Population-scale variability of the human UDP-glycosyltransferase gene family

Daianna Gonz&#225;lez-Padilla; Mahamadou D. Camara; Volker M. Lauschke; Yitian Zhou

doi:10.1016/j.jgg.2024.06.018

Volume 51 Issue 11

Nov. 2024

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Article Navigation > Journal of Genetics and Genomics > 2024 > 51(11): 1228-1236

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Population-scale variability of the human UDP-glycosyltransferase gene family

doi: 10.1016/j.jgg.2024.06.018

a. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden;
b. Center for Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden;
c. Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany;
d. University of Tübingen, Tübingen, Germany

Funds:

The authors received support from the Swedish Research Council (grant numbers 2021-02801 and 2023-03015), Cancerfonden (grant 23-0763 PT), by the SciLifeLab and Wallenberg National Program for Data-Driven Life Science (grant WASPDDLS22:006), the Robert Bosch Foundation, Stuttgart, Germany and from the National Autonomous University of Mexico (UNAM) DGECI program Initiation to Research 2023. MDC is supported in part by the South African Medical Research Council (SAMRC) with funds received from Novartis and GSK R&D for Project Africa GRADIENT (RCA# 3000038516).

Received Date: 2024-05-12
Accepted Date: 2024-06-26
Rev Recd Date: 2024-06-10

Available Online: 2025-06-06

Publish Date: 2024-07-04

Abstract

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.
- UDP-Glycosyltransferases,
- Genetic variants,
- Populations,
- Drug response,
- Cancer risk,
- Pharmacogenomics

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References(69)

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