<i><scp>TPMT</scp></i> and <i><scp>NUDT</scp>15</i> genes are both related to mercaptopurine intolerance in acute lymphoblastic leukaemia patients from Uruguay

Soler, Antonio Palanca; Olano, Natalia; Méndez, Yessika; Lopes, Ana Cristina dos Santos; Silveira, Anaulina; Dabezies, Agustín; Castillo, Luis; Luz, Julio A. da

doi:10.1111/bjh.14532

Cited by 28 publications

(39 citation statements)

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“…NUDT15 p.Arg139Cys had a high sensitivity (89.4%) and specificity (93.2%) for early leukopenia. The association was also confirmed in populations in Japan, China, India, Thai, Singapore, Guatemala, and Uruguay [ 71 – 81 ]. Furthermore, we have reported that almost all of the patients homozygous for p.Arg139Cys had severe early leukopenia and severe alopecia [ 72 ].…”

Section: Nucleoside Diphosphate-linked Moiety X -Tmentioning

confidence: 75%

“…2 Nucleoside diphosphate-linked moiety X -type motif 15 (NUDT15) haplotype structures and frequencies in East Asian populations. Common haplotypes *1 to *6 have been defined previously [ 81 ]. Rare variants (a), (b), (c) are from Moriyama et al [ 92 ], and rare variants (d), (e), and (f) and estimated haplotype frequencies in Japanese populations were from the 3.5KJPN data by the Tohoku Medical Megabank Project ( https://ijgvd.megabank.tohoku.ac.jp/ ) [ 51 , 52 , 91 ].…”

Section: Additional Variants Of Nudt15 and Their Enzymatic Activitiesmentioning

confidence: 99%

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Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping

2017

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The thiopurine drugs 6-mercaptopurine (6-MP) and azathiopurine (AZA) are widely used to treat inflammatory bowel disease. However, the incidence of adverse reactions is high, particularly in Asia, and the mechanisms of toxicity in Asian populations remain unclear. Thiopurine S-methyltransferase (TPMT) is a well-known enzyme that inactivates AZA or 6-MP through methylation and is one of the few pharmacogenetic predictors used in clinical settings in Western countries. Individuals carrying TPMT-deficient genetic variants require reduced drug doses, but this treatment modification is are not applicable to East Asian populations. Several genes code thiopurine-metabolizing enzymes, including TPMT, multidrug-resistance protein 4, and inosine triphosphatase. These genes have been studied as candidate pharmacogenetic markers; however, it remains unclear why Asian populations seem to be more intolerant than other ethnic groups to a full dose of thiopurines. A genome-wide association approach to identify Asian-specific pharmacogenetic markers in Korean patients with Crohn’s disease revealed that a non-synonymous single nucelotide polymorphism in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) which causes p.Arg139Cys was strongly associated with thiopurine-induced early leukopenia. Six common haplotypes of NUDT15 were reported, and five variants showed medium-to-low enzyme activities, compared with the wild haplotype. NUDT15 hydrolyzes the thiopurine active metabolites 6-thio-GTP and 6-thio-dGTP; variants of NUDT15 had lower enzyme activities, causing higher levels of thiopurine active metabolites, resulting in thiopurine-induced leukopenia. In clinical application, NUDT15 genotyping is a good candidate for predicting thiopurine toxicity in East Asian populations. However, the association of NUDT15 diplotypes with thiopurine toxicity remains unclear. Further analyses with large cohorts to confirm the clinical effects of each haplotype are planned.

