Clinically Important Alterations in Pharmacogene Expression in Histologically Severe Nonalcoholic Fatty Liver Disease

Abstract

Abstract Background Polypharmacy is common in patients with nonalcoholic fatty liver disease (NAFLD) and previous reports suggest that NAFLD is associated with altered drug disposition. This study aimed to determine if patients with histologically severe NAFLD are at risk for altered drug response by characterizing changes in hepatic mRNA expression of genes mediating drug disposition (pharmacogenes) across the spectrum of NAFLD severity. Methods We utilized hepatic RNA-seq from 93 patients with histologically staged NAFLD to test the relationship between pharmacogene expression and histological NAFLD Activity Score (NAS), fibrosis stage, and steatohepatitis (NASH). We then validated our results by meta-analysis of 16 studies, including ours. Results We identified 37 pharmacogene-NAFLD severity associations that were statistically significant after Bonferroni correction. Among all of the significant associations were 4 CYP enzymes (CYP2C19, CYP1B1, CYP2C8, CYP27B1), 3 phase II metabolic enzymes (GSTP1, GSTT1, GSTZ1), 6 ABC transporters (ABCB1, ABCB4, ABCB8, ABCC1, ABCC3, ABCC4), and 7 SLC transporters (SLC22A12, SLC16A1, SLCO3A1, SLC28A3, SLC2A4, SLC22A17, SLC6A6). We chose to validate CYP2C19 due to its actionability in clopidogrel prescribing and found that, compared to controls, it is significantly downregulated to 46% in NASH, to 58% in high NAS, and to 43% in severe fibrosis in our meta-analysis. In the regression analyses, CYP2C19 transcript abundance decreases to 69% with every 1 unit increase in fibrosis stage; reducing CYP2C19 mRNA expression levels by 77% in individuals with stage 4 fibrosis as compared to stage 0. With every 1 unit increase in NAS, CYP2C19 transcript abundance decreases to 83%; reducing CYP2C19 mRNA expression levels by 73% in individuals with a NAS of 7 as compared to 0. Hepatic CYP2C19 transcript abundance is 63% lower in NASH compared to those without. Conclusions Our data demonstrate that mRNA expression levels of several pharmacogenes are altered in livers of patients with NAFLD. Of these, the marked down-regulation of CYP2C19 presents a clear opportunity to further develop individualized treatment modifications for drugs that are sensitive substrates of the CYP2C19 enzyme (e.g., clopidogrel).