Pregnane X Receptor Gene Variation and Total Mortality in Nonalcoholic Fatty Liver Disease

Abstract

The pregnane X receptor (PXR) is a nuclear receptor that plays a role in regulating the metabolism and clearance of drugs and xenobiotics in the liver. Variations in the PXR gene, including the rs7643645 variant, have been associated with altered PXR activity and potential implications for various liver-related conditions, including nonalcoholic fatty liver disease (NAFLD). It is known that the more progressive the NAFLD, the higher the hepatic and extra-hepatic mortality and morbidity. Käräjämäki et al investigated the total mortality in Finnish middle-aged ultrasonographically verified NAFLD patients with PXR rs7643645 variants. In up to 30 years of follow-up, PXR rs7643645 GG subjects were at an increased risk of total mortality compared with AA/AG subjects. The statistically significant difference prevailed after multiple adjustments for potentially confounding factors, RR, 2.024 (1.191-3.440), P = 0.009. In the subjects without NAFLD, the mortality risk was not associated with rs7643645 variants, 1.051 (0.708-1.560; P = 0.804). As the rs7643645 G variant disrupts a putative hepatocyte nuclear factor 4α binding site located in the PXR gene promoter and is associated with lower hepatic expression of PXR and its target genes, their result suggests that genetic disruption of xenobiotic metabolism increases mortality in subjects with NAFLD. Pharmacogenet Genomics. 2023 Feb 1;33(2):35-39. doi: 10.1097/FPC.0000000000000489.