Validating Disease Associations of Drug-Metabolizing Enzymes through Genome-Wide Association Study Data Analysis.

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 gene and hyperbilirubinemia. Additionally, over ten studies reported a link between the gene and increased low-density lipoprotein (LDL) cholesterol levels. 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 to ovarian cancer. Further investigations are necessary to fill the gap between in vitro, animal, and human in vivo data.