Phenotyping and genotyping study of thiopurine S‐methyltransferase in healthy Chinese children: A comparison of Han and Yao ethnic groups

Abstract

AimsEthnicity is an important variable influencing drug response. Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurine drugs. Previous population studies have identified ethnic variations in both phenotype and genotype of TPMT , but limited information is available within Chinese population that comprises at least 56 ethnic groups . The current study was conducted to compare both phenotype and genotype of TPMT in healthy Han and Yao Chinese children. MethodsTPMT activity was measured in healthy Chinese children by a H PLC assay ( n = 213, 87 Han Chinese and 126 Yao Chinese). Allele-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP) were used to determine the frequency of TPMT mutant alleles ( TPMT * 2 , TPMT * 3 A, TPMT * 3B and TPMT * 3C ) in these children. ResultsThere was no significant difference in the mean TPMT activity between Han and Yao Chinese children. A unimodal distribution of TPMT activity in Chinese children was found and the mean TPMT activity was 13.32 ± 3.49 U ml -1 RBC. TPMT activity was not found to differ with gender, but tended to increase with age in Yao Chinese children. TPMT * 2, TPMT * 3B and TPMT * 3A were not detected, and only one TPMT * 3C heterozygote (Han child) was identified in 213 Chinese children. Erythrocyte TPMT activity of this TPMT * 3C heterozygote was 12.36 U ml -1 RBC. The frequency of the known mutant TPMT alleles was 0.2% [1/426] in Chinese children. ConclusionThe frequency distribution of RBC TPMT activity was unimodal. The frequency of the known mutant TPMT alleles in Chinese Children is low and TPMT * 3C appears to be the most prevalent among the tested mutant TPMT alleles in this population.J.-P. Zhang et al. 16458 :2 Br J Clin Pharmacol

Liquid Chromatography–Tandem Mass Spectrometry Analysis of Erythrocyte Thiopurine Nucleotides and Effect of Thiopurine Methyltransferase Gene Variants on These Metabolites in Patients Receiving Azathioprine/6-Mercaptopurine Therapy

“…Among variant TPMT alleles, the TPMT*3A allele was the most common, followed by the TPMT*3C and TPMT*2 alleles. Several studies have established interethnic differences in the frequencies of TPMT alleles, with the TPMT*3A and TPMT*2 alleles most common in Caucasians and the TPMT*3C allele most common in individuals of black or Asian ethnicity (33)(34)(35). In our population, the ethnicities were not known; therefore, the allelic frequencies reported here are representative only of a US-based diverse population.…”

The low frequency of defective TPMT alleles in Turkish population: A study on pediatric patients with acute lymphoblastic leukemia

“…TPMT*2 is one of the three common mutant alleles which are generally confined to Caucasians and Latin American populations, with allele frequency of 0.2-0.7% [19,20,25,26]. Besides the interethnic variability, studies indicated that populations within the same ethnic origin can demonstrate significant differences in the distribution of common defective alleles [27]. For example, Wei et al recently reported that Kazak population, which is Caucasian in ethnic origin, has a very distinct pattern and lower frequency distribution for common TPMT mutant alleles compared to other Caucasians [28].…”

Thiopurine S-Methyltransferase Pharmacogenetics: Genotype to Phenotype Correlation in the Slovenian Population

“…The frequency distribution of TPMT enzyme activity in the Caucasian population is trimodal, such that wild-type homozygotes (TPMT*1) have high enzyme activity (89.5%), while heterozygous and homozygous individuals for TPMT*2, TPMT*3A and TPMT*3C alleles show intermediate and low enzyme activity (9.9 and 0.6%, respectively) [12] . Such a distribution has not been found in non-Caucasian populations [17][18][19][20][21] . Individuals with intermediate or defi cient TPMT activity thus have a higher risk for toxic events such as life-threatening myelosuppression and/or secondary tumor development after receiving standard doses of thiopurine drugs [22] .…”