Distribution of Genetic Polymorphisms of Genes Implicated in Thiopurine Drugs Metabolism (original) (raw)
Related papers
Thiopurine S-methyltransferase genetic polymorphism in the Tunisian population
Egyptian Journal of Medical Human Genetics, 2011
Background: Determine the incidence of four thiopurine S-methyltransferase (TPMT) mutant alleles, TPMT * 2, * 3A, * 3B and * 3C in the Tunisian population involved in adverse drug reactions. Genomic DNAs were isolated from peripheral blood leucocytes of 119 healthy Tunisian volunteers. The frequencies of four allelic variants of the TPMT gene, TPMT * 2, * 3A, * 3B, * 3C were determined using allele specific polymerase chain reaction (PCR) or PCR-restriction fragment length polymorphism technique. Results: Of the 119 Tunisian subjects participating in this study, 117 subjects (98.3%) were homozygous for TPMT * 1 and only two subjects (1.68%) were heterozygous for TPMT * 1/ * 3A. The frequency of TPMT * 3A mutant allele was 0.009. Conclusions: Our study provides the first data on the frequency of common TPMT variants in the Tunisian population. TPMT * 3A, which causes the largest decrease in enzyme activity, seemed to be a unique variant allele found in this our population.
Polymorphisms of the thiopurine S-methyltransferase gene among the Libyan population
Libyan Journal of Medicine, 2015
Background: Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that catalyses the S-methylation of 6-mercaptopurine and azathioprine. Low activity phenotypes are correlated with polymorphism in the TPMT gene. Patients with low or undetectable TMPT activity could develop severe myelosuppression when they are treated with standard doses of thiopurine drugs. Since ethnic differences in the TPMT gene polymorphism have been demonstrated worldwide, assessing it in the Libyan population is worthwhile. Methods: We investigated TPMT gene polymorphism in a total of 246 Libyan healthy adult blood donors from three different Libyan regions (Tripoli, Yefren, and Tawargha) and 50 children with acute lymphoblastic leukaemia (ALL). We used polymerase chain reaction restriction length polymorphism (PCR-RFLP) and allele-specific PCR-based assays to analyse the TPMT gene for the variants *2 c.238 G !C, *3A (c.460 G !A and c.719 A !G), *3B (c.460 G !A), and *3C (c.719 A !G). Results: Our results show that the TPMT variants associated with low enzymatic activity were detected in 3.25% (8 in 246) of adult Libyan individuals and the frequency of total mutant alleles was 1.63%. Heterozygous genotypes were TPMT*3A in three subjects (0.61%) and TPMT*3C in five subjects (1.02%). No TPMT*2 and TPMT*3B allelic variants and no homozygous or compound heterozygous mutant alleles were detected. The normal allele (wild-type) was found in 98.4% of the adult individuals studied. No mutant alleles were detected among the 50 children who had ALL. Conclusions: We report on the presence of the TPMT*3C and *3A mutant alleles in the Libyan population. Therefore, monitoring the patients to be treated with doses of thiopurine drugs for TPMT variants is worthwhile to avoid the development of severe myelosuppression.
Genetic polymorphism of thiopurine S-methyltransferase in Argentina
Annals of Clinical Biochemistry, 2003
Background: Thiopurine methyltransferase (TPMT) catalyses the S-methylation of 6-thiopurine drugs, which are commonly used in the treatment of autoimmune diseases, leukaemia and organ transplantation. TPMT activity is polymorphic as a result of gene mutations. Ethnic variations in phenotype and genotype have been identified in previous population studies, but no information was available within Latin-American populations. Aim: To establish the genetic polymorphism of TPMT in an Argentine population. Methods: TPMT enzymatic activity of 147 healthy Argentine subjects was measured using a high-performance liquid chromatography method. The genotyping assay for nine defective alleles (TPMT*2 - *8) was based on restriction fragment length polymorphism polymerase chain reaction and allele-specific polymerase chain reaction methods. Results: All subjects had detectable TPMT activity. Twelve individuals with low to intermediate activity were heterozygous for one of the mutant alleles: nine w...
