201. Population-scale variability of the human UDP-glycosyltransferase gene family.
- Author
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González-Padilla D, Camara MD, Lauschke VM, and Zhou Y
- Subjects
- Humans, Glucuronosyltransferase genetics, Genetic Variation genetics, Multigene Family genetics, Glycosyltransferases genetics
- Abstract
Human UDP-glycosyltransferases (UGTs) are responsible for the glycosylation of a wide variety of endogenous substrates and 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 7 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 interindividual differences in phase 2 metabolism and facilitate the translation of sequencing data into personalized predictions of UGT substrate disposition., Competing Interests: Conflict of interest VML is the co-founder, CEO, and shareholder of HepaPredict AB. YZ and VML are co-founders and shareholders of Shanghai Hepo Biotechnology Ltd. The other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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