Preemptive NUDT15 genotyping: redefining the management of patients with thiopurine-induced toxicity

Shah, Swarup A V; Desai, Devendra; Ashavaid, Tester F.

doi:10.1515/dmpt-2017-0038

Cited by 15 publications

(21 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…IBD is on the rise in the previously low incidence regions of South higher compared to that of the Caucasian population (5%). 11,16,18,21,22 The efficacy of AZA is appreciable at least 2-3 months after initiation of treatment but leucopenia tends to occur early necessitating the need for an effective predictive tool.…”

Section: Discussionmentioning

confidence: 99%

“…15,19,20,30 In our study the association of the variant with the phenotype was significant following an additive model confirming the dominant mode of inheritance of the allele in Indian patients ( Table 2) Two earlier studies from India have also concluded that preemptive NUDT15 testing can help optimise thiopurine therapy. 21,22 Lower mean doses were required in variant genotypes than wild type. However, these were small, retrospective studies which in- was limited with significant proportion of missing data (73%) to draw strong conclusions.…”

Section: Discussionmentioning

confidence: 99%

“…However, these were small, retrospective studies which in- was limited with significant proportion of missing data (73%) to draw strong conclusions. 21,22 Apart from multiple individual studies, a systemic review and meta-analysis including total 1138 patients (311 carried NUDT15…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13][15][16][17] Two small, retrospective studies from western India (69 and 101 patients) have suggested a similar association of NUDT15 polymorphism and thiopurine-induced leucopenia in the Indian population. 21,22 This study prospectively evaluated the association between C415T variant in NUDT15 gene and the development of AZAinduced leucopenia (white blood cells-WBC count < 3 × 10 9 /L) in a large cohort of Indian IBD patients on AZA with matched controls.…”

Section: Introductionmentioning

confidence: 99%

“… 20 Most Asian studies were done in the Mongoloid population of East Asia 11‐13,15‐17 . Two small, retrospective studies from western India (69 and 101 patients) have suggested a similar association of NUDT15 polymorphism and thiopurine‐induced leucopenia in the Indian population 21,22 …”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

NUDT15 C415T variant compared with TPMT genotyping in predicting azathioprine‐induced leucopenia: prospective analysis of 1014 inflammatory bowel disease patients in India

Banerjee

Vishnubhotla

Pal

et al. 2020

Aliment Pharmacol Ther

View full text Add to dashboard Cite

SummaryBackgroundRecent studies reported that Nudix Hydrolase 15(NUDT 15) gene variant (C415T) can better predict thiopurine induced leucopenia in Asian patients with inflammatory bowel disease (IBD) than thiopurine S‐methyl transferase (TPMT).AimTo evaluate the role of the NUDT variant compared with TPMT in predicting azathioprine induced leucopenia in Indian IBD patients.MethodsProspectively collected data of consecutive patients treated with azathioprine from a large IBD registry were analysed for side effects, discontinuation time, and initial and maximum dose tolerated. Genotyping of NUDT15 C415T (rs116855232; p.R139C) was carried out retrieving blood samples from bio‐repository employing real time polymerase chain reaction with age and sex‐matched healthy volunteers. The association of NUDT15 C415T with leucopenia (<3 × 109/L) and neutropenia (<1.5 × 109/L) was evaluated. TPMT genotyping was done in patients who developed leucopenia.ResultsAmong 1014 patients (mean age 35.84 ± 12.74 years; 61% males; 54% ulcerative colitis, 44% Crohn's disease and 2% IBD‐unclassified), 79 were excluded due to inadequate blood samples. Of the remaining 935, 81 (9%) developed leucopenia and 70 (7.5%) developed neutropenia. The variant “T” allele [heterozygous (CT) and homozygous (TT) versus wild type (CC)] was associated with a 19‐fold higher odds (OR19.35, 95% CI11.55‐32.42; P < 0.0001) of leucopenia and 21‐fold higher odds of neutropenia (OR21.41, 95% CI12.25‐37.41). There was significant difference in median dose tolerated between CC, CT and TT (1.35, 1.38 and 0.92 mg/kg body weight, respectively) (P = 0.037) and median duration of therapy (18, 15 and 10 months for CC/CT/TT) (P = 0.003). NUDT15 genotype was an independent risk factor for leucopenia (hazard ratio (HR): CT 11.31, 95% CI6.85‐18.03, P < 0.0001 and TT 31.283, 95% CI14.76‐66.30 compared to CC) and neutropenia (HR: CT 13.04, 95% CI7.65‐22.22, P < 0.0001 and TT 43.39, 95% CI20.21‐92.68 compared to CC). The sensitivities for predicting leucopenia and neutropenia by number of mutant NUDT 15 alleles based on additive predictive model were 66.67% and 70% with a receptor operator characteristic curve area under curve value of 0.791 and 0.807, respectively. Among patients with leucopenia, only 6.2% were heterozygous and none were homozygous for TPMT variants.ConclusionNUDT15 variant genotyping appears to be a better predictor for azathioprine‐induced leucopenia in an Indian population than TPMT with high accuracy and can be useful in optimizing azathioprine dosage.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

