Landscape of <i>TPMT</i> and <i>NUDT15</i> Pharmacogenetic Variation in a Cohort of Canadian Pediatric Inflammatory Bowel Disease Patients-Reference-Cited by-同舟云学术

Landscape of TPMT and NUDT15 Pharmacogenetic Variation in a Cohort of Canadian Pediatric Inflammatory Bowel Disease Patients

Published:2024-05-24 Issue: Volume: Page:
ISSN:1078-0998
Container-title:Inflammatory Bowel Diseases
language:en
Short-container-title:

Author:

Kennedy April M¹,Griffiths Anne M²³⁴^ORCID,Muise Aleixo M²⁴⁵⁶⁷,Walters Thomas D²⁴^ORCID,Ricciuto Amanda²³⁴,Huynh Hien Q⁸^ORCID,Wine Eytan⁸^ORCID,Jacobson Kevan⁹^ORCID,Lawrence Sally⁹,Carman Nicholas²,Mack David R¹⁰,deBruyn Jennifer C¹¹,Otley Anthony R¹²,Deslandres Colette¹³,El-Matary Wael¹⁴,Zachos Mary¹⁵,Benchimol Eric I²³⁴¹⁶,Critch Jeffrey¹⁷,Schneider Rilla¹⁸,Crowley Eileen¹⁹^ORCID,Li Michael²⁰,Warner Neil⁶²,McGovern Dermot P B²¹,Li Dalin²¹,Haritunians Talin²¹^ORCID,Rudin Sarah¹,Cohn Iris¹⁴^ORCID

Affiliation:

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

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

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

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

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

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

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

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

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

10. CHEO 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

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

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

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

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

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

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

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

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

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

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

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

Abstract

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.

Funder

Canadian Institute of Health Research

Children’s Intestinal and Liver Disease

The Hospital for Sick Children Inflammatory Bowel Disease Center

Hemsley Charitable Trust

Publisher

Oxford University Press (OUP)

Link

https://academic.oup.com/ibdjournal/advance-article-pdf/doi/10.1093/ibd/izae109/57890301/izae109.pdf

Reference45 articles.

1. Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN evidence-based consensus guidelines;Turner;J Pediatr Gastroenterol Nutr.,2012

2. The medical management of paediatric Crohn’s disease: an ECCO-ESPGHAN guideline update;van Rheenen;J Crohns Colitis.,2020

3. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017;GBD 2017 Inflammatory Bowel Disease Collaborators;Lancet Gastroenterol Hepatol,2020

4. Impact of thiopurine dose in anti-tumor necrosis factor combination therapy on outcomes in inflammatory bowel disease;Nawaz;Ann Gastroenterol,2023

5. Epidemiology, burden of disease, and unmet needs in the treatment of ulcerative colitis in Asia;Wei;Expert Rev Gastroenterol Hepatol,2021