Analysis of Thiopurine S-Methyltransferase Genotypes in Japanese Patients with Inflammatory Bowel Disease

Ban, Hiromitsu; Andoh, Akira; Tanaka, Aiko; Tsujikawa, Tomoyuki; Sasaki, Makoto; Saito, Yasuharu; Fujiyama, Yoshihide

doi:10.2169/internalmedicine.47.1268

Cited by 36 publications

(38 citation statements)

References 14 publications

(11 reference statements)

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“…The allelic frequency of TPMT A719G was 0.9% (5/558). This result agrees with previous reports on TPMT polymorphism analyses in the Japanese population [7,[14][15][16]. For four patients with the TPMT variant, thiopurines were not administered to avoid side effects.…”

Section: Allelic Frequencysupporting

confidence: 92%

“…Several variant TPMT alleles of low metabolization have been described recently in many ethnic groups [14]. In the Japanese population, TPMT A719G (TPMT*3C) is the most prevalent allele, and other variants are very rare [7,[14][15][16]. TPMT A719 G is associated with intermediate to low TPMT enzyme activity [12,13], and its frequency is around 2% in the Japanese population [7,15].…”

Section: Introductionmentioning

confidence: 99%

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The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

et al. 2010

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Section: Allelic Frequencysupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

et al. 2010

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“…Thus, there was no significant association of TPMT*3C with thiopurineinduced leukopenia, as previously reported. 12,13 NUDT15 R139C causes thiopurine-induced hair loss in IBD patients Y Kakuta et al R139C was associated with early but not late leukopenia R139C genotypes were significantly associated with early leukopenia (leukopenia developing within 8 weeks) (Table 3), and all of the patients with the T/T genotype developed early severe (Grade 3 or 4) leukopenia (P = 3.82 × 10 − 16 , odds ratio = 212). These associations were not observed for late leukopenia (P = 0.907).…”

Section: Resultsmentioning

confidence: 99%

“…[8][9][10][11] In Caucasian patients, the genetic polymorphisms of thiopurine S-methyltransferase, an enzyme involved in the inactivation of 6MP, were reported to be associated with thiopurine-induced leukopenia; 11 however, the association was not replicated in Japanese subjects. 12,13 In a recent study, NUDT15 R139C was strongly associated with thiopurine-induced leukopenia in Koreans. 14 It is well known that most genes conferring susceptibility to IBD were common in Japanese and Korean individuals.…”

Section: Introductionmentioning

confidence: 95%

NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD

et al. 2015

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The efficacy of thiopurines, including azathioprine (AZA) and 6-mercaptopurine (6MP), has been demonstrated for the treatment of inflammatory bowel disease (IBD). The most common and serious adverse event of treatment with thiopurines altered by doctors is leukopenia. Hair loss is also a serious event that could be a critical reason for patients to decline thiopurine treatment. Thiopurine-induced severe hair loss causes cosmetic problems, and it takes a long time to recover. In a recent study, NUDT15 R139C was strongly associated with thiopurine-induced leukopenia in Korean and Caucasian populations. In this study, we performed an association study to investigate and replicate the association of R139C with adverse events of thiopurines in Japanese patients. A total of 142 Japanese patients with IBD, with histories of thiopurine treatment, were examined. NUDT15 R139C was genotyped using a custom TaqMan genotyping assay. Adverse events including leukopenia were reviewed from medical records. The 6MP dose was adjusted to AZA equivalents by multiplying with 2 as a thiopurine dose. Five patients developed severe hair loss and all of them were risk homozygous (T/T) for R139C. No early severe hair loss was observed in patients with the C/T or C/C genotype (P=3.82 × 10(-16), odds ratio=212). The association of R139C with early (<8 weeks) leukopenia (white blood cells<3000 mm(-3)), which was previously reported in Korean patients, was replicated in our Japanese IBD cohort (P=1.92 × 10(-16), odds ratio=28.4). However, we could not confirm the association with late leukopenia in the Japanese subjects. Patients with the C/T genotype discontinued treatment or required thiopurine dose reduction significantly earlier than patients with the C/C genotype (P=1.45 × 10(-4)); however, on manipulating the doses, there was no significant difference in the thiopurine continuation rates between the groups. In the maintenance period, the frequencies of 6MP usage were higher, and the doses of thiopurines were significantly lower in patients with the C/T genotype than in those with the C/C genotype (0.574±0.316 mg kg(-1) per day vs 1.03±0.425 mg kg(-1) per day, P=6.21 × 10(-4)). NUDT R139C was significantly associated with early severe hair loss in Japanese patients with IBD. We also verified the previously reported association of R139C with early leukopenia in a different East Asian population. It is recommended that treatment with thiopurines should be avoided for patients with the T/T genotype. Low-dose 6MP (0.2-0.3 mg kg(-1) per day) could be used rather than AZA for the patients with C/T genotype to continue thiopurine treatments. However, late leukopenia and other several adverse events could not be completely predicted by R139C genotypes.

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“…Susceptibility to bone marrow toxicity upon AZA/6-MP therapy is genetically dependent on inter-individual variations in thiopurine S-methyltransferase (TPMT) enzyme activity, based on the genetic polymorphisms of low-metabolizing alleles (12,13). In the Japanese population, a single nucleotide polymorphism (SNP), TPMT A719G, is the most prevalent allele (~2%), and other variants are very rare (7,(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Accuracy of genotyping using the TaqMan PCR assay for single nucleotide polymorphisms responsible for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

Osaki¹,

Imaeda²,

Ban³

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Thiopurine drugs are the most common drugs used to maintain clinical remission in inflammatory bowel disease (IBD). Three single-nucleotide polymorphisms (SNPs), TPMT A719G (rs1142345), inosine triphosphate pyrophosphatase (ITPase) C94A (rs1127354) and multidrug resistance protein 4 MRP4 G2269A (rs3765534), have been reported to account for heightened sensitivity to thiopurine drugs in the Japanese population. We investigated the usefulness of the TaqMan ® PCR assay (Applied Biosystems) for the rapid detection of these SNPs to improve the safety of thiopurine therapy. We enrolled 44 healthy volunteers and 235 IBD patients. Genotyping of the SNPs was performed using Custom TaqMan SNP genotyping assays, direct sequencing and PCR-RFLP. Genotyping for MRP4 G2269A by the TaqMan PCR assay was successfully achieved in all samples. Comparison with our previous data using direct sequencing indicated one discordant result, and re-sequencing showed that the TaqMan PCR assay was correct. The overall accuracy of the TaqMan assay for MRP4 G2269A was 100%. The TaqMan PCR genotyping for TPMT A719G and ITPase C94A was successfully performed in all samples. The results of TPMT A719G by the TaqMan assay were identical with those of PCR-RFLP. In ITPase C94A, a comparison of the TaqMan assay and PCR-RFLP yielded 12 discordant results, and direct sequencing showed that the TaqMan PCR assay was correct. The allelic frequency determined by the TaqMan assay was 0.145 for MRP4 G2269A, 0.009 for TPMT A719G and 0.121 for ITPase C94A, respectively. In conclusion, the TaqMan ® PCR assay is useful for genotyping of SNPs responsible for thiopurine sensitivity in Japanese IBD patients.

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Analysis of Thiopurine S-Methyltransferase Genotypes in Japanese Patients with Inflammatory Bowel Disease

Cited by 36 publications

References 14 publications

The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD

Accuracy of genotyping using the TaqMan PCR assay for single nucleotide polymorphisms responsible for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

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