TPMT*26 (208F→L), a novel mutation detected in a Chinese (original) (raw)
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Characterization of a novel TPMT mutation associated with azathioprine-induced myelosuppression
British Journal of Clinical Pharmacology, 2009
Azathioprine (AZA), a prodrug of 6-mercaptopurine, is prescribed in evolving forms of inflammatory bowel disease (IBD), affecting predominantly White adolescents and young adults. Thiopurine S-methyltransferase (TPMT) catabolizes AZA and its genetic polymorphism affects the balance between active 6-thioguanine nucleotides (6-TGN) intracellular concentrations [recommended target 235-400 pmol per 8 ¥ 10 8 red blood cells (RBC)] and hepatotoxic 6-methylmercaptopurine ribonucleotides (6-MMP) [1]. Three polymorphisms (TPMT*2, *3B, *3C; rs1800462, rs1800460, rs1142345, respectively) account for >95% of variant alleles, but additional rare variants are described (TPMT*1S to TPMT*25) [2]. Approximately 90% of Whites are extensive metabolizers with two wild-type TPMT alleles, 6-11% are intermediate metabolizers and 0.2-0.6% are TPMT-deficient patients, exposed to severe myelotoxicity as they accumulate high 6-TGN concentrations under AZA conventional doses [3]. This case reports a pancytopenia under AZA treatment for IBD. As 6-TGN and 6-MMP concentrations and TPMT genotype based on the three predominant polymorphisms were discordant, we conducted additional genetic analysis and identified a new, never described TPMT mutation affecting TPMT activity.
Indian Journal of Gastroenterology, 2014
Background Thiopurine methyltransferase (TPMT) enzyme plays a key role in the metabolism of azathioprine/6mercaptopurine (6-MP). Mutations in the enzyme lead to generation of excess thioguanine, which causes suppression of various cell lineages, especially neutrophils. Data on the prevalence of TPMT polymorphism are available from Western and some Asian countries; such data from India are sparse. Aims The aim of this research is to study the prevalence of TPMT mutation in Indian patients requiring immunomodulator therapy and its relation to the development of neutropenia on azathioprine therapy. Methods In this retrospective study, data of all patients who underwent TPMT genotyping by PCR-RFLP and allele-specific PCR prior to immunomodulator therapy were analyzed. The frequency of on-treatment development of neutropenia (total neutrophil count <1,500 per cubic millimeters) was noted. Results Data were available on 126 patients (mean age, 42 [SD 13.6] years; 73 men and 53 women). The disease indications included ulcerative colitis (61), Crohn's disease (43), indeterminate colitis (1), autoimmune hepatitis (16), and others (5). TPMT genotype was wild in 120 patients (95.23 %) and heterozygous in 6 patients (4.77 %); no patient had homozygous mutation. Seven of 87 patients (6.8 %) who received azathioprine developed neutropenia; blood counts normalized on cessation of the drug in all. The incidence of neutropenia in patients with wild type was 6/84 (7.14 %) and with heterozygous type 1/3 (33 %) (p=0.5764). Conclusion Nearly 5 % of this population of patients requiring immunomodulator therapy was heterozygous carriers of the TPMT gene. Neutropenia was equally common in patients without and with the mutation.
