HLA Class II Polymorphism 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.

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“…Because HLA Class II Polymorphism is already known to be a modifier of the pulmonary phenotype in CF [78, 79] our finding is not new.…”

Section: Resultsmentioning

confidence: 80%

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

2017

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“…The five associated loci contain genes with pathophysiological relevance for lung function in CF, and genes in these regions are expressed in lung 3 15 16 17 18 19 . Identification of the gene or genes responsible for the modifying effect of each locus will require functional study; however, each locus contains genes of compelling biologic plausibility based on extensive understanding of CF pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis

et al. 2015

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The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease. Regions on chr3q29 (MUC4/MUC20; P=3.3 × 10−11), chr5p15.3 (SLC9A3; P=6.8 × 10−12), chr6p21.3 (HLA Class II; P=1.2 × 10−8) and chrXq22-q23 (AGTR2/SLC6A14; P=1.8 × 10−9) contain genes of high biological relevance to CF pathophysiology. The fifth locus, on chr11p12-p13 (EHF/APIP; P=1.9 × 10−10), was previously shown to be associated with lung disease. These results provide new insights into potential targets for modulating lung disease severity in CF.

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“…Published studies have examined mostly immune or inflammatory genes, including ACE [19,20], ADRβ2 [20–23], ATB 0 [24], CAPN10 [25], ClCN2 [26], DEFβ4 [27], ENaC [28], FcβRII [29], GCLC [30], GSTM1 [20,31–35], GSTM3 [34], GSTP1 [20,33–35], GSTT1 [34], HFE [36,37], HLA-I [38], HLA-II [38–41], HLA-III [38], HSP70 [39], IFN-γ [19], IL1-β [39], IL6 [25], IL10 [19,20,42], IL18 [25], KCNJ11 [25], MBL2 [20,43–52,53 •• ], MIF [54], NOS1 [55–57], NOS3 [20,58], MASP-2 [48,51], PPARβ [25], SERPINA1 [20,59–67], SERPINA3 [68], SFTPA1 [50], SFTPA2 [50], TLR4 [69], TGFB1 [19,20,52,53 ββ ,67,70–72 •• ,73 •• ], TNFα [19,20,25,32,52,74–76], TNFα -receptor [28], and TNFβ [39]. …”

Section: Candidate Gene Studiesmentioning

confidence: 99%

Update on gene modifiers in cystic fibrosis

Collaco¹,

Cutting

2008

Current Opinion in Pulmonary Medicine

119

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Purpose of review Cystic fibrosis (CF) is a common, life-limiting monogenic disease, which typically manifests as progressive bronchiectasis, exocrine pancreatic dysfunction, and recurrent sinopulmonary infections. Although the gene responsible for CF (CFTR) was described in 1989, it has become increasingly evident that modifier genes and environmental factors play substantial roles in determining the severity of disease, particularly lung disease. Identifying these factors is crucial in devising therapies and other interventions to decrease the morbidity and mortality associated with this disorder. Recent findings Although many genes have been proposed as potential modifiers of CF, only a handful have withstood the test of replication. Several of the replicated findings reveal that genes affecting inflammation and infection response play a key role in modifying CF lung disease severity. Interactions between CFTR genotype, modifier genes, and environmental factors have been documented to influence lung function measures and infection status in CF patients. Summary Several genes have been demonstrated to affect disease severity in CF. Furthermore, it is likely that gene–gene and gene–environment interactions can explain a substantial portion of the variation of lung disease. Ongoing genome-wide studies are likely to identify novel genetic modifiers. Continued exploration of the role of genetic and nongenetic modifiers of CF is likely to yield new options for combating this debilitating disease.

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HLA Class II Polymorphism in Cystic Fibrosis

Cited by 71 publications

References 28 publications

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

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

Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis

Update on gene modifiers in cystic fibrosis

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