title: Genes implicated in thiopurine-induced toxicity: Comparing TPMT enzyme activity with clinical phenotype and exome data in a paediatric IBD cohort.
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.
authors.affiliation: Human Genetics and Genomic medicine, University of Southampton, Southampton, UK.|Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, UK.
authors.forename: Tracy
authors.initials: T
authors.lastname: Coelho
authors.affiliation: Human Genetics and Genomic medicine, University of Southampton, Southampton, UK.
authors.forename: Gaia
authors.initials: G
authors.lastname: Andreoletti
authors.affiliation: Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, UK.
authors.forename: James J
authors.initials: JJ
authors.lastname: Ashton
authors.affiliation: Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, UK.
authors.forename: Akshay
authors.initials: A
authors.lastname: Batra
authors.affiliation: Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, UK.
authors.forename: Nadeem Ahmad
authors.initials: NA
authors.lastname: Afzal
authors.affiliation: Cancer Sciences Division, Faculty of Medicine, University Hospital Southampton, Southampton, UK.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Cancer Sciences Division, Faculty of Medicine, University Hospital Southampton, Southampton, UK.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Williams
authors.affiliation: Department of Paediatric Gastroenterology, University Hospital Southampton, Southampton, UK.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Beattie
authors.affiliation: Human Genetics and Genomic medicine, University of Southampton, Southampton, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ennis
mesh_terms: D000293:Adolescent; D001379:Azathioprine / Q000008:administration & dosage / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000201:enzymology; D003424:Crohn Disease / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D059472:Exome; D005260:Female; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000009:adverse effects*; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D013466:Sulfurtransferases / Q000235:genetics / Q000378:metabolism
chemical_list: D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; C425823:MOCOS protein, human; D013466:Sulfurtransferases; D001379:Azathioprine