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Tobias J Weismüller - One of the best experts on this subject based on the ideXlab platform.
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genetic association analysis identifies variants associated with Disease progression in primary sclerosing cholangitis
Gut, 2018Co-Authors: Rudi Alberts, Elisabeth M G De Vries, Elizabeth C Goode, Xiaojun Jiang, Fotis Sampaziotis, Krista Rombouts, Katrin Bottcher, Trine Folseraas, Tobias J WeismüllerAbstract:Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory Bile Duct Disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC Disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their Disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07x10(-9)). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC Disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.
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Bile proteomic profiles differentiate cholangiocarcinoma from primary sclerosing cholangitis and choledocholithiasis
Hepatology, 2011Co-Authors: Tim O Lankisch, Tobias J Weismüller, Jochen Metzger, A Negm, Katja Voβkuhl, Eric Schiffer, Justyna Siwy, Andrea Schneider, Kathrin Thedieck, Ralf BaumeisterAbstract:Early detection of malignant biliary tract Diseases, especially cholangiocarcinoma (CC) in patients with primary sclerosing cholangitis (PSC), is very difficult and often comes too late to give the patient a therapeutic benefit. We hypothesize that Bile proteomic analysis distinguishes CC from nonmalignant lesions. We used capillary electrophoresis mass spectrometry (CE-MS) to identify Disease-specific peptide patterns in patients with choledocholithiasis (n = 16), PSC (n = 18), and CC (n = 16) in a training set. A model for differentiation of choledocholithiasis from PSC and CC (PSC/CC model) and another model distinguishing CC from PSC (CC model) were subsequently validated in independent cohorts (choledocholithiasis [n = 14], PSC [n = 18] and CC [n = 25]). Peptides were characterized by sequencing. Application of the PSC/CC model in the independent test cohort resulted in correct exclusion of 12/14 Bile samples from patients with choledocholithiasis and identification of 40/43 patients with PSC or CC (86% specificity, 93% sensitivity). The corresponding receiver operating characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.93 (95% confidence interval [CI]: 0.82-0.98, P = 0.0001). The CC model succeeded in an accurate detection of 14/18 Bile samples from patients with PSC and 21/25 samples with CC (78% specificity, 84% sensitivity) in the independent cohort, resulting in an AUC value of 0.87 (95% CI: 0.73-0.95, P = 0.0001) in ROC analysis. Eight out of 10 samples of patients with CC complicating PSC were identified. Conclusion: Bile proteomic analysis discriminates benign conditions from CC accurately. This method may become a diagnostic tool in future as it offers a new possibility to diagnose malignant Bile Duct Disease and thus enables efficient therapy particularly in patients with PSC. (HEPATOLOGY 2010;)
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Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci
Nature Genetics, 2011Co-Authors: Espen Melum, Andre Franke, Christoph Schramm, Tobias J Weismüller, Daniel Nils Gotthardt, Felix A Offner, Brian D Juran, Jon K Laerdahl, Verena Labi, Einar BjörnssonAbstract:Primary sclerosing cholangitis (PSC) is a chronic Bile Duct Disease affecting 2.4–7.5% of individuals with inflammatory bowel Disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10^−16 and P = 4.1 × 10^−8, respectively). Tom Karlsen and colleagues report a genome-wide association study for primary sclerosing cholangitis, a chronic Bile Duct Disease. They identify susceptibility loci at MST1 and near BCL2L11 .
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genome wide association analysis in primary sclerosing cholangitis identifies two non hla susceptibility loci
Nature Genetics, 2011Co-Authors: Espen Melum, Andre Franke, Christoph Schramm, Tobias J Weismüller, Daniel Nils Gotthardt, Brian D Juran, Jon K Laerdahl, Verena Labi, Felix Offner, Einar BjörnssonAbstract:Primary sclerosing cholangitis (PSC) is a chronic Bile Duct Disease affecting 2.4–7.5% of individuals with inflammatory bowel Disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively).
T M Van Gulik - One of the best experts on this subject based on the ideXlab platform.
