Primary biliary cholangitis(PBC)is an autoimmune liver disease characterized by the destruction of intrahepatic small bile ducts and progressive cholestasis,eventually leading to liver cirrhosis and hepatic failure wi...Primary biliary cholangitis(PBC)is an autoimmune liver disease characterized by the destruction of intrahepatic small bile ducts and progressive cholestasis,eventually leading to liver cirrhosis and hepatic failure without appropriate treatment(Terziroli Beretta-Piccoli et al.,2019).展开更多
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 la...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 integrate whole exome sequencing with integrative network analysis to investigate genes harboring de novo mutations. 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 gene MEF2 D and the DNA repair gene PARP2 are highlighted as hub genes and identified to be up-and down-regulated, respectively, in peripheral blood data set. Enrichment analysis demonstrates that altered expression of MEF2 D and PARP2 may trigger a series of molecular and cellular processes with pivotal roles in PBC pathophysiology. Our study identifies genes with de novo mutations in PBC and suggests that 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.展开更多
基金supported by grants from the National Natural Science Foundation of China,China(Nos.81870397,82000534,and 82073156)Shenzhen Kangzhe Pharmaceutical Co.Ltd,China(URC-126/PBC)+1 种基金The Fifth Suzhou Health Talent Project(GSWS201903)The Suzhou Radiotherapy Clinical Medical Center Project,Suzhou,Jiangsu,China(Szlcyxzx202103).
文摘Primary biliary cholangitis(PBC)is an autoimmune liver disease characterized by the destruction of intrahepatic small bile ducts and progressive cholestasis,eventually leading to liver cirrhosis and hepatic failure without appropriate treatment(Terziroli Beretta-Piccoli et al.,2019).
基金supported in part by grants from the National Natural Science Foundation of China (81870397 to X.D.L.81620108002, 81771732, 81830016 to X.M+2 种基金and 81570469 to R.Q.T.)by grants from Jiangsu provincial research fund (BE2017713 to X.D.L and BL2018657 to Y.T.)a grant from National Key R&D Program of China (2016YFC0900400)。
文摘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 integrate whole exome sequencing with integrative network analysis to investigate genes harboring de novo mutations. 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 gene MEF2 D and the DNA repair gene PARP2 are highlighted as hub genes and identified to be up-and down-regulated, respectively, in peripheral blood data set. Enrichment analysis demonstrates that altered expression of MEF2 D and PARP2 may trigger a series of molecular and cellular processes with pivotal roles in PBC pathophysiology. Our study identifies genes with de novo mutations in PBC and suggests that 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.