NUDT15 C415T variant compared with TPMT genotyping in predicting azathioprine‐induced leucopenia: prospective analysis of 1014 inflammatory bowel disease patients in India

Banerjee

Vishnubhotla

Pal

et al. 2020

Aliment Pharmacol Ther

View full text Add to dashboard Cite

show abstract

Optimization of infliximab therapy in inflammatory bowel disease using a dashboard approach—an Indian experience

Dave

Dherai

Desai

et al. 2020

Eur J Clin Pharmacol

View full text Add to dashboard Cite

Population pharmacogenomics: an update on ethnogeographic differences and opportunities for precision public health

Zhou

Lauschke

2021

Hum Genet

View full text Add to dashboard Cite

Both safety and efficacy of medical treatment can vary depending on the ethnogeographic background of the patient. One of the reasons underlying this variability is differences in pharmacogenetic polymorphisms in genes involved in drug disposition, as well as in drug targets. Knowledge and appreciation of these differences is thus essential to optimize population-stratified care. Here, we provide an extensive updated analysis of population pharmacogenomics in ten pharmacokinetic genes (CYP2D6, CYP2C19, DPYD, TPMT, NUDT15 and SLC22A1), drug targets (CFTR) and genes involved in drug hypersensitivity (HLA-A, HLA-B) or drug-induced acute hemolytic anemia (G6PD). Combined, polymorphisms in the analyzed genes affect the pharmacology, efficacy or safety of 141 different drugs and therapeutic regimens. The data reveal pronounced differences in the genetic landscape, complexity and variant frequencies between ethnogeographic groups. Reduced function alleles of CYP2D6, SLC22A1 and CFTR were most prevalent in individuals of European descent, whereas DPYD and TPMT deficiencies were most common in Sub-Saharan Africa. Oceanian populations showed the highest frequencies of CYP2C19 loss-of-function alleles while their inferred CYP2D6 activity was among the highest worldwide. Frequencies of HLA-B*15:02 and HLA-B*58:01 were highest across Asia, which has important implications for the risk of severe cutaneous adverse reactions upon treatment with carbamazepine and allopurinol. G6PD deficiencies were most frequent in Africa, the Middle East and Southeast Asia with pronounced differences in variant composition. These variability data provide an important resource to inform cost-effectiveness modeling and guide population-specific genotyping strategies with the goal of optimizing the implementation of precision public health.

show abstract

Preemptive NUDT15 genotyping: redefining the management of patients with thiopurine-induced toxicity

Abstract: A preemptive NUDT15 genotyping approach can therefore help identify high-risk patients (NUDT15 C415T positive) who could benefit from thiopurine dose reduction, thereby preventing fatal thiopurine-induced toxicity.

Cited by 15 publications

References 15 publications

NUDT15 C415T variant compared with TPMT genotyping in predicting azathioprine‐induced leucopenia: prospective analysis of 1014 inflammatory bowel disease patients in India

NUDT15 C415T variant compared with TPMT genotyping in predicting azathioprine‐induced leucopenia: prospective analysis of 1014 inflammatory bowel disease patients in India

Optimization of infliximab therapy in inflammatory bowel disease using a dashboard approach—an Indian experience

Population pharmacogenomics: an update on ethnogeographic differences and opportunities for precision public health

Contact Info

Product

Resources

About