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Volume 12, Issue 3 (Vol.12 No.3 Oct 2023)
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Ali N, Abdulkareem R. Pharmacogenetic Effect of Thiopurine Methyl Transferase (TPMT) Gene Expression and Serum TNF on the Imuran Response in Ulcerative Colitis (UC) Iraqi Patients. rbmb.net 2023; 12 (3) :438-447
URL: http://rbmb.net/article-1-1234-en.html
URL: http://rbmb.net/article-1-1234-en.html
Institute of Genetic Engineering and Biotechnology for Postgraduate Studies, University of Bagdad, Baghdad, Iraq.
Abstract: (1510 Views)
Background: Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), exerts its impact on both rectal and colonic mucosa, with a growing incidence. This study aims to explore the pharmacogenetic influence of thiopurine methyl transferase (TPMT) gene expression and serum tumor necrosis factor (TNF) levels on the response to Imuran in Iraqi patients with UC.
Methods: Seventy individuals with chronic UC and 30 healthy controls were enrolled in this investigation. RNA extraction using the triazole method and enzyme-linked immunosorbent assay (ELISA) for TNF measurement were employed. Patients, aged 15-50 years, underwent Imuran treatment.
Results: Diverse responses to Imuran were observed among patients, with TPMT gene expression levels below 1 in 35 patients leading to side effects, while the remaining 35 patients exhibited positive responses with TPMT gene expression exceeding 1. Patients with varying degrees of severe, moderate, and mild UC associated with TNF showed a significant correlation with Imuran non-response.
Conclusions: A distinct correlation was identified between TPMT gene expression and Imuran therapy outcomes in UC patients. Further investigation is warranted to elucidate the underlying mechanism, positioning the TPMT gene as a potential therapeutic target for mitigating the impact of UC.
Methods: Seventy individuals with chronic UC and 30 healthy controls were enrolled in this investigation. RNA extraction using the triazole method and enzyme-linked immunosorbent assay (ELISA) for TNF measurement were employed. Patients, aged 15-50 years, underwent Imuran treatment.
Results: Diverse responses to Imuran were observed among patients, with TPMT gene expression levels below 1 in 35 patients leading to side effects, while the remaining 35 patients exhibited positive responses with TPMT gene expression exceeding 1. Patients with varying degrees of severe, moderate, and mild UC associated with TNF showed a significant correlation with Imuran non-response.
Conclusions: A distinct correlation was identified between TPMT gene expression and Imuran therapy outcomes in UC patients. Further investigation is warranted to elucidate the underlying mechanism, positioning the TPMT gene as a potential therapeutic target for mitigating the impact of UC.
Keywords: Gene expression, Imuran response, Thiopurine Methyl Transferase, Tumor Necrosis Factor, Ulcerative Colitis.
Type of Article: Original Article |
Subject:
Biochemistry
Received: 2023/08/28 | Accepted: 2023/09/24 | Published: 2024/02/25
Received: 2023/08/28 | Accepted: 2023/09/24 | Published: 2024/02/25
References
1. Sturm A, Maaser C, Calabrese E, Annese V, Fiorino G, Kucharzik T. ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 2: IBD scores and general principles and technical aspects. J Crohns Colitis. 2019;13(3):273-284. [DOI:10.1093/ecco-jcc/jjy114] [PMID]
2. Karimkhani S, Chaleshi V, Balaii H, Tarban P, Nourian M, Irani S, Shahrokh S. Lack of Association between Interleukin 23R (IL-23R) rs10889677 Polymorphism and Inflammatory Bowel Disease Susceptibility In an Iranian Population. Rep Biochem Mol Biol. 2018;7(1):16-22.
3. Abdel-Tawab MS, Mostafa Tork O, Mostafa-Hedeab G, Ewaiss Hassan M, Azmy Elberry D. Protective Effects of Quercetin and Melatonin on Indomethacin Induced Gastric Ulcers in Rats. Rep Biochem Mol Biol. 2020;9(3):278-290. [DOI:10.29252/rbmb.9.3.278] [PMID] []
4. Langan RC, Gotsch PB, Krafczyk MA, Skillinge DD. Ulcerative colitis: diagnosis and treatment. Am Fam Physician. 2007 Nov 1;76(9):1323-30. Erratum in: Am Fam Physician. 2008;77(8):1079.
