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Association of IFIH1 and DDX58 genes polymorphism with susceptibility to COVID-19

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Abstract

Pattern recognition receptors of the innate immune system, such as RIG-I and MDA5, are responsible for recognizing viruses and inducing interferon production. Genetic polymorphisms in the coding regions of RLR may be associated with the severity of COVID-19. Considering the contribution of the RLR signaling in immune-mediated reactions, this study investigated the association between three SNP in the coding region of IFIH1 and DDX58 genes with the susceptibility to COVID-19 in the Kermanshah population, Iran. 177 patients with severe and 182 with mild COVID-19 were admitted for this study. Genomic DNA was extracted from peripheral blood leukocytes of patients to determine the genotypes of two SNPs, rs1990760(C>T) and rs3747517(T>C) IFIH1 gene and rs10813831(G>A) DDX58 gene using PCR–RFLP method. Our results showed that the frequency of the AA genotype of rs10813831(G>A) was associated with susceptibility to COVID-19 compared to the GG genotype (p = 0.017, OR = 2.593, 95% CI 1.173–5.736). We also observed a statistically significant difference in the recessive model for SNPs rs10813831 variant (AA versus GG + GA, p = 0.003, OR = 2.901, 95% CI 1.405–6.103). Furthermore, No significant association was found between rs1990760 (C>T) and rs3747517(T>C) of IFIH1 gene polymorphisms with COVID-19. Our findings suggest that DDX58 rs10813831(A>G) polymorphism may be associated with COVID-19 severity in the Kermanshah population, Iran.

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Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

MDA5:

Melanoma differentiation-associated protein 5

RIG-I:

Retinoic acid-inducible gene I

SARS-COV-2:

Severe acute respiratory syndrome coronavirus 2

IFN:

Interferon

RLR:

Retinoic acid-inducible gene-I (RIG-)-like receptors

NLR:

Nucleotide Oligomerization Domain (NOD)-like receptors

SNP:

Single nucleotide polymorphisms

ARDS:

Acute respiratory disease syndrome

PRR:

Pattern recognition receptors

IFIH1 :

Interferon-Induced Helicase 1

DDX58 :

DExD/H-box helicase 58

ARDS:

Acute respiratory distress syndrome

RFLP:

Polymerase chain reaction-restriction fragment length polymorphism

MAF:

Minor allele frequency

COVID-19:

Coronavirus disease-2019

OR:

Odds ratio

References

  1. Alagarasu K, Memane R, Shah P (2015) Polymorphisms in the retinoic acid-1 like-receptor family of genes and their association with clinical outcome of dengue virus infection. Adv Virol 160:1555–1560

    CAS  Google Scholar 

  2. Amado-Rodríguez L, Del Riego ES, de Ona JG, Alonso IL, Gil-Pena H, López-Martínez C, Martín-Vicente P, Lopez-Vazquez A, Lopez AG, Cuesta-Llavona E (2022) Effects of IFIH1 rs1990760 variants on systemic inflammation and outcome in critically ill COVID-19 patients in an observational translational study. Elife 11:e73012

    Article  PubMed  PubMed Central  Google Scholar 

  3. Amado-Rodriguez L, del Riego ES, de Ona JG, Lopez-Alonso I, Gil-Pena H, Lopez-Martinez C, Martin-Vicente P, Lopez-Vazquez A, Lopez AG, Cuesta-Llavona E (2021) IFIH1 rs1990760 variants, systemic inflammation and outcome in critically-ill COVID-19 patients. medRxiv

  4. Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann H-H, Zhang Y, Dorgham K, Philippot Q, Rosain J, Béziat V (2020) Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science 370:eabd4585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Biggins SW, Trotter J, Gralla J, Burton JR Jr, Bambha KM, Dodge J, Brocato M, Cheng L, McQueen M, Forman L (2013) Differential effects of donor and recipient IL28B and DDX58 SNPs on severity of HCV after liver transplantation. J Hepatol 58:969–976

    Article  CAS  PubMed  Google Scholar 

  6. Biswas M, Rahaman S, Biswas TK, Haque Z, Ibrahim B (2021) Association of sex, age, and comorbidities with mortality in COVID-19 patients: a systematic review and meta-analysis. Intervirology 64:36–47