Drugs & Therapy Perspectives, 2020
Background Thiopurine methyltransferase (TPMT) enzymes play a crucial role in azathioprine metabolism. Mutations in the enzyme initiate generation of excess thioguanine, which causes suppression of various cell lineages. Objectives The objectives of this study were to investigate the prevalence of TPMT mutation in Bangladeshi patients with systemic lupus erythematosus (SLE) requiring azathioprine therapy and its relation to the development of myelosuppression. Methods 250 patients with SLE were enrolled, then monitored for myelosuppression adverse events for 4 months. TPMT*3C (rs1142345), TPMT*3B (rs1800460), and TPMT*2 (rs1800462) polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism. The risk of myelosuppression (i.e., leukopenia, thrombocytopenia, and anemia) was estimated as the odds ratio (OR) with 95% confidence intervals (CIs) and p values. Results Of the 250 patients, 17 (6.8%) were heterozygous for the TPMT*3 mutation and 233 (93.2%) were homozygous for the wild type; no patients carried a homozygous mutation. Grade III/IV leukopenia, thrombocytopenia, and anemia occurred in 12.0%, 12.0%, and 27.9% of wild-type TPMT patients respectively; corresponding rates in heterozygous TPMT*3C patients were 70.6%, 64.7%, and 5.9%. Patients with Grade III/IV azathioprine-induced leukopenia were significantly more likely to have the heterozygous TPMT*3C genotype than the wild-type variant (OR 17.6; 95% CI 5.8-53.6; p < 0.0001), with comparable results for Grade III/IV azathioprine-induced thrombocytopenia (OR 13.4; 95% CI 4.6-39.2; p < 0.0001). Conclusion Patients with SLE carrying the TPMT*3C heterozygous genotype are at risk of azathioprine-induced myelosuppression. teers, nurses, physicians, and scientists of Bangabandhu Sheikh Mujib Medical University (BSMMU). The authors are also thankful to the
Lupus, 2008
Azathioprine (AZA) is a commonly used immunosuppressant for systemic lupus erythematosus (SLE). Myelosuppression is a serious adverse reaction due to AZA and its metabolites. Thiopurine S-methyltransferase (TPMT) is the rate-limiting enzyme. Variations of TPMT enzyme activity may be responsible for myelosuppression. However, a correlation between certain mutant alleles of low TPMT enzyme activity and myelotoxicity has also been suggested as a factor. We describe herein a case of AZA-induced severe myelosuppression associated with TPMT*3C heterozygous mutant allele in a SLE patient. The patient presented with pancytopenia, sepsis, typhlitis and disseminated intravascular coagulopathy after a short period of AZA therapy. The patient had low TPMT activity and TPMT*3C genotype. Measurement of TPMT activity and determination of TPMT variant allele may identify patients at risk for AZA-induced myelosuppression. Lupus (2008) 17, 132—134.
Validation of a Genotyping Method for Analysis of TPMT Polymorphisms
Clinical Therapeutics, 2012
Background: Thiopurine methyltransferase (TPMT) catalyzes the methylation of thiopurine drugs such as azathioprine and 6-mercaptopurine. Several mutations in the TPMT gene correlate with low enzyme activity and adverse effects such as myelotoxicity. Hence, genotyping TPMT makes it possible to identify patients at high risk for drug toxicity. Objective: The aim of this study was to validate a TPMT genotyping method by comparing it with a conventional polymerase chain reaction (PCR) approach. Methods: LightSNiP is a real-time PCR method for the detection of TPMT*2, *3B, and *3C without a sequencing step. We evaluated the frequencies of 3 TPMT alleles in 111 white adult patients by comparing genotyping by LightSNiP with conventional PCR (sequencing). Results: No differences were observed between conventional genotyping with sequencing and LightSNiP for *2, *3B, and *3C, suggesting the validity of this method. Conclusions: Compared with the conventional PCR sequencing method, the data suggest that LightSNiP correctly detected the TPMT *2, *3B, and *3C in this select population.
Drug Metabolism and Personalized Therapy, 2019
Background The thiopurine S-methyltransferase (TPMT)/azathioprine (AZA) gene-drug pair is one of the most well-known pharmacogenetic markers. Despite this, few studies investigated the implementation of TPMT testing and the combined evaluation of genotype and phenotype in multidisciplinary clinical settings where patients are undergoing chronic therapy with AZA. Methods A total of 356 AZA-treated patients for chronic autoimmune diseases were enrolled. DNA was isolated from whole blood and the samples were analyzed for the c.460G>A and c.719A>G variants by the restriction fragment length polymorphism (RFLP) technique and sequenced for the c.238G>C variant. The TPMT enzyme activity was determined in erythrocytes by a high-performance liquid chromatography (HPLC) assay. Results All the patients enrolled were genotyped while the TPMT enzyme activity was assessed in 41 patients. Clinical information was available on 181 patients. We found no significant difference in the odds of...