Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05

    • Most studies on the correlation between TPMT polymorphism

    2018-11-15

    Most studies on the correlation between TPMT polymorphism and ARD are in patients with IBD, mainly in Westerners in which the TPMT gene predicts hematological ADRs, in 5–10% of patients treated with thiopurine drugs. Other studies have demonstrated that only 29% of leukopenic patients had mutant polymorphisms and indicated that only one-third of myelosuppressive episodes can be attributed to genetic polymorphism. The remaining causes may be mediated by immune mechanisms or by other variables affecting the metabolism of the drug. TPMT activity does not usually predict azathioprine-induced hepatotoxicity or gastrointestinal upset. TPMT activity itself varies among races and it has been reported that the enzyme activity of TPMT in the Japanese population is about 50% and is approximately 70% lower than in Jewish and white Americans, respectively. Therefore, screening for the TPMT gene mutation alone may be inappropriate for predicting azathioprine/6-MP-induced adverse reactions. More recently, ITPA deficiency has also been associated with thiopurine toxicity. ITPA converts 6-thio inosine triphosphate to phosphorylated 6-thio IMP, an intermediate metabolite of azathioprine/6-MP. When ITPA activity is reduced or defective, toxic 6-thio inosine triphosphate accumulates and induces adverse reactions, such as myelotoxicity. Five functional SNPs of the ITPA gene have been reported. ITPA enzyme activity in red blood Rosiglitazone is reportedly zero in individuals with the homozygous 94C > A missense mutation (Pro to Thr) in the open reading frame, and is markedly lower (22.5–27% of the activity) in those with heterozygous mutations. Homozygotes for the other functional polymorphism in intron 2 (IVS2 + 21A > C) and compound heterozygous subjects express about 30% of the wild-type median value of enzyme activity. The frequency of the 94C > A polymorphism is higher in Asian populations (11–23%), than in Caucasian populations (5–7%), and is likely to be the major ITPA polymorphism in the Chinese population. In our series, the allele frequency of the 94C > A polymorphism is 0.1648, similar to 0.155 in the Japanese population. This frequency is 2.75 fold higher than in Caucasians (0.06), showing that ITPA gene mutation is more important in Han-Chinese individuals whereas TPMT gene mutation is more frequent in Caucasians. Our result showed a significant association between ITPA 94C > A homozygote and azathioprine-related gastrointestinal toxicity and flu-like symptoms, which is similar to another Chinese study. However, contradictory results also exist. Various treatment guidelines for azathioprine have advocated pretherapeutic testing of TPMT status. However, pretreatment tests are still controversial due to the following reasons. First, there is a lack of direct evidence that TPMT or ITPA testing would decrease myelotoxicity-specific mortality. Second, regular complete blood counts measurement alone may be sufficient to early detect severe myelotoxicity. Third, the regimens of azathioprine vary between different specialties and different disease, which would cause variable results in different studies. Fourth, adverse reactions occurred in the presence of wild type TPMT and ITPA genes in more than 50% of patients. Fifth, mutations in other enzymes (such as HPRT1), drug interactions, concurrent infections, and immune-mediated drug reactions could lead to toxicity. Sixth, the low prevalence of homozygotes means that current evidences are underpowered to prove the effectiveness of pretesting for detection of patients at risk. Seventh, dosing according to the results of TPMT or ITPA status, may lead to underdosing of thiopurine and reduce clinical effectiveness. Major drawbacks of our study are the small sample size and the lack of concurrent testing for enzymatic activity of TPMT and ITPA. At least 56 AZA-intolerable patients and 280 AZA-tolerable patients were required in our study to detect the significant differences of TPMT∗3C and ITPAC94A polymorphism between AZA-treated Taiwanese patients with and without ADR. Heterogeneous diseases entities are included in the study, which will affect the dosing of azathioprine. Azathioprine is usually used as monotherapy in eczema, whereas in autoimmune and immunobullous diseases, it is used as a steroid sparing agent in our series. However, concurrent medication is relatively simple in our series and is free of drugs known to interact with azathioprine, such as 5-aminosalicylic acid which is often used for the treatment of IBS.