Skip to main content

Advertisement

SpringerLink
Log in

IRAK2 is associated with systemic lupus erythematosus risk

  • Original Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

Introduction

Interleukin-1 receptor-associated kinases (IRAKs) are serine-threonine kinases involved in toll-like receptor and interleukin-1 signaling pathways. They play a key role in inflammation and innate immunity. IRAKs have been previously incriminated in autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis and inhibition of IRAKs has been recently regarded as a potential therapeutic strategy for SLE.

Objectives

The aim of the present study was to test the association between IRAK2 rs708035 and rs3844283 with SLE.

Material and methods

IRAK2 rs708035 and rs3844283 were genotyped by mutagenically separated polymerase chain reaction (MS-PCR) in 142 SLE patients and 149 age- and gender-matched controls.

Results

The hyperfunctional IRAK2 rs708035 A allele was more frequent among SLE patients than controls (62.9% versus 54.7%, p = 0.046). IRAK2 rs3844283 C allele was present in 66.5% of patients and 75.5% of controls. The CC genotype was the most frequently exhibited genotype. It was carried by 45.1% of patients with SLE and 57.7% of controls. The G allele was associated with an increased risk of SLE (OR = 1.54, 95%, CI = 1.07–2.22, p = 0.017). IRAK2 rs708035 and IRAK2 rs3844283 were in linkage disequilibrium (D′ = 0.64). The AG haplotype was more frequently observed in SLE patients than in controls (0.292 versus 0.194, p = 0.008).

Conclusion

This study for the first time ever reveals the association of IRAK2 rs708035 and IRAK2 rs3844283 and the corresponding haplotypes with SLE. Our findings give additional rationale to target IRAKs in the treatment of SLE.

Key Points

• IRAK2 rs708035 A allele is more frequent in SLE patients than in controls and IRAK2 rs3844283 G allele is associated with SLE susceptibility.

• These two alleles are in linkage disequilibrium.

• The AG haplotype is associated with SLE.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Mok CC (2003) Pathogenesis of systemic lupus erythematosus. J Clin Pathol 56:481–490

    Article  CAS  Google Scholar 

  2. Ohl K, Tenbrock K (2011) Inflammatory cytokines in systemic lupus erythematosus. J Biomed Biotechnol 2011:1–14

    Article  Google Scholar 

  3. Barrat FJ, Meeker T, Gregorio J et al (2002) Nucleic acids of mammalian origin can act as endogenous ligands for toll-like receptors and may promote systemic lupus erythematosus. J Exp Med 202:1131–1139 4

    Article  Google Scholar 

  4. Kato Y, Park J, Takamatsu H et al (2018) Apoptosis-derived membrane vesicles drive the cGAS–STING pathway and enhance type I IFN production in systemic lupus erythematosus. Ann Rheum Dis 77:1507–1515

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Kim JM, Park SH, Kim HY, Kwok SK (2015) A plasmacytoid dendritic cells-type I interferon axis is critically implicated in the pathogenesis of systemic lupus erythematosus. Int J Mol Sci 16:14158–14170

    Article  CAS  Google Scholar 

  6. Berggren O, Hagberg N, Alexsson A, Weber G, Rönnblom L, Eloranta ML (2017) Plasmacytoid dendritic cells and RNA containing immune complexes drive expansion of peripheral B cell subsets with an SLE-like phenotype. PLoS One 12(8):e0183946

    Article  Google Scholar 

  7. Mackern-Oberti JP, Llanos C, Vega F, Salazar-Onfray F, Riedel CA, Bueno SM, Kalergis AM (2015) Role of dendritic cells in the initiation, progress and modulation of systemic autoimmune diseases. Autoimmun Rev 14:127–139

    Article  CAS  Google Scholar 

  8. Walsh MC, Lee J, Choi Y (2015) Tumor necrosis factor receptor- associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system. Immunol Rev 266(1):72–92

    Article  CAS  Google Scholar 

  9. Lin SC, Lo YC, Wu H (2010) Helical assembly in the MyD88-IRAK-4- IRAK-2 complex in TLR/IL-1R signalling. Nature 465:885–890 12

    Article  CAS  Google Scholar 

  10. Motshwene PG, Moncrieffe MC, Grossmann JG (2009) An oligomeric signaling platform formed by the toll-like receptor signal transducers MyD88 and IRAK-4. J Biol Chem 284:25404–25411

    Article  CAS  Google Scholar 

  11. Dominic DN, Katherine RB, Yamel CG (2018) Interleukin-1 receptor–associated kinase 4 (IRAK4) plays a dual role in myddosome formation and Toll-like receptor signaling. J Biol Chem 293:15195–15207

    Article  Google Scholar 

  12. Ferrao R, Zhou H, Shan Y, Liu Q, Li Q, Shaw DE, Li X, Wu H (2014) IRAK4 dimerization and trans-autophosphorylation are induced by myddosome assembly. Mol Cell 55:891–903

    Article  CAS  Google Scholar 

  13. Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ (2000) Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103:351–361

    Article  CAS  Google Scholar 

  14. Wang L, Qiao Q, Ferrao R (2017) Crystal structure of human IRAK1. Proc Natl Acad Sci U S A 114:13507–13512

    Article  CAS  Google Scholar 

  15. Kawagoe T, Sato S, Matsushita K, Kato H, Matsui K, Kumagai Y, Saitoh T, Kawai T, Takeuchi O, Akira S (2008) Sequential control of Toll-like receptor-dependent responses by IRAK-1 and IRAK-2. Nat Immunol 9:684–691

    Article  CAS  Google Scholar 

  16. Wang H, El Maadidi S, Fischer J et al (2015) A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance. Hepatology 62:1375–1387

    Article  CAS  Google Scholar 

  17. Hassine HB, Sghiri R, Chabchoub E, Boumiza A, Slama F, Baccouche K, Shakoor Z, Almogren A, Mariaselvam C, Tamouza R, Bouajina E, Zemni R (2018) IRAK2 is associated with susceptibility to rheumatoid arthritis. Clin Rheumatol 37:927–933

    Article  Google Scholar 

  18. Aringer M, Costenbader K, Brinks R et al (2018) OP0020 validation of new systemic lupus erythematosus classification criteria. Ann Rheum 77(Suppl 2):60

    Google Scholar 

  19. Cao Z, Henzel WJ, Gao X (1996) IRAK: a kinase associated with the interleukin-1 receptor. Science 271:1128–1131

    Article  CAS  Google Scholar 

  20. Muzio M, Ni J, Feng P, Dixit VM (1997) IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278:1612–1615 13

    Article  CAS  Google Scholar 

  21. Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z (1999) IRAK-M is a novel member of the Pelle/interleukin-1 receptor associated kinase (IRAK) family. J Biol Chem 274:19403–19410

    Article  CAS  Google Scholar 

  22. Li S, Strelow A, Fontana EJ, Wesche H (2002) IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci U S A 99:5567–5572

    Article  CAS  Google Scholar 

  23. Ye H, Arron JR, Lamothe B, Cirilli M, Kobayashi T, Shevde NK, Segal D, Dzivenu OK, Vologodskaia M, Yim M, du K, Singh S, Pike JW, Darnay BG, Choi Y, Wu H (2002) Distinct molecular mechanism for initiating TRAF6 signalling. Nature 418:443–447

    Article  CAS  Google Scholar 

  24. Pauls E, Nanda SK, Smith H, Toth R, Arthur JSC, Cohen P (2013) Two phases of inflammatory mediator production defined by the study of IRAK2 and IRAK1 knock-in mice. J Immunol 191:2717–2730

    Article  CAS  Google Scholar 

  25. Wan Y, Xiao H, Affolter J, Kim TW, Bulek K, Chaudhuri S, Carlson D, Hamilton T, Mazumder B, Stark GR, Thomas J, Li X (2009) Interleukin-1 receptor associated kinase 2 is critical for lipopolysaccharide-mediated post-transcriptional control. J Biol Chem 284:10367–10375

    Article  CAS  Google Scholar 

  26. Flannery SM, Keating SE, Szymak J, Bowie AG (2011) Human interleukin-1 receptor–associated kinase-2 is essential for Toll-like receptor–mediated transcriptional and post-transcriptional regulation of tumor necrosis factor alpha. J Biol Chem 286:23688–23697

    Article  CAS  Google Scholar 

  27. Zhang W, He T, Wang Q, Li X, Wei J, Hou X, Zhang B, Huang L, Wang L (2014) Interleukin-1 receptor-associated kinase-2 genetic variant rs708035 increases NF-κB activity through promoting TRAF6 ubiquitination. J Biol Chem 289:12507–12519

    Article  CAS  Google Scholar 

  28. Kaufman KM, Zhao J, Kelly JA, Hughes T, Adler A, Sanchez E, Ojwang JO, Langefeld CD, Ziegler JT, Williams AH, Comeau ME, Marion MC, Glenn SB, Cantor RM, Grossman JM, Hahn BH, Song YW, Yu CY, James JA, Guthridge JM, Brown EE, Alarcón GS, Kimberly RP, Edberg JC, Ramsey-Goldman R, Petri MA, Reveille JD, Vilá LM, Anaya JM, Boackle SA, Stevens AM, Freedman BI, Criswell LA, Bernardo A Pons-Estel on behalf of the Argentine Collaborative Group, Lee JH, Lee JS, Chang DM, Scofield RHA, Gilkeson GS, Merrill JT, Niewold TB, Vyse TJ, Bae SC, Marta E Alarcón-Riquelme on behalf of the BIOLUPUS network, Jacob CO, Moser Sivils K, Gaffney PM, Harley JB, Sawalha AH, Tsao BP (2013) Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups. Ann Rheum Dis 72:437–444

    Article  CAS  Google Scholar 

  29. Dieude’ P, Bouaziz M, Guedj M et al (2013) Evidence of the contribution of the X chromosome to systemic sclerosis susceptibility: association with the functional IRAK1 196Phe/532Ser haplotype. Arthritis Rheum 63:3979–87 14

    Article  Google Scholar 

  30. Hassine HB, Boumiza A, Sghiri R, Baccouche K, Boussaid I, Atig A, Shakoor Z, Bouajina E, Zemni R (2017) Micro RNA-146a but not IRAK1 is associated with rheumatoid arthritis in the Tunisian population. Genet Test Mol Biomarkers 21:92–96

    Article  Google Scholar 

  31. Nanda SK, Lopez-Pelaez M, Arthur JS et al (2016) Suppression of IRAK1 or IRAK4 catalytic activity, but not type 1 IFN signaling, prevents lupus nephritis in mice expressing a ubiquitin binding-defective mutant of ABIN1. J Immunol 197:4266–4273

    Article  CAS  Google Scholar 

  32. Dudhgaonkar S, Ranade S, Nagar J, Subramani S, Prasad DS, Karunanithi P, Srivastava R, Venkatesh K, Selvam S, Krishnamurthy P, Mariappan TT, Saxena A, Fan L, Stetsko DK, Holloway DA, Li X, Zhu J, Yang WP, Ruepp S, Nair S, Santella J, Duncia J, Hynes J, McIntyre KW, Carman JA (2017) Selective IRAK4 inhibition attenuates disease in murine lupus models and demonstrates steroid sparing activity. J Immunol 198:1308–1319

    Article  CAS  Google Scholar 

  33. Hjorton K, Hagberg N, Israelsson E et al (2018) Cytokine production by activated plasmacytoid dendritic cells and natural killer cells is suppressed by an IRAK4 inhibitor. Arthritis Res Ther 20:238

    Article  Google Scholar 

  34. Kelly PN, Romero DL, Yang Y, Shaffer AL III, Chaudhary D, Robinson S, Miao W, Rui L, Westlin WF, Kapeller R, Staudt LM (2015) Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy. J Exp Med 212:2189–2201

    Article  CAS  Google Scholar 

  35. Chasset F, Arnaud L (2018) Targeting interferons and their pathways in systemic lupus erythematosus. Autoimmun Rev 17:44–52

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the College of Medicine Research Center, Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia.

Author information

Authors and Affiliations

  1. Immunogenetics Unit, Faculty of Medicine, University of Sousse, Sousse, Tunisia

    Asma Boumiza, Ramzi Zemni, Rim Sghiri, Nadia Idriss, Hana Ben Hassine, Elyes Chabchoub & Foued Ben Hadj Slama

  2. Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia

    Rim Sghiri

  3. Laboratory of Immunology, Faculty of Medicine of Sousse, Ibn Al Jazzar Street, 4000, Sousse, Tunisia

    Rim Sghiri

  4. Department of Internal Medicine, University Hospital Sahloul, University of Sousse, Sousse, Tunisia

    Anis Mzabi

  5. Department of Internal Medicine, University Hospital Farhat Hached, University of Sousse, Sousse, Tunisia

    Neirouz Ghannouchi

  6. Department of Rheumatology, Farhat Hached Hospital, Sousse, Tunisia

    Elyes Bouajina

Authors
  1. Asma Boumiza
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ramzi Zemni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rim Sghiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nadia Idriss
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hana Ben Hassine
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elyes Chabchoub
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anis Mzabi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Neirouz Ghannouchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Elyes Bouajina
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Foued Ben Hadj Slama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rim Sghiri.

Ethics declarations

Disclosures

None.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Boumiza, A., Zemni, R., Sghiri, R. et al. IRAK2 is associated with systemic lupus erythematosus risk. Clin Rheumatol 39, 419–424 (2020). https://doi.org/10.1007/s10067-019-04781-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-019-04781-1

Keywords

Search

Navigation