TPMT*26 (208F→L), a novel mutation detected in a Chinese (original) (raw)
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...
Journal of Biological Research - Bollettino della Società Italiana di Biologia Sperimentale
Azathioprine is an immunosuppressant drug belonging to the class of thiopurines widely used in clinical therapy. Its immunosuppressive action is linked to the substantial action mechanism in the inhibition of the synthesis of nitrogenous bases purine carried out in T-lymphocyte. The level of such medication limit resides in side effects such as myelosuppression and the development of tumours. The occurrence of side effects is linked to the presence of genetic polymorphisms of Thiopurine methyltransferase (TPMT). To date, 40 allelic variants for TPMT have been detected. However, those responsible for the reduction of enzyme activity are three: *2, *3A, *3C. The presence of one of the three polymorphisms makes the enzyme susceptible to degradation at proteasome level, and exposes the patient to high levels of the active drug that increases the probability of an occurrence of its side effects. Therefore, the Food and Drug Administration imposed the execution of a genetic test of TPMT t...
Clinical Therapeutics, 2009
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.
Molecular Diagnosis & Therapy, 2016
Thiopurine methyltransferase (TPMT) and inosine triphosphatase (ITPA) are crucial enzymes involved in the metabolism of thiopurine drugs: azathioprine and 6-mercaptopurine, used in the treatment of leukemia or inflammatory bowel diseases (IBD). The activity in these enzymes correlates with the genetic polymorphism of the TPMT and ITPA genes, respectively, which determines an individual reaction and dosing of thiopurines. Three main TPMT alleles: TPMT*2 (c.238G[C), TPMT*3A (c.460G[A, c.719A[G) and TPMT*3C (c.719A[G) account for 80-95 % of inherited TPMT deficiency in different populations in the world. In the ITPA gene, a c.94C[A mutation is significantly associated with an adverse thiopurine reaction. The aim of this study was to develop a quick and highly sensitive method for determining major TPMT and ITPA alleles. Here we present the molecular test for genotyping c.238G[C, c.460G[A, c.719A[G and c.94C[A changes based on multiplex high resolution melting analysis (HRMA). We analyzed DNA samples from 100 clinically diagnosed IBD patients treated with thiopurine drugs, and a known genotype in the positions 238, 460 and 719 of the TPMT gene as well as in position 94 of the ITPA gene. Our results obtained with multiplex HRMA indicated 100 % accuracy in comparison with data from restriction fragments length polymorphism (RFLP) and standard DNA sequencing. We conclude, that multiplex HRMA can be used as a quick, sensitive and efficient alternative diagnostic method compared to conventional techniques for the determination of TPMT*2, TPMT*3A and TPMT*3C alleles and c.94C[A change in the ITPA gene.
Frequency of thiopurine S-methyltransferase genetic variation in Thai children with acute leukemia
Medical and Pediatric Oncology, 2000
Background. Thiopurine S-methyltransferase (TPMT) catalyzes the S-methylation (inactivation) of mercaptopurine, azathioprine, and thioguanine, and exhibits genetic variation. About 11% of Caucasians have intermediate TPMT activity because of heterozygosity, and about 1 in 300 inherits TPMT deficiency as an autosomal codominant trait. If patients who have intermediate or deficient TPMT activity receive the standard dose of thiopurine medications, they can accumulate excessive thiopurine nucleotides in hematopoietic tissue, which could lead to severe and possibly fatal myelosuppression. There is very little information about TPMT genetic variation among Asian populations. We investigated the frequency of TPMT genetic variation among Thai children with acute leukemia. Procedure. Fresh whole blood was obtained from 75 Thai children with acute leukemia at the time of remission. Genomic DNA was isolated from total peripheral white blood cells. We performed polymerase chain reaction (PCR) to detect 3 types of variant of the human TPMT gene. Results. Among 75 patients, the frequency of heterozygotes for the TPMT gene among Thai children with acute leukemia was ∼11%. However, the TPMT*3C was the only variant TPMT allele found among Thai children. This is different from the North American Caucasian populations, in which TPMT*3A is the predominant variant allele, and TPMT*3C is rare (∼5% of variant alleles). Conclusions. There is no difference in the frequency of this genetic variation between Asian and North American Caucasian populations. Determination of the TPMT genotype by PCR method before antileukemic therapy is practical and may have clinical relevance. This knowledge could be applied towards organ transplant recipients who require these medications for immunosuppression. Med. Pediatr. Oncol. 35:410-414, 2000.