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Published on: July 27, 2021
Validating Disease Associations of Drug-Metabolizing Enzymes through Genome-Wide Association Study Data Analysis
Evan Leskiw1, Adeline Whaley2, Peter Hopwood1
1Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
Background And Objectives:
Phase I and phase II drug-metabolizing enzymes are crucial for the metabolism and elimination of various endogenous and exogenous compounds, such as small-molecule hormones, drugs, and xenobiotic carcinogens. While in vitro and animal studies have suggested a link between genetic mutations in these enzymes and an increased risk of cancer, human in vivo studies have provided limited supportive evidence.
Methods:
Genome-wide association studies (GWASs) are a powerful tool for identifying genes associated with specific diseases by comparing two large groups of individuals. In the present study, we analyzed a GWAS database to identify key diseases genetically associated with drug-metabolizing enzymes, focusing on UDP-glucuronosyltransferases (UGTs).
Results:
Our analysis confirmed a strong association between the UGT1 gene and hyperbilirubinemia. Additionally, over ten studies reported a link between the UGT1 gene and increased low-density lipoprotein (LDL) cholesterol levels. UGT2B7 was found to be associated with testosterone levels, total cholesterol levels, and vitamin D levels.
Conclusions:
Despite the in vitro capability of UGT1 and UGT2 family enzymes to metabolize small-molecule carcinogens, the GWAS data did not indicate their genetic association with cancer, except for one study that linked UGT2B4 to ovarian cancer. Further investigations are necessary to fill the gap between in vitro, animal, and human in vivo data.
Insights
Genome-wide association studies found genetic links between drug-metabolizing enzymes, specifically UGT1 and UGT2B7, and conditions like hyperbilirubinemia and cholesterol levels, but not cancer.
Area of Science:
- Pharmacogenomics
- Metabolomics
- Human Genetics
Background:
- Phase I and II drug-metabolizing enzymes (DMEs) are vital for processing endogenous and exogenous compounds.
- In vitro and animal studies suggest genetic mutations in DMEs increase cancer risk.
- Human in vivo evidence linking DME genetic variations to cancer remains limited.
Purpose of the Study:
- To identify diseases genetically associated with drug-metabolizing enzymes using genome-wide association studies (GWASs).
- To focus on the UDP-glucuronosyltransferase (UGT) enzyme family.
Main Methods:
- Analysis of a genome-wide association studies (GWASs) database.
- Comparison of genetic data between large groups of individuals.
- Focus on identifying associations with UDP-glucuronosyltransferases (UGTs).
Main Results:
- Confirmed a strong association between the UGT1 gene and hyperbilirubinemia.
- Identified over ten studies linking the UGT1 gene to elevated low-density lipoprotein (LDL) cholesterol.
- Found UGT2B7 associated with testosterone, total cholesterol, and vitamin D levels.
Conclusions:
- GWAS data did not show a genetic link between UGT1/UGT2 enzymes and cancer, despite their in vitro carcinogen-metabolizing capabilities.
- One study linked UGT2B4 to ovarian cancer, warranting further investigation.
- Further research is needed to reconcile in vitro, animal, and human in vivo findings.
