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1. HLA haplotypes in primary sclerosing cholangitis patients of admixed and non‐European ancestry

Author

Henriksen, EKK, Viken, MK, Wittig, M, Holm, K, Folseraas, T, Mucha, S, Melum, E, Hov, JR, Lazaridis, KN, Juran, BD, Chazouillères, O, Färkkilä, M, Gotthardt, DN, Invernizzi, P, Carbone, M, Hirschfield, GM, Rushbrook, SM, Goode, E, Consortium, The UK‐PSC, Ponsioen, CY, Weersma, RK, Eksteen, B, Yimam, KK, Gordon, SC, Goldberg, D, Yu, L, Bowlus, CL, Franke, A, Lie, BA, and Karlsen, TH

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, Autoimmune Disease, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Alleles, Cholangitis, Sclerosing, Ethnicity, Gene Expression, Gene Frequency, Genetic Predisposition to Disease, HLA-DQ beta-Chains, HLA-DRB1 Chains, Haplotypes, Humans, Linkage Disequilibrium, Scandinavian and Nordic Countries, White People, causative, human leukocyte antigen, multi-ethnic, PSC, trans-ancestry, UK-PSC Consortium, PSC, Clinical Sciences, Immunology
Abstract

Primary sclerosing cholangitis (PSC) is strongly associated with several human leukocyte antigen (HLA) haplotypes. Due to extensive linkage disequilibrium and multiple polymorphic candidate genes in the HLA complex, identifying the alleles responsible for these associations has proven difficult. We aimed to evaluate whether studying populations of admixed or non-European descent could help in defining the causative HLA alleles. When assessing haplotypes carrying HLA-DRB1*13:01 (hypothesized to specifically increase the susceptibility to chronic cholangitis), we observed that every haplotype in the Scandinavian PSC population carried HLA-DQB1*06:03. In contrast, only 65% of HLA-DRB1*13:01 haplotypes in an admixed/non-European PSC population carried this allele, suggesting that further assessments of the PSC-associated haplotype HLA-DRB1*13:01-DQA1*01:03-DQB1*06:03 in admixed or multi-ethnic populations could aid in identifying the causative allele.

Published
2017

3. Pump-less, recirculating organ-on-a-chip (rOoC) platform

Author

Busek, M., primary, Aizenshtadt, A., additional, Koch, T., additional, Frank, A., additional, Delon, L., additional, Martinez, M. Amirola, additional, Golovin, A., additional, Dumas, C., additional, Stokowiec, J., additional, Gruenzner, S., additional, Melum, E., additional, and Krauss, S., additional

Published
2022
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8. Liver Transplantation for Acute Intermittent Porphyria

Author

Lissing, M. (Mattias), Nowak, G. (Greg), Adam, R. (René), Karam, V. (Vincent), Boyd, A. (Alexander), Gouya, L. (Laurent), Meersseman, W. (Wouter), Melum, E. (Espen), Ołdakowska-Jedynak, U. (Urszula), Reiter, F.P. (Florian P.), Colmenero, J. (Jordi), Sanchez, R. (Rosario), Herden, U. (Uta), Langendonk, J.G. (Janneke), Ventura, P. (Paolo), Isoniemi, H. (Helena), Boillot, O. (Olivier), Braun, F. (Felix), Perrodin, S. (Stéphanie), Mowlem, E. (Elizabeth), Wahlin, S. (Staffan), Lissing, M. (Mattias), Nowak, G. (Greg), Adam, R. (René), Karam, V. (Vincent), Boyd, A. (Alexander), Gouya, L. (Laurent), Meersseman, W. (Wouter), Melum, E. (Espen), Ołdakowska-Jedynak, U. (Urszula), Reiter, F.P. (Florian P.), Colmenero, J. (Jordi), Sanchez, R. (Rosario), Herden, U. (Uta), Langendonk, J.G. (Janneke), Ventura, P. (Paolo), Isoniemi, H. (Helena), Boillot, O. (Olivier), Braun, F. (Felix), Perrodin, S. (Stéphanie), Mowlem, E. (Elizabeth), and Wahlin, S. (Staffan)

