Identification of Alcoholic Hepatitis-related Genes using Liver and Blood Transcriptomes

Background Alcoholic hepatitis (AH) is a widespread and life-threatening chronic liver condition that poses a risk of short-term mortality if not properly managed. Clinicians often encounter challenges due to insufficient knowledge about the underlying mechanisms of AH. This study employs a meta-analysis to identify the molecular mechanisms and potential cell therapy targets for AH. Methods We collected eight gene expression datasets, six from liver tissues and two from blood tissues, to identify AH-associated genes. Two liver datasets that had data on deaths after steroid treatment in patients with alcoholic hepatitis were also examined to uncover signatures associated with poor prognosis. Candidate genes were selected using the inverse weighted variance-based method implemented in the METAL software. We utilized prior knowledge to prioritize potential upstream genes, including a transcription factor (TF) catalog, protein-protein interaction (PPI) networks, disease-gene association databases, and summary statistics for single nucleotide polymorphisms (SNP) linked to disease and expression. Results Through four stepwise meta-analyses of nine gene expression datasets, we identified the robust AH liver genes. In detail, the first, second, third, and fourth steps of meta-analysis provided the liver-specific, liver-blood, and severe-mortality meta-genes linked to AH condition, respectively. Multiple lines of evidence (TF, PPI, and SNP databases) were used to identify 29 AH-related upstream genes. Among the candidates, 14 genes were replicated in the severe acute AH mouse model. Conclusions This study presented the candidate upstream AH genes, providing a foundation for developing AH therapeutic targets.