Clinical Utility and Cost-Effectiveness of Pretreatment NUDT15 Pharmacogenetic Testing to Prevent Thiopurine-Induced Myelosuppression: A Genotype-First Reverse Phenotyping Cohort Study Within the UK NIHR Inflammatory Bowel Disease Bioresource

Christopher Roberts; Jaime Peters; Aleksejs Sazonvos; Neil Goodman; Mohmmed Sharip; Rebecca Smith; Maria Bishara; Claire Bewshea; Simeng Lin; Neil Chanchlani; Phoebe Hodges; Fakhirah Badrulhisham; Aamir Saifuddin; Sean Carlson; Andrea Centritto; Alexandra Marley; Muhammad Saad; Karishma Sethi-Aora; Laura White; Alaa Abdelmeguid; Laetitia Pele; Shaji Sebastian; Christian Selinger; Peter Irving; Laura Fachal; Gareth Walker; Rachel Palmer; Nick Kennedy; Jayne Houghton; Mary Doona; Christopher Lamb; Chris Hyde; Miles Parkes; James Goodhand; Tariq Ahmad

doi:10.1111/apt.70232

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Clinical Utility and Cost-Effectiveness of Pretreatment NUDT15 Pharmacogenetic Testing to Prevent Thiopurine-Induced Myelosuppression: A Genotype-First Reverse Phenotyping Cohort Study Within the UK NIHR Inflammatory Bowel Disease Bioresource

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Clinical Utility and Cost-Effectiveness of Pretreatment NUDT15 Pharmacogenetic Testing to Prevent Thiopurine-Induced Myelosuppression: A Genotype-First Reverse Phenotyping Cohort Study Within the UK NIHR Inflammatory Bowel Disease Bioresource

Christopher Roberts, Jaime Peters, Aleksejs Sazonvos, Neil Goodman, Mohmmed Sharip, Rebecca Smith, Maria Bishara, Claire Bewshea, Simeng Lin, Neil Chanchlani, …

Alimentary pharmacology & therapeutics, Vol.62(6), pp.630-645

09/2025

DOI: https://doi.org/10.1111/apt.70232

PMID: 40548539

Résumé

Adult

Azathioprine - adverse effects

Case-Control Studies

Cohort Studies

Cost-Benefit Analysis

Female

Genotype

Humans

Inflammatory Bowel Diseases - drug therapy

Inflammatory Bowel Diseases - genetics

Male

Mercaptopurine - adverse effects

Middle Aged

Nudix Hydrolases

Pharmacogenomic Testing - economics

Phenotype

Pyrophosphatases - genetics

Retrospective Studies

United Kingdom

The clinical utility and cost-effectiveness of pre-thiopurine NUDT15 pharmacogenetic testing in European and admixed populations are unknown. To report the prevalence, penetrance, expressivity, and pathogenicity of NUDT15 variant allele carriage and the diagnostic accuracy and cost-effectiveness of an inexpensive loop-mediated isothermal amplification (LAMP) test. Retrospective case-matched cohort study of rates of severe myelosuppression in patients with and without loss-of-function NUDT15 variant allele(s) treated with a thiopurine. Overall, 1.3% of Europeans and 11.7% of South Asians carried a variant allele. Severe myelosuppression was associated with NUDT15 variant allele carriage (11.3% vs 0.95%; p < 0.001). Carriage of a single *3, *6 or *9 variant allele was associated with a shorter time to severe myelosuppression. Numbers needed to genotype to prevent myelosuppression in Europeans and South Asians were 786 and 23. Variant calling using the LAMP assay was fully concordant with Sanger sequencing (n = 154). It improved the safety of thiopurine dosing and was cost-effective when used to reduce the frequency and cost of thiopurine blood monitoring for patients without risk variants. We recommend TPMT and NUDT15 genetic testing in patients of Asian and admixed ancestry. In Europeans, reflex NUDT15 testing should be considered in patients with reduced TPMT activity or loss-of-function genotype. Thiopurines should be avoided in patients with > 1 NUDT15 variant allele and in patients with both NUDT15 and TPMT variant alleles. In patients with a single NUDT15 variant allele, we recommend thiopurine dose reduction (< 1 mg/kg/day) and intensified blood test monitoring.

