TPMT frequency

Based on the population genotype-phenotype studies performed to date, assays for the molecular diagnosis of TPMT deficiency have focussed on alleles TPMT 2, TPMT 3A and TPMT 3C, as these represent 80-95% of all mutant alleles of this gene in Caucasians [46, 50]. However, the frequency and pattern of mutant alleles of this gene is different among various ethnic populations. For example, Southwest Asians (Indian, Pakistani) have a lower frequency of mutant TPMT alleles and all mutant alleles identified to date are TPMT 3A (Table 24.1) [52]. This is in contrast to Kenyans and Ghanaians where the frequency of mutant alleles is similar to Caucasians, and all mutant alleles are TPMT 3C (Table 24.1) [53, 54]. Among African Americans, TPMT 3C is the most prevalent allele, but TPMT 2... 

Fig. 24.2 TPMT 3C allele frequency (%) in different ethnic groups. 

Fig. 24.6 Mutant allele frequencies of SNPs in distinct ethnic populations. B2AR-/I2 adrenoreceptor, COMT-catechol-O-methyltransferase. Glu27 and TPMT 3C allele frequencies were used for the B2AR and TPMTgenes, respectively.

Deficiency of thiopurine S-methyl transferase (TPMT) is another phenotype that exhibits inter-ethnic differences in frequency. TPMT is an enzyme that catalyzes methylation of therapeutic agents used in the treatment of acute lymphoblastic leukemia, rheumatoid arthritis, and autoimmune/inflammatory diseases, as well as in organ transplantation. Patients who have TPMT deficiency experience less efficient methylation and are at greater risk of fatal toxicity when treated with standard doses of fhiopurines. TPMT phenotype is defined by erythrocyte 6-mercapto-purine methylation. African American populations exhibit a 20% lower erythrocyte TPMT than Caucasian Americans, and persons of Chinese descent tend to exhibit greater activity than either of these other American subpopulations. 

Eight TPMT alleles have been identified. Three of these alleles, TPMT 2 (45), 3A, and 3C (G460A), account for 80-95% of intermediate or low enzyme activity cases. High concentrations of variant TPMT (TPMT 3A, 3B, and 3C) are found in patients with decreased TPMT activity Patients with TMPT-3A have a complete loss of TPMT catalytic activity, patients with TPMT 3B have a 9-fold reduction, and those with TPMT 3C have a 1.4-fold reduction (43,46). The frequency of loss of TPMT activity (TPMT 3A) appears to vary with ethnicity but not with gender or age. In addition, haplotyping methods have been developed to discriminate the genotypes TPMT 1/ 3A (intermediate metabolizer) and TPMT 3B/ 3C (poor metabolizer) (47). 

Population Frequencies of Clinically Relevant TPMT Variant Alleles in Different Ethnic... 

In this study, 21 patients had a heterozygous TPMT phenotype. With a frequency of 85%, TPMT 3A was the most prevalent variant allele, followed by TPMT 2 and TPMT 3C with about 5% each. All 6 patients who phenotypically displayed TPMT deficiency had two mutant alleles 20 of the 21 patients with intermediate TPMT activity had one variant allele and all of the selected 21 patients with high activity did not carry one of the tested JPMT variant alleles. Thus, the major inactivating TPMT variants can be detected reliably by a PCR-based method and demonstrated an excellent concordance with TPMT phenotype. 

The most comprehensive analysis of TPMT phenotype versus genotype published to date was conducted by Schaeffeler et al. (140). In their study, RBC TPMT activity and genotype TPMT 2 and 3 alleles) were analyzed in 1214 healthy Caucasian blood donors. Discordant cases between phenotype and genotype were systematically sequenced. The frequencies of the mutant alleles were 4.4% for TPMT 3A, 0.4% for TPMT 3C, and 0.2% for TPMT 2. All seven TPMT-deficient subjects identified by Schaeffeler and colleagues were homozygous or compound heterozygous carriers for these alleles. 

In contrast, successful TPMT genotyping of 72 patients out of a total of 115 patients with subsequent secondary malignant neoplasms after treatment for childhood ALL on seven consecutive BFM protocols (ALL-BFM 79, 81, 83, 86, 90, 95, and 2000) did not reveal a higher frequency of TPMT alleles associated with lower TPMT activity among these patients (208). Also, in stratified analyses by entities of secondary malignant neoplasms, no significant associations with TPMT alleles conferring lower enzyme activity have been observed. 

Kubota T, Chiba K. Frequencies of thiopurine S-methyltransferase mutant alleles (TPMT 2, 3A, " 3B and 3C) in 151 healthy Japanese subjects and the inheritance of TPMT 3C in the family... 

In contrast, an earlier study failed to demonstrate a significant association between the presence of ITPA alleles and AZA related toxicity. In this study by Gearry et al., genotyping was performed for the 94C>A missense mutation in ITPA, TPMT 2, and TPMT 3 in 73 patients with inflammatory bowel disease who had side effects from AZA, and 74 patients who had tolerated AZA without adverse events. There was no significant difference in the frequency of the ITPA allele between patients who had experienced an adverse event versus those who had not (16/146 versus 16/148, p=0.56). There was no association of the ITPA 94C>A polymorphism with adverse events such as rash or pancreatitis or flu-like symptoms [81]. 

In 155 Chinese kidney transplant recipients, the allele frequency of the 94C>A polymorphism, which leads to reduced ITPA activity, was 0.12 [169. Patients with the ITPA 94C>A homozygous allele are at high risk of azathioprine-related gastrointestinal toxicity and flu-like symptoms. The TPMT wild-type/homozygous ITPA variant is closely related to azathioprine-induced adverse reactions. 

The frequencies of TPMT mutant alleles have been studied retrospectively in 147 Japanese patients with inflammatory bowel disease taking azathioprine, of whom 144 were wild-type for TPMT (TPMT 1/ 1) and three carried a mutant TPMT allele (TPMT 1/ 3C) [145 ]. The incidence of adverse reactions to azathioprine was 38/ 114 in the wild-type group. Leukopenia occurred in 16% of the patients with wild-type TPMT. The authors concluded that determination of TPMT genotype may not be useful in Japanese patients in predicting adverse reactions to azathioprine. 

---