Association between interleukin-2 (rs2069762) gene polymorphism and FVIII inhibitor development in Indonesian patients with severe hemophilia A

  • Sri Marwanta Department of Internal Medicine, Faculty of Medicine, Universitas Sebelas Maret, Dr. Moewardi General Hospital, Surakarta, Indonesia https://orcid.org/0000-0002-9105-595X
  • Faizal Muhammad Department of Neurology, Faculty of Medicine, Universitas Sebelas Maret, Universitas Sebelas Maret Hospital, Surakarta, Indonesia
  • Suradi Maryono Department of Internal Medicine, Faculty of Medicine, Universitas Sebelas Maret, Dr. Moewardi General Hospital, Surakarta, Indonesia
  • Kun Salimah Department of Internal Medicine, Faculty of Medicine, Universitas Sebelas Maret, Dr. Moewardi General Hospital, Surakarta, Indonesia
  • Sihwidhi Dimas Sudarmadi Department of Internal Medicine, Faculty of Medicine, Universitas Sebelas Maret, Dr. Moewardi General Hospital, Surakarta, Indonesia
  • Bambang Purwanto Department of Internal Medicine, Faculty of Medicine, Universitas Sebelas Maret, Dr. Moewardi General Hospital, Surakarta, Indonesia
  • Brian Wasita Department of Anatomical Pathology, Faculty of Medicine, Universitas Sebelas Maret, Dr. Moewardi General Hospital, Surakarta, Indonesia
  • Tonang Dwi Ardyanto Department of Clinical Pathology, Faculty of Medicine, Universitas Sebelas Maret, Universitas Sebelas Maret Hospital, Surakarta, Indonesia https://orcid.org/0000-0003-4267-7282
  • Soetrisno Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Sebelas Maret, Dr. Moewardi General Hospital, Surakarta, Indonesia
Keywords: antibodies, factor VIII, hemophilia A, interleukin-2, single nucleotide polymorphism
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Abstract

BACKGROUND Factor VIII (FVIII) inhibitors in hemophilia A (HA) patients render FVIII replacement therapy ineffective. Although its development cause is unclear, it has been classified into therapeutic and genetic-related etiologies. Single nucleotide polymorphisms (SNPs) in several cytokine genes, including interleukin (IL)-2, could increase the risk of FVIII inhibitor development. This study aimed to evaluate the association between IL-2 (rs2069762) gene SNP and FVIII inhibitor development in Indonesian patients with severe HA.

METHODS The IL-2 (rs2069762) gene SNP was examined in 119 HA patients. The presence of FVIII inhibitors was quantified using an enzyme-linked immunosorbent assay, with a titer of <0.28 ng/ml considered negative. Patients were divided into two groups: 59 with FVIII inhibitors (positive group) and 60 without inhibitors (negative group). The genotype of the subjects was determined using peripheral blood mononuclear cells and tetra-primer amplification refractory mutation system-polymerase chain reaction.

RESULTS There was no association between IL-2 (rs2069762) gene polymorphism and FVIII inhibitor development on genotypes (p = 0.138) and allele frequencies (p = 0.780).

CONCLUSIONS IL-2 (rs2069762) gene polymorphism is not a risk factor in the development of FVIII inhibitors in Indonesian patients with severe HA. Thus, further polymorphism studies in other cytokine genes are required to gain a comprehensive understanding of the FVIII inhibitor development.

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References

  1. Charlebois J, Rivard GÉ, St-Louis J. Management of acquired hemophilia A: review of current evidence. Transfus Apher Sci. 2018;57(6):717-20. https://doi.org/10.1016/j.transci.2018.10.011

  2. Kadhim KAR, Al-Lami FH, Baldawi KH. Epidemiological profile of hemophilia in Baghdad-Iraq. Inquiry. 2019;56:46958019845280. https://doi.org/10.1177/0046958019845280

  3. Mannucci PM, Shi Q, Bonanad S, Klamroth R. Novel investigations on the protective role of the FVIII/VWF complex in inhibitor development. Haemophilia. 2014;20 Suppl 6:2-16. Erratum in: Haemophilia. 2014;20(5):e376. https://doi.org/10.1111/hae.12465

  4. Walsh CE, Jiménez-Yuste V, Auerswald G, Grancha S. The burden of inhibitors in haemophilia patients. Thromb Haemost. 2016;116 Suppl 1:S10-7. https://doi.org/10.1160/TH16-01-0049

  5. Kim JY, You CW. The prevalence and risk factors of inhibitor development of FVIII in previously treated patients with hemophilia A. Blood Res. 2019;54(3):204-9. https://doi.org/10.5045/br.2019.54.3.204

  6. Castaman G, Fijnvandraat K. Molecular and clinical predictors of inhibitor risk and its prevention and treatment in mild hemophilia A. Blood. 2014;124(15):2333-6. https://doi.org/10.1182/blood-2014-02-546127

  7. Astermark J, Donfield SM, Gomperts ED, Schwarz J, Menius ED, Pavlova A, et al. The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort. Blood. 2013;121(8):1446-54. https://doi.org/10.1182/blood-2012-06-434803

  8. Lozier JN, Rosenberg PS, Goedert JJ, Menashe I. A case-control study reveals immunoregulatory gene haplotypes that influence inhibitor risk in severe haemophilia A. Haemophilia. 2011;17(4):641-9. https://doi.org/10.1111/j.1365-2516.2010.02473.x

  9. Marwanta S, Soetrisno S, Purwanto B, Wasita B, Ardyanto TD, Muhammad F, et al. The effects of low-dose methylprednisolone as adjuvant therapy for hemophilia A patients with factor VIII inhibitors. J Appl Pharm Sci. 2021;11(12):196-9. https://doi.org/10.7324/JAPS.2021.1101219

  10. Susanah S, Raspati H, Sari NM, Rakhmilla LE, Sribudiani Y, Moestopo O, et al. Serum TNF-α level as a possible predictor of inhibitor levels in severe hemophilia A. Biomed Res Int. 2021;2021:6483490. https://doi.org/10.1155/2021/6483490

  11. Sun J, Yuan Z, Abajas YL, Szollosi DE, Hu G, Hua B, et al. A retrospective study of the cytokine profile changes in mice with FVIII inhibitor development after adeno-associated virus-mediated gene therapy in a hemophilia A mouse model. Hum Gene Ther. 2018;29(3):381-9. https://doi.org/10.1089/hum.2017.094

  12. Waters RS, Perry JSA, Han S, Bielekova B, Gedeon T. The effects of interleukin-2 on immune response regulation. Math Med Biol. 2018;35(1):79-119. https://doi.org/10.1093/imammb/dqw021

  13. National Library of Medicine. Homo sapiens interleukin 2 (Gene ID: 3558) [Internet]. National Center for Biotechnology Information; 2022 [cited 2022 Jul 9]. Available from: https://www.ncbi.nlm.nih.gov/gene/?term=Homo+sapiens+interleukin+2.

  14. Naderi N, Ebrahimzadeh F, Jazebi M, Namvar A, Hashemi M, Bolhassani A. Polymorphisms in the TGF-β1 (rs1982037) and IL-2 (rs2069762, rs4833248) genes are not associated with inhibitor development in Iranian patients with hemophilia A. Hematology. 2018;23(10):839-43. https://doi.org/10.1080/10245332.2018.1498168

  15. Witmer C, Young G. Factor VIII inhibitors in hemophilia A: rationale and latest evidence. Ther Adv Hematol. 2013;4(1):59-72. https://doi.org/10.1177/2040620712464509

  16. Liu CL, Ye P, Lin J, Djukovic D, Miao CH. Long-term tolerance to factor VIII is achieved by administration of interleukin-2/interleukin-2 monoclonal antibody complexes and low dosages of factor VIII. J Thromb Haemost. 2014;12(6):921-31. https://doi.org/10.1111/jth.12576

  17. Vandenbroeck K. Cytokine gene polymorphisms and human autoimmune disease in the era of genome-wide association studies. J Interferon Cytokine Res. 2012;32(4):139-51. https://doi.org/10.1089/jir.2011.0103

  18. Fichna M, Żurawek M, Bratland E, Husebye ES, Kasperlik-Załuska A, Czarnocka B, et al. Interleukin-2 and subunit alpha of its soluble receptor in autoimmune Addison's disease--an association study and expression analysis. Autoimmunity. 2015;48(2):100-7. https://doi.org/10.3109/08916934.2014.976628

  19. Martelossi Cebinelli GC, Paiva Trugilo K, Badaró Garcia S, Brajão de Oliveira K. TGF-β1 functional polymorphisms: a review. Eur Cytokine Netw. 2016;27(4):81-9. https://doi.org/10.1684/ecn.2016.0382

  20. Ahmed BT, Saeed MY, Noori SH, Amin DM. TGF-β1 gene polymorphism and its correlation with serum level of TGF-β1 in psoriasis vulgaris among Iraqi people. Clin Cosmet Investig Dermatol. 2020;13:889-96. https://doi.org/10.2147/CCID.S281585

  21. Fidancı ID, Zülfikar B, Kavaklı K, Ar MC, Kılınç Y, Başlar Z, et al. A polymorphism in the IL-5 gene is associated with inhibitor development in severe hemophilia A patients. Turk J Haematol. 2014;31(1):17-24. https://doi.org/10.4274/Tjh.2012.0197

  22. Pelaia C, Paoletti G, Puggioni F, Racca F, Pelaia G, Canonica GW, et al. Interleukin-5 in the pathophysiology of severe asthma. Front Physiol. 2019;10:1514. https://doi.org/10.3389/fphys.2019.01514

Published
2023-03-08
How to Cite
1.
Marwanta S, Muhammad F, Maryono S, Salimah K, Sudarmadi SD, Purwanto B, Wasita B, Ardyanto TD, Soetrisno. Association between interleukin-2 (rs2069762) gene polymorphism and FVIII inhibitor development in Indonesian patients with severe hemophilia A. Med J Indones [Internet]. 2023Mar.8 [cited 2024Jun.18];31(4):213-7. Available from: https://mji.ui.ac.id/journal/index.php/mji/article/view/6439
Section
Basic Medical Research