Study on the association between interleukin-6 receptor Asp358Ala (rs2228145) single nucleotide polymorphism, with the severity of clinical symptoms in patients with COVID-19

Document Type : Original Article

Authors

1 Department of Immunology, Faculty of Medicine, Shahed University, Tehran, Iran

2 Immunoregulation Research Center, Shahed University, Tehran, Iran

3 Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran

4 Non-communicable Diseases Research Center, Fasa University of Medical Science, Fasa, Iran

Abstract

Background and Objective: Increasing of interleukin-6 (IL-6) in Covid-19 patients has been reported in various studies. Genetic variants of the IL-6 receptor are involved in the beginning and progression of severe infections, autoimmunity, and also inflammatory diseases. The aim of this study was to investigate the association between SNP (rs2228145) of IL-6 receptor with the severity of Covid-19 patients.
Materials and Methods: In the present cross-sectional and analytical study, 180 patients with Covid-19 entered voluntarily and were classified based on the severity of the disease in 4 groups: mild (90 patients, age 46.40 ± 15.8), moderate (45 patients, age 50.4 ±16.4), severe (25 patients, age 59.70 ±24) and critical (20 patients, age 15.30 ± 60.8). Peripheral blood samples were taken from patients and after DNA extraction, genotyping was performed by RFLP PCR and electrophoresis on 2% agarose gel. Data were analyzed using SPSS software and Chi-Square or ANOVA.
Results: The mean age of patients in the outpatient group and the intubated inpatients were 46.40 ± 15.8 and 60.30 ± 15.8, respectively (P-value <0.001). Also, the frequency of diabetic patients in the outpatient group and intubated group were about 21% and 45%, respectively (P-value <0.05). A significant difference was observed in the CC genotype between outpatient and inpatient groups (P-value <0.01) as well as intubated patients (P-value <0.05).
Conclusion: The frequency of rs2228145 variants in Covid-19 patients with different severity is diverse and CC genotype can be a predictor of prognosis in admission to the ICU and intubation.

Keywords


  1. Millán-Oñate J, Rodriguez-Morales AJ, Camacho-Moreno G, Mendoza-Ramírez H, Rodríguez-Sabogal IA, Álvarez-Moreno CJI. A new emerging zoonotic virus of concern: the 2019 novel Coronavirus (SARS CoV-2). Infection 2020;24(3):187-92.
  2. Fan W, Su Z, Bin Y, Yan-Mei C, Wen W, Zhi-Gang S, et al. Holmes Edward C., Zhang Yong-Zhen. A new coronavirus associated with human respiratory disease in China. Nature 2020;579(7798):265-9.
  3. Wu Z, McGoogan JMJJ. 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(13):1239-42.
  4. Yang X, Yu Y, Xu J, Shu H, Liu H, Wu Y, et al. 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 2020.
  5. Ruan Q, Yang K, Wang W, Jiang L, Song JJIcm. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Medicine 2020;46(5):846-8.
  6. Rostamian A, Ghazanfari T, Arabkheradmand J, Edalatifard M, Ghaffarpour S, Salehi MR, et al. Interleukin-6 as a Potential Predictor of COVID-19 disease severity in hospitalized patients and its association with clinical laboratory routine tests. Immunoregulation 2020;3(1):29-36.
  7. 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. The lancet 2020;395(10223):497-506.
  8. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet Respiratory Medicine 2020;8(4):420-2.
  9. Wu F, Zhao S, Yu B, Chen Y-M, Wang W, Song Z-G, et al. A new coronavirus associated with human respiratory disease in China. Nature 2020;579(7798):265-9.
  10. Catanzaro M, Fagiani F, Racchi M, Corsini E, Govoni S, Lanni CJST, et al. Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2. Signal Transduction and Targeted Therapy 2020;5(1):1-10.
  11. Kirtipal N, Bharadwaj SJJoBS, Dynamics. Interleukin 6 polymorphisms as an indicator of COVID-19 severity in humans. Journal of Biomolecular Structure and Dynamics 2020(just-accepted):1-4.
  12. Terry CF, Loukaci V, Green FRJJoBC. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. Journal of Biological Chemistry 2000;275(24):18138-44.
  13. Hunter CA, Jones SAJNi. IL-6 as a keystone cytokine in health and disease. Nature Immunology 2015;16(5):448-57.
  14. Ferreira RC, Freitag DF, Cutler AJ, Howson JM, Rainbow DB, Smyth DJ, et al. Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases. PLoS Genetics 2013;9(4):e1003444.
  15. Garbers C, Heink S, Korn T, Rose-John SJNRDD. Interleukin-6: designing specific therapeutics for a complex cytokine. Nature Reviews Drug Discovery 2018;17(6):395-412.
  16. Emilsson V, Ilkov M, Lamb JR, Finkel N, Gudmundsson EF, Pitts R, et al. Co-regulatory networks of human serum proteins link genetics to disease. Science 2018;361(6404):769-73.
  17. Garbers C, Rose-John SJTLR. Genetic IL-6R variants and therapeutic inhibition of IL-6 receptor signalling in COVID-19. The Lancet Rheumatology 2021;3(2):e96-e7.
  18. Bovijn J, Lindgren CM, Holmes MVJTLR. Genetic variants mimicking therapeutic inhibition of IL-6 receptor signaling and risk of COVID-19. The Lancet Rheumatology 2020;2(11):e658-e9.
  19. Hayashida K, Bartlett AH, Chen Y, Park PWJTARAiIA, Biology E. Molecular and cellular mechanisms of ectodomain shedding. Advances in Integrative Anatomy and Evolutionary Biology 2010;293(6):925-37.
  20. Ahluwalia TS, Prins BP, Abdollahi M, Armstrong NJ, Aslibekyan S, Bain L, et al. Genome-wide association study of circulating interleukin 6 levels identifies novel loci. Human Molecular Genetics 2021;30(5):393-409.
  21. Hawkins GA, Robinson MB, Hastie AT, Li X, Li H, Moore WC, et al. The IL6R variation Asp358Ala is a potential modifier of lung function in subjects with asthma. Journal of Allergy and Clinical Immunology 2012;130(2):510-5. e1.
  22. Hekim NJJoMV. Correlation between interleukin gene polymorphisms and current prevalence and mortality rates due to novel coronavirus disease 2019 (COVID-2019) in 23 countries. Journal of Medical Virology 2021.
  23. Stephens OW, Zhang Q, Qu P, Zhou Y, Chavan S, Tian E, et al. An intermediate-risk multiple myeloma subgroup is defined by sIL-6r: levels synergistically increase with incidence of SNP rs2228145 and 1q21 amplification. Blood, The Journal of the American Society of Hematology 2012;119(2):503-12.
  24. Enevold C, Baslund B, Linde L, Josephsen NL, Tarp U, Lindegaard H, et al. Interleukin-6-receptor polymorphisms rs12083537, rs2228145, and rs4329505 as predictors of response to tocilizumab in rheumatoid arthritis. Pharmacogenetics and Genomics 2014;24(8):401-5.
  25. Jones SA, Hunter CA. Is IL-6 a key cytokine target for therapy in COVID-19.Nature Reviews Immunology 2021;21(6):337-9.