Gene Polymorphisms Involved in Manifestation of Leucopenia, Digestive Intolerance, and Pancreatitis in Azathioprine-Treated Patients

被引:24
作者
Wroblova, Katerina [1 ]
Kolorz, Michal [1 ]
Batovsky, Marian [2 ]
Zboril, Vladimir [3 ]
Suchankova, Jana [1 ]
Bartos, Milan [4 ]
Ulicny, Boris [5 ]
Pav, Igor [2 ]
Bartosova, Ladislava [1 ]
机构
[1] Univ Vet & Pharmaceut Sci Brno, Dept Human Pharmacol & Toxicol, Fac Pharm, Brno 61242, Czech Republic
[2] Univ Hosp Bratislava Petrzalka, Gastroenterol Clin, Bratislava 85107, Slovakia
[3] Univ Hosp, Dept Internal Med & Hepatogastroenterol, Brno 62500, Czech Republic
[4] Univ Vet & Pharmaceut Sci, Dept Nat Drugs, Fac Pharm, Brno 61242, Czech Republic
[5] YBUX Ltd, Brno 61600, Czech Republic
关键词
Azathioprine; Inflammatory bowel disease; Inosine triphosphate diphosphatase; Thiopurine S-methyltransferase; Xanthine dehydrogenase; Pharmacogenomics; THIOPURINE S-METHYLTRANSFERASE; INFLAMMATORY-BOWEL-DISEASE; INOSINE TRIPHOSPHATE PYROPHOSPHATASE; ADVERSE DRUG-REACTIONS; CROHNS-DISEASE; XANTHINE-OXIDASE; PYROPHOSPHOHYDROLASE DEFICIENCY; FUNCTIONAL-CHARACTERIZATION; INDUCED MYELOSUPPRESSION; CAUCASIAN POPULATION;
D O I
10.1007/s10620-012-2163-y
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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. 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. 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. 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). 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.
引用
收藏
页码:2394 / 2401
页数:8
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