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).
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).