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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.

SUBMITTER: Trouve P

PROVIDER: S-EPMC5365109 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Trouvé Pascal P Génin Emmanuelle E Férec Claude C

PloS one 20170324 3

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 ...[more]

PMID: 28339466

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Project description:Lung disease progression is variable among cystic fibrosis (CF) patients and depends on DNA mutations in the CFTR gene, polymorphic variations in disease modifier genes, and environmental exposure. The contribution of genetic factors has been extensively investigated, whereas the mechanism whereby environmental factors modulate the lung disease is unknown. In this project, we hypothesized that (i) reiterative stress alters the epigenome in CF-affected tissues and (ii) DNA methylation variations at disease modifier genes modulate the lung function in CF patients.We profiled DNA methylation at CFTR, the disease-causing gene, and at 13 lung modifier genes in nasal epithelial cells and whole blood samples from 48 CF patients and 24 healthy controls. CF patients homozygous for the p.Phe508del mutation and ?18-year-old were stratified according to the lung disease severity. DNA methylation was measured by bisulfite and next-generation sequencing. The DNA methylation profile allowed us to correctly classify 75% of the subjects, thus providing a CF-specific molecular signature. Moreover, in CF patients, DNA methylation at specific genes was highly correlated in the same tissue sample. We suggest that gene methylation in CF cells may be co-regulated by disease-specific trans-factors. Three genes were differentially methylated in CF patients compared with controls and/or in groups of pulmonary severity: HMOX1 and GSTM3 in nasal epithelial samples; HMOX1 and EDNRA in blood samples. The association between pulmonary severity and DNA methylation at EDNRA was confirmed in blood samples from an independent set of CF patients. Also, lower DNA methylation levels at GSTM3 were associated with the GSTM3*B allele, a polymorphic 3-bp deletion that has a protective effect in cystic fibrosis.DNA methylation levels are altered in nasal epithelial and blood cell samples from CF patients. Analysis of CFTR and 13 lung disease modifier genes shows DNA methylation changes of small magnitude: some of them are a consequence of the disease; other changes may result in small expression variations that collectively modulate the lung disease severity.

Project description:BackgroundAbnormal biliary secretion leads to the thickening of bile and the formation of plugs within the bile ducts; the consequent obstruction and abnormal bile flow ultimately results in the development of cystic fibrosis-related liver disease. This condition peaks in adolescence with up to 20% of adolescents with cystic fibrosis developing chronic liver disease. Early changes in the liver may ultimately result in end-stage liver disease with people needing transplantation. One therapeutic option currently used is ursodeoxycholic acid. This is an update of a previous review.ObjectivesTo analyse evidence that ursodeoxycholic acid improves indices of liver function, reduces the risk of developing chronic liver disease and improves outcomes in general in cystic fibrosis.Search methodsWe searched the Cochrane CF and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also contacted drug companies and searched online trial registries.Date of the most recent search of the Group's trials register: 09 April 2017.Selection criteriaRandomised controlled trials of the use of ursodeoxycholic acid for at least three months compared with placebo or no additional treatment in people with cystic fibrosis.Data collection and analysisTwo authors independently assessed trial eligibility and quality. The authors used GRADE to assess the quality of the evidence.Main resultsTwelve trials have been identified, of which four trials involving 137 participants were included; data were only available from three of the trials (118 participants) since one cross-over trial did not report appropriate data. The dose of ursodeoxycholic acid ranged from 10 to 20 mg/kg/day for up to 12 months. The complex design used in two trials meant that data could only be analysed for subsets of participants. There was no significant difference in weight change, mean difference -0.90 kg (95% confidence interval -1.94 to 0.14) based on 30 participants from two trials. Improvement in biliary excretion was reported in only one trial and no significant change after treatment was shown. There were no data available for analysis for long-term outcomes such as death or need for liver transplantation.Authors' conclusionsThere are few trials assessing the effectiveness of ursodeoxycholic acid. The quality of the evidence identified ranged from low to very low. There is currently insufficient evidence to justify its routine use in cystic fibrosis.

Project description:ContextA subset (approximately 3%-5%) of patients with cystic fibrosis (CF) develops severe liver disease with portal hypertension.ObjectiveTo assess whether any of 9 polymorphisms in 5 candidate genes (alpha(1)-antitrypsin or alpha(1)-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor beta1 [TGFB1]) are associated with severe liver disease in patients with CF.Design, setting, and participantsTwo-stage case-control study enrolling patients with CF and severe liver disease with portal hypertension (CFLD) from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America, with the University of North Carolina at Chapel Hill as the coordinating site. In the initial study, 124 patients with CFLD (enrolled January 1999-December 2004) and 843 control patients without CFLD were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 patients with CFLD (enrolled January 2005-February 2007) and 1088 with no CFLD.Main outcome measuresDifferences in distribution of genotypes in patients with CFLD vs patients without CFLD.ResultsThe initial study showed CFLD to be associated with the SERPINA1 Z allele (odds ratio [OR], 4.72; 95% confidence interval [CI], 2.31-9.61; P = 3.3 x 10(-6)) and with TGFB1 codon 10 CC genotype (OR, 1.53; 95% CI, 1.16-2.03; P = 2.8 x 10(-3)). In the replication study, CFLD was associated with the SERPINA1 Z allele (OR, 3.42; 95% CI, 1.54-7.59; P = 1.4 x 10(-3)) but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (OR, 5.04; 95% CI, 2.88-8.83; P = 1.5 x 10(-8)).ConclusionsThe SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (OR, approximately 5) of developing severe liver disease with portal hypertension.

Project description:Cystic Fibrosis (CF) exhibits morbidity in several organs, including progressive lung disease in all patients and intestinal obstruction at birth (meconium ileus) in ~15%. Individuals with the same causal CFTR mutations show variable disease presentation which is partly attributed to modifier genes. With >6,500 participants from the International CF Gene Modifier Consortium, genome-wide association investigation identified a new modifier locus for meconium ileus encompassing ATP12A on chromosome 13 (min p = 3.83x10(-10)); replicated loci encompassing SLC6A14 on chromosome X and SLC26A9 on chromosome 1, (min p<2.2x10(-16), 2.81x10(-11), respectively); and replicated a suggestive locus on chromosome 7 near PRSS1 (min p = 2.55x10(-7)). PRSS1 is exclusively expressed in the exocrine pancreas and was previously associated with non-CF pancreatitis with functional characterization demonstrating impact on PRSS1 gene expression. We thus asked whether the other meconium ileus modifier loci impact gene expression and in which organ. We developed and applied a colocalization framework called the Simple Sum (SS) that integrates regulatory and genetic association information, and also contrasts colocalization evidence across tissues or genes. The associated modifier loci colocalized with expression quantitative trait loci (eQTLs) for ATP12A (p = 3.35x10(-8)), SLC6A14 (p = 1.12x10(-10)) and SLC26A9 (p = 4.48x10(-5)) in the pancreas, even though meconium ileus manifests in the intestine. The meconium ileus susceptibility locus on chromosome X appeared shifted in location from a previously identified locus for CF lung disease severity. Using the SS we integrated the lung disease association locus with eQTLs from nasal epithelia of 63 CF participants and demonstrated evidence of colocalization with airway-specific regulation of SLC6A14 (p = 2.3x10(-4)). Cystic Fibrosis is realizing the promise of personalized medicine, and identification of the contributing organ and understanding of tissue specificity for a gene modifier is essential for the next phase of personalizing therapeutic strategies.

Dataset Information

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

Publications

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

Similar Datasets

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