Abstract

Recurrent attacks of acute intermittent porphyria (AIP) result in poor quality of life and significant risks of morbidity and mortality. Liver transplantation (LT) offers a cure, but published data on outcomes after LT are limited. We assessed the pretransplant characteristics, complications, and outcomes for patients with AIP who received a transplant. Data were collected retrospectively from the European Liver Transplant Registry and from questionnaires sent to identified transplant and porphyria centers. We studied 38 patients who received transplants in 12 countries from 2002 to 2019. Median age at LT was 37 years (range, 18-58), and 34 (89%) of the patients were women. A total of 9 patients died during follow-up, and 2 patients were retransplanted. The 1-year and 5-year overall survival rates were 92% and 82%, which are comparable with other metabolic diseases transplanted during the same period. Advanced pretransplant neurological impairment was associated with increased mortality. The 5-year survival rate was 94% among 19 patients with moderate or no neuropathy at LT and 83% among 10 patients with severe neuropathy (P = 0.04). Pretransplant renal impairment was common. A total of 19 (51%) patients had a GFR < 60 mL/minute. Although few patients improved their renal function after LT, neurological impairments improved, and no worsening of neurological symptoms was recorded. No patient had AIP attacks after LT, except for a patient who received an auxiliary graft. LT is a curative treatment option for patients with recurrent attacks of AIP. Severe neuropathy and impaired renal function are common and increase the risk for poor outcomes. If other treatment options fail, an evaluation for LT should be performed early.

Published
2020
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9. Lipid antigens in bile from patients with chronic liver diseases activate natural killer T cells.

Author

Valestrand, L., Berntsen, N. L., Zheng, F., Schrumpf, E., Hansen, S. H., Karlsen, T. H., Blumberg, R. S., Hov, J. R., Jiang, X., and Melum, E.

Subjects
CYTOTOXIC T cells, KILLER cells, CHRONICALLY ill, BILE, ANTIGENS
Abstract

Summary: Natural killer T (NKT) cells are an abundant subset of liver lymphocytes activated by lipid antigens presented on CD1d molecules that are expressed by cholangiocytes. We aimed to determine if bile from patients with chronic liver diseases contains antigenic lipids that can activate NKT cells. Using murine invariant (24.7, 24.8 and DN32.D3) and non‐invariant (14S.6, 14S.7 and 14S.10) NKT hybridomas we investigated the presence of lipid antigens in bile collected from the gallbladder of patients undergoing liver transplantation due to end‐stage liver disease. Biliary microbiota profiles were generated using 16S rRNA amplicon sequencing. We found that the patient bile samples contain antigens that activate both invariant and non‐invariant NKT hybridomas (24.7, 24.8, DN32.D3, 14S.6, 14S.7 and 14S.10), as demonstrated by activation of at least one hybridoma by eight of 10 bile samples. Activation at high dilutions suggests that some antigens are highly potent. We used the non‐invariant NKT hybridoma 14S.6 to screen 21 additional patient bile samples for NKT‐reactivity and demonstrated that 12 of 21 bile samples resulted in activation, three of which gave a strong activation. Four of 12 activating bile samples contained microbial DNA. Our results reveal an immunological pathway that could be of critical importance in biliary immunology. [ABSTRACT FROM AUTHOR]

Published
2021
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10. Ageing-related expression of Twinfilin-1 regulates cholangiocyte biological response to injury

Author

Pinto, C., primary, Maroni, L., additional, Giordano, D.M., additional, Saccomanno, S., additional, Banales, J.M., additional, Albertini, M.C., additional, Orlando, F., additional, Milkiewicz, M., additional, Melum, E., additional, Ciriza, I.L., additional, Milkiewicz, P., additional, Rychlicki, C., additional, Trozzi, L., additional, Scarpelli, M., additional, Benedetti, A., additional, Baroni, G. Svegliati, additional, and Marzioni, M., additional

Published
2018
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12. Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

