title: Association between inosine triphosphate pyrophosphohydrolase deficiency and azathioprine-related adverse drug reactions in the Chinese kidney transplant recipients.
abstract: 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).
authors.affiliation: Department of Clinical Pharmacology, Wuhan General Hospital of Guangzhou Command, Wuhan 430070, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xiong
authors.forename: Hua-Wen
authors.initials: HW
authors.lastname: Xin
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Wu
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Xiong
authors.forename: Ai-Rong
authors.initials: AR
authors.lastname: Yu
mesh_terms: D000368:Aged; D044466:Asian People / Q000235:genetics*; D001379:Azathioprine / Q000009:adverse effects*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000235:genetics; D006580:Genetic Carrier Screening; D014644:Genetic Variation / Q000187:drug effects / Q000502:physiology; D006084:Graft Rejection / Q000201:enzymology* / Q000235:genetics* / Q000517:prevention & control; D006402:Hematologic Diseases / Q000139:chemically induced / Q000235:genetics; D006720:Homozygote; D006801:Humans; D016030:Kidney Transplantation / Q000009:adverse effects / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D011755:Pyrophosphatases / Q000172:deficiency* / Q000235:genetics; D012189:Retrospective Studies; D000097630:Inosine Triphosphatase
chemical_list: D001379:Azathioprine; D011755:Pyrophosphatases; D000097630:Inosine Triphosphatase