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.
In a large, pediatric inflammatory bowel disease cohort comprised of 5 genetic ancestry groups, we evaluated the distribution of loss-of-function pharmacogenetic variants in TPMT and NUDT15 and predicted phenotypes (impact on thiopurine metabolism).
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.
In a large, pediatric inflammatory bowel disease cohort comprised of 5 genetic ancestry groups, we evaluated the distribution of loss-of-function pharmacogenetic variants in TPMT and NUDT15 and predicted phenotypes (impact on thiopurine metabolism).
摘要：
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，强调需要精准医学方法来优化和定制治疗。药物遗传学（PGx）通过检查药物代谢基础的遗传因素，例如硫嘌呤，提供了个体化给药的能力。药物遗传学测试可以识别可能存在硫嘌呤剂量依赖性不良反应（包括骨髓抑制）风险的个体。我们旨在评估由临床指南支持的基因中的PGx变异，这些指南告知了硫嘌呤的剂量，并表征了不同祖先群体中可操作PGx变异的分布差异。
方法：通过来自不同加拿大队列的1083名儿科IBD患者的全基因组基因分型，捕获了TPMT和NUDT15的药物遗传学变异。使用主成分分析推断遗传祖先。在队列中的5个遗传祖先群体中比较了PGx变异和相关代谢状态表型的比例(混合美国，非洲,东亚,欧洲,和南亚)以及来自相应人口的先前全球估计。
结果：总的来说，11％的队列被归类为硫代嘌呤的中度或不良代谢，这将保证显著减少剂量或选择替代疗法。TPMT的临床可操作变异在欧洲和美国/拉丁美洲混合血统的参与者中更为普遍（8.7％和7.5％，分别)，而NUDT15的变异在东亚和美国/拉丁美洲混合血统的参与者中更为普遍(分别为16%和15%).
结论：这些发现证明了PGx变异在硫代嘌呤代谢基础上具有相当大的种群间差异，这应该是测试不同患者人群的因素。
在一个大的，儿科炎症性肠病队列由5个遗传祖先组组成，我们评估了TPMT和NUDT15中功能缺失的药物遗传变体的分布以及预测的表型(对硫嘌呤代谢的影响).
方法：通过来自不同加拿大队列的1083名儿科IBD患者的全基因组基因分型，捕获了TPMT和NUDT15的药物遗传学变异。使用主成分分析推断遗传祖先。在队列中的5个遗传祖先群体中比较了PGx变异和相关代谢状态表型的比例(混合美国，非洲,东亚,欧洲,和南亚)以及来自相应人口的先前全球估计。
结果：总的来说，11％的队列被归类为硫代嘌呤的中度或不良代谢，这将保证显著减少剂量或选择替代疗法。TPMT的临床可操作变异在欧洲和美国/拉丁美洲混合血统的参与者中更为普遍（8.7％和7.5％，分别)，而NUDT15的变异在东亚和美国/拉丁美洲混合血统的参与者中更为普遍(分别为16%和15%).
结论：这些发现证明了PGx变异在硫代嘌呤代谢基础上具有相当大的种群间差异，这应该是测试不同患者人群的因素。
在一个大的，儿科炎症性肠病队列由5个遗传祖先组组成，我们评估了TPMT和NUDT15中功能缺失的药物遗传变体的分布以及预测的表型(对硫嘌呤代谢的影响).