    Article  CAS  Google Scholar 

  7. Cao Y, Li L, Feng Z, Wan S, Huang P, Sun X, Wen F, Huang X, Ning G, Wang W (2020) Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov 6:1–4

    Article  Google Scholar 

  8. Chistiakov DA (2010) Interferon induced with helicase C domain 1 (IFIH1) and virus-induced autoimmunity: a review. Viral Immunol 23:3–15

    Article  CAS  PubMed  Google Scholar 

  9. Creagh EM, O’Neill LA (2006) TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol 27:352–357

    Article  CAS  PubMed  Google Scholar 

  10. De Wit E, Van Doremalen N, Falzarano D, Munster VJ (2016) SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol 14:523–534

    Article  PubMed  PubMed Central  Google Scholar 

  11. Dieter C, de Almeida Brondani L, Lemos NE, Schaeffer AF, Zanotto C, Ramos DT, Girardi E, Pellenz FM, Camargo JL, Moresco KS (2022) Polymorphisms in ACE1, TMPRSS2, IFIH1, IFNAR2, and TYK2 genes are associated with worse clinical outcomes in COVID-19. Genes 14:29

    Article  PubMed  PubMed Central  Google Scholar 

  12. Fumagalli M, Cagliani R, Riva S, Pozzoli U, Biasin M, Piacentini L, Comi GP, Bresolin N, Clerici M, Sironi M (2010) Population genetics of IFIH1: ancient population structure, local selection, and implications for susceptibility to type 1 diabetes. Mol Biol Evol 27:2555–2566

    Article  CAS  PubMed  Google Scholar 

  13. Gorman JA, Hundhausen C, Errett JS, Stone AE, Allenspach EJ, Ge Y, Arkatkar T, Clough C, Dai X, Khim S (2017) The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity. Nat Immunol 18:744–752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Harrison AG, Lin T, Wang P (2020) Mechanisms of SARS-CoV-2 transmission and pathogenesis. Trends Immunol 41:1100–1115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hu J, Nistal-Villán E, Voho A, Ganee A, Kumar M, Ding Y, García-Sastre A, Wetmur JG (2010) A common polymorphism in the caspase recruitment domain of RIG-I modifies the innate immune response of human dendritic cells. J Immunol 185:424–432

    Article  CAS  PubMed  Google Scholar 

  16. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395:497–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Imaizumi T, Arikawa T, Sato T, Uesato R, Matsumiya T, Yoshida H, Ueno M, Yamasaki S, Nakajima T, Hirashima M (2008) Involvement of retinoic acid-inducible gene-I in inflammation of rheumatoid fibroblast-like synoviocytes. Clin Exp Immunol 153:240–244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Junior AGD, Sampaio NG, Rehwinkel J (2019) A balancing act: MDA5 in antiviral immunity and autoinflammation. Trends Microbiol 27:75–85

    Article  Google Scholar 

  19. Kassir R (2020) Risk of COVID‐19 for patients with obesity. Obes Rev 21(6):e13034. https://doi.org/10.1111/obr.13034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K, Hiiragi A, Dermody TS, Fujita T, Akira S (2008) Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med 205:1601–1610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105

    Article  CAS  PubMed  Google Scholar 

  22. Kennedy RB, Ovsyannikova IG, Haralambieva IH, O’Byrne MM, Jacobson RM, Pankratz VS, Poland GA (2012) Multigenic control of measles vaccine immunity mediated by polymorphisms in measles receptor, innate pathway, and cytokine genes. Vaccine 30:2159–2167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li X, Geng M, Peng Y, Meng L, Lu S (2020) Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal 10:102–108

    Article  PubMed  PubMed Central  Google Scholar 

  24. Liu S, Wang H, Jin Y, Podolsky R, Reddy MPL, Pedersen J, Bode B, Reed J, Steed D, Anderson S (2009) IFIH1 polymorphisms are significantly associated with type 1 diabetes and IFIH1 gene expression in peripheral blood mononuclear cells. Hum Mol Genet 18:358–365

    Article  CAS  PubMed  Google Scholar 

  25. Maiti AK (2020) The African-American population with a low allele frequency of SNP rs1990760 (T allele) in IFIH1 predicts less IFN-beta expression and potential vulnerability to COVID-19 infection. Immunogenetics 72:387–391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Marr N, Hirschfeld AF, Lam A, Wang S, Lavoie PM, Turvey SE (2014) Assessment of genetic associations between common single nucleotide polymorphisms in RIG-I-like receptor and IL-4 signaling genes and severe respiratory syncytial virus infection in children: a candidate gene case–control study. PLoS ONE 9:e100269