Author

Alberts, R, De Vries, E, Goode, E, Jiang, X, Sampaziotis, F, Rombouts, K, Böttcher, K, Folseraas, T, Weismüller, T, Mason, A, Wang, W, Alexander, G, Alvaro, D, Bergquist, A, Björkström, N, Beuers, U, Björnsson, E, Boberg, K, Bowlus, C, Bragazzi, M, Carbone, M, Chazouillères, O, Cheung, A, Dalekos, G, Eaton, J, Eksteen, B, Ellinghaus, D, Färkkilä, M, Festen, E, Floreani, A, Franceschet, I, Gotthardt, D, Hirschfield, G, Hoek, B, Holm, K, Hohenester, S, Hov, J, Imhann, F, Invernizzi, P, Juran, B, Lenzen, H, Lieb, W, Liu, J, Marschall, H, Marzioni, M, Melum, E, Milkiewicz, P, Müller, T, Pares, A, Rupp, C, Rust, C, Sandford, R, Schramm, C, Schreiber, S, Schrumpf, E, Silverberg, M, Srivastava, B, Sterneck, M, Teufel, A, Vallier, L, Verheij, J, Vila, A, Vries, B, Zachou, K, Chapman, R, Manns, M, Pinzani, M, Rushbrook, S, Lazaridis, K, Franke, A, Anderson, C, Karlsen, T, Ponsioen, C, Weersma, R, Alberts, R, De Vries, E, Goode, E, Jiang, X, Sampaziotis, F, Rombouts, K, Böttcher, K, Folseraas, T, Weismüller, T, Mason, A, Wang, W, Alexander, G, Alvaro, D, Bergquist, A, Björkström, N, Beuers, U, Björnsson, E, Boberg, K, Bowlus, C, Bragazzi, M, Carbone, M, Chazouillères, O, Cheung, A, Dalekos, G, Eaton, J, Eksteen, B, Ellinghaus, D, Färkkilä, M, Festen, E, Floreani, A, Franceschet, I, Gotthardt, D, Hirschfield, G, Hoek, B, Holm, K, Hohenester, S, Hov, J, Imhann, F, Invernizzi, P, Juran, B, Lenzen, H, Lieb, W, Liu, J, Marschall, H, Marzioni, M, Melum, E, Milkiewicz, P, Müller, T, Pares, A, Rupp, C, Rust, C, Sandford, R, Schramm, C, Schreiber, S, Schrumpf, E, Silverberg, M, Srivastava, B, Sterneck, M, Teufel, A, Vallier, L, Verheij, J, Vila, A, Vries, B, Zachou, K, Chapman, R, Manns, M, Pinzani, M, Rushbrook, S, Lazaridis, K, Franke, A, Anderson, C, Karlsen, T, Ponsioen, C, and Weersma, R

Abstract

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=6.07×10 -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.

Published
2018

14. Identification of Twinfilin-1 as a key regulator of cholangiocyte biological response to injury: Evidence for a possible role of ageing in the progression of cholangiopathies

Author

Maroni, L., primary, Pinto, C., additional, Giordano, D.M., additional, Saccomanno, S., additional, Rychlicki, C., additional, Trozzi, L., additional, Albertini, M.C., additional, Orlando, F., additional, Melum, E., additional, Banales, J., additional, Benedetti, A., additional, Baroni, G. Svegliati, additional, and Marzioni, M., additional

Published
2017
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15. HLA haplotypes in primary sclerosing cholangitis patients of admixed and non-European ancestry

