Cystic fibrosis transmembrane conductance regulator gene polymorphisms in patients with primary sclerosing cholangitis

Sclerosing cholangitis is a rare progressive cholestatic liver disease affecting the biliary tract. It may be associated with other diseases including autoimmune hepatitis, immunodeficiencies, cystic fibrosis, and sickle cell disease. Sclerosing cholangitis not associated with other diseases is termed "primary sclerosing cholangitis," which has a strong association with male gender, Caucasian race, and inflammatory bowel disease. Diagnosis is based on typical biochemical, radiologic, and histologic features. Medical management is directed mainly at managing complications (pruritus, cholangitis, strictures, and nutritional deficiencies). Administration of ursodeoxycholic acid results in biochemical improvement, but has not been proven to prolong transplant-free survival. Patients with autoimmune overlap respond to immunosuppression. The disease is typically progressive and evolves to biliary cirrhosis and possibly cholangiocarcinoma. Orthotopic liver transplantation remains the only life-extending alternative for patients with sclerosing cholangitis, with good long-term patient and graft survival, and recurrent graft primary sclerosing cholangitis in about 10% of children.

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“…Genes of interest include CARD4, CARD15, BSEP, MDR3, and CFTR [7]. Several CFTR-variants offer protection against the development of PSC [8].…”

Section: Epidemiologymentioning

confidence: 99%

Sclerosing Cholangitis: Pediatric Perspective

Kerkar

Miloh

2010

Curr Gastroenterol Rep

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“…Also, patients with inflammatory bowel disease who are (heterozygous) carriers of CFTR mutations may be at increased risk of developing PSC. Recent studies, however, suggest that CFTR variants may protect against (instead of predispose to) sclerosing cholangitis via modulation of pathogen internalization resulting in reduced inflammation and damage to cholangiocytes [19] .…”

Section: Animal Models Of Pscmentioning

confidence: 99%

New Insights into Autoimmune Cholangitis through Animal Models

Trauner

Fickert

Baghdasaryan

et al. 2010

Dig Dis

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Improving our understanding of the pathogenesis of chronic immune-mediated cholangiopathies such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), as well as the development of novel diagnostic, prognostic and therapeutic tools for these disorders critically depends on easily reproducible animal models. Recently, several spontaneous mouse models for PBC (not requiring previous manipulations for breakdown of immunotolerance) have been reported, including NOD.c3c4 and NOD.c3c4-derived mice, IL-2Rα^–/– mice, dominant negative TGF-β receptor II mice and Ae2_a,b^–/– mice. To date, no animal model exhibits all of the attributes of PSC. Rodent models induced by bacterial cell components or colitis may help to explain the strong association between PSC and inflammatory bowel disease. Other models include direct injury to biliary epithelia, peribiliary vascular endothelia or portal venous endothelia. Mice with targeted disruption of the Mdr2 (Abcb4) gene encoding a canalicular phospholipid flippase (Mdr2^–/– mice) spontaneously develop sclerosing cholangitis with macroscopic and microscopic features of human PSC. Another example for a transporter involved in the pathogenesis of sclerosing cholangitis is the cystic fibrosis transmembrane conductance regulator (CFTR/ABCC7). Xenobiotics and drugs may also lead to bile duct injury and biliary fibrosis via direct toxic and indirect immune-mediated injury. Hydrophobic bile acids, such as lithocholic acid, cause bile duct injury and destructive cholangitis with periductal fibrosis resembling sclerosing cholangitis. These models have enhanced our understanding of the pathogenesis of PBC and PSC and will hopefully result in improved treatment of these disorders.

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“…In line with TGR5 involvement in glucose regulation, different CFTR genotypes do affect the risk of diabetes development, and intriguingly, other genes are probably also involved [28]. Studies of CFTR variation have been performed in PSC with variable conclusions [29,30,31,32,33], but reduced CFTR function have been reported in PSC patients [29,30], even in the absence of CFTR mutations [30]. In one study, dextran sodium sulfate-induced colitis in Cftr knockout mice led to significant bile duct injury at day 14, as evaluated by histology (mononuclear cell inflammatory infiltrates associated with bile duct proliferation) and alkaline phosphatase levels [34], while the wild-type mice were unaffected.…”

Section: Chromosome 2q35 and The Bile Acid Receptor Tgr5mentioning

confidence: 99%

TGR5 Sequence Variation in Primary Sclerosing Cholangitis

Hov

Keitel²,

Schrumpf³

et al. 2011

Dig Dis

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TGR5, the G-protein-coupled bile acid receptor 1 (GPBAR1), has been linked to inflammatory pathways and homeostasis, and could therefore be involved in primary sclerosing cholangitis (PSC), a chronic inflammatory bile duct disease associated with ulcerative colitis (UC). In addition, the TGR5 gene is localized at chromosome 2q35, close to a genetic variant associated with both PSC and UC in recent genome-wide association studies. This provided a strong rationale for a recent study searching for novel genetic variants of TGR5 in PSC. In the study, resequencing of TGR5 was performed in 267 PSC patients and 274 healthy controls. Six nonsynonymous mutations were identified in addition to 16 other novel single-nucleotide polymorphisms. In experimental studies, five of the nonsynonymous mutations were found to reduce or abolish TGR5 function by affecting localization or activity. Fine-mapping of the chromosome 2q35 locus in large patient panels revealed an overall association between a common TGR5 single-nucleotide polymorphism and PSC and UC, but strong linkage disequilibrium precluded demarcation of TGR5 from neighboring genes. In conclusion, the data from the experimental evaluation of novel nonsynonymous mutations represent an important insight into the structural biology of TGR5. In addition, the combination of the known roles of the receptor, the genetic associations and the mutations which affect receptor function, suggests that TGR5 variation may contribute to PSC and UC susceptibility. However, this conclusion needs to be strengthened in further research.

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Cystic fibrosis transmembrane conductance regulator gene polymorphisms in patients with primary sclerosing cholangitis

Cited by 42 publications

References 35 publications

Sclerosing Cholangitis: Pediatric Perspective

Sclerosing Cholangitis: Pediatric Perspective

New Insights into Autoimmune Cholangitis through Animal Models

TGR5 Sequence Variation in Primary Sclerosing Cholangitis

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