5. Aardoom MA, Veereman G, de Ridder L. A Review on the Use of Anti-TNF in Children and Adolescents with Inflammatory Bowel Disease. Int J Mol Sci. 2019;20(10):2529. [DOI:10.3390/ijms20102529] [PMID] []
6. Cui G, Fan Q, Li Z, Goll R, Florholmen J. Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease: Current and novel biomarkers. EBioMedicine. 2021;66:103329. [DOI:10.1016/j.ebiom.2021.103329] [PMID] []
7. Sands BE, Kaplan GG. The role of TNFalpha in ulcerative colitis. J Clin Pharmacol. 2007;47(8):930-41. [DOI:10.1177/0091270007301623] [PMID]
8. Arora Z, Shen B. Biological therapy for ulcerative colitis. Gastroenterol Rep (Oxf). 2015;3(2):103-9. [DOI:10.1093/gastro/gou070] [PMID] []
9. Al-Ali SA, Al-Musawi RA. The relevance of rs34598529 SNP of HBB gene among β-thalassemic patients dependent on blood transfusions in Thi-Qar Governate. Iraqi J Biotechnol. 2022;21(2):668-76.
10. Abdulkareem RA, Rafaa TA, Jasim HA, Suleiman AAJ. Pharmacokinetic Effect of MDR Gene Polymorphism rs2032582 on the Therapeutic Response in Iraqi Patients with Acute Myeloid Leukemia. Avicenna J Med Biotechnol. 2020;12(4):241-245.
11. Iu YPH, Helander S, Kahlin AZ, Cheng CW, Shek CC, Leung MH, et al. One amino acid makes a difference-Characterization of a new TPMT allele and the influence of SAM on TPMT stability. Sci Rep. 2017;7:46428. [DOI:10.1038/srep46428] [PMID] []
12. Amin J, Huang B, Yoon J, Shih DQ. Update 2014: advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD. Inflamm Bowel Dis. 2015;21(2):445-52. [DOI:10.1097/MIB.0000000000000197] [PMID]
13. Harmand PO, Solassol J. Thiopurine Drugs in the Treatment of Ulcerative Colitis: Identification of a Novel Deleterious Mutation in TPMT. Genes (Basel). 2020;11(10):1212. [DOI:10.3390/genes11101212] [PMID] []
14. Abaji R, Krajinovic M. Thiopurine S-methyltransferase polymorphisms in acute lymphoblastic leukemia, inflammatory bowel disease and autoimmune disorders: influence on treatment response. Pharmgenomics Pers Med. 2017;10:143-156. [DOI:10.2147/PGPM.S108123] [PMID] []
15. Bramantya RR, Nusi IA, Setiawan PB, Purbayu H, Sugihartono TS, Maimunah U, et al., editors. Diagnosis and management of ulcerative colitis. Proceedings of Surabaya International Physiology Seminar (SIPS 2017); 2018: 405-412. [DOI:10.5220/0007339804050412]
16. Park SC, Jeen YT. Genetic Studies of Inflammatory Bowel Disease-Focusing on Asian Patients. Cells. 2019;8(5):404. [DOI:10.3390/cells8050404] [PMID] []
17. Panaccione R, Ghosh S, Middleton S, Márquez JR, Scott BB, Flint L, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014;146(2):392-400.e3. [DOI:10.1053/j.gastro.2013.10.052] [PMID]
18. Chao YS, Loshak H. Biologics versus Immunomodulators for the Treatment of Ulcerative Colitis: A Review of Comparative Clinical Effectiveness and Cost-Effectiveness [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2019.
19. Mallick B, Malik S. Use of Azathioprine in Ulcerative Colitis: A Comprehensive Review. Cureus. 2022;14(5):e24874. [DOI:10.7759/cureus.24874]
20. Roberts RL, Barclay ML. Current relevance of pharmacogenetics in immunomodulation treatment for Crohn's disease. J Gastroenterol Hepatol. 2012;27(10):1546-54. [DOI:10.1111/j.1440-1746.2012.07220.x] [PMID]
21. Winter JW, Gaffney D, Shapiro D, Spooner RJ, Marinaki AM, Sanderson JD, Mills PR. Assessment of thiopurine methyltransferase enzyme activity is superior to genotype in predicting myelosuppression following azathioprine therapy in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2007;25(9):1069-77. [DOI:10.1111/j.1365-2036.2007.03301.x] [PMID]
22. Hindorf U, Appell ML. Genotyping should be considered the primary choice for pre-treatment evaluation of thiopurine methyltransferase function. J Crohns Colitis. 2012;6(6):655-9. [DOI:10.1016/j.crohns.2011.11.014] [PMID]
23. Kadhim SJ, Jassim HA, Abdulkareem RA. Expression assessment for prolactin receptor gene in a sample of Iraqi women with recurrent miscarriage. Ann Trop Med Public Health. 2020;23(9):1-8. [DOI:10.36295/ASRO.2020.232117]
24. Ali NS, Abdulkareem RA, Ali RS. Study of diarrheageneic E. coli in Iraqi children. AIP Conf Proc. 2022;2386(1):020015.