Author

Henriksen, E, Viken, M, Wittig, M, Holm, K, Folseraas, T, Mucha, S, Melum, E, Hov, J, Lazaridis, K, Juran, B, Chazouillãres, O, Fã¤rkkilã¤, M, Gotthardt, D, Invernizzi, P, Carbone, M, Hirschfield, G, Rushbrook, S, Goode, E, Ponsioen, C, Weersma, R, Eksteen, B, Yimam, K, Gordon, S, Goldberg, D, Yu, L, Bowlus, C, Franke, A, Lie, B, Karlsen, T, Karlsen, T., INVERNIZZI, PIETRO, CARBONE, MARCO, Henriksen, E, Viken, M, Wittig, M, Holm, K, Folseraas, T, Mucha, S, Melum, E, Hov, J, Lazaridis, K, Juran, B, Chazouillãres, O, Fã¤rkkilã¤, M, Gotthardt, D, Invernizzi, P, Carbone, M, Hirschfield, G, Rushbrook, S, Goode, E, Ponsioen, C, Weersma, R, Eksteen, B, Yimam, K, Gordon, S, Goldberg, D, Yu, L, Bowlus, C, Franke, A, Lie, B, Karlsen, T, Karlsen, T., INVERNIZZI, PIETRO, and CARBONE, MARCO

Abstract

Primary sclerosing cholangitis (PSC) is strongly associated with several human leukocyte antigen (HLA) haplotypes. Due to extensive linkage disequilibrium and multiple polymorphic candidate genes in the HLA complex, identifying the alleles responsible for these associations has proven difficult. We aimed to evaluate whether studying populations of admixed or non-European descent could help in defining the causative HLA alleles. When assessing haplotypes carrying HLA-DRB1*13:01 (hypothesized to specifically increase the susceptibility to chronic cholangitis), we observed that every haplotype in the Scandinavian PSC population carried HLA-DQB1*06:03. In contrast, only 65% of HLA-DRB1*13:01 haplotypes in an admixed/non-European PSC population carried this allele, suggesting that further assessments of the PSC-associated haplotype HLA-DRB1*13:01-DQA1*01:03-DQB1*06:03 in admixed or multi-ethnic populations could aid in identifying the causative allele.

Published
2017

16. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

Author

Ji, S, Juran, B, Mucha, S, Folseraas, T, Jostins, L, Melum, E, Kumasaka, N, Atkinson, E, Schlicht, E, Liu, J, Shah, T, Gutierrez Achury, J, Boberg, K, Bergquist, A, Vermeire, S, Eksteen, B, Durie, P, Farkkila, M, Müller, T, Schramm, C, Sterneck, M, Weismüller, T, Gotthardt, D, Ellinghaus, D, Braun, F, Teufel, A, Laudes, M, Lieb, W, Jacobs, G, Beuers, U, Weersma, R, Wijmenga, C, Marschall, H, Milkiewicz, P, Pares, A, Kontula, K, Chazouillères, O, Invernizzi, P, Goode, E, Spiess, K, Moore, C, Sambrook, J, Ouwehand, W, Roberts, D, Danesh, J, Floreani, A, Gulamhusein, A, Eaton, J, Schreiber, S, Coltescu, C, Bowlus, C, Luketic, V, Odin, J, Chopra, K, Kowdley, K, Chalasani, N, Manns, M, Srivastava, B, Mells, G, Sandford, R, Alexander, G, Gaffney, D, Chapman, R, Hirschfield, G, de Andrade, M, Rushbrook, S, Franke, A, Karlsen, T, Lazaridis, K, Anderson, C, INVERNIZZI, PIETRO, Anderson, C., Ji, S, Juran, B, Mucha, S, Folseraas, T, Jostins, L, Melum, E, Kumasaka, N, Atkinson, E, Schlicht, E, Liu, J, Shah, T, Gutierrez Achury, J, Boberg, K, Bergquist, A, Vermeire, S, Eksteen, B, Durie, P, Farkkila, M, Müller, T, Schramm, C, Sterneck, M, Weismüller, T, Gotthardt, D, Ellinghaus, D, Braun, F, Teufel, A, Laudes, M, Lieb, W, Jacobs, G, Beuers, U, Weersma, R, Wijmenga, C, Marschall, H, Milkiewicz, P, Pares, A, Kontula, K, Chazouillères, O, Invernizzi, P, Goode, E, Spiess, K, Moore, C, Sambrook, J, Ouwehand, W, Roberts, D, Danesh, J, Floreani, A, Gulamhusein, A, Eaton, J, Schreiber, S, Coltescu, C, Bowlus, C, Luketic, V, Odin, J, Chopra, K, Kowdley, K, Chalasani, N, Manns, M, Srivastava, B, Mells, G, Sandford, R, Alexander, G, Gaffney, D, Chapman, R, Hirschfield, G, de Andrade, M, Rushbrook, S, Franke, A, Karlsen, T, Lazaridis, K, Anderson, C, INVERNIZZI, PIETRO, and Anderson, C.