    Article  PubMed  PubMed Central  Google Scholar 

  27. Minashkin MM, Grigortsevich NY, Kamaeva AS, Barzanova VV, Traspov AA, Godkov MA, Ageev FA, Petrikov SS, Pozdnyakova NV (2022) The role of genetic factors in the development of acute respiratory viral infection COVID-19: predicting severe course and outcomes. Biomedicines 10:549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mohamed Khosroshahi L, Rezaei N (2021) Dysregulation of the immune response in coronavirus disease 2019. Cell Biol Int 45:702–707

    Article  CAS  PubMed  Google Scholar 

  29. Nejentsev S, Walker N, Riches D, Egholm M, Todd JA (2009) Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324:387–389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pang L, Gong X, Liu N, Xie G, Gao W, Kong G, Li X, Zhang J, Jin Y, Duan Z (2014) A polymorphism in melanoma differentiation-associated gene 5 may be a risk factor for enterovirus 71 infection. Clin Microbiol Infect 20:O711–O717

    Article  CAS  PubMed  Google Scholar 

  31. Rehwinkel J, Gack MU (2020) RIG-I-like receptors: their regulation and roles in RNA sensing. Nat Rev Immunol 20:537–551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schneider WM, Chevillotte MD, Rice CM (2014) Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol 32:513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schoggins JW (2019) Interferon-stimulated genes: what do they all do? Annu Rev Virol 6:567–584

    Article  CAS  PubMed  Google Scholar 

  34. Suguna S, Nandal D, Kamble S, Bharatha A, Kunkulol R (2014) Genomic DNA isolation from human whole blood samples by non enzymatic salting out method. Int J Pharm Pharm Sci 6:198–199

    Google Scholar 

  35. Takaoka A, Yamada T (2019) Regulation of signaling mediated by nucleic acid sensors for innate interferon-mediated responses during viral infection. Int Immunol 31:477–488

    Article  CAS  PubMed  Google Scholar 

  36. Totura AL, Baric RS (2012) SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon. Curr Opin Virol 2:264–275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wu X, Zang F, Liu M, Zhuo L, Wu J, Xia X, Feng Y, Yu R, Huang P, Yang S (2019) Genetic variants in RIG-I-like receptor influences HCV clearance in Chinese Han population. Epidemiol Infect 147:e195. https://doi.org/10.1017/S0950268819000827

  38. Wu X, Zang F, Liu M, Zhuo L, Wu J, Xia X, Feng Y, Yu R, Huang P, Yang S (2019) Genetic variants in RIG-I-like receptor influences HCV clearance in Chinese Han population. Epidemiol Infect 147:e195

    Article  PubMed  PubMed Central  Google Scholar 

  39. Yamada T, Sato S, Sotoyama Y, Orba Y, Sawa H, Yamauchi H, Sasaki M, Takaoka A (2021) RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells. Nat Immunol 22:820–828

    Article  CAS  PubMed  Google Scholar 

  40. Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K, Foy E, Loo Y-M, Gale M, Akira S (2005) Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol 175:2851–2858

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the deputy of Research and Technology of Kermanshah University of Medical Sciences for financial support.

Funding

This research has been supported by Grants from Kermanshah University of Medical Sciences (Grant number: 4010493).

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Authors

Contributions

AR: Conceptualization, Visualization and Writing—Review and Editing. PF: Writing—Original draft preparation. AGK and FS: formal analysis and Validation. Pf and SF: Investigation and performing the laboratory experiments. ZM, EF and MHZ: resources and preparing the samples. AR critically revised the manuscript and provided the final approval. All authors read and approved the final manuscript and had full access to all the data in the study.

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Correspondence to Alireza Rezaiemanesh.

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Edited by Hanna-Mari Baldauf.

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Feizollahi, P., Zamanian, M.H., Falahi, S. et al. Association of IFIH1 and DDX58 genes polymorphism with susceptibility to COVID-19. Med Microbiol Immunol 212, 221–229 (2023). https://doi.org/10.1007/s00430-023-00764-x

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