Center for Translational Genetics, B. Rappaport Institute for Research in the Medical Sciences, Faculty of Medicine, Technion - Israel Institute of Technology and Rambam Health Care Campus, Haifa, Israel.
Individuals with intermediate or no thiopurine S-methyltransferase (TPMT) activity are at risk of hematotoxicity when treated with standard doses of thiopurines, thus, pretreatment identification of these individuals is of major importance. The purpose of this study was to determine the frequency and distribution of TPMT polymorphic variants, known to functionally impair TPMT activity, in the highly heterogeneous Israeli population.
TPMT genotyping of individuals representing three major demographic groups in Israel was carried out by PCR restriction fragment length polymorphism and high-resolution melting.
Frequencies of TPMT risk alleles differed significantly among the screened Israeli subpopulations: Druze showed fivefold and twofold higher frequencies than Jews and Moslems, respectively. Specifically, allelic frequencies of TPMT*3A were 0.73% (95% CI 0.34-1.45%), 0.79% (95% CI 0.16-2.39%), and 3.19% (95% CI 1.78-5.58%) in Jews, Moslems, and Druze, respectively. Although not found in Jews, TPMT*3C was found at an allelic frequency of 1.05% (95% CI 0.31-2.76%) and 0.75% (95% CI 0.02-2.84%) in Moslems and Druze. TPMT*2 and TPMT*3B were not detected in any of the Israeli subpopulations studied.
These data indicate that the Israeli population displays a distinct TPMT genetic variability that is comprised of a mix of three major genetically diverse subpopulations, each with its unique TPMT allelic frequency distribution pattern and likelihood of developing an adverse reaction to thiopurine drugs.
"No TPMT*2, *3B or *3C alleles were detected. TPMT*3A allele frequency is consistent with ethnically related Israeli Arab subpopulations (0.79%) . The frequency of TPMT*3A allele is also similar in Jordanian population (0.59) , Turkish population (0.9%) , and Iranian population (0.87%) . "
[Show abstract][Hide abstract] ABSTRACT: Background
The genetic polymorphism of thiopurine methyltransferase (TPMT) is well characterized in most populations. Four common polymorphic alleles are associated with impaired activity of the enzyme. These are TPMT*2 (238G>C), TPMT*3B (c.460G>A), TPMT*3A (c.460G>A and c.719A>G) and TPMT*3C (c.719A>G). The aim of the present study was to determine the frequency of TPMT polymorphisms and their association with the occurrence of adverse events, during 6-mercaptopurine therapy in pediatric acute lymphoblastic leukemic (ALL) patients in Gaza Strip.
A total of 56 DNA samples from all pediatric ALL patients admitted to the pediatric hematology departments of Gaza strip hospitals were analyzed. Genomic DNA from peripheral blood leukocytes was isolated and the TPMT*2, TPMT*3B TPMT*3A and TPMT*3C allelic polymorphism was determined by PCR-RFLP and allele specific PCR technique.
No TPMT*2, *3B or *3C alleles were detected. Only one, out of 56 patients, was found heterozygous for the TPMT*3A allele. Thus, the frequency of TPMT*3A allele was calculated to be 0.89%. Fourteen patients of ALL were suffering from myelotoxicity during 6-MP therapy. From our results, no significant association could be established between clinical and laboratory data and/or the presence of the mutation in TPMT gene.
TPMT*3A was the only deficiency allele detected in our population with an allelic frequency of 0.89%. Other polymorphic alleles in TPMT gene, or factors other than TPMT polymorphisms may be responsible for the development of myelosuppression in cases that don’t carry the investigated TPMT alleles (*2, *3A, *3B and *3C). Therefore, more studies are recommended to study such factors.
"To date, at least 30 variant alleles of TPMT have been identified, the majority of which have been associated with lower TPMT enzymatic activity or protein expression in comparison with the wild type enzyme (Appendix A) . The four most common variant alleles seen in Caucasians, Asians and Africans (TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3 C) account for 80%– 95% of individuals with lower TPMT activity      . Approximately 0.3% of patients are homozygous for a variant allele and have very low or absent enzyme activity; while 5%–15% of patients are heterozygous and have intermediate enzymatic activity   . "
[Show abstract][Hide abstract] ABSTRACT: Low thiopurine S-methyltransferase (TPMT) enzyme activity is associated with increased thiopurine drug toxicity, particularly myelotoxicity. Pre-analytic and analytic variables for TPMT genotype and phenotype (enzyme activity) testing were reviewed.
A systematic literature review was performed, and diagnostic laboratories were surveyed.
Thirty-five studies reported relevant data for pre-analytic variables (patient age, gender, race, hematocrit, co-morbidity, co-administered drugs and specimen stability) and thirty-three for analytic variables (accuracy, reproducibility). TPMT is stable in blood when stored for up to 7 days at room temperature, and 3 months at -30°C. Pre-analytic patient variables do not affect TPMT activity. Fifteen drugs studied to date exerted no clinically significant effects in vivo. Enzymatic assay is the preferred technique. Radiochemical and HPLC techniques had intra- and inter-assay coefficients of variation (CVs) below 10%.
TPMT is a stable enzyme, and its assay is not affected by age, gender, race or co-morbidity.
[Show abstract][Hide abstract] ABSTRACT: In this issue of the European Journal of Clinical Pharmacology, the impact of thiopurine S-methyltransferase (TPMT) polymorphisms on thiopurine use in clinical practice is presented. Xin et al. investigated the relationship between TPMT phenotype and genotype (TPMT*2, *3A, *3B, and *3C) and adverse drug reactions (ADR) in 150 Chinese kidney transplant patients under azathioprine treatment . Twentyfour patients showed intermediate TPMT activity, and 126 had a normal or high activity. TPMT deficiency was not observed. Genetically, seven patients were heterozygous carriers for the TPMT*3C allele (allele frequency of 2.3%), the most frequent allele in Asians. Other TPMT variants (TPMT*2, *3A, *3B) were not detected. Twelve patients experienced hematological ADR and another 18 patients experienced hepatological ADR followed by azathioprine treatment cessation or dose reductions. Generally, patients with hematological ADR, but not those with hepatological ADR, had a significantly lower TPMT activity than patients without ADR (P
European Journal of Clinical Pharmacology 03/2009; 65(3):219-21. DOI:10.1007/s00228-009-0618-7 · 2.97 Impact Factor
Yuan Gao, Fengzhi Liu, Kun Wang, Dajiang Wang, Xin Gong, Lijun Liu, Christopher M. Richards, Adam D. Henk, Gayle M. Volk
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