In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis.
Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance.
Inserm, UMR1078, Brest, France.
Pascal
http://orcid.org/0000-0002-4675-6394
P
Trouvé
Inserm, UMR1078, Brest, France.
Emmanuelle
E
Génin
Inserm, UMR1078, Brest, France.|Université de Bretagne Occidentale, Faculté de Médecine et des sciences de la santé, Brest, France.|C.H.U. Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest, France.|Etablissement Français du Sang - Bretagne, Brest, France.
Claude
C
Férec
D003198:Computer Simulation; D016213:Cyclins / Q000235:genetics; D003550:Cystic Fibrosis / Q000150:complications / Q000235:genetics*; D030541:Databases, Genetic; D060045:Genes, Modifier; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics; D008107:Liver Diseases / Q000150:complications / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D010182:Pancreatic Diseases / Q000150:complications / Q000235:genetics*; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics
C503688:CCNE2 protein, human; D016213:Cyclins; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D009687:Nuclear Proteins; D010750:Phosphoproteins; C076700:IFI16 protein, human