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immunoglobulin g4 related sclerosing cholangitis in patients resected for presumed malignant Bile Duct strictures
British Journal of Surgery, 2008Co-Authors: Deha Erdogan, Jaap J Kloek, F Ten J W Kate, E A J Rauws, O R C Busch, D J Gouma, T M Van GulikAbstract:Background: Immunoglobulin (Ig) G(4)-related lymphoplasmacytic sclerosing pancreatitis has been described in the context of autoimmune pancreatitis mimicking distal cholangiocarcinoma. The aim of this study was to assess the occurrence of this entity in benign Bile Duct strictures in patients resected for presumed hilar cholangiocarcinoma. Methods: Of 185 patients who had undergone resection of proximal Bile Ducts on suspicion of hilar cholangiocarcinoma between January 1984 and June 2005, 32 (17.3 per cent) had a benign Bile Duct stricture on histopathological examination. After re-evaluation, further immunohistochemical analysis was performed on specimens from patients with features of autoimmune-like Disease. Results: The PeriDuctal stroma in 15 patients showed features of autoimmune-like Disease (diffuse, moderate to severe lymphoplasmacytic infiltration with marked fibrosis). Abundant IgG(4)-positive plasma cell infiltration around the Bile Duct lesions was seen in two of these. Although not significant, patients with features of autoimmune-like Disease on histological changes showed a higher incidence of recurrent biliary complications than those without (P = 0.250). Conclusion: Features of autoimmune-like Bile Duct Disease were seen in almost half (15 of 32) of patients with benign hilar strictures resected for presumed hilar cholangiocarcinoma. Frank IgG(4)-related sclerosing Disease was found in only two of the 15 patients with autoimmune-like Bile Duct Disease
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immunoglobulin g4 related sclerosing cholangitis in patients resected for presumed malignant Bile Duct strictures
British Journal of Surgery, 2008Co-Authors: Deha Erdogan, Jaap J Kloek, F Ten J W Kate, E A J Rauws, O R C Busch, D J Gouma, T M Van GulikAbstract:Background: Immunoglobulin (Ig) G4-related lymphoplasmacytic sclerosing pancreatitis has been described in the context of autoimmune pancreatitis mimicking distal cholangiocarcinoma. The aim of this study was to assess the occurrence of this entity in benign Bile Duct strictures in patients resected for presumed hilar cholangiocarcinoma. Methods: Of 185 patients who had undergone resection of proximal Bile Ducts on suspicion of hilar cholangiocarcinoma between January 1984 and June 2005, 32 (17·3 per cent) had a benign Bile Duct stricture on histopathological examination. After re-evaluation, further immunohistochemical analysis was performed on specimens from patients with features of autoimmune-like Disease. Results: The periDuctal stroma in 15 patients showed features of autoimmune-like Disease (diffuse, moderate to severe lymphoplasmacytic infiltration with marked fibrosis). Abundant IgG4-positive plasma cell infiltration around the Bile Duct lesions was seen in two of these. Although not significant, patients with features of autoimmune-like Disease on histological changes showed a higher incidence of recurrent biliary complications than those without (P = 0·250). Conclusion: Features of autoimmune-like Bile Duct Disease were seen in almost half (15 of 32) of patients with benign hilar strictures resected for presumed hilar cholangiocarcinoma. Frank IgG4-related sclerosing Disease was found in only two of the 15 patients with autoimmune-like Bile Duct Disease. Copyright © 2008 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
Espen Melum - One of the best experts on this subject based on the ideXlab platform.
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Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci
Nature Genetics, 2011Co-Authors: Espen Melum, Andre Franke, Christoph Schramm, Tobias J Weismüller, Daniel Nils Gotthardt, Felix A Offner, Brian D Juran, Jon K Laerdahl, Verena Labi, Einar BjörnssonAbstract:Primary sclerosing cholangitis (PSC) is a chronic Bile Duct Disease affecting 2.4–7.5% of individuals with inflammatory bowel Disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10^−16 and P = 4.1 × 10^−8, respectively). Tom Karlsen and colleagues report a genome-wide association study for primary sclerosing cholangitis, a chronic Bile Duct Disease. They identify susceptibility loci at MST1 and near BCL2L11 .
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genome wide association analysis in primary sclerosing cholangitis identifies two non hla susceptibility loci
Nature Genetics, 2011Co-Authors: Espen Melum, Andre Franke, Christoph Schramm, Tobias J Weismüller, Daniel Nils Gotthardt, Brian D Juran, Jon K Laerdahl, Verena Labi, Felix Offner, Einar BjörnssonAbstract:Primary sclerosing cholangitis (PSC) is a chronic Bile Duct Disease affecting 2.4–7.5% of individuals with inflammatory bowel Disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively).
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mutational characterization of the Bile acid receptor tgr5 in primary sclerosing cholangitis
PLOS ONE, 2010Co-Authors: Espen Melum, Jon K Laerdahl, Johannes R Hov, Verena Keitel, Lina Spomer, Eva Ellinghaus, Abdou Elsharawy, Kirsten Muri BobergAbstract:Background: TGR5, the G protein-coupled Bile acid receptor 1 (GPBAR1), has been linked to inflammatory pathways as well as Bile homeostasis, and could therefore be involved in primary sclerosing cholangitis (PSC) a chronic inflammatory Bile Duct Disease. We aimed to extensively investigate TGR5 sequence variation in PSC, as well as functionally characterize detected variants. Methodology/Principal Findings: Complete 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. To investigate the impact from the nonsynonymous variants on TGR5, we created a receptor model, and introduced mutated TGR5 constructs into human epithelial cell lines. By using confocal microscopy, flow cytometry and a cAMP-sensitive luciferase assay, five of the nonsynonymous mutations (W83R, V178M, A217P, S272G and Q296X) were found to reduce or abolish TGR5 function. Fine-mapping of the previously reported PSC and UC associated locus at chromosome 2q35 in large patient panels revealed an overall association between the TGR5 single-nucleotide polymorphism rs11554825 and PSC (odds ratio =1.14, 95% confidence interval: 1.03–1.26, p=0.010) and UC (odds ratio =1.19, 95% confidence interval 1.11– 1.27, p=8.5610 27 ), but strong linkage disequilibrium precluded demarcation of TGR5 from neighboring genes. Conclusions/Significance: Resequencing of TGR5 along with functional investigations of novel variants provided unique insight into an important candidate gene for several inflammatory and metabolic conditions. While significant TGR5 associations were detected in both UC and PSC, further studies are needed to conclusively define the role of TGR5 variation in these Diseases.
