Impact of the heterozygous TPMT*1/*3C genotype on azathioprine-induced myelosuppression in kidney transplant recipients in Thailand |
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Authors: | Suda Vannaprasaht Susothorn Angsuthum Yingyos Avihingsanon Dhavee Sirivongs Cholatip Pongskul Pattarapong Makarawate Kearkiat Praditpornsilpa Wongwiwat Tassaneeyakul Wichittra Tassaneeyakul |
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Institution: | 1. University of Ljubljana, Faculty of Medicine, Institute of Biochemistry, Pharmacogenetics Laboratory, Vrazov trg 2, 1000 Ljubljana, Slovenia;2. University Medical Center, University Children''s Hospital, Oncology and Haematology Unit, Bohori?eva 20, Ljubljana, Slovenia;3. University Medical Center, University Children''s Hospital, Center for Medical Genetics, Vrazov trg 1, Ljubljana, Slovenia;1. Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran;2. Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran;3. Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran;1. Department of Urology & Center of Renal Transplantation, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China;2. Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China;3. Department of Cardiothoracic Surgery, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China |
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Abstract: | Background: Thiopurine S-methyltransferase (TPMT) is a polymorphic enzyme associated with detoxification of azathioprine, an immunosuppressant used after renal transplantation in several Asian countries. Patients with variations of the TPMT gene may be at risk for myelosuppression after they receive a standard dosage of the drug. The frequency of TPMT*3C has been reported to be higher in the Thai population than in other Asian populations, possibly putting the Thais at higher risk for myelosuppression.Objective: The aim of this study was to assess the impact of the heterozygous TPMT*1/*3C genotype on azathioprine-induced myelosuppression in kidney transplant recipients in Thailand.Methods: This study was conducted at Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand, and Chulalongkorn Hospital, Chulalongkorn University, Bangkok, Thailand. Eligible patients underwent kidney transplantation from deceased or living-related donors from 1984 to 2007. Electronic medical records were assessed retrospectively for the 6-month period after initiation of azathioprine treatment. TPMT genotyping and phenotyping were studied prospectively using real-time polymerase chain reaction and biochemical assay, respectively. The odds ratios (ORs), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined.Results: A total of 139 patients were enrolled (89 men, 50 women; median age, 42 years range, 17–70 years]; mean weight, 58 kg range, 37–87 kg]). The heterozygous TPMT*1/*3C genotype was found in 9 of the 139 patients (6.47%) (95% CI, 3.00–11.94). The TPMT activity of those patients was significantly lower than that of patients with the homozygous wild-type genotype (median, 21.37 vs 37.12 nmol 6-methylthioguanine/g · Hb/h, respectively; P < 0.001). The risk for azathioprine-induced myelosuppression in the patients with the heterozygous TPMT*1/*3C genotype was significantly higher than that in patients with the wild-type genotype (adjusted OR, 14.18 95% CI, 3.07–65.40]; P < 0.005). The sensitivity and specificity of TPMT*3C genotyping for the prediction of azathioprine-induced myelosuppression in these kidney transplant recipients were 27% and 97%, respectively. Assuming a prevalence of azathioprine-induced myelotoxicity of 7% according to previously published data, the PPV and NPV were estimated to be 50% and 95%, respectively.Conclusion: In these kidney transplant recipients, patients who carried the TPMT*3C allele were at a higher risk for azathioprine-induced myelosuppres-sion than noncarriers. |
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