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

IF 4.5 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
April M Kennedy, Anne M Griffiths, Aleixo M Muise, Thomas D Walters, Amanda Ricciuto, Hien Q Huynh, Eytan Wine, Kevan Jacobson, Sally Lawrence, Nicholas Carman, David R Mack, Jennifer C deBruyn, Anthony R Otley, Colette Deslandres, Wael El-Matary, Mary Zachos, Eric I Benchimol, Jeffrey Critch, Rilla Schneider, Eileen Crowley, Michael Li, Neil Warner, Dermot P B McGovern, Dalin Li, Talin Haritunians, Sarah Rudin, Iris Cohn
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引用次数: 0

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.

加拿大儿科炎症性肠病患者队列中的 TPMT 和 NUDT15 药物基因变异情况
背景:炎症性肠病(IBD)患者在药物反应方面表现出相当大的个体差异,这凸显了采用精准医学方法优化和定制治疗的必要性。药物遗传学(PGx)通过研究硫嘌呤等药物代谢的遗传因素,提供了个体化用药的能力。药物基因学检测可以确定哪些人可能会出现硫嘌呤剂量依赖性不良反应,包括骨髓抑制。我们的目的是评估临床指南支持的基因中的 PGx 变异,这些指南为硫嘌呤类药物的剂量提供了依据,并描述了不同祖先群体中可操作的 PGx 变异分布的差异:方法:通过对来自加拿大不同群体的 1083 名小儿 IBD 患者进行全基因组基因分型,发现了 TPMT 和 NUDT15 的药物基因变异。采用主成分分析法推断遗传祖先。比较了队列中 5 个遗传祖先群体(混血美洲人、非洲人、东亚人、欧洲人和南亚人)的 PGx 变异比例和相关代谢状态表型,并与之前相应人群的全球估计值进行了比较:结果:总体而言,队列中有 11% 的人被归类为硫嘌呤中度或低度代谢者,需要大幅减少剂量或选择替代疗法。具有临床可操作性的TPMT变异在欧洲血统和美国/拉美混血血统的参与者中更为普遍(分别为8.7%和7.5%),而NUDT15变异在东亚血统和美国/拉美混血血统的参与者中更为普遍(分别为16%和15%):这些研究结果表明,硫嘌呤代谢的基础 PGx 变异在人群间存在相当大的差异,在对不同患者进行检测时应将这一因素考虑在内。
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来源期刊
Inflammatory Bowel Diseases
Inflammatory Bowel Diseases 医学-胃肠肝病学
CiteScore
9.70
自引率
6.10%
发文量
462
审稿时长
1 months
期刊介绍: Inflammatory Bowel Diseases® supports the mission of the Crohn''s & Colitis Foundation by bringing the most impactful and cutting edge clinical topics and research findings related to inflammatory bowel diseases to clinicians and researchers working in IBD and related fields. The Journal is committed to publishing on innovative topics that influence the future of clinical care, treatment, and research.
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