Bioinformatic prediction revealed the potential effects of THBS1 mutation on liver fibrosis and inflammation [Poster presentation]

Abstract

<p>Biliary atresia (BA) is a rare, life-threatening inflammatory disease of the liver and bile ducts that occurs in newborns. Patients with BA may develop profound liver fibrosis, leading to liver transplantation. We performed whole genome sequencing on the patients with BA and their unaffected parents. Bioinformatic analysis, including protein-protein interaction network and hub genes analysis, identified THBS1 (Thrombospondin 1) as the most vital hub gene of the candidate disease-causing genes of BA. Here, we identified a compound heterozygous variant in one BA trio. Protein structure perdition using AlphaFold and SWISS-MODEL suggested that the compound heterozygous variant on THBS1 could affect the tertiary structure, stability, or calcium ions environment of THBS1. From the RNA-seq data, we observed differential expression between BA patients and normal controls of THBS1 in the human liver (Luo et al. 2019). Moreover, we also observed abnormal expression of THBS1 in the murine model of biliary atresia from a previously published paper (Bessho et al. 2014). To investigate the potential mechanism of cell activities on BA, we applied the gene deconvolution method to impute cell type-specific expression from bulk RNA-seq data of BA and normal controls. Notably, THBS1 showed dysregulation in BA samples in hepatocytes and inflammatory macrophages. Together with a literature review on THBS1, we hypothesized that dysregulation of THBS1 and its associated pathways would promote liver fibrosis and inflammation, contributing to the etiology and progression of BA. <br></p>