COVID-19 mortality. Genomics. 2021 Apr 7;113(4):1733-1741. doi: 10.1016/j.ygeno.2021.04.002. Epub ahead of print. PMID: 33838280; PMCID: PMC8025598.
27. Huang IC, Bailey CC, Weyer JL, Radoshitzky SR, Becker MM, Chiang JJ, et al. Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus. PLoS Pathog. 2011 Jan 6;7(1):e1001258. doi: 10.1371/journal.ppat.1001258. PMID: 21253575; PMCID: PMC3017121.
28. Everitt AR, Clare S, Pertel T, John SP, Wash RS, Smith SE, et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature. 2012 Mar 25;484(7395):519-23. doi: 10.1038/nature10921. PMID: 22446628; PMCID: PMC3648786.
29. Pinto BGG, Oliveira AER, Singh Y, Jimenez L, Gonçalves ANA, Ogava RLT, et al. ACE2 Expression Is Increased in the Lungs of Patients With Comorbidities Associated With Severe COVID-19. J Infect Dis. 2020 Jul 23;222(4):556-563. doi: 10.1093/infdis/jiaa332. PMID: 32526012; PMCID: PMC7377288.
30. Stawiski EW, Diwanji D, Suryamohan K, Gupta R, Fellouse FA, Sathirapongsasuti F, et al. Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility. BioRxiv. 2020.
31. Li Q, Cao Z, Rahman P. Genetic variability of human angiotensin‐converting enzyme 2 (hACE2) among various ethnic populations. Mol Genet Genomic Med. 2020;8(8):e1344. doi: 10.1002/mgg3.1344
32. Calcagnile M, Forgez P, Iannelli A, Bucci C, Alifano M, Alifano P. Molecular docking simulation reveals ACE2 polymorphisms that may increase the affinity of ACE2 with the SARS-CoV-2 Spike protein. Biochimie. 2021 Jan;180:143-148. doi: 10.1016/j.biochi.2020.11.004. Epub 2020 Nov 9. PMID: 33181224; PMCID: PMC7834737.
33. Crabtree GR, Olson EN. NFAT signaling: choreographing the social lives of cells. Cell. 2002 Apr;109 Suppl:S67-79. doi: 10.1016/s0092-8674(02)00699-2. PMID: 11983154.
34. Barash A, Machluf Y, Ariel I, Dekel Y. The Pursuit of COVID-19 Biomarkers: Putting the Spotlight on ACE2 and TMPRSS2 Regulatory Sequences. Front Med (Lausanne). 2020 Oct 30;7:582793. doi: 10.3389/fmed.2020.582793. PMID: 33195331; PMCID: PMC7661736.
35. Roos AB, Barton JL, Miller-Larsson A, Dahlberg B, Berg T, Didon L, et al. Lung epithelial-C/EBPβ contributes to LPS-induced inflammation and its suppression by formoterol. Biochem Biophys Res Commun. 2012 Jun 22;423(1):134-9. doi: 10.1016/j.bbrc.2012.05.096. Epub 2012 May 24. PMID: 22634316.
36. Dhawan L, Liu B, Blaxall BC, Taubman MB. A novel role for the glucocorticoid receptor in the regulation of monocyte chemoattractant protein-1 mRNA stability.
J Biol Chem. 2007 Apr 6;282(14):10146-52. doi: 10.1074/jbc.M605925200. Epub 2007 Feb 2. PMID: 17276989.
37. Cho H, Park OH, Park J, Ryu I, Kim J, Ko J, Kim YK. Glucocorticoid receptor interacts with PNRC2 in a ligand-dependent manner to recruit UPF1 for rapid mRNA degradation. Proc Natl Acad Sci U S A. 2015 Mar 31;112(13):E1540-9. doi: 10.1073/pnas.1409612112. Epub 2015 Mar 16. PMID: 25775514; PMCID: PMC4386400.
38. Delanghe JR, Speeckaert MM, De Buyzere ML. The host's angiotensin-converting enzyme polymorphism may explain epidemiological findings in COVID-19 infections. Clin Chim Acta. 2020 Jun;505:192-193. doi: 10.1016/j.cca.2020.03.031. Epub 2020 Mar 24. PMID: 32220422; PMCID: PMC7102561.
39. Delanghe JR, De Buyzere ML, Speeckaert MM. C3 and ACE1 polymorphisms are more
important confounders in the spread and outcome of COVID-19 in comparison with ABO polymorphism. Eur J Prev Cardiol. 2020 Aug;27(12):1331-1332. doi: 10.1177/2047487320931305. Epub 2020 May 27. PMID: 32460534; PMCID: PMC7717311.
40. Hatami N, Ahi S, Sadeghinikoo A, Foroughian M, Javdani F, Kalani N, et al. Worldwide ACE (I/D) polymorphism may affect COVID-19 recovery rate: an ecological meta-regression. Endocrine. 2020 Jun;68(3):479-484. doi: 10.1007/s12020-020-02381-7. Epub 2020 Jun 15. PMID: 32542429; PMCID: PMC7294766.
41. Srivastava A, Bandopadhyay A, Das D, et al. Genetic Association of ACE2 rs2285666 Polymorphism With COVID-19 Spatial Distribution in India. Front Genet. 2020;11:564741. Published 2020 Sep 25. doi:10.3389/fgene.2020.564741
42. Martínez-Sanz J, Jiménez D, Martínez-Campelo L, Cruz R, Vizcarra P, Sánchez-Conde M, et al. Role of ACE2 genetic polymorphisms in susceptibility to SARS-CoV-2 among highly exposed but non infected healthcare workers. Emerg Microbes Infect. 2021 Dec;10(1):493-496. doi: 10.1080/22221751.2021.1902755. PMID: 33704002; PMCID: PMC7993370.
