Gene polymorphisms involved in manifestation of leucopenia, digestive intolerance, and pancreatitis in azathioprine-treated patients
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Azathioprine adverse effects therapeutic use MeSH
- Gastrointestinal Diseases chemically induced genetics MeSH
- Genetic Predisposition to Disease MeSH
- Genotype MeSH
- Inflammatory Bowel Diseases drug therapy MeSH
- Immunosuppressive Agents adverse effects therapeutic use MeSH
- Leukopenia chemically induced genetics MeSH
- Humans MeSH
- Methyltransferases genetics metabolism MeSH
- Pancreatitis chemically induced genetics MeSH
- Polymerase Chain Reaction methods MeSH
- Polymorphism, Genetic * MeSH
- Prohibitins MeSH
- Gene Expression Regulation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Azathioprine MeSH
- Immunosuppressive Agents MeSH
- Methyltransferases MeSH
- PHB2 protein, human MeSH Browser
- Prohibitins MeSH
- thiopurine methyltransferase MeSH Browser
BACKGROUND: Approximately 10-28 % of patients experience adverse drug reactions related to treatment with thiopurines. The most serious reaction is myelosuppression, typically manifested as leucopenia, which occurs in approximately 2-5 % of patients. Other adverse drug reactions that often accompany thiopurine therapy are pancreatitis, hepatotoxicity, allergic reactions, digestive intolerance, arthralgia, febrile conditions, and rash. OBJECTIVE: The objective of this study was to assess the relationship between variant alleles of thiopurine S-methyltransferase (SNPs 238G > C, 460G > A and 719A > G), inosine triphosphate diphosphatase (SNPs 94C > A and IVS2 + 21A > C), and xanthine dehydrogenase (837C > T) and the occurrence of adverse drug reactions to azathioprine therapy. METHODS: Genotype was determined for 188 Caucasians diagnosed with inflammatory bowel disease treated with a standard dose of azathioprine (1.4-2.0 mg/kg/day). Allelic variants were determined by PCR-REA and real-time PCR methods. Results were statistically evaluated by use of Fisher's test and by odds ratio calculation. RESULTS: Variant genotype thiopurine S-methyltransferase predisposes to development of leucopenia (P = 0.003, OR = 5, CI 95 %, 1.8058-13.8444). Although not statistically significant, we observed a trend that suggested correlation between the occurrence of digestive intolerance and the variant genotype inosine triphosphate diphosphatase (P = 0.1102; OR 15.63, CI 95 %, 1.162-210.1094), and between the occurrence of pancreatitis and the variant allele xanthine dehydrogenase 837T (P = 0.1124; OR 12,1, CI 95 %, 1.15-126.37). CONCLUSION: The variant genotype thiopurine S-methyltransferase has been associated with the occurrence of leucopenia. The involvement of polymorphisms in inosine triphosphate diphosphatase and xanthine dehydrogenase genes in the development of digestive intolerance and pancreatitis will require further verification.
See more in PubMed
Curr Pharm Des. 2010;16(2):145-54 PubMed
J Hepatol. 2004 Mar;40(3):454-63 PubMed
Pharmacogenetics. 2004 Mar;14(3):181-7 PubMed
Ann Clin Biochem. 2004 Jul;41(Pt 4):294-302 PubMed
Clin Pharmacol Ther. 1991 Dec;50(6):663-72 PubMed
Acta Physiol Scand Suppl. 1986;548:87-99 PubMed
Am J Gastroenterol. 2005 Oct;100(10):2239-47 PubMed
Pharmacogenomics. 2007 Sep;8(9):1221-8 PubMed
Gastroenterology. 2000 Jun;118(6):1025-30 PubMed
Dig Liver Dis. 2005 Apr;37(4):282-97 PubMed
Liver Transpl. 2005 Jul;11(7):826-833 PubMed
Clin Gastroenterol Hepatol. 2008 Jun;6(6):654-60; quiz 604 PubMed
J Gastrointestin Liver Dis. 2011 Sep;20(3):247-53 PubMed
Aliment Pharmacol Ther. 2002 Oct;16(10):1743-50 PubMed
Aliment Pharmacol Ther. 2009 Aug 15;30(4):375-84 PubMed
Gut. 1993 Aug;34(8):1081-5 PubMed
Biochim Biophys Acta. 2010 Feb;1802(2):269-74 PubMed
Clin Pharmacol Ther. 2009 Feb;85(2):164-72 PubMed
Clin Pharmacol Ther. 1992 Dec;52(6):643-58 PubMed
Clin Pharmacol Ther. 2001 Aug;70(2):183-8 PubMed
Gut. 2003 Jan;52(1):140-2 PubMed
Br J Clin Pharmacol. 2008 Oct;66(4):517-28 PubMed
Hum Genet. 2002 Oct;111(4-5):360-7 PubMed
Gut. 2005 Apr;54(4):565 PubMed
Mol Genet Metab. 2005 Aug;85(4):271-9 PubMed
Clin Chem. 2004 Nov;50(11):2182-4 PubMed
Ann Intern Med. 1997 Apr 15;126(8):608-14 PubMed
Pharmacogenet Genomics. 2008 Oct;18(10):887-93 PubMed
Pharmacoeconomics. 2006;24(8):767-81 PubMed
J Hum Genet. 2004;49(10):579-581 PubMed
Biochim Biophys Acta. 2007 Jan;1772(1):96-102 PubMed
J Gastroenterol Hepatol. 2005 Jun;20(6):955 PubMed
Gastroenterology. 2000 Apr;118(4):705-13 PubMed
J Clin Gastroenterol. 2002 Sep;35(3):240-4 PubMed
J Am Acad Dermatol. 2006 Sep;55(3):369-89 PubMed
Clin Chem. 2006 Feb;52(2):240-7 PubMed
Eur J Clin Pharmacol. 2004 Apr;60(2):89-96 PubMed
Br J Pharmacol. 1998 Oct;125(4):879-87 PubMed
Clin Gastroenterol Hepatol. 2006 Jan;4(1):44-9 PubMed
Eur J Clin Pharmacol. 2009 May;65(5):533-40 PubMed
Gut. 2005 Nov;54(11):1664 PubMed
J Hum Genet. 2002;47(11):620-2 PubMed
Pharmacogenet Genomics. 2008 Mar;18(3):243-51 PubMed
J Clin Oncol. 2001 Apr 15;19(8):2293-301 PubMed
Neuro Endocrinol Lett. 2009;30 Suppl 1:137-42 PubMed
