Inflamm Bowel Dis. 2024 May 24:izae109. doi: 10.1093/ibd/izae109. Online ahead of print.

April M Kennedy ¹, Anne M Griffiths ^2 3 4, Aleixo M Muise ^{2 4 5 6 7}, Thomas D Walters ^2 4, Amanda Ricciuto ^2 3 4, Hien Q Huynh ⁸, Eytan Wine ⁸, Kevan Jacobson ⁹, Sally Lawrence ⁹, Nicholas Carman ², David R Mack ¹⁰, Jennifer C deBruyn ¹¹, Anthony R Otley ¹², Colette Deslandres ¹³, Wael El-Matary ¹⁴, Mary Zachos ¹⁵, Eric I Benchimol ^2 3 4 16, Jeffrey Critch ¹⁷, Rilla Schneider ¹⁸, Eileen Crowley ¹⁹, Michael Li ²⁰, Neil Warner ^6 2, Dermot P B McGovern ²¹, Dalin Li ²¹, Talin Haritunians ²¹, Sarah Rudin ¹, Iris Cohn ^1 4

Author information

¹Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada.

²SickKids IBD Centre, Division of Gastroenterology, Hepatology & Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada.

³Child Health Evaluative Sciences, SickKids Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.

⁴Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.

⁵Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

⁶Cell Biology Program, SickKids Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.

⁷Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.

⁸Edmonton Pediatric IBD Clinic, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.

⁹Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.

¹⁰CHEO IBD Centre, Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital of Eastern Ontario, CHEO Research Institute and Department of Pediatrics, University of Ottawa, Ottawa, Canada.

¹¹Department of Pediatrics, Alberta Children's Hospital Research Institute (ACHRI), University of Calgary, Calgary, Alberta, Canada.

¹²Division of Pediatric Gastroenterology & Nutrition, Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada.

¹³Division of Pediatric Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montréal, Quebec, Canada.

¹⁴Section of Pediatric Gastroenterology, Winnipeg Children's Hospital, University of Manitoba, Winnipeg, MB, Canada.

¹⁵Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.

¹⁶Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.

¹⁷Faculty of Medicine, Memorial University, St John's, Newfoundland & Labrador, Canada.

¹⁸Division of Gastroenterology and Nutrition, Department of Pediatrics, Montreal Children's Hospital, Montreal, Quebec, Canada.

¹⁹Department of Pediatrics, Division of Pediatric Gastroenterology & Hepatology, Children's Hospital Western Ontario, Western University, London, Ontario, Canada.

²⁰The Centre for Computational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.

²¹F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Abstract

Background: Patients with inflammatory bowel disease (IBD) exhibit considerable interindividual variability in medication response, highlighting the need for precision medicine approaches to optimize and tailor treatment. Pharmacogenetics (PGx) offers the ability to individualize dosing by examining genetic factors underlying the metabolism of medications such as thiopurines. Pharmacogenetic testing can identify individuals who may be at risk for thiopurine dose-dependent adverse reactions including myelosuppression. We aimed to evaluate PGx variation in genes supported by clinical guidelines that inform dosing of thiopurines and characterize differences in the distribution of actionable PGx variation among diverse ancestral groups.

Methods: Pharmacogenetic variation in TPMT and NUDT15 was captured by genome-wide genotyping of 1083 pediatric IBD patients from a diverse Canadian cohort. Genetic ancestry was inferred using principal component analysis. The proportion of PGx variation and associated metabolizer status phenotypes was compared across 5 genetic ancestral groups within the cohort (Admixed American, African, East Asian, European, and South Asian) and to prior global estimates from corresponding populations.

Results: Collectively, 11% of the cohort was categorized as intermediate or poor metabolizers of thiopurines, which would warrant a significant dose reduction or selection of alternate therapy. Clinically actionable variation in TPMT was more prevalent in participants of European and Admixed American/Latino ancestry (8.7% and 7.5%, respectively), whereas variation in NUDT15 was more prevalent in participants of East Asian and Admixed American/Latino ancestry (16% and 15% respectively).

Conclusions: These findings demonstrate the considerable interpopulation variability in PGx variation underlying thiopurine metabolism, which should be factored into testing diverse patient populations.