TPMT Genotype and Adverse Effects of Azathioprine among Jordanian Group

Author(s): Mohammed Mhanna, Munir Garaiba Gharaibeh, Mohammad Rashid, Ahmad Sharab, Mohammad Shehab, Malek Zihlif*.

Journal Name: Current Drug Metabolism

Volume 20 , Issue 11 , 2019


Graphical Abstract:


Abstract:

Background: Inflammatory Bowel Disease (IBD) is a common disease affecting many patients. This disease is treated by azathioprine and TPMT genetic polymorphism affecting the patient’s tolerance. The aim of this study is to investigate the importance of TMPT genotyping in reducing the incidence of adverse effects of azathioprine.

Methods: One hundred and forty-one IBD patients were followed for azathioprine Adverse Drug Reaction (ADR). Patients were genotyped for TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C.

Results: The frequency of Azathioprine adverse effect was about 35.5%. An association between TPMT genotypes 1/3A and 3B/3B and azathioprine related bone marrow suppression was found (P value ≤ 0.05).

Conclusion: The findings suggest that there was a significant association between TPMT genotypes 1/3A and 3B/3B and azathioprine related bone marrow suppression.

Keywords: Azathioprine, TPMT genotype, adverse effects, inflammatory bowel disease (IBD), gastrointestinal tract, chronic granulmatous inflammation.

