A robust gene expression signature for NASH in liver expression data

Abstract

Non-Alcoholic Fatty Liver Disease (NAFLD) is a progressive liver disease that affects up to 30% of worldwide population, of which up to 25% progress to Non-Alcoholic SteatoHepatitis (NASH), a severe form of the disease that involves inflammation and predisposes the patient to liver cirrhosis. Despite its epidemic proportions, there is no reliable diagnostics that generalizes to global patient population for distinguishing NASH from NAFLD. We performed a comprehensive multicohort analysis of publicly available transcriptome data of liver biopsies from Healthy Controls (HC), NAFLD and NASH patients. Altogether we analyzed 812 samples from 12 different datasets across 7 countries, encompassing real world patient heterogeneity. We used 7 datasets for discovery and 5 datasets were held-out for independent validation. Altogether we identified 130 genes significantly differentially expressed in NASH versus a mixed group of NAFLD and HC. We show that our signature is not driven by one particular group (NAFLD or HC) and reflects true biological signal. Using a forward search we were able to downselect to a parsimonious set of 19 mRNA signature with mean AUROC of 0.98 in discovery and 0.79 in independent validation. Methods for consistent diagnosis of NASH relative to NAFLD are urgently needed. We showed that gene expression data combined with advanced statistical methodology holds the potential to serve basis for development of such diagnostic tests for the unmet clinical need.

AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease

“…Additional factors such as hepatocyte uric acid production, exposure to products derived from the gut microbiome, and perhaps low hepatic magnesium levels, may also contribute to the NASH phenotype 64–69. Transcriptomic profiling of large cohorts of patients is further contributing to our understanding of this disease heterogeneity and its progression 70,71. The response of the liver to lipotoxic injury includes activation and recruitment of resident macrophages, which further contributes to hepatocellular injury and stellate cell activation as part of a complex interplay among hepatic cell types 60,72,73.…”

Comprehensive meta-analysis reveals distinct gene expression signatures of MASLD progression

“…In the second study ( 32 ), a comprehensive analysis of 12 datasets comprising a total of 812 samples was performed to identify a gene expression signature specific to MASH. Although there were seven datasets that overlapped with our study, several notable differences emerged between the two analyses.…”

Inflammation-induced TRIM21 represses hepatic steatosis by promoting the ubiquitination of lipogenic regulators

“…Although those 2 ubiquitin ligases have been suggested as regulators of FA metabolism, their role in vivo and their contribution in the context of NAFLD and NASH development has not been studied. Nevertheless, considering that their expression is not induced in these disease conditions ( 65 ), we may predict that those ubiquitin ligases are likely not involved in the physiological turnover of their targets.…”