Pharmacogenomic assessment of genes implicated in thiopurine metabolism and toxicity in a UK cohort of paediatric patients with inflammatory bowel disease
Pharmacogenomic assessment of genes implicated in thiopurine metabolism and toxicity in a UK cohort of paediatric patients with inflammatory bowel disease
Background: Thiopurine drugs are effective treatment options in IBD and other conditions but discontinued in some patients due to toxicity.
Methods: We investigated thiopurine-induced toxicity in a paediatric IBD cohort by utilising exome sequencing data across a panel of 46 genes, including TPMT and NUDT15.
Results: The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to thiopurines, myelosuppression was observed in 11%, GI intolerance 11%, hepatotoxicity 4.5%, pancreatitis 1.8% and ‘other’ adverse effects in 2.8%. TPMT enzyme activity was normal in 87.4%, intermediate 12.3% and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to thiopurines.
Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 patients (7%); TPMT*3A (4.5%), *3B (1%), *3C (1.5%). Of these, only 6 patients (21%) developed toxic responses. Three rare TPMT alleles (*3D, *39 and *40), not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses.
The missense variant p.R139C (NUDT15*3 allele) was identified in four patients (Azathioprine- 1.6mg/kg/day) but only one developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes.
Conclusions: A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harbouring the NUDT15*3 allele which is associated with myelosuppression did not show an increased risk of toxicity.
Pharmacogenomics, Thiopurines, Toxicity, Inflammatory bowel disease
Coelho, Tracy
a78b627c-ea78-41e1-9553-0390921e3c93
Cheng, Guo
fdfb3e03-f185-49b1-9c53-05b93bb6c8d0
Lewis, Sophie
34d0f6b4-1d92-4431-a0cd-170757eeedac
Ashton, James J.
03369017-99b5-40ae-9a43-14c98516f37d
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Coelho, Tracy
a78b627c-ea78-41e1-9553-0390921e3c93
Cheng, Guo
fdfb3e03-f185-49b1-9c53-05b93bb6c8d0
Lewis, Sophie
34d0f6b4-1d92-4431-a0cd-170757eeedac
Ashton, James J.
03369017-99b5-40ae-9a43-14c98516f37d
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Coelho, Tracy, Cheng, Guo and Lewis, Sophie
,
et al.
(2024)
Pharmacogenomic assessment of genes implicated in thiopurine metabolism and toxicity in a UK cohort of paediatric patients with inflammatory bowel disease.
Inflammatory Bowel Diseases.
(In Press)
Abstract
Background: Thiopurine drugs are effective treatment options in IBD and other conditions but discontinued in some patients due to toxicity.
Methods: We investigated thiopurine-induced toxicity in a paediatric IBD cohort by utilising exome sequencing data across a panel of 46 genes, including TPMT and NUDT15.
Results: The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to thiopurines, myelosuppression was observed in 11%, GI intolerance 11%, hepatotoxicity 4.5%, pancreatitis 1.8% and ‘other’ adverse effects in 2.8%. TPMT enzyme activity was normal in 87.4%, intermediate 12.3% and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to thiopurines.
Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 patients (7%); TPMT*3A (4.5%), *3B (1%), *3C (1.5%). Of these, only 6 patients (21%) developed toxic responses. Three rare TPMT alleles (*3D, *39 and *40), not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses.
The missense variant p.R139C (NUDT15*3 allele) was identified in four patients (Azathioprine- 1.6mg/kg/day) but only one developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes.
Conclusions: A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harbouring the NUDT15*3 allele which is associated with myelosuppression did not show an increased risk of toxicity.
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Figure 1 Metabolism of thiopurine drugs
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Accepted/In Press date: 1 April 2024
Keywords:
Pharmacogenomics, Thiopurines, Toxicity, Inflammatory bowel disease
Identifiers
Local EPrints ID: 489074
URI: http://eprints.soton.ac.uk/id/eprint/489074
ISSN: 1536-4844
PURE UUID: d390482d-9cc3-4459-a057-b7389a63bbc8
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Date deposited: 12 Apr 2024 16:33
Last modified: 31 Jul 2024 01:53
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Author:
Tracy Coelho
Author:
Guo Cheng
Author:
Sophie Lewis
Corporate Author: et al.
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