In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis

Abstract

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.

Impaired liver regeneration and lipid homeostasis in CCl4 treated WDR13 deficient mice

“…Also the expression levels of WDR13 was found to be altered in hepatic oxidative stress and steatosis conditions via BIM activation [38]. Other studies too indicate indirect dysregulation of WDR13 in in-silico or obesity conditions [39],[40]. All these studies along with the present study reveal that loss of WDR13 per se increases the PPARγ expression.…”

Transcriptomic profile of cystic fibrosis patients identifies type I interferon response and ribosomal stalk proteins as potential modifiers of disease severity

“…Though previous studies reported the association of type I interferon genes ( IFIT1 , IFIT3 , and ISG15 ) with CF [ 12 ], the present study confirms the role of the type I IFN pathway in modifying CF. A very recent study using a systems biology approach identified a type I interferon gene IFI16 , as a major CF modifier gene that alters lung function [ 28 ]. The type I IFNs are well-known for anti-viral response, and viral infections are potential contributors for a decline in lung function in CF patients [ 29 ].…”

Current Treatment Options for Cystic Fibrosis-Related Liver Disease

“…In patients carrying the Z-allele the α1-antitrypsin variant accumulates in hepatocytes and cholangiocytes [ 22 ], which could lead to further endoplasmatic reticulum stress and predispose cholangiocytes to injury of other causes [ 23 ]. A recent in silico analysis identified further candidate modifier genes potentially involved in CFLD (i.e., Solute carrier family 33 acetyl-coenzyme A transporter member 1 (SLC33A1), glycoprotein NMB (GPNMB), neutrophil cytosolic Factor 2 (NCF2), RAS guanyl nucleotide-releasing protein 1 (RASGRP1), lectin galactosidase-binding soluble 3 (LGALS3), and protein-tyrosine phosphatase nonreceptor-type 13 (PTPN13)) [ 24 ].…”