Clinically important alterations in pharmacogene expression in histologically severe nonalcoholic fatty liver disease

Abstract

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 aims to determine if patients with NAFLD are at risk for altered drug response by characterizing changes in hepatic mRNA expression of genes mediating drug disposition (pharmacogenes) across the histological NAFLD severity spectrum. We utilize RNA-seq for 93 liver biopsies with histologically staged NAFLD Activity Score (NAS), fibrosis stage, and steatohepatitis (NASH). We identify 37 significant pharmacogene-NAFLD severity associations including CYP2C19 downregulation. We chose to validate CYP2C19 due to its actionability in drug prescribing. Meta-analysis of 16 independent studies demonstrate that CYP2C19 is significantly downregulated to 46% in NASH, to 58% in high NAS, and to 43% in severe fibrosis. Our data demonstrate the downregulation of CYP2C19 in NAFLD which supports developing personalized medicine approaches for drugs sensitive to metabolism by the CYP2C19 enzyme.

Transcriptomic signatures of progressive and regressive liver fibrosis and portal hypertension

“… 47 ENA: PRJEB27201 Human RNA-seq validation dataset (F3-4 and F0) 48 Powell et al. 48 GEO: GSE225740 Human RNA-seq validation dataset (cirrhotic portal hypertension) 49 Hernández-Gea et al. 49 GEO: GSE171248 Human RNA-seq validation dataset (cured from hepatitis C virus) 50 Hamdane et al.…”

“… 47 GSE225740 : liver biopsies from patients with steatohepatitis and non-diseased (n = 74); patients with F3-4 and F0 (n = 46). 48 GSE171248 : liver biopsies from patients with cirrhotic portal hypertension and non-diseased (n = 16). 49 PRJNA506130: liver biopsies from patients cured from hepatitis C infection (HCV, n = 3) and patients prior treatment (n = 3).…”

Virgin flaxseed oil supplemented or not with tocopherols and phytosterols prevents liver steatosis induced by high‐fat diets in male Wistar rats

“…Nonalcoholic fatty liver disease (NAFLD) is the most common liver condition worldwide, affecting about 25% of the global population. [1] NAFLD is characterized by hepatic steatosis without other underlying causes such as excessive alcohol consumption or certain medications.…”

“…Nonalcoholic fatty liver disease (NAFLD) is the most common liver condition worldwide, affecting about 25% of the global population. [ 1 ] NAFLD is characterized by hepatic steatosis without other underlying causes such as excessive alcohol consumption or certain medications. If these factors are maintained over time, it can progress to more severe forms like nonalcoholic steatohepatitis (NASH), cirrhosis, or hepatocarcinoma.…”

Enformer: An encoder-decoder generative model to enhance prediction of disease outcomes using electronic health records

“…However, their pretraining objectives were limited in predicting a fraction of ICD codes within each visit. In reality, most patients have multiple diseases or outcomes at once, 16 many of which are highly correlated (such as obesity, diabetes, and hypertension [17][18][19] ) and thus collectively contribute to the disease or outcome trajectories. Therefore, a novel pretraining strategy, which predicts the complete set of diseases and outcomes within a visit, might improve clinical predictive modeling.…”