Abstract

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC

Published
2017

17. Replacement of the murine common bile duct with a bioengineered conduit incorporating primary human cholangiocyte organoids

Author

Sampaziotis, F., primary, Justin, A.W., additional, Tysoe, O.C., additional, Sawiak, S., additional, Gieseck, R.L., additional, de Brito, M.C., additional, Berntsen, N.L., additional, Gomez-Vazquez, M.J., additional, Ortmann, D., additional, Yiangou, L., additional, Bargehr, J., additional, Bertero, A., additional, Zonneveld, M.C., additional, Pedersen, M.T., additional, Pawlowski, M., additional, Georgakopoulos, N., additional, Pirmadjid, N., additional, Skeldon, G.M., additional, Godfrey, E.M., additional, Shu, W., additional, Materek, P.M., additional, Snijders, K.E., additional, Brown, S.E., additional, Rimland, C.A., additional, Simonic, I., additional, Davies, S., additional, Jensen, K., additional, Gelson, W.T., additional, Alexander, G., additional, Sinha, S., additional, Hannan, N.R., additional, Wynn, T., additional, Karlsen, T.H., additional, Melum, E., additional, Markaki, A.E., additional, Saeb-Parsy, K., additional, and Vallier, L., additional

Published
2017
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22. Genotype-Phenotype Analysis across 130,422 Genetic Variants Identifies Rspo3 as the First Genome-Wide Significant Modifier Gene in Primary Sclerosing Cholangitis

Author

Alberts, R., primary, de Vries, E.M., additional, Alexander, G., additional, Alvaro, D., additional, Bergquist, A., additional, Beuers, U., additional, Björnsson, E., additional, Boberg, K.M., additional, Bowlus, C.L., additional, Chapman, R.W., additional, Chazouilléres, O., additional, Cheung, A., additional, Dalekos, G., additional, Eksteen, B., additional, Eaton, J.E., additional, Ellinghaus, D., additional, Färkkilä, M., additional, Festen, E.A., additional, Floreani, A., additional, Folseraas, T., additional, Goode, E., additional, Gotthardt, D.N., additional, Hirschfield, G.M., additional, van Hoek, B., additional, Hohenester, S., additional, Holm, K., additional, Hov, J.R., additional, Imhann, F., additional, Invernizzi, P., additional, Jiang, X., additional, Juran, B.D., additional, Lazaridis, K.N., additional, Leppa, V., additional, Liu, J.Z., additional, Löfberg, J., additional, Manns, M.P., additional, Marschall, H.-U., additional, Marzioni, M., additional, Mason, A.L., additional, Melum, E., additional, Müller, T., additional, Milkiewicz, P., additional, Pares, A., additional, Pelkonen, V., additional, Pinzani, M., additional, Rombouts, K., additional, Rupp, C., additional, Rushbrook, S.M., additional, Rust, C., additional, Sampaziotis, F., additional, Sandford, R.N., additional, Schramm, C., additional, Schreiber, S., additional, Schrumpf, E., additional, Silverberg, M., additional, Srivastava, B., additional, Sterneck, M., additional, Teufel, A., additional, Tittmann, L., additional, Vallier, L., additional, Vila, A.V., additional, de Vries, B.A., additional, Weismüller, T.J., additional, Wijmenga, C., additional, Zachou, K., additional, Franke, A., additional, Anderson, C.A., additional, Karlsen, T.H., additional, Ponsioen, C.Y., additional, and Weersma, K., additional

Published
2016
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25. Characterization of animal models for primary sclerosing cholangitis (PSC)