43. Glowacka I, Bertram S, Müller MA, Allen P, Soilleux E, Pfefferle S, et al. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for
membrane fusion and reduces viral control by the humoral immune response. J Virol. 2011 May;85(9):4122-34. doi: 10.1128/JVI.02232-10. Epub 2011 Feb 16. PMID: 21325420; PMCID: PMC3126222.
44. Bhattacharyya C, Das C, Ghosh A, Singh AK, Mukherjee S, Majumder PP, et al. Global spread of SARS-CoV-2 subtype with spike protein mutation D614G is shaped by human genomic variations that regulate expression of TMPRSS2 and MX1 genes. BioRxiv. 2020;1-30.
45. Cheng Z, Zhou J, To KK, Chu H, Li C, Wang D, et al. Identification of TMPRSS2 as a Susceptibility Gene for Severe 2009 Pandemic A(H1N1) Influenza and A(H7N9) Influenza.
J Infect Dis. 2015 Oct 15;212(8):1214-21. doi: 10.1093/infdis/jiv246. Epub 2015 Apr 22. PMID: 25904605; PMCID: PMC7107393.
46. Laamarti M, Kartti S, Alouane T, Laamarti R, Allam L, Ouadghiri M, et al. Genetic analysis of SARS-CoV-2 strains collected from North Africa: viral origins and mutational spectrum. bioRxiv. 2020;1-19.
47. 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 Jun 5;12(11):10087-10098. doi: 10.18632/aging.103415. Epub 2020 Jun 5. PMID: 32501810; PMCID: PMC7346072.
48. Wu C, Zheng S, Chen Y, Zheng M. Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCoV, in the nasal tissue. MedRxiv. 2020;1-6.
49. Tukiainen T, Villani AC, Yen A, Rivas MA, Marshall JL, Satija R, et al. Landscape of X chromosome inactivation across human tissues. Nature. 2017 Oct 11;550(7675):244-248. doi: 10.1038/nature24265. Erratum in: Nature. 2018 Mar 7;555(7695):274. PMID: 29022598; PMCID: PMC5685192.
50. Nowak A, Boesch L, Andres E, Battegay E, Hornemann T, Schmid C, et al. Effect of vitamin D3 on self-perceived fatigue: A double-blind randomized placebo-controlled trial. Medicine (Baltimore). 2016 Dec;95(52):e5353. doi: 10.1097/MD.0000000000005353. Erratum in: Medicine (Baltimore). 2017 Jan 20;96(3):e6038. PMID: 28033244; PMCID: PMC5207540.
51. Xu J, Yang J, Chen J, Luo Q, Zhang Q, Zhang H. Vitamin D alleviates lipopolysaccharide‑induced acute lung injury via regulation of the renin‑angiotensin system. Mol Med Rep. 2017 Nov;16(5):7432-7438. doi: 10.3892/mmr.2017.7546. Epub 2017 Sep 20. PMID: 28944831; PMCID: PMC5865875.
52. Carlberg C, Muñoz A. An update on vitamin D signaling and cancer. Semin Cancer Biol. 2020 May 30:S1044-579X(20)30114-0. doi: 10.1016/j.semcancer.2020.05.018. Epub ahead of print. PMID: 32485310.
53. Sadeghi K, Wessner B, Laggner U, Ploder M, Tamandl D, Friedl J, et al. Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol. 2006 Feb;36(2):361-70. doi: 10.1002/eji.200425995. PMID: 16402404.
54. Bizzaro G, Antico A, Fortunato A, Bizzaro N. Vitamin D and Autoimmune Diseases: Is Vitamin D Receptor (VDR) Polymorphism the Culprit? Isr Med Assoc J. 2017 Jul;19(7):438-443. PMID: 28786260.
55. Jolliffe DA, Greiller CL, Mein CA, Hoti M, Bakhsoliani E, Telcian AG, et al. Vitamin D receptor genotype influences risk of upper respiratory infection. Br J Nutr. 2018 Oct;120(8):891-900. doi: 10.1017/S000711451800209X. Epub 2018 Aug 22. PMID: 30132432.
56. Arnaud J, Constans J. Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP). Hum Genet. 1993 Sep;92(2):183-8. doi: 10.1007/BF00219689. PMID: 8370586.
57. Chishimba L, Thickett DR, Stockley RA, Wood AM. The vitamin D axis in the lung: a key role for vitamin D-binding protein. Thorax. 2010 May;65(5):456-62. doi: 10.1136/thx.2009.128793. PMID: 20435872.
58. Powe CE, Ricciardi C, Berg AH, Erdenesanaa D, Collerone G, Ankers E, et al. Vitamin D-binding protein modifies the vitamin D-bone mineral density relationship. J Bone Miner Res. 2011 Jul;26(7):1609-16. doi: 10.1002/jbmr.387. Erratum in: J Bone Miner Res. 2012 Jun;27(6):1438. PMID: 21416506; PMCID: PMC3351032.
59. Ebadi M, Montano-Loza AJ. Perspective: improving vitamin D status in the management of COVID-19. Eur J Clin Nutr. 2020 Jun;74(6):856-859. doi: 10.1038/s41430-020-0661-0. Epub 2020 May 12. PMID: 32398871; PMCID: PMC7216123.