Whole-Blood Thiopurine S-Methyltransferase Genotype and Phenotype Concordance in Iranian Kurdish Ulcerative Colitis (UC) Patients

Bahrehmand, Fariborz; Vaisi‐Raygani, Asad; Kiani, Amir; Bashiri, Homayoon; Zobeiri, Mahdi; Tanhapour, Maryam; Pourmotabbed, Tayebeh

doi:10.7754/clin.lab.2017.161201

Cited by 2 publications

(5 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly, NUDT15 , an enzyme involved in detoxification of 6-MP metabolites, showed a strong association with 6-MP intolerance in the maintenance phase of ALL therapy (Moriyama et al, 2016), and it has hence been recently integrated in the updated CPIC guidelines for thiopurine dosing (Relling et al, 2019). However, the frequency of these genetic polymorphisms is noticeably lower in some ethnic groups when compared to others (Hakooz et al, 2010; Albayrak et al, 2011; Bahrehmand et al, 2017; Moriyama et al, 2017; Zgheib et al, 2017; Zhou et al, 2018), hence the need to elicit the role of other variants in other genes that are more relevant to specific populations. This study reports on the frequency and role of TPMT , NUDT15 , and ITPA polymorphisms with 6-MP dose intensity and toxicity in two cohorts from the Middle East, one from Lebanon and another from Kurdistan.…”

Section: Discussionmentioning

confidence: 99%

“…To our knowledge, no data are yet available on the prevalence and role of ITPA genetic polymorphisms with 6-MP toxicity in Middle Eastern populations except for one from Turkey, though with a very small sample size and negative results (Eldem et al, 2018). In addition, although there are few reports on the frequency of TPMT polymorphisms and their association with 6-MP from this area of the world (Hakooz et al, 2010; Albayrak et al, 2011; Bahrehmand et al, 2017), NUDT15 was only recently evaluated in our Lebanese cohort (Zgheib et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

ITPA, TPMT, and NUDT15 Genetic Polymorphisms Predict 6-Mercaptopurine Toxicity in Middle Eastern Children With Acute Lymphoblastic Leukemia

et al. 2019

View full text Add to dashboard Cite

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer seen in children worldwide and in the Middle East. Although there have been major advances in treatment approaches for childhood ALL, serious toxicities do occur but with significant inter-individual variability. The aim of this study is to measure the frequency of polymorphisms in candidate genes involved in 6-Mercaptopurine (6-MP) disposition in a combined cohort of Middle Eastern Children with ALL, and evaluate whether these polymorphisms predict 6-MP intolerance and toxicity during ALL maintenance therapy. Methods: The study includes children treated for ALL on two treatment protocols from two cohorts; one from Lebanon (N = 136) and another from Kurdistan province of Iran (N = 74). Genotyping for the following six candidate genetic polymorphisms: ITPA 94C > A (rs1127354) and IVS2+21A > C (rs7270101), TPMT*2 238G > C (rs1800462), TPMT*3B 460G > A (rs1800460) and *3C 719A > G (rs1142345), and NUDT15 415C > T (rs116855232) was performed and analyzed in association with 6-MP dose intensity and toxicity. Results: As expected, TPMT and NUDT15 variants were uncommon. As for ITPA , both polymorphisms were more common in the Lebanese as compared to the Kurdish cohort with a minor allele frequency of 0.05 for 94C > A and 0.14 for IVS2+21A > C in the Lebanese only (N = 121), and of 0.01 for either ITPA polymorphism in Kurds. The most significant toxic effects were depicted with the NUDT15 polymorphism with a median 6-MP dose intensity of 33.33%, followed by 46.65% for TPMT*3A polymorphism, followed by 65.33% for two ITPA risk allele carriers and 74% for one ITPA risk allele carriers, in comparison to a median of 100% for the homozygous wild type in the combined cohort (P < 0.001). In addition, the onset of febrile neutropenia was significantly higher in variant allele carriers in the combined cohorts. Conclusions: These data confirm the predictive role of TPMT , NUDT15 , and ITPA in 6-MP intolerance in Middle Eastern children with ALL. Given the relatively high frequency of ITPA variants in our study and their significant association with 6-MP dose intensity, we recommend that physicians consider genotyping for ITPA variants in conjunction with TPMT and NUDT15 prior to 6-MP therapy in these children.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ITPA, TPMT, and NUDT15 Genetic Polymorphisms Predict 6-Mercaptopurine Toxicity in Middle Eastern Children With Acute Lymphoblastic Leukemia

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Several studies have evaluated the phenotype and genotype concordance for determining the TPMT status. It has been stated that the association between TPMT genotypes and phenotypes does not reach 100% (20,23).…”

Section: Discussionmentioning

confidence: 99%

“…Routine blood specimens could be served for genotyping and phenotyping assays, as white and red blood cells harbor the necessary genetic material and source of TPMT enzyme, respectively (8,23). There are some inactivating alleles, i.e.…”

Section: Introductionmentioning

confidence: 99%

“…TPMT*2 allele (c.238G>C) causes approximately 100-fold decrease in TPMT activity and very low levels of immunological protein. TPMT*3A allele (c.460G>A and c.719A>G) causes no detectable enzyme activity with around 400fold decrease in protein levels but TPMT*3B allele (c.460G>A) and TPMT*3C allele (c.719A>G) cause a fourfold and 1.4 fold reduction in protein levels, respectively (6,7,10,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Thiopurine S-methyltransferase and Pemphigus Vulgaris: A Phenotype-Genotype Study

et al. 2020

View full text Add to dashboard Cite

Scan to discover online Background & Objective: Thiopurine drugs are considered as a treatment modality in various autoimmune disorders including pemphigus vulgaris (PV). These drugs are metabolized by an enzyme "Thiopurine S-methyl transferase" (TPMT). Various variants of this enzyme may have decreased activity leading to serious drug side effects. To investigate the phenotype and genotype of TPMT in PV patients receiving thiopurine drugs. Methods: A total of 50 patients (29 women and 21 men) with pemphigus vulgaris treating with standard dose of Thiopurine drugs were selected. Sex, age, result of liver function test and complete blood count were recorded. Genotyping of two common non-functional allele (TPMT*2 and TPMT*3C) by Allele-specific and RFLP-PCR was performed. TPMT enzymatic level was determined by an ELISA based method. Results: Of patients, 36 (72%) were found to have normal TPMT level; and 12, (24%) had higher level of enzyme and 2, 4% had low TPMT enzyme, but none of the patients showed mutant TPMT*2 and TPMT*3C alleles. None of the patients showed hepatotoxicity and bone marrow suppression. Conclusion: The phenotypic assay based on ELISA method may have false positive and misleading results but genotyping using PCR-RFLP and allele specific PCR is accurate, simple and cost-effective and can be used in patients decided to undergo thiopurine treatment.

show abstract

Whole-Blood Thiopurine S-Methyltransferase Genotype and Phenotype Concordance in Iranian Kurdish Ulcerative Colitis (UC) Patients

Cited by 2 publications

References 0 publications

ITPA, TPMT, and NUDT15 Genetic Polymorphisms Predict 6-Mercaptopurine Toxicity in Middle Eastern Children With Acute Lymphoblastic Leukemia

ITPA, TPMT, and NUDT15 Genetic Polymorphisms Predict 6-Mercaptopurine Toxicity in Middle Eastern Children With Acute Lymphoblastic Leukemia

Thiopurine S-methyltransferase and Pemphigus Vulgaris: A Phenotype-Genotype Study

Contact Info

Product

Resources

About