Author

Fickert, P, Pollheimer, M, Beuers, U, Lackner, C, Hirschfield, G, Housset, C, Keitel, V, Schramm, C, Marschall, H, Karlsen, T, Melum, E, Kaser, A, Eksteen, B, Strazzabosco, M, Manns, M, Trauner, M, Trauner, M., STRAZZABOSCO, MARIO, Fickert, P, Pollheimer, M, Beuers, U, Lackner, C, Hirschfield, G, Housset, C, Keitel, V, Schramm, C, Marschall, H, Karlsen, T, Melum, E, Kaser, A, Eksteen, B, Strazzabosco, M, Manns, M, Trauner, M, Trauner, M., and STRAZZABOSCO, MARIO

Abstract

Primary sclerosing cholangitis (PSC) is a chronic cholangiopathy characterized by biliary fibrosis, development of cholestasis and end stage liver disease, high risk of malignancy, and frequent need for liver transplantation. The poor understanding of its pathogenesis is also reflected in the lack of effective medical treatment. Well-characterized animal models are utterly needed to develop novel pathogenetic concepts and study new treatment strategies. Currently there is no consensus on how to evaluate and characterize potential PSC models, which makes direct comparison of experimental results and effective exchange of study material between research groups difficult. The International Primary Sclerosing Cholangitis Study Group (IPSCSG) has therefore summarized these key issues in a position paper proposing standard requirements for the study of animal models of PSC.

Published
2014

29. GS-005 - Replacement of the murine common bile duct with a bioengineered conduit incorporating primary human cholangiocyte organoids

Author

Sampaziotis, F., Justin, A.W., Tysoe, O.C., Sawiak, S., Gieseck, R.L., de Brito, M.C., Berntsen, N.L., Gomez-Vazquez, M.J., Ortmann, D., Yiangou, L., Bargehr, J., Bertero, A., Zonneveld, M.C., Pedersen, M.T., Pawlowski, M., Georgakopoulos, N., Pirmadjid, N., Skeldon, G.M., Godfrey, E.M., Shu, W., Materek, P.M., Snijders, K.E., Brown, S.E., Rimland, C.A., Simonic, I., Davies, S., Jensen, K., Gelson, W.T., Alexander, G., Sinha, S., Hannan, N.R., Wynn, T., Karlsen, T.H., Melum, E., Markaki, A.E., Saeb-Parsy, K., and Vallier, L.

Published
2017
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32. SAT-372 - Genotype-Phenotype Analysis across 130,422 Genetic Variants Identifies Rspo3 as the First Genome-Wide Significant Modifier Gene in Primary Sclerosing Cholangitis

Author

Alberts, R., de Vries, E.M., Alexander, G., Alvaro, D., Bergquist, A., Beuers, U., Björnsson, E., Boberg, K.M., Bowlus, C.L., Chapman, R.W., Chazouilléres, O., Cheung, A., Dalekos, G., Eksteen, B., Eaton, J.E., Ellinghaus, D., Färkkilä, M., Festen, E.A., Floreani, A., Folseraas, T., Goode, E., Gotthardt, D.N., Hirschfield, G.M., van Hoek, B., Hohenester, S., Holm, K., Hov, J.R., Imhann, F., Invernizzi, P., Jiang, X., Juran, B.D., Lazaridis, K.N., Leppa, V., Liu, J.Z., Löfberg, J., Manns, M.P., Marschall, H.-U., Marzioni, M., Mason, A.L., Melum, E., Müller, T., Milkiewicz, P., Pares, A., Pelkonen, V., Pinzani, M., Rombouts, K., Rupp, C., Rushbrook, S.M., Rust, C., Sampaziotis, F., Sandford, R.N., Schramm, C., Schreiber, S., Schrumpf, E., Silverberg, M., Srivastava, B., Sterneck, M., Teufel, A., Tittmann, L., Vallier, L., Vila, A.V., de Vries, B.A., Weismüller, T.J., Wijmenga, C., Zachou, K., Franke, A., Anderson, C.A., Karlsen, T.H., Ponsioen, C.Y., and Weersma, K.

