Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.67 (thiopurine methyltransferase)
 551 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adverse drug reactions to azathioprine (AZA), the pro-drug of 6-mercaptopurine (6-MP), occur in 15% to 28% of patients and the majority are not explained by thiopurine methyltransferase (TPMT) deficiency. Inosine triphosphate pyrophosphatase (ITPase) deficiency results in the benign accumulation of the inosine nucleotide ITP. 6-MP is activated through a 6-thio-IMP intermediate and, in ITPase deficient patients, potentially toxic 6-thio-ITP is predicted to accumulate. The association between polymorphism in the ITPA gene and adverse drug reactions to AZA therapy was studied in patients treated for inflammatory bowel disease. Sixty-two patients with inflammatory bowel disease suffering adverse drug reactions to AZA therapy were genotyped for ITPA 94C>A and IVS2 + 21A>C polymorphisms, and TPMT*3A, *3C, *2 polymorphisms. Genotype frequencies were compared to a consecutive series of 68 controls treated with AZA for a minimum of 3 months without adverse effect. The ITPA 94C>A deficiency-associated allele was significantly associated with adverse drug reactions [odds ratio (OR) 4.2, 95% confidence interval (CI) 1.6-11.5, P = 0.0034]. Significant associations were found for flu-like symptoms (OR 4.7, 95% CI 1.2-18.1, P = 0.0308), rash (OR 10.3, 95% CI 4.7-62.9, P = 0.0213) and pancreatitis (OR 6.2,CI 1.1-32.6, P = 0.0485). Overall, heterozygous TPMT genotypes did not predict adverse drug reactions but were significantly associated with a subgroup of patients experiencing nausea and vomiting as the predominant adverse reaction to AZA therapy (OR 5.5, 95% CI 1.4-21.3, P = 0.0206). Polymorphism in the ITPA gene predicts AZA intolerance. Alternative immunosuppressive drugs, particularly 6-thioguanine, should be considered for AZA-intolerant patients with ITPase deficiency.
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PMID:Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). 1516 6

Azathioprine (AZA) is a thiopurine prodrug commonly used in patients with kidney transplantation. The aim of this study is to explore in patients with kidney transplantation whether AZA-related side effects can be explained by the inosine triphophate pyrophosphatase (ITPA) or thiopurine S-methyltransferase (TPMT) polymorphisms using both pheno-and genotyping. Erythrocyte ITPA and TPMT activity of 155 patients with kidney transplantation and AZA therapy was determined by HPLC. The frequencies of ITPA and TPMT polymorphisms were detected. Among 155 patients, three cases with zero activity were homozygote for 94C>A. The allele frequency of the 94C>A polymorphism was 0.12. Allele for the IVS2+21A>C mutation in the patients of this study was not found. Thirty-five cases had stopped azathioprine medication or were on reduced dose due to AZA-related side effects, including hematotoxicity (n = 12), hepatotoxicity (n = 18), gastrointestinal toxicity (n = 5, one patient developed hepatotoxicity simultaneously) and flu-like symptoms (n = 1). No statistical significant associations between ITPA 94C>A phenotype or genotype and AZA-related hematotoxicity or hepatotoxicity could be detected. However, five patients who developed gastrointestinal disturbance, two patients were homozygote for 94C>A and other three patients had 94C>A heterozygous allele. The patient who experienced flu-like symptoms were the remaining homozygote for 94C>A. This study demonstrates that ITPA activity reduced in patients with 94C>A mutation (P < 0.01). Patients with ITPA 94C>A homozygous allele are at high risk to develop AZA-related gastrointestinal toxicity and flu-like symptoms (P < 0.01). TPMT wild-type/ITPA variant (homozygote) is closely related to the AZA-induced side effects (P < 0.01).
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PMID:Association between inosine triphosphate pyrophosphohydrolase deficiency and azathioprine-related adverse drug reactions in the Chinese kidney transplant recipients. 1968 85