人 UDP-糖基转移酶 (UGT) 负责多种内源性底物和多种常用处方药物的葡萄糖醛酸化。 UGT 基因的不同遗传多态性与药物反应和癌症风险的个体差异有关。然而，这些变异之外的遗传复杂性尚未得到全面评估。我们利用来自七个主要人群的 141,456 个无关个体的全外显子组和全基因组测序数据，提供人类 UGT 基因家族遗传变异性的全面概况。总体而言，观察到 9666 个外显子变异，其中 98.9% 是罕见的。为了解释 UGT 错义变异的功能影响，我们开发了一种基因家族特异性变异效应预测器。该算法总共识别出 1208 个有害变异，其中大部分在非洲和南亚人群中发现。结构分析证实了底物结合位点多种变化的预测效果。结合起来，我们的分析提供了 UGT 变异性的系统概述，这可以深入了解第 2 相代谢的个体间差异，并促进将测序数据转化为 UGT 底物处置的个性化预测。版权所有 © 2024。由 Elsevier Ltd 出版。

Human UDP-glycosyltransferases (UGTs) are responsible for the glucuronidation of a wide variety of endogenous substrates and multiple commonly prescribed drugs. Different genetic polymorphisms in UGT genes are implicated in interindividual differences in drug response and cancer risk. However, the genetic complexity beyond these variants has not been comprehensively assessed. We here leveraged whole-exome and whole-genome sequencing data from 141,456 unrelated individuals across seven major human populations to provide a comprehensive profile of genetic variability across the human UGT gene family. Overall, 9666 exonic variants were observed of which 98.9% were rare. To interpret the functional impact of UGT missense variants, we developed a gene family-specific variant effect predictor. This algorithm identified a total of 1208 deleterious variants, most of which were found in African and South Asian populations. Structural analysis corroborated the predicted effects for multiple variations in substrate binding sites. Combined, our analyses provide a systematic overview of UGT variability, which can yield insights into inter-individual differences in phase 2 metabolism and facilitate the translation of sequencing data into personalized predictions of UGT substrate disposition.Copyright © 2024. Published by Elsevier Ltd.