[1]
Van Assche, G.; Dignass, A.; Panes, J.; Beaugerie, L.; Karagiannis, J.; Allez, M.; Ochsenkühn, T.; Orchard, T.; Rogler, G.; Louis, E.; Kupcinskas, L.; Mantzaris, G.; Travis, S.; Stange, E. European Crohn’s and Colitis Organisation (ECCO). The second European evidence-based consensus on the diagnosis and management of Crohn’s disease: Definitions and diagnosis. J. Crohn’s Colitis, 2010, 4(1), 7-27.
[http://dx.doi.org/10.1016/j.crohns.2009.12.003] [PMID: 21122488]
[2]
Kiely, C.J.; Pavli, P.; O’Brien, C.L. The role of inflammation in temporal shifts in the inflammatory bowel disease mucosal microbiome. Gut Microbes, 2018, 9(6), 477-485.
[http://dx.doi.org/10.1080/19490976.2018.1448742] [PMID: 29543557]
[3]
Harris, V.; Ali, A.; Fuentes, S.; Korpela, K.; Kazi, M.; Tate, J.; Parashar, U.; Wiersinga, W.J.; Giaquinto, C.; De Weerth, C.; De Vos, W.M. Rotavirus vaccine response correlates with the infant gut microbiota composition in Pakistan. Gut Microbes, 2018, 9(2), 93-101.
[http://dx.doi.org/10.1080/19490976.2017.1376162] [PMID: 28891751]
[4]
Ibarra, A.; Latreille-Barbier, M.; Donazzolo, Y.; Pelletier, X.; Ouwehand, A.C. Effects of 28-day Bifidobacterium animalis subsp. lactis HN019 supplementation on colonic transit time and gastrointestinal symptoms in adults with functional constipation: A double-blind, randomized, placebo-controlled, and dose-ranging trial. Gut Microbes, 2018, 9(3), 236-251.
[http://dx.doi.org/10.1080/19490976.2017.1412908] [PMID: 29227175]
[5]
Elion, G.B. The purine path to chemotherapy. Science, 1989, 244(4900), 41-47.
[http://dx.doi.org/10.1126/science.2649979] [PMID: 2649979]
[6]
Lennard, L. The clinical pharmacology of 6-mercaptopurine. Eur. J. Clin. Pharmacol., 1992, 43(4), 329-339.
[http://dx.doi.org/10.1007/BF02220605] [PMID: 1451710]
[7]
Prefontaine, E.; Macdonald, J.K.; Sutherland, L.R. Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst. Rev., 2009, 4CD000545
[http://dx.doi.org/10.1002/14651858.CD000545.pub2] [PMID: 19821270]
[8]
Bermejo San José, F.; Algaba, A.; López Durán, S.; Guerra, I.; Aicart, M.; Hernández-Tejero, M.; Garrido, E.; de Lucas, M.; Bonillo, D.; López Sanromán, A. Mercaptopurine and inflammatory bowel disease: The other thiopurine. Rev. Esp. Enferm. Dig., 2017, 109(1), 10-16.
[PMID: 27809554]
[9]
Jharap, B.; Seinen, M.L.; De Boer, N.K.; Van Ginkel, J.R.; Linskens, R.K.; Kneppelhout, J.C.; Mulder, C.J.; Van Bodegraven, A.A. Thiopurine therapy in inflammatory bowel disease patients: Analyses of two 8-year intercept cohorts. Inflamm. Bowel Dis., 2010, 16(9), 1541-1549.
[http://dx.doi.org/10.1002/ibd.21221] [PMID: 20155846]
[10]
Chaparro, M.; Ordás, I.; Cabré, E.; Garcia-Sanchez, V.; Bastida, G.; Peñalva, M.; Gomollón, F.; García-Planella, E.; Merino, O.; Gutiérrez, A.; Esteve, M.; Márquez, L.; Garcia-Sepulcre, M.; Hinojosa, J.; Vera, I.; Muñoz, F.; Mendoza, J.L.; Cabriada, J.L.; Montoro, M.A.; Barreiro-de Acosta, M.; Ceña, G.; Saro, C.; Aldeguer, X.; Barrio, J.; Maté, J.; Gisbert, J.P. Safety of thiopurine therapy in inflammatory bowel disease: Long-term follow-up study of 3931 patients. Inflamm. Bowel Dis., 2013, 19(7), 1404-1410.
[http://dx.doi.org/10.1097/MIB.0b013e318281f28f] [PMID: 23665964]
[11]
de Jong, D.J.; Derijks, L.J.; Naber, A.H.; Hooymans, P.M.; Mulder, C.J. Safety of thiopurines in the treatment of inflammatory bowel disease. Scand. J. Gastroenterol. Suppl., 2003, 239(239), 69-72.
[http://dx.doi.org/10.1080/00855920310002726] [PMID: 14743886]
[12]
Gisbert, J.P.; González-Lama, Y.; Maté, J. Thiopurine-induced liver injury in patients with inflammatory bowel disease: A systematic review. Am. J. Gastroenterol., 2007, 102(7), 1518-1527.
[http://dx.doi.org/10.1111/j.1572-0241.2007.01187.x] [PMID: 17391318]
[13]
Colombel, J.F.; Ferrari, N.; Debuysere, H.; Marteau, P.; Gendre, J.P.; Bonaz, B.; Soulé, J.C.; Modigliani, R.; Touze, Y.; Catala, P.; Libersa, C.; Broly, F. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy. Gastroenterology, 2000, 118(6), 1025-1030.
[http://dx.doi.org/10.1016/S0016-5085(00)70354-4] [PMID: 10833476]
[14]
Coelho, T.; Andreoletti, G.; Ashton, J.J.; Batra, A.; Afzal, N.A.; Gao, Y.; Williams, A.P.; Beattie, R.M.; Ennis, S. Genes implicated in thiopurine-induced toxicity: Comparing TPMT enzyme activity with clinical phenotype and exome data in a paediatric IBD cohort. Sci. Rep., 2016, 6, 34658.
[http://dx.doi.org/10.1038/srep34658] [PMID: 27703193]
[15]
Fangbin, Z.; Xiang, G.; Liang, D.; Hui, L.; Xueding, W.; Baili, C.; Huichang, B.; Yinglian, X.; Peng, C.; Lizi, Z.; Yanjun, C.; Feng, X.; Minhu, C.; Min, H.; Pinjin, H. Prospective evaluation of pharmacogenomics and metabolite measurements upon azathioprine therapy in inflammatory bowel disease: An observational study. Medicine (Baltimore), 2016, 95(15)e3326
[http://dx.doi.org/10.1097/MD.0000000000003326] [PMID: 27082580]
[16]
Di Salvo, A.; Fabiano, C.; Mannara, V.; Dimarco, M.; Orlando, A.; Affronti, M.; Macaluso, F.S.; Cottone, M. Frequency of thiopurine methyltransferase mutation in patients of Mediterranean area with inflammatory bowel disease and autoimmune disorders. Dig. Liver Dis., 2016, 48(12), 1506-1509.
[http://dx.doi.org/10.1016/j.dld.2016.08.125] [PMID: 27665263]
[17]
Hakooz, N.; Arafat, T.; Payne, D.; Ollier, W.; Pushpakom, S.; Andrews, J.; Newman, W. Genetic analysis of thiopurine methyltransferase polymorphism in the Jordanian population. Eur. J. Clin. Pharmacol., 2010, 66(10), 999-1003.
[http://dx.doi.org/10.1007/s00228-010-0826-1] [PMID: 20521035]
[18]
Elawi, A.M.; Irshaid, Y.M.; Ismail, S.I.; Mustafa, K.N. Thiopurine S-methyltransferase gene polymorphism in rheumatoid arthritis. Arch. Med. Res., 2013, 44(2), 105-109.
[http://dx.doi.org/10.1016/j.arcmed.2013.01.006] [PMID: 23398787]
[19]
Murugesan, R.; Vahab, S.A.; Patra, S.; Rao, R.; Rao, J.; Rai, P.; Gopinath, P.M.; Satyamoorthy, K. Thiopurine S-methyltransferase alleles, TPMT(*)2, (*)3B and (*)3C, and genotype frequencies in an Indian population. Exp. Ther. Med., 2010, 1(1), 121-127.
[PMID: 23136604]


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 20
ISSUE: 11
Year: 2019
Page: [889 - 897]
Pages: 9
DOI: 10.2174/1389200220666191021100953
Price: $58

Article Metrics

PDF: 18
HTML: 2

Special-new-year-discount