[Frequency of thiopurine S-methyltransferase alleles in different ethnic groups living in Spain]
Medicina clínica, 2006
Thiopurine S-methyltransferase (TPMT) metabolizes thiopurine drugs regulating their cytotoxicity and clinical response. TPMT activity is inherited as an autosomal recessive trait and several mutations in the TPMT gene have been identified which correlate with a low activity phenotype. A variable number of tandem repeat within the TPMT promoter has been reported to modulate the levels of this enzyme activity. The allelic variants of the TPMT gene were analyzed in ethnic groups living in Spain. The frequency of 4 allelic variants of the TPMT gene as well as the genotype in the promoter region were analyzed in 138 Spanish blood donors, 95 gypsies and 51 Basque subjects. In the group of 138 blood donors, we identified: 13 carriers of a mutated TPMT allele (*3A, *3B, *3C), one homozygous TPMT*3B and a compound heterozygote (TPMT*3A/TPMT*3B). In the Basque group, 3 subjects were TPMT*3A carriers and one case was a TPMT*3B heterozygote. In the gypsy group one subject carried a TPMT*3A alle...
Experimental and therapeutic medicine, 2010
Thiopurine S-methyltransferase (TPMT) catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds including thiopurine drugs such as 6-mercaptopurine, 6-thioguanine and azathioprine. TPMT activity exhibits genetic variation and shows tri-modal distribution with 89-94% of individuals possessing high activity, 6-11% intermediate activity and approximately 0.3% low activity. Patients with intermediate or deficient TPMT activity exposed to thiopurine drugs show severe hematopoietic toxicity. Three single nucleotide polymorphisms (SNPs) in TPMT (NM_000367.2:c.238G>C, NM_000367.2:c.460G>A and NM_000367.2:c.719A>G) define the most prevalent mutant alleles associated with loss of catalytic activity reported in several populations. The present study investigated, for the first time, the frequency distribution of these three SNPs of TPMT, their alleles and genotypes in a Southern Indian population. Peripheral blood was obtained from 326 individuals of a Southern Ind...
Nomenclature for alleles of the thiopurine methyltransferase gene
Pharmacogenetics and Genomics, 2013
The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors' articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is
Thiopurine methyltransferase alleles in British and Ghanaian populations
Human Molecular Genetics, 1999
Thiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs such as 6-mercaptopurine, 6-thioguanine and azathioprine. TPMT activity is inherited as an autosomal co-dominant trait, and several mutations in the TPMT gene have been identified which correlate with a low activity phenotype. Although ethnic differences in TPMT activity have been described, population frequency analysis of TPMT alleles has not been well defined in different ethnic groups. The frequency of four allelic variants of the TPMT gene, TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C were compared in British Caucasian (n = 199) and Ghanaian (n = 217) populations using PCR-RFLP and allelespecific PCR-based assays. TPMT*3C was found in 14.8% of Ghanaians (31 heterozygotes, one homozygote). The TPMT*2, TPMT*3A and TPMT*3B alleles were not detected in any of the Ghanaian samples analysed. In contrast, 10.1% of British subjects had variant alleles, consisting of TPMT*2 (n = 2), TPMT*3A (n = 17) and TPMT*3C (n = 1) alleles. The frequencies of mutant alleles in this study were 5.3 and 7.6% in British Caucasians and Ghanaians, respectively. Among Ghanaian tribes, Ewe subjects had a lower frequency of mutant alleles (5.9%) than Ga (13.2%) or Fanti (11.6%), although this did not reach statistical significance. This study provides the first analysis of TPMT mutant allele frequency in an African population and indicates that, unlike Caucasians, TPMT*3C is the most common allele in African subjects.
Allele frequencies of thiopurine S-methyltransferase (TPMT) variants in the Nigerian population
Polish Annals of Medicine, 2017
Introduction: Thiopurine S-methyltransferase (TPMT) methylates clinically relevant thiopurine drugs most of which are noted for adverse reactions in certain users, largely due to polymorphisms in the TPMT gene. Aim: This study investigated the prevalence of functionally relevant TPMT alleles in the Nigerian population. Material and methods: One hundred eighty unrelated subjects consisting of 123 males and 57 females from the main Nigerian ethnicities (44 Igbo, 101 Yoruba, 23 Hausa and 12 from other minor ethnic groups) were genotyped for TPMT*2, *3B, *3C and *4 alleles using the iPLEX genotyping assay technique. The genotype calls were validated with Sanger sequencing in a random set of samples and the acquired data were assessed for Hardy-Weinberg equilibrium using the Fisher's exact test. Results and discussion: Defective TMPT alleles were found in individuals representing 10% of the study population. TPMT*3C constituted 9.4% (95% CI, 5.6-14.7) of all alleles detected, with one homozygote and 17 heterozygotes recorded. The prevalence of the TPMT*3C allele in the population conformed with Hardy-Weinberg equilibrium. TPMT*2, 3B and *4 were, however, not detected in the population. Conclusions: TPMT*3C was the only defective allele identified in Nigerians and may hence be the major underlying genetic contributor to adverse reactions due to thiopurine drugs in the population.