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The 5’ untranslated region variant rs3811050 C/T of the interleukin-38 encoding gene is associated with susceptibility to rheumatoid arthritis in Iraqi women

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Abstract

Background

Interleukin (IL)-38, the latest member of the IL-1 cytokine family, is proposed to have a pathogenic role in rheumatoid arthritis (RA). It is encoded by the IL1F10 gene, which harbors single nucleotide polymorphisms (SNPs) that may predict the risk of autoimmune diseases. Among them are 5′ untranslated region (UTR) SNPs, which play a key role in post-transcriptional control, but have not been studied in Iraqi RA patients.

Methods

Two novel IL1F10 5’UTR SNPs (rs3811050 C/T and rs3811051 T/G) were explored in RA and control women (n = 120 and 110, respectively). SNPs were genotyped using TaqMan assay. An ELISA kit was used to measure serum IL-38 concentrations.

Results

A reduced risk of RA was associated with rs3811050 T allele and CT genotype (corrected probability [pc] = 0.01 and < 0.001, respectively), while there was no significant association with rs3811051. Haplotype analysis demonstrated that C-T haplotype was associated with a 1.65-fold greater risk of RA, whereas a reduced risk was linked to T-G haplotype. IL-38 concentrations were higher in patients than in controls (p < 0.001). In addition, IL-38 showed acceptable performance in distinguishing between RA and control women (p < 0.001). When IL-38 concentrations were stratified according to SNP genotypes, no significant differences were found.

Conclusions

The rs3811050 variant was more likely to affect RA susceptibility in Iraqi women, and the T allele may play a role in reducing disease risk. IL-38 concentrations were elevated in RA patients, but were not affected by the rs3811050 and rs3811051 genotypes.

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Data availability

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

References

  1. Radu AF, Bungau SG (2021) Management of rheumatoid arthritis: an overview. Cells 10:2857. https://doi.org/10.3390/cells10112857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Deane KD, Demoruelle MK, Kelmenson LB et al (2017) Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol 31:3–18

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zhang C (2020) Flare-up of cytokines in rheumatoid arthritis and their role in triggering depression: Shared common function and their possible applications in treatment (review). Biomed Rep 14:1–8. https://doi.org/10.3892/br.2020.1392

    Article  CAS  Google Scholar 

  4. Chen Z, Bozec A, Ramming A, Schett G (2019) Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis. Nat Rev Rheumatol 15:9–17. https://doi.org/10.1038/s41584-018-0109-2

    Article  CAS  PubMed  Google Scholar 

  5. Markovics A, Rosenthal KS, Mikecz K et al (2022) Restoring the balance between pro-inflammatory and anti-inflammatory cytokines in the treatment of rheumatoid arthritis: new insights from animal models. Biomedicines 10:44

    Article  CAS  Google Scholar 

  6. Yucel B (2020) Associations between cytokine gene polymorphisms and rheumatoid arthritis in Turkish population. North Clin Istanbul 7:563. https://doi.org/10.14744/nci.2020.70845

    Article  Google Scholar 

  7. Bani-Wais DFN, Ad’hiah AH (2023) A novel intergenic variant, rs2004339 A/G, of the gene encoding interleukin-40, C17orf99, is associated with risk of rheumatoid arthritis in Iraqi women. Mol Immunol 164:39–46. https://doi.org/10.1016/j.molimm.2023.11.002

    Article  CAS  PubMed  Google Scholar 

  8. Tsujimoto S, Ozaki Y, Ito T, Nomura S (2021) Usefulness of cytokine gene polymorphisms for the therapeutic choice in Japanese patients with rheumatoid arthritis. Int J Gen Med 14:131–139. https://doi.org/10.2147/IJGM.S287505

    Article  PubMed  PubMed Central  Google Scholar 

  9. de Graaf DM, Teufel LU, Joosten LAB, Dinarello CA (2022) Interleukin-38 in Health and Disease. Cytokine 152:155824. https://doi.org/10.1016/J.CYTO.2022.155824

    Article  PubMed  Google Scholar 

  10. Chen W, Xi S, Ke Y, Lei Y (2023) The emerging role of IL-38 in diseases: a comprehensive review. Immun Inflamm Dis 11:e991. https://doi.org/10.1002/iid3.991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jaber AS, Ad’hiah AH (2023) A novel signature of interleukins 36α, 37, 38, 39 and 40 in ankylosing spondylitis. Cytokine 162:156117. https://doi.org/10.1016/j.cyto.2022.156117