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Titre: Clinical Utility and Cost-Effectiveness of Pretreatment NUDT15 Pharmacogenetic Testing to Prevent Thiopurine-Induced Myelosuppression: A Genotype-First Reverse Phenotyping Cohort Study Within the UK NIHR Inflammatory Bowel Disease Bioresource
Créateurs - sans rôle: Christopher Roberts - Department of Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, Devon, UK
Jaime Peters - Exeter Test Group, Department of Health and Community Sciences, The Medical School, University of Exeter, Exeter, UK
Aleksejs Sazonvos - Wellcome Sanger Institute, Hinxton, Cambridgeshire, UK
Neil Goodman - Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, Devon, UK
Mohmmed Sharip - Department of Medicine, University of Cambridge, Cambridge, UK
Rebecca Smith - Department of Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, Devon, UK
Maria Bishara - Department of Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, Devon, UK
Claire Bewshea - University of Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, Exeter, UK
Simeng Lin - University of Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, Exeter, UK
Neil Chanchlani - University of Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, Exeter, UK
Phoebe Hodges - University of Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, Exeter, UK
Fakhirah Badrulhisham - University of Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, Exeter, UK
Aamir Saifuddin - Department of Gastroenterology, St Marks Hospital and Academic Institute, Gastroenterology, London, UK
Sean Carlson - Department of Gastroenterology, Bart's Health NHS Trust, London, UK
Andrea Centritto - Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK
Alexandra Marley - Department of Gastroenterology, Royal Wolverhampton NHS Trust, Wolverhampton, UK
Muhammad Saad - Department of Gastroenterology, Royal Wolverhampton NHS Trust, Wolverhampton, UK
Karishma Sethi-Aora - Department of Gastroenterology, Northern Care Alliance NHS Foundation Trust (Bury Care Organisation), Salford, UK
Laura White - Department of Gastroenterology, St Marks Hospital and Academic Institute, Gastroenterology, London, UK
Alaa Abdelmeguid - Department of Gastroenterology, Hull University Teaching Hospitals NHS Trust, Hull, UK
Laetitia Pele - National Institute for Health and Care Research IBD BioResource for Translational Research, Cambridge, UK
Shaji Sebastian - Department of Gastroenterology, Hull University Teaching Hospitals NHS Trust, Hull, UK
Christian Selinger - Leeds Gastroenterology Institute, Leeds Teaching Hospitals NHS Trust, Leeds, UK
Peter Irving - School of Immunology and Microbial Sciences, King's College London, London, UK
Laura Fachal - Wellcome Sanger Institute
Gareth Walker - Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital Brisbane, Brisbane, Queensland, Australia
Rachel Palmer - NHS Southwest Genomic Medicine Service Alliance, Bristol Genetics Laboratory, Southmead Hospital, Bristol, UK
Nick Kennedy - Department of Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, Devon, UK
Jayne Houghton - Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, Devon, UK
Mary Doona - Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
Christopher Lamb - Translational & Clinic Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Type, UK
Chris Hyde - Exeter Test Group, Department of Health and Community Sciences, The Medical School, University of Exeter, Exeter, UK
Miles Parkes - National Institute for Health and Care Research IBD BioResource for Translational Research, Cambridge, UK
James Goodhand - Department of Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, Devon, UK
Tariq Ahmad - Department of Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, Devon, UK
Détails de publication: Alimentary pharmacology & therapeutics, Vol.62(6), pp.630-645
Note de subvention: Wellcome Trust Nova laboratories MRC/X502820/1 / Medical Research Council University of Exeter
Identifiants: 99158976809311
Unité académique: Maladies Infectieuses et Vecteurs : Ecologie, Génétique, Evolution et Contrôle - MIVEGEC
Langue: English
Type de ressource: Journal article