부산대학교 도서관

Primary biliary cholangitis (PBC) is an autoimmune disease involving dysregulation of a broad array of homeostatic and metabolic processes. Although considerable single-nucleotide polymorphisms have been unveiled, a large fraction of risk factors remains enigmatic. Candidate genes with rare mutations that tend to confer more deleterious effects need to be identified. To help pinpoint cellular and developmental mechanisms beyond common noncoding variants, we integrated whole exome sequencing with integrative network analysis to investigate genes harboring de novomutations. Prominent convergence has been revealed on a network of disease-specific co-expression comprised of 55 genes associated with homeostasis and metabolism. The transcription factor MEF2D and the DNA repair gene PARP2 were highlighted as hub genes and identified to be up- and down-regulated, respectively, in peripheral blood data set. Enrichment analysis demonstrated altered expression of MEF2D and PARP2 may trigger a series of molecular and cellular processes with pivotal roles in PBC pathophysiology. Our study identified genes with de novomutations in PBC and suggested a subset of genes in homeostasis and metabolism tend to act in synergy through converging on co-expression network, providing novel insights into the etiology of PBC and expanding the pool of molecular candidates for discovering clinically actionable biomarkers.