Association Between Human Leukocyte Antigen and COVID-19 Severity


In the last days of 2019, a new coronavirus emerged in Wuhan, China, and less than three months its disease, now called COVID-19, was announced a global pandemic by WHO. COVID-19 usually causes respiratory symptoms and can lead to more severe conditions like ARDS. HLA has a crucial role in regulating the immune system; thus, different HLA allele types can be a protective or risk factor for some diseases, so we aimed to find such associations to determine whether some alleles can predict susceptibility or resistibility to COVID-19 and finally facilitate vaccine development. In this case-control study, 15 admitted COVID-19 cases with severe symptoms and ten individuals with mild COVID-19 symptoms were enrolled in the case and control groups, respectively. They were genotyped for HLA A/B/DR loci using a low-resolution HLA typing test. These alleles were more prevalent in case (severe COVID-19) group: A*24 (53.33% vs 10%), B*50 (20% vs 10%), B*55 (20% vs 10%), DRB1*04 (40% vs 20%) and DRB1*11 (53.33% vs 30%) but the difference was only statically significant in A*24 allele (P=0.027; odd ratio=10.286). A*24 was also more prevalent in all patients than the general population in Iran. A*24 was the only allele more prevalent in severe COVID-19 cases with statistical significance. This allele was reported to be a risk factor for such autoimmune diseases as type 1 diabetes, myasthenia gravis, and systemic lupus erythematosus, which may be related to reported immune system hyperresponsiveness in severe COVID-19 cases.

1. Szczepanski A, Owczarek K, Bzowska M, Gula K, Drebot I, Ochman M, et al. Canine respiratory coronavirus, bovine coronavirus, and human coronavirus OC43: receptors and attachment factors. Viruses 2019;11:328.
2. Salehi S, Abedi A, Balakrishnan S, Gholamrezanezhad A. Coronavirus Disease 2019 (COVID-19): A Systematic Review of Imaging Findings in 919 Patients. AJR Am J Roentgenol 2020;215:87-93.
3. Cao Y, Liu X, Xiong L, Cai K. Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2: A systematic review and meta-analysis. J Med Virol 2020;92:1449-59.
4. WHO, World Health Organization. (2020, August 23). Coronavirus disease 2019 (COVID-19) Situation Report – Retrieved. (Accessed at
5. Adhikari SP, Meng S, Wu YJ, Mao YP, Ye RX, Wang QZ, et al. Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review. Infect Dis Poverty 2020;9:29.
6. Costa A, Bak T, Caffarra P, Caltagirone C, Ceccaldi M, Collette F, et al., The need for harmonisation and innovation of neuropsychological assessment in neurodegenerative dementias in Europe: consensus document of the Joint Program for Neurodegenerative Diseases Working Group. Alzheimers Res Ther 2017;9:27.
7. Hajeer AH, Balkhy H, Johani S, Yousef MZ, Arabi Y. Association of human leukocyte antigen class II alleles with severe Middle East respiratory syndrome-coronavirus infection. Ann Thorac Med 2016;11:211-3.
8. Wang SF, Chen KH, Chen M, Li WY, Chen YJ, Tsao CH, et al. "Human-leukocyte antigen class I Cw 1502 and class II DR 0301 genotypes are associated with resistance to severe acute respiratory syndrome (SARS) infection." Viral Immunol 2011;24:421-6.
9. Talebpour M, Hadadi A, Oraii A, Afshar H. Rationale and Design of a Registry in a Referral and Educational Medical Center in Tehran, Iran: Sina Hospital Covid-19 Registry (SHCo-19R). Adv J Emerg Med 2020;4:1-5.
10. World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects. Jama 2013;310:2191-4.
11. World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: interim guidance, 13 March 2020. (Accessed 2020, at (
12. Behdasht. COVID-19 Epidemiology Committee. (Accessed at Accessed April 29, 2020.)
13. Wu Z. McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA 2020;323:1239-42.
14. Middleton D, Menchaca L, Rood H, Komerofsky R. New allele frequency database: Tissue Antigens 2003;61:403-7.
15. Esmaeili A, Zamani Taghizadeh Rabe S, Mahmoudi M, Rastin M. Frequencies of HLA-A, B and DRB1 alleles in a large normal population living in the city of Mashhad, Northeastern Iran. Iran J Basic Med Sci 2017;20:940-3.
16. Arab M, Pourpak Z, Mohammadian S, Zare A, Shakiba Y, Shokouhi Shoormasti R, et al. The Frequency of Human Leukocyte Antigen Class I and II Alleles and the Relationship Between Haplotypes in Gilaks Population of Iran. Immunoregulation 2019;2: 57-66.
17. Einollahi B, Rostami Z, Teimoori M. Human leukocyte antigen variation among Iranian renal transplant recipients. J Nephropathol 2012;1:164-9.
18. Sun Y, Xi Y. Association between HLA gene polymorphism and the genetic susceptibility of SARS infection. Book: HLA and associated important diseases. IntechOpen 2014;12:311-21.
19. Adamashvili I, McVie R, Gelder F, Gautreaux M, Jaramillo J, Roggero T, et al. "Soluble HLA class I antigens in patients with type I diabetes and their family members". Human Immunol 1997;55:176-83.
20. Kronenberg D, Knight RR, Estorninho M, Ellis RJ, Kester MG, de Ru A, et al Circulating preproinsulin signal peptide-specific CD8 T cells restricted by the susceptibility molecule HLA-A24 are expanded at onset of type 1 diabetes and kill β-cells. Diabetes 2012;61:1752-9.
21. Adamashvili I, Wolf R, Aultman D, Milford EL, Jaffe S, Hall V, et al Soluble HLA-I (s-HLA-I) synthesis in systemic lupus erythematosus. Rheumatol Int 2003;23:294-300.
22. Machens A, Löliger C, Pichlmeier U, Emskötter T, Busch C, Izbicki JR. Correlation of thymic pathology with HLA in myasthenia gravis. Clin Immunol 1999;91:296-301.
23. Numano F, Sasazuki T, Koyama T, Shimokado K, Takeda Y, Nishimura Y, et al. HLA in Buerger's disease. Exp Clin Immunogenetics 1986;3:195-200.
24. Rodríguez Y, Novelli L, Rojas M, De Santis M, Acosta-Ampudia Y, Monsalve DM, et al. Autoinflammatory and autoimmune conditions at the crossroad of COVID-19. J Autoimmun 2020;114:102506 .
25. Prachar M, Justesen S, Steen-Jensen DB, Thorgrimsen SP, Jurgons E, Winther O, et al. Covid-19 vaccine candidates: Prediction and validation of 174 sars-cov-2 epitopes. bioRxiv 2020 (Peer Review).
IssueVol 59, No 7 (2021) QRcode
Coronavirus disease 2019 (COVID-19) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Human leukocyte antigen (HLA)

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Hajebi R, Ajam A, Karbalai S, Ashraf H, Ostadali Dehaghi MR, Moradi Tabriz H, Pazoki M, Khalili F. Association Between Human Leukocyte Antigen and COVID-19 Severity. Acta Med Iran. 2021;59(7):400-405.