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Genes implicated in thiopurine-induced toxicity: comparing TPMT enzyme activity with clinical phenotype and exome data in a paediatric IBD cohort

Genes implicated in thiopurine-induced toxicity: comparing TPMT enzyme activity with clinical phenotype and exome data in a paediatric IBD cohort
Genes implicated in thiopurine-induced toxicity: comparing TPMT enzyme activity with clinical phenotype and exome data in a paediatric IBD cohort
The aim of our study was to assess the utility of next generation sequencing (NGS) for predicting toxicity and clinical response to thiopurine drugs in paediatric patients with inflammatory bowel disease. Exome data for 100 patients were assessed against biochemically measured TPMT enzyme activity, clinical response and adverse effects. The TPMT gene and a panel of 15 other genes implicated in thiopurine toxicity were analysed using a gene based statistical test (SKAT-O test).

Nine patients out of 100 (Crohn’s disease- 67, ulcerative colitis- 23 and IBDU-10) had known TPMT mutations associated with deficient enzyme activity. A novel and a highly pathogenic TPMT variant not detectable through standard genotyping, was identified through NGS in an individual intolerant to thiopurines. Of the 14 patients intolerant to thiopurines, NGS identified deleterious TPMT variants in 5 individuals whereas the biochemical test identified 8 individuals as intolerant (sensitivity 35.7% and 57.14%; specificity 93.75% and 50% respectively). SKAT-O test identified a significant association between MOCOS gene and TPMT activity (p=0.0015), not previously reported. Although NGS has the ability to detect rare or novel variants not otherwise identified through standard genotyping, it demonstrates no clear advantage over the biochemical test in predicting toxicity in our modest cohort.
34658
Coelho, Tracy
a78b627c-ea78-41e1-9553-0390921e3c93
Andreoletti, Gaia
75cfc74e-f938-48c8-b3d5-5b377297d008
Ashton, James
03369017-99b5-40ae-9a43-14c98516f37d
Batra, Akshay
822f891e-87ca-41d9-b68d-27c395e88809
Afzal, Nadeem
5148f35e-6788-4dbd-a50f-c303a4948d60
Gao, Yifang
eea234ba-f566-4f21-a65e-234b84cba285
Williams, Anthony
973ff46f-46f1-4d7c-b27d-0f53221e4c44
Beattie, Robert
9a66af0b-f81c-485c-b01d-519403f0038a
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Coelho, Tracy
a78b627c-ea78-41e1-9553-0390921e3c93
Andreoletti, Gaia
75cfc74e-f938-48c8-b3d5-5b377297d008
Ashton, James
03369017-99b5-40ae-9a43-14c98516f37d
Batra, Akshay
822f891e-87ca-41d9-b68d-27c395e88809
Afzal, Nadeem
5148f35e-6788-4dbd-a50f-c303a4948d60
Gao, Yifang
eea234ba-f566-4f21-a65e-234b84cba285
Williams, Anthony
973ff46f-46f1-4d7c-b27d-0f53221e4c44
Beattie, Robert
9a66af0b-f81c-485c-b01d-519403f0038a
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9

Coelho, Tracy, Andreoletti, Gaia, Ashton, James, Batra, Akshay, Afzal, Nadeem, Gao, Yifang, Williams, Anthony, Beattie, Robert and Ennis, Sarah (2016) Genes implicated in thiopurine-induced toxicity: comparing TPMT enzyme activity with clinical phenotype and exome data in a paediatric IBD cohort. Scientific Reports, 6, 34658. (doi:10.1038/srep34658).

Record type: Article

Abstract

The aim of our study was to assess the utility of next generation sequencing (NGS) for predicting toxicity and clinical response to thiopurine drugs in paediatric patients with inflammatory bowel disease. Exome data for 100 patients were assessed against biochemically measured TPMT enzyme activity, clinical response and adverse effects. The TPMT gene and a panel of 15 other genes implicated in thiopurine toxicity were analysed using a gene based statistical test (SKAT-O test).

Nine patients out of 100 (Crohn’s disease- 67, ulcerative colitis- 23 and IBDU-10) had known TPMT mutations associated with deficient enzyme activity. A novel and a highly pathogenic TPMT variant not detectable through standard genotyping, was identified through NGS in an individual intolerant to thiopurines. Of the 14 patients intolerant to thiopurines, NGS identified deleterious TPMT variants in 5 individuals whereas the biochemical test identified 8 individuals as intolerant (sensitivity 35.7% and 57.14%; specificity 93.75% and 50% respectively). SKAT-O test identified a significant association between MOCOS gene and TPMT activity (p=0.0015), not previously reported. Although NGS has the ability to detect rare or novel variants not otherwise identified through standard genotyping, it demonstrates no clear advantage over the biochemical test in predicting toxicity in our modest cohort.

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More information

Accepted/In Press date: 13 September 2016
e-pub ahead of print date: 5 October 2016
Organisations: Cancer Sciences, Human Development & Health

Identifiers

Local EPrints ID: 400972
URI: http://eprints.soton.ac.uk/id/eprint/400972
PURE UUID: 4448fb07-545d-41f0-98ac-d892b354bf34
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869

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Date deposited: 30 Sep 2016 15:14
Last modified: 07 Oct 2020 01:43

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