Published
2016
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36. 102 NOVEL SUSCEPTIBILITY LOCI FOR PRIMARY SCLEROSING CHOLANGITIS IDENTIFIED BY GENOME-WIDE ASSOCIATION AND REPLICATION ANALYSIS

Author

Folseraas, T., primary, Melum, E., additional, Juran, B., additional, Weersma, R.K., additional, Schramm, C., additional, Weismüller, T.J., additional, Gotthardt, D.N., additional, Boberg, K.M., additional, Janse, M., additional, Buchert, E., additional, Björnsson, E., additional, Henckaerts, L., additional, Rust, C., additional, Teufel, A., additional, Bergquist, A., additional, Ryu, E., additional, Hov, J.R., additional, Holm, K., additional, Ponsioen, C.Y., additional, Runz, H., additional, Sterneck, M., additional, Vermeire, S., additional, Wijmenga, C., additional, Beuers, U., additional, Schrumpf, E., additional, Manns, M.P., additional, Lazaridis, K., additional, Schreiber, S., additional, Franke, A., additional, and Karlsen, T.H., additional

Published
2011
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40. The 32-base pair deletion of the chemokine receptor 5 gene ( CCR5-Δ 32) is not associated with primary sclerosing cholangitis in 363 Scandinavian patients.

Author

Melum, E., Karlsen, T. H., Broomé, U., Thorsby, E., Schrumpf, E., Boberg, K. M., and Lie, B. A.

Subjects
*CHEMOKINES, *SCLEROTHERAPY, *GENES, *HEREDITY, *GENOMES, *DISEASES
Abstract

CCR5 is a chemokine receptor expressed on T-cells and macrophages. A 32-base pair deletion in the chemokine receptor 5 gene (CCR5-Δ32) leads to a non-functional receptor. Conflicting evidence exists whether this deletion is associated with primary sclerosing cholangitis (PSC). We genotyped the CCR5-Δ32 variant in 363 PSC patients and 366 controls. No significant increase in the Δ32 allele frequency was detected in the PSC patients compared to controls (12.7% vs 10.7% OR = 1.22, 95% CI [0.88, 1.68], P = 0.23). Survival analysis did not reveal any significant effects from CCR5-Δ32 genotypes on disease progression. Thus, in this study (power > 90%, given OR = 2, α = 0.05), we were unable to replicate previous findings and our results do not support an involvement of CCR5-Δ32 in either PSC susceptibility or progression. [ABSTRACT FROM AUTHOR]

Published
2006
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42. Genotype-phenotype analysis across 130 422 genetic variants identifies RSPO3 as the first genome-wide significant modifier gene in primary sclerosing cholangitis

Author

Albert Pares, Vries, E. M., Alexander, G., Alvaro, D., Bergquist, A., Beuers, U., Bjornsson, E., Boberg, K. M., Bowlus, C. L., Chapman, R. W., Chazouilleres, O., Cheung, A., Dalekos, G., Eksteen, B., Ellinghaus, D., Farkkila, M., Festen, E. A., Floreani, A., Folseraas, T., Goode, E., Gotthardt, D. N., Hirschfield, G. M., Hoek, B., Holm, K., Hohenester, S., Hov, J. R., Imhann, F., Invernizzi, P., Jiang, X., Eaton, J., Juran, B. D., Lazaridis, K. N., Leppa, V., Liu, J. Z., Lofberg, J., Manns, M. P., Marschall, H-U, Marzioni, M., Mason, A. L., Melum, E., Milkiewicz, P., Muller, T., Pares, A., Rupp, C., Rushbrook, S. M., Rust, C., Sampaziotis, F., Sandford, R. N., Schramm, C., Schreiber, S., Schrumpf, E., Silverberg, M., Srivastava, B., Sterneck, M., Teufel, A., Tittmann, L., Vallier, L., Vila, A. V., Vries, B., Weismuller, T. J., Wijmenga, C., Zachou, K., Franke, A., Anderson, C. A., Karlsen, T. H., Ponsioen, C. Y., Weersma, R. K., Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Department of Health and Life Sciences