https://doi.org/10.1063/5.0067848 [DOI:10.1063/5.0107887]
25. Sarlos P, Kovesdi E, Magyari L, Banfai Z, Szabo A, Javorhazy A, Melegh B. Genetic update on inflammatory factors in ulcerative colitis: Review of the current literature. World J Gastrointest Pathophysiol. 2014;5(3):304-21. [DOI:10.4291/wjgp.v5.i3.304] [PMID] []
26. Thomas CW, Myhre GM, Tschumper R, Sreekumar R, Jelinek D, McKean DJ, et al. Selective inhibition of inflammatory gene expression in activated T lymphocytes: a mechanism of immune suppression by thiopurines. J Pharmacol Exp Ther. 2005;312(2):537-45. [DOI:10.1124/jpet.104.074815] [PMID]
27. Lee SH, Kwon JE, Cho ML. Immunological pathogenesis of inflammatory bowel disease. Intest Res. 2018;16(1):26-42. [DOI:10.5217/ir.2018.16.1.26] [PMID] []
28. Breese EJ, Michie CA, Nicholls SW, Murch SH, Williams CB, Domizio P, et al. Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology. 1994;106(6):1455-66. [DOI:10.1016/0016-5085(94)90398-0] [PMID]
29. Nielsen OH, Vainer B, Madsen SM, Seidelin JB, Heegaard NH. Established and emerging biological activity markers of inflammatory bowel disease. Am J Gastroenterol. 2000;95(2):359-67.
https://doi.org/10.1111/j.1572-0241.2000.t01-1-01790.x [DOI:10.1016/S0002-9270(99)00849-7] [PMID]
30. Gareb B, Otten AT, Frijlink HW, Dijkstra G, Kosterink JGW. Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease. Pharmaceutics. 2020;12(6):539. [DOI:10.3390/pharmaceutics12060539] [PMID] []
31. Delgado ME, Brunner T. The many faces of tumor necrosis factor signaling in the intestinal epithelium. Genes Immun. 2019;20(8):609-626. [DOI:10.1038/s41435-019-0057-0] [PMID]
32. Leppkes M, Roulis M, Neurath MF, Kollias G, Becker C. Pleiotropic functions of TNF-α in the regulation of the intestinal epithelial response to inflammation. Int Immunol. 2014;26(9):509-15. [DOI:10.1093/intimm/dxu051] [PMID]
33. Abdulhameed SA, Mohammed BJ. The Relationship of Gene Expression between TNF and TNF-Like Cytokine 1A Genes in Sample of Multiple Sclerosis Iraqi Patients. Iraqi J Biotechnol. 2022;21(2):88-95.
34. Friedrich M, Pohin M, Powrie F. Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. Immunity. 2019;50(4):992-1006. [DOI:10.1016/j.immuni.2019.03.017] [PMID]
35. Biondi A, Zoccali M, Costa S, Troci A, Contessini-Avesani E, Fichera A. Surgical treatment of ulcerative colitis in the biologic therapy era. World J Gastroenterol. 2012;18(16):1861-70. [DOI:10.3748/wjg.v18.i16.1861] [PMID] []
36. Ali AK, Abdul-Kareem WARA, Muttar AJ, Shatha KK. Chromosomal Aberrations and Gene Expression Study in Breast Cancer Patients Undergoing Radiotherapy. Iraqi J Biotechnol. 2019;18(2):277-88.
37. Duricova D, Burisch J, Jess T, Gower-Rousseau C, Lakatos PL; ECCO-EpiCom. Age-related differences in presentation and course of inflammatory bowel disease: an update on the population-based literature. J Crohns Colitis. 2014;8(11):1351-61. [DOI:10.1016/j.crohns.2014.05.006] [PMID]
38. Greuter T, Manser C, Pittet V, Vavricka SR, Biedermann L; on behalf of Swiss IBDnet, an official working group of the Swiss Society of Gastroenterology. Gender Differences in Inflammatory Bowel Disease. Digestion. 2020;101 Suppl 1:98-104. [DOI:10.1159/000504701] [PMID]
39. Rustgi SD, Kayal M, Shah SC. Sex-based differences in inflammatory bowel diseases: a review. Therap Adv Gastroenterol. 2020;13:1756284820915043. [DOI:10.1177/1756284820915043] [PMID] []
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