Complete sequence-based screening of TPMT variants in the Korean population

Abstract

Thiopurine S-methyltransferase (TPMT) is a cytoplasmic enzyme involved in the metabolism of thiopurine drugs and its activity is largely influenced by polymorphisms of the TPMT gene. To date, more than 35 TPMT variants are known to be associated with reduced enzyme activity, but most studies on the TPMT genotype have included only common nonfunctional variants, such as TPMT*2 and TPMT*3. In this study, we carried out a complete sequencing analysis to screen all TPMT variants in Korean patients. A total of 900 Korean patients were genotyped for TPMT and 30 patients (3.3%) had the known TPMT variant alleles. TPMT*3C was found in 25 patients (2.8%): 24 patients with TPMT*1/*3 and one with TPMT*3/*3. Rare TPMT variants including TPMT*6, TPMT*16, and TPMT*32 were detected in five patients (0.6%) and a novel variant, TPMT*38 (c.514T>C, p.S172P), was identified in two patients. This is the first complete sequence-based screening study evaluating all TPMT variants in Asian populations.

Clinical Pharmacogenetic Testing and Application: Laboratory Medicine Clinical Practice Guidelines

“…Thus, common alleles can be preferentially selected to perform TPMT genotyping [86]. The TPMT * 3 has the highest prevalence (0.8–2.5%) in the Korean population, but the presence of * 6 , * 16 , * 32 , and * 38 has been reported [87]. The TPMT phenotypes based on each genotype are described in Table 6.…”

Thiopurine S-methyltransferase polymorphisms in acute lymphoblastic leukemia, inflammatory bowel disease and autoimmune disorders: influence on treatment response

“…For instance, most of the presented studies inferred TPMT activity by genotyping the most common nonfunctional TPMT alleles while results of a recent study that explored the sequencing data suggest that in certain populations, the inferred activity can be refined by incorporating the genotypes of other alleles. The study also identified a new variant in the TPMT gene, TPMT*38 (T514C), which had an allelic frequency of 0.11% and was predicted to be a damaging mutation 15. Moreover, as increasingly reported by different studies, genetic variants in other genes involved in thiopurines metabolism like ITPA, HGPRT and MTHFR as well as variants in genes independent of TPMT can influence thiopurines treatment outcome 14,20,25,41,70,77.…”

“…TPMT deficiency was first described around 3 decades ago and it is currently well established that homozygous or compound heterozygous carriers of TPMT-deficient alleles have a significantly higher risk of early severe myelosuppression than patients homozygous for the wild-type 14,15. Patients with absent or reduced TPMT activity accumulate high doses of 6-TGNs, resulting in thiopurine-induced myelotoxicity that is characterized by early onset of severe neutropenia when such patients are treated with standard doses of thiopurine drugs.…”

“…Genetic polymorphisms in the TPMT gene can affect the enzymatic activity of TPMT and have been studied extensively. To date, over 38 variant alleles have been identified 2,15,30–32. They have been correlated with variability in response to thiopurine drugs, which provides an important example of the clinical importance of pharmacogenetics.…”

“…The mutant TPMT*2 allele is defined by the G238C transversion whereas the TPMT*3 family alleles are defined by the G460A and A719G transitions (i.e., TPMT*3A [G460A and A719G], TPMT*3B [G460A] and TPMT*3C [A719G]) 12,18,31–33. The prevalence of TPMT variants is much higher among Caucasians (8.1%–10.1%) than Asian populations (2.3%–4.2%)15 and it is well established that TPMT*3A is the most prevalent mutant allele in Caucasians, making up to (85%) of all observed mutant alleles,14,18 while TPMT*3C is the most frequently found allele in African and Southeast Asian populations 14,34…”