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Section: Nucleoside Diphosphate-linked Moiety X -Tmentioning

confidence: 75%

Section: Additional Variants Of Nudt15 and Their Enzymatic Activitiesmentioning

confidence: 99%

Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping

2017

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“…It has already been reported that, in Uruguayan pediatric patients under ALL therapy, approximately 30% of the hematological toxicities are explained by SNPs at TPMT and NUDT15 genes (Soler et al, 2018). This result demonstrates once again the importance of specific studies for each population, especially in admixed ones such as Uruguayan population.…”

Section: Introductionmentioning

confidence: 72%

“…Genomic DNA was isolated from peripheral blood leukocytes by the saline extraction method (Miller et al, 1988). Patients were previously genotyped for TPMT and NUDT15 genes which are the most common variants (Soler et al, 2018). The number and type of tandem repeats were determined by TPMT first-exon PCR amplification, including the promoter region, followed by Sanger sequencing.…”

Section: Tpmt Tpmt-vntr and Nudt15 Genotypingmentioning

confidence: 99%

“…Furthermore, in order to discard other possible mutations, the TPMT gene was completely characterized by the amplification and sequencing of its nine exons. In addition, since NUDT15 variants analyzed by Soler et al (2018) were in exons 1 and 3, we also sequenced NUDT15 exon 2. Amplification primers and PCR conditions are shown in Supplementary Table S1.…”

Section: Tpmt Tpmt-vntr and Nudt15 Genotypingmentioning

confidence: 99%

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Ancestry and TPMT-VNTR Polymorphism: Relationship with Hematological Toxicity in Uruguayan Patients with Acute Lymphoblastic Leukemia

et al. 2020

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6-Mercaptopurine (6-MP) is a thiopurine drug widely used in childhood acute lymphoblastic leukemia (ALL) therapy. Genes such as TPMT and NUDT15 have an outstanding role in 6-MP metabolism. Mutations in both genes explain a significant portion of hematological toxicities suffered by ALL Uruguayan pediatric patients. A variable number tandem repeat in the TPMT promoter (TPMT-VNTR) has been associated with TPMT expression. This VNTR has a conservative architecture (AnBmC). To explore new causes of hematological toxicities related to ALL therapy, we genotyped the TPMT-VNTR of 130 Uruguayan pediatric patients. Additionally, individual genetic ancestry was estimated by 45 ancestry-informative markers (AIMs). Hematological toxicity was measured as the number of leukopenia events and 6-MP dose along the maintenance phase. As previously reported, we found TPMT*2 and TPMT*3C alleles were associated to TPMT-VNTR A2BC and AB2C, respectively. However, contrasting with other reports, TPMT*3A allele was found in a heterogeneous genetic background in linkage equilibrium. Patients carrying more than 5 A repeats present a significant higher number of leukopenia events among patients without TPMT and/or NUDT15 variants. Native American ancestry and the number of A repeats were significantly correlated with the number of leukopenia events. However, the correlation between Native American ancestry and the number of leukopenia events was lost when the number of A repeats was considered as covariate. This suggests that TPMT-VNTR alleles are more relevant than Native American ancestry in the hematological toxicity. Our results emphasize that TPMT-VNTR may be used as a pharmacogenetic biomarker to predict 6-MP-related hematological toxicity in ALL childhood therapy.

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Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease

Walker¹,

Harrison²,

Heap³

et al. 2019

JAMA

132

129

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IMPORTANCEUse of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM).OBJECTIVE To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). DESIGN, SETTING, AND PARTICIPANTSCase-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. EXPOSURES Genetic variants associated with TIM.MAIN OUTCOMES AND MEASURES Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 10 9 /L or less or a decline in absolute neutrophil cell count to 1.0 × 10 9 /L or less leading to a dose reduction or drug withdrawal. RESULTS Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10 −9 ). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10 −8 ), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10 −7 ) of TIM, independent of TPMT genotype and thiopurine dose.CONCLUSIONS AND RELEVANCE Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

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TPMT and NUDT15 genes are both related to mercaptopurine intolerance in acute lymphoblastic leukaemia patients from Uruguay

Cited by 28 publications

References 8 publications

Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping

Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping

Ancestry and TPMT-VNTR Polymorphism: Relationship with Hematological Toxicity in Uruguayan Patients with Acute Lymphoblastic Leukemia

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease

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