44. SNPexp - A web tool for calculating and visualizing correlation between HapMap genotypes and gene expression levels

Author

Franke Andre, Melum Espen, Holm Kristian, and Karlsen Tom H

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Expression levels for 47294 transcripts in lymphoblastoid cell lines from all 270 HapMap phase II individuals, and genotypes (both HapMap phase II and III) of 3.96 million single nucleotide polymorphisms (SNPs) in the same individuals are publicly available. We aimed to generate a user-friendly web based tool for visualization of the correlation between SNP genotypes within a specified genomic region and a gene of interest, which is also well-known as an expression quantitative trait locus (eQTL) analysis. Results SNPexp is implemented as a server-side script, and publicly available on this website: http://tinyurl.com/snpexp. Correlation between genotype and transcript expression levels are calculated by performing linear regression and the Wald test as implemented in PLINK and visualized using the UCSC Genome Browser. Validation of SNPexp using previously published eQTLs yielded comparable results. Conclusions SNPexp provides a convenient and platform-independent way to calculate and visualize the correlation between HapMap genotypes within a specified genetic region anywhere in the genome and gene expression levels. This allows for investigation of both cis and trans effects. The web interface and utilization of publicly available and widely used software resources makes it an attractive supplement to more advanced bioinformatic tools. For the advanced user the program can be used on a local computer on custom datasets.

Published
2010
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45. Lack of association between the chemokine receptor 5 polymorphism CCR5delta32 in rheumatoid arthritis and juvenile idiopathic arthritis

Author

Kvien Tore K, Thorsby Erik, Selvaag Anne, Flatø Berit, Melum Espen, Nordang Gry BN, Lindner Ewald, Førre Øystein T, and Lie Benedicte A

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background The chemokine receptor CCR5 has been detected at elevated levels on synovial T cells, and a 32 bp deletion in the CCR5 gene leads to a non-functional receptor. A negative association between the CCR5Δ32 and rheumatoid arthritis (RA) has been reported, although with conflicting results. In juvenile idiopathic arthritis (JIA), an association with CCR5 was recently reported. The purpose of this study was to investigate if the CCR5Δ32 polymorphism is associated with RA or JIA in Norwegian cohorts. Methods 853 RA patients, 524 JIA patients and 658 controls were genotyped for the CCR5Δ32 polymorphism. Results The CCR5Δ32 allele frequency was 11.5% in the controls vs. 10.4% in RA patients (OR = 0.90; P = 0.36) and 9.7% in JIA patients (OR = 0.85; P = 0.20). No decreased homozygosity was observed for CCR5Δ32, as previously suggested. Conclusion Our data do not support an association between the CCR5Δ32 allele and Norwegian RA or JIA patients. Combining our results with those from a recently published meta-analysis still provide evidence for a role for CCR5Δ32 in RA, albeit substantially weaker than the effect first reported.

Published
2007
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46. Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

Author

Martina Sterneck, Wolfgang Lieb, Christian Rust, Tom H. Karlsen, Massimo Pinzani, Erik Schrumpf, John E. Eaton, Gideon M. Hirschfield, Christoph Schramm, Richard Sandford, Ulrich Beuers, Andrew Mason, Espen Melum, Daniel Gotthardt, A. Boudewijn de Vries, I. Franceschet, Konstantinos N. Lazaridis, Floris Imhann, Marco Carbone, Pietro Invernizzi, Mark S. Silverberg, Simon Hohenester, Maria Consiglia Bragazzi, Andreas Teufel, Bart van Hoek, Martti Färkkilä, Einar Bjornsson, Cyriel Y. Ponsioen, Brijesh Srivastava, Joanne Verheij, Roger W. Chapman, Krista Rombouts, Niklas K. Björkström, Johannes R. Hov, Weiwei Wang, F. Sampaziotis, Ludovic Vallier, Albert Parés, Eleonora A. M. Festen, Kristian Holm, Kalliopi Zachou, Katrin Böttcher, Christopher L. Bowlus, Xiaojun Jiang, Trine Folseraas, Elisabeth M.G. de Vries, Simon M. Rushbrook, Piotr Milkiewicz, Carl A. Anderