NUDT15 genotype distributions in the Korean population

Kim, Hyoung-Tae; Choi, Rihwa; Won, Hong-Hee; Choe, Yon Ho; Kang, Ben; Lee, Kiwuk; Koo, Hong Hoe; Yoo, Keon Hee; Kim, Young‐Ho; Lee, Soo-Youn

doi:10.1097/fpc.0000000000000274

Cited by 37 publications

(33 citation statements)

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“…This finding was comparable to previous studies performed in Asian populations (variant allele frequency 2.3–5.0%) which was lower than for individuals of European descent . Meanwhile, in this study, the frequency of NUDT15 variant alleles was 14.0% which was comparable to a previous study in the Korean population . NUDT15 , another important gene with a similar pathway as TPMT , was first identified as a candidate gene by a genome‐wide association study (GWAS) of inflammatory bowel disease patients and in children with ALL .…”

Section: Discussionsupporting

confidence: 88%

“…In this study, two SNPs of NUDT15 (rs116855232 and rs186364861) were identified in association with thiopurine metabolites and therapeutic interruption which confirmed and reflected previous findings on its association with thiopurine‐related hematopoietic toxicity (Tables ). Because the frequency of the variant alleles range from 0.2–17.2% in different ethnic populations and the variant alleles are more common in East Asian populations, standard guidelines including thiopurine dosage adjustment on the basis of NUDT15 genotyping is needed for safe thiopurine therapy . In this study, patients with NUDT15 variants showed significantly lower 6‐TGN/6‐MP dose ratios (Figure ).…”

Section: Discussionmentioning

confidence: 81%

“…Single nucleotide polymorphisms (SNPs) were genotyped using the MassARRAY ® system with SpectroTYPER™ software (Sequenom, Inc., CA, USA) . The TPMT genotype and NUDT15 genotype of each patient were determined by direct sequencing analysis as described previously . The TYMS polymorphism (28‐bp repeat) was analysed using polymerase chain reaction as described previously .…”

Section: Methodsmentioning

confidence: 99%

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Pathway genes and metabolites in thiopurine therapy in Korean children with acute lymphoblastic leukaemia

Choi

Sohn

Kim

et al. 2019

Brit J Clinical Pharma

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Aims: We aimed to investigate the impact of various genetic polymorphisms affecting thiopurine metabolism pathways and toxicity in paediatric acute lymphoblastic leukaemia patients for the first time in Korea. Methods: From May 2006 to September 2016, 139 paediatric acute lymphoblastic leukaemia patients treated with combination chemotherapy including 6-mercaptopurine were included in the study. One hundred and twenty-three variants in 43 genes, including TMPT and NUDT15, were screened using targeted genotyping, such as a MassARRAY system, direct sequencing and polymerase chain reaction-restriction fragment length polymorphism methods. Among the polymorphisms screened, 103 polymorphisms of 43 genes were included for further analyses. Results: The genetic polymorphisms in the ABCC4, AHCY, ATIC, FAM8A6P, GART, GNG2, GSTA1, MTHFD1, MTHFR, NUDT15, PACSIN2, TYMS and XDH genes, and an intronic polymorphism between HIVEP2 and AIG1, and TPMT genotype were associated with thiopurine metabolism (P < 0.05). Genetic polymorphisms in the ABCC4, ADK, ATIC, GART, GMPS, GSTP1, IMPDH1, ITPA, KCNMA1, MOCOS, MTRR, NUDT15, SLC19A1, SLC28A3, SLC29A1, SLCO1B1, TYMP and XDH genes were associated with thiopurine-related toxicities; neutropenia, hepatotoxicity and treatment interruption (P < 0.05).Conclusions: Findings of this study may provide basic knowledge for personalized medicine for thiopurinxe treatment in paediatric acute lymphoblastic leukaemia patients.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 81%

Section: Methodsmentioning

confidence: 99%

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Pathway genes and metabolites in thiopurine therapy in Korean children with acute lymphoblastic leukaemia

Choi

Sohn

Kim

et al. 2019

Brit J Clinical Pharma

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“…Such drugs are purine analogues like anticancer and anti-gout drugs. During the last decade, the importance of NUDT15 is being appreciated and a strong association between thiopurine toxicity and this gene's polymorphisms in patients with Asian ethnicity has been reported (Moriyama et al, 2016;Kim et al, 2017;Singh et al, 2017). Even though the frequency of risk alleles in the European and African individuals is low, such studies were important to be reported.…”

Section: Discussionmentioning

confidence: 99%

The Nudix Hydrolase 15 (NUDT15) Gene Variants among Jordanian Arab Population

Jarrar¹,

Ghishan²

2019

Asian Pac J Cancer Prev

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Background:Nudix Hydrolase 15 gene (NUDT15) encodes nucleotide triphosphate diphosphatase which metabolizes the purine analog drugs, such as anticancer thiopurine and anti-gout allopurinol. Genetic variants on Nudix Hydrolase 15 gene (NUDT15) gene effects the drug’s hydrolyses and hence increases the susceptibility to drug-induced toxicity. The NUDT15 gene has been genotyped in various ethnic groups, however, it has not been genotyped among the Middle Eastern Arab Jordanian population.Aim:The current study aimed to identify NUDT15 genetic variants among Jordanian Arab population.Method:The DNA samples were isolated from leukocytes of 85 unrelated Jordanian Arab volunteers. The coding regions of NUDT15 gene; Exon 1,2 and 3, in addition to some regions of intron 1,2 and 3’UTR, were amplified using polymerase chain reaction (PCR). the PCR products were then subjected to purification and sequenced using Applied Biosystems Model (ABI3730x1).Results:Six NUDT15 genetic variants were found among the volunteers. The results were as followed: A novel synonymous variant 36A>G on exon 1 (6%, 95%CI= 3- 9%), the intronic IVS1 +116C>T variant on intron 1 (0.6%, 95%CI= 0-2%), the non-synonymous variant on exon 3; 415C>T (0.6%, 95%CI= 0-2%), A novel non-synonymous variant on exon 3; 404C>A (0.6%, 95%CI= 0-2%) , and two novel variants on 3’UTR ;502G>A (2%, 95%CI= 0.5-4%) and 588T>C (0.6%, 95%CI= 0-2%). NUDT15 36A>G wasfound to be the most common allele among Jordanians was. In silico softwares predicted that the novel NUDT15 404C>A was harmful and affected NUDT15 enzyme’sstability and function. Furthermore, the frequency of NUDT15 IVS1 +116C>T , among Jordanians, showed to be significantly lower from what was reported in other ethnicities with ap value > 0.05 on the other hand, the frequency of 415C>T variant showed to be similar to Europeans in contrast to Asians and Indians that showed to be significantly lower (p value > 0.05).Conclusions:The frequency of NUDT15 genetic variants is low among the Jordanian volunteers and significantly lower than other ethnic groups. The findings of this study may increase our understanding of the inter-individual variation in the response to purine analog drugs. Further clinical studies are needed to investigate the influence of novel NUDT15 404C>A on drug metabolism and response.

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“…It was revealed that the common missense variant NUDT15 :NM_018283.2:c.415C>T (Arg139Cys, dbSNP: rs116855232 T allele) conferred susceptibility to thiopurine-induced leukopenia in a genetic dose-dependent manner, with an odds ratio (OR) of 35.6 [16]. The finding has since been replicated in other patient populations, and has confirmed the prognostic value of NUDT15 c.415C>T genotyping in East Asian populations, where up to more than 20% of the population may be affected and require dose-adjustment or discontinuation [17]. …”

Section: Introductionmentioning

confidence: 99%

Comparison of Direct Sequencing, Real-Time PCR-High Resolution Melt (PCR-HRM) and PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) Analysis for Genotyping of Common Thiopurine Intolerant Variant Alleles NUDT15 c.415C>T and TPMT c.719A>G (TPMT*3C)

Fong

Poon

2017

Diagnostics

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Thiopurine intolerance and treatment-related toxicity, such as fatal myelosuppression, is related to non-function genetic variants encoding thiopurine S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15). Genetic testing of the common variants NUDT15:NM_018283.2:c.415C>T (Arg139Cys, dbSNP rs116855232 T allele) and TPMT: NM_000367.4:c.719A>G (TPMT*3C, dbSNP rs1142345 G allele) in East Asians including Chinese can potentially prevent treatment-related complications. Two complementary genotyping approaches, real-time PCR-high resolution melt (PCR-HRM) and PCR-restriction fragment length morphism (PCR-RFLP) analysis were evaluated using conventional PCR and Sanger sequencing genotyping as the gold standard. Sixty patient samples were tested, revealing seven patients (11.7%) heterozygous for NUDT15 c.415C>T, one patient homozygous for the variant and one patient heterozygous for the TPMT*3C non-function allele. No patient was found to harbor both variants. In total, nine out of 60 (15%) patients tested had genotypic evidence of thiopurine intolerance, which may require dosage adjustment or alternative medication should they be started on azathioprine, mercaptopurine or thioguanine. The two newly developed assays were more efficient and showed complete concordance (60/60, 100%) compared to the Sanger sequencing results. Accurate and cost-effective genotyping assays by real-time PCR-HRM and PCR-RFLP for NUDT15 c.415C>T and TPMT*3C were successfully developed. Further studies may establish their roles in genotype-informed clinical decision-making in the prevention of morbidity and mortality due to thiopurine intolerance.

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NUDT15 genotype distributions in the Korean population

Cited by 37 publications

References 11 publications

Pathway genes and metabolites in thiopurine therapy in Korean children with acute lymphoblastic leukaemia

Pathway genes and metabolites in thiopurine therapy in Korean children with acute lymphoblastic leukaemia

The Nudix Hydrolase 15 (NUDT15) Gene Variants among Jordanian Arab Population

Comparison of Direct Sequencing, Real-Time PCR-High Resolution Melt (PCR-HRM) and PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) Analysis for Genotyping of Common Thiopurine Intolerant Variant Alleles NUDT15 c.415C>T and TPMT c.719A>G (TPMT*3C)

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