    Article  CAS  PubMed  Google Scholar 

  12. Pei B, Chen K, Zhou S et al (2020) IL-38 restrains inflammatory response of collagen-induced arthritis in rats via SIRT1/HIF-1α signaling pathway. Biosci Rep 40:BSR20182431. https://doi.org/10.1042/BSR20182431

    Article  PubMed  PubMed Central  Google Scholar 

  13. Xia Hsong, Liu Y, Fu Y et al (2021) Biology of interleukin-38 and its role in chronic inflammatory diseases. Int Immunopharmacol 95:107528. https://doi.org/10.1016/j.intimp.2021.107528

    Article  CAS  PubMed  Google Scholar 

  14. Xie L, Huang Z, Li H et al (2019) IL-38: a new player in inflammatory autoimmune disorders. Biomolecules 9:345. https://doi.org/10.3390/biom9080345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Renz PF, Valdivia Francia F, Sendoel A (2020) Some like it translated: small ORFs in the 5′UTR. Exp Cell Res 396:112229. https://doi.org/10.1016/j.yexcr.2020.112229

    Article  CAS  PubMed  Google Scholar 

  16. Soukarieh O, Meguerditchian C, Proust C et al (2022) Common and rare 5′UTR variants altering Upstream Open Reading frames in Cardiovascular Genomics. Front Cardiovasc Med 9:1–10. https://doi.org/10.3389/fcvm.2022.841032

    Article  CAS  Google Scholar 

  17. Aletaha D, Neogi T, Silman AJ et al (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum 62:2569–2581. https://doi.org/10.1002/art.27584

    Article  PubMed  Google Scholar 

  18. Fleischmann RM, Van Der Heijde D, Gardiner PV et al (2017) DAS28-CRP and DAS28-ESR cut-offs for high disease activity in rheumatoid arthritis are not interchangeable. RMD Open 3:e000382. https://doi.org/10.1136/rmdopen-2016-000382

    Article  PubMed  PubMed Central  Google Scholar 

  19. Shi YY, He L (2005) SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 15:97–98. https://doi.org/10.1038/sj.cr.7290272

    Article  CAS  PubMed  Google Scholar 

  20. Kang H (2021) Sample size determination and power analysis using the G*Power software. J Educ Eval Health Prof 18:17. https://doi.org/10.3352/JEEHP.2021.18.17

    Article  PubMed  PubMed Central  Google Scholar 

  21. Boutet MA, Bart G, Penhoat M et al (2016) Distinct expression of interleukin (IL)-36α, β and γ, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn’s disease. Clin Exp Immunol 184:159–173. https://doi.org/10.1111/cei.12761

    Article  CAS  PubMed  Google Scholar 

  22. Takenaka SI, Kaieda S, Kawayama T et al (2015) IL-38: a new factor in rheumatoid arthritis. Biochem Biophys Rep 4:386–391. https://doi.org/10.1016/j.bbrep.2015.10.015

    Article  PubMed  PubMed Central  Google Scholar 

  23. Xu WD, Su LC, He CS, Huang AF (2018) Plasma interleukin-38 in patients with rheumatoid arthritis. Int Immunopharmacol 65:1–7. https://doi.org/10.1016/j.intimp.2018.09.028

    Article  CAS  PubMed  Google Scholar 

  24. Migliorini P, Italiani P, Pratesi F et al (2020) The IL-1 family cytokines and receptors in autoimmune diseases. Autoimmun Rev 19:102617. https://doi.org/10.1016/j.autrev.2020.102617

    Article  CAS  PubMed  Google Scholar 

  25. Dinarello CA (2018) Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev 281:8–27. https://doi.org/10.1111/imr.12621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Abed RM, Abdulmalek HW, Yaaqoob LA et al (2023) Serum level and genetic polymorphism of IL-38 and IL-40 in autoimmune thyroid disease. Iraqi J Sci 64:2786–2797. https://doi.org/10.24996/ijs.2023.64.6.12

    Article  Google Scholar 

  27. Gao X, Wu G, Tsang MSM et al (2022) Novel insights into the role of anti-inflammatory IL-38 in immunity against infection. Cell Mol Immunol 19:1322–1324. https://doi.org/10.1038/s41423-022-00876-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nijeeb RA, Aljber AA, Ad’hiah AH (2024) Low heterozygosity for rs3811050, a 5 prime untranslated region variant of the gene encoding interleukin-38 (IL1F10), is associated with a reduced risk of systemic lupus erythematosus. Egypt J Med Hum Genet 25:1–9. https://doi.org/10.1186/s43042-024-00503-8

    Article  Google Scholar 

  29. Steri M, Idda ML, Whalen MB, Orrù V (2018) Genetic variants in mRNA untranslated regions. Wiley Interdiscip Rev RNA 9:e1474. https://doi.org/10.1002/wrna.1474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ellingford JM, Ahn JW, Bagnall RD et al (2022) Recommendations for clinical interpretation of variants found in non-coding regions of the genome. Genome Med 14:1–19. https://doi.org/10.1186/s13073-022-01073-3

    Article  CAS  Google Scholar 

  31. Ciechomska M, Roszkowski L, Maslinski W (2019) DNA methylation as a future therapeutic and diagnostic target in rheumatoid arthritis. Cells 8:953. https://doi.org/10.3390/cells8090953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bashi MA, Ad’hiah AH (2024) Molecular landscape of the interleukin-40 encoding gene, C17orf99, in patients with acute myeloid leukemia. Gene 904:148214. https://doi.org/10.1016/J.GENE.2024.148214

    Article  CAS  PubMed  Google Scholar 

  33. Padala C, Puranam K, Shyamala N et al (2022) Genotypic and haplotype analysis of Interleukin-6 and – 18 gene polymorphisms in association with clinicopathological factors in breast cancer. Cytokine 160:156024. https://doi.org/10.1016/j.cyto.2022.156024

    Article  CAS  PubMed  Google Scholar 

  34. Budhiparama NC, Lumban-Gaol I, Sudoyo H et al (2023) The role of genetic polymorphisms of interleukin-1 (IL-1R1 and IL-1RN) in primary knee osteoarthritis in Indonesia. Sci Rep 13:7967. https://doi.org/10.1038/s41598-023-34824-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ramsuran V, Ewy R, Nguyen H, Kulkarni S (2018) Variation in the untranslated genome and susceptibility to infections. Front Immunol 9:381868. https://doi.org/10.3389/fimmu.2018.02046

    Article  CAS  Google Scholar 

  36. Ryczek N, Łyś A, Makałowska I (2023) The functional meaning of 5′UTR in protein-coding genes. Int J Mol Sci 24:2976. https://doi.org/10.3390/ijms24032976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sha Q, Zhang S (2011) A test of Hardy-Weinberg equilibrium in structured populations. Genet Epidemiol 35:671–678. https://doi.org/10.1002/gepi.20617

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors appreciate the assistance of the medical staff at the Rheumatology Unit of the Medical Education Complex in Baghdad. We also thank the rheumatologist Mohammed H. M. Alosami for his role in RA diagnosis. In addition, we thank Dr. Ziarih Hawi (Monash University, Australia) for his assistance in designing the primers used in the study.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Biotechnology, College of Science, University of Baghdad, Baghdad, Iraq

    Dhuha F. N. Bani-Wais

  2. Tropical-Biological Research Unit, College of Science, University of Baghdad, Al-Jadriya, Al-Karrada, Baghdad, 10070, Iraq

    Ali H. Ad’hiah

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  1. Dhuha F. N. Bani-Wais
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  2. Ali H. Ad’hiah
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Contributions

D.B. and A.A. contributed equally to the manuscript; methodology, analysis, and writing.

Corresponding author

Correspondence to Ali H. Ad’hiah.

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Ethical approval

Approval to conduct the study was obtained from the Training and Human Development Center at the Educational Medical City (Baghdad; Approval No. 46731). All participants gave written consent to participate in the study.

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The authors declare no competing interests.

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Bani-Wais, D.F.N., Ad’hiah, A.H. The 5’ untranslated region variant rs3811050 C/T of the interleukin-38 encoding gene is associated with susceptibility to rheumatoid arthritis in Iraqi women. Mol Biol Rep 51, 589 (2024). https://doi.org/10.1007/s11033-024-09529-y

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