Einar Björnsson - One of the best experts on this subject based on the ideXlab platform.
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Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci
Nature Genetics, 2011Co-Authors: Espen Melum, Andre Franke, Christoph Schramm, Tobias J Weismüller, Daniel Nils Gotthardt, Felix A Offner, Brian D Juran, Jon K Laerdahl, Verena Labi, Einar BjörnssonAbstract:Primary sclerosing cholangitis (PSC) is a chronic Bile Duct Disease affecting 2.4–7.5% of individuals with inflammatory bowel Disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10^−16 and P = 4.1 × 10^−8, respectively). Tom Karlsen and colleagues report a genome-wide association study for primary sclerosing cholangitis, a chronic Bile Duct Disease. They identify susceptibility loci at MST1 and near BCL2L11 .
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genome wide association analysis in primary sclerosing cholangitis identifies two non hla susceptibility loci
Nature Genetics, 2011Co-Authors: Espen Melum, Andre Franke, Christoph Schramm, Tobias J Weismüller, Daniel Nils Gotthardt, Brian D Juran, Jon K Laerdahl, Verena Labi, Felix Offner, Einar BjörnssonAbstract:Primary sclerosing cholangitis (PSC) is a chronic Bile Duct Disease affecting 2.4–7.5% of individuals with inflammatory bowel Disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively).
Deha Erdogan - One of the best experts on this subject based on the ideXlab platform.
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immunoglobulin g4 related sclerosing cholangitis in patients resected for presumed malignant Bile Duct strictures
British Journal of Surgery, 2008Co-Authors: Deha Erdogan, Jaap J Kloek, F Ten J W Kate, E A J Rauws, O R C Busch, D J Gouma, T M Van GulikAbstract:Background: Immunoglobulin (Ig) G(4)-related lymphoplasmacytic sclerosing pancreatitis has been described in the context of autoimmune pancreatitis mimicking distal cholangiocarcinoma. The aim of this study was to assess the occurrence of this entity in benign Bile Duct strictures in patients resected for presumed hilar cholangiocarcinoma. Methods: Of 185 patients who had undergone resection of proximal Bile Ducts on suspicion of hilar cholangiocarcinoma between January 1984 and June 2005, 32 (17.3 per cent) had a benign Bile Duct stricture on histopathological examination. After re-evaluation, further immunohistochemical analysis was performed on specimens from patients with features of autoimmune-like Disease. Results: The PeriDuctal stroma in 15 patients showed features of autoimmune-like Disease (diffuse, moderate to severe lymphoplasmacytic infiltration with marked fibrosis). Abundant IgG(4)-positive plasma cell infiltration around the Bile Duct lesions was seen in two of these. Although not significant, patients with features of autoimmune-like Disease on histological changes showed a higher incidence of recurrent biliary complications than those without (P = 0.250). Conclusion: Features of autoimmune-like Bile Duct Disease were seen in almost half (15 of 32) of patients with benign hilar strictures resected for presumed hilar cholangiocarcinoma. Frank IgG(4)-related sclerosing Disease was found in only two of the 15 patients with autoimmune-like Bile Duct Disease
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immunoglobulin g4 related sclerosing cholangitis in patients resected for presumed malignant Bile Duct strictures
British Journal of Surgery, 2008Co-Authors: Deha Erdogan, Jaap J Kloek, F Ten J W Kate, E A J Rauws, O R C Busch, D J Gouma, T M Van GulikAbstract:Background: Immunoglobulin (Ig) G4-related lymphoplasmacytic sclerosing pancreatitis has been described in the context of autoimmune pancreatitis mimicking distal cholangiocarcinoma. The aim of this study was to assess the occurrence of this entity in benign Bile Duct strictures in patients resected for presumed hilar cholangiocarcinoma. Methods: Of 185 patients who had undergone resection of proximal Bile Ducts on suspicion of hilar cholangiocarcinoma between January 1984 and June 2005, 32 (17·3 per cent) had a benign Bile Duct stricture on histopathological examination. After re-evaluation, further immunohistochemical analysis was performed on specimens from patients with features of autoimmune-like Disease. Results: The periDuctal stroma in 15 patients showed features of autoimmune-like Disease (diffuse, moderate to severe lymphoplasmacytic infiltration with marked fibrosis). Abundant IgG4-positive plasma cell infiltration around the Bile Duct lesions was seen in two of these. Although not significant, patients with features of autoimmune-like Disease on histological changes showed a higher incidence of recurrent biliary complications than those without (P = 0·250). Conclusion: Features of autoimmune-like Bile Duct Disease were seen in almost half (15 of 32) of patients with benign hilar strictures resected for presumed hilar cholangiocarcinoma. Frank IgG4-related sclerosing Disease was found in only two of the 15 patients with autoimmune-like Bile Duct Disease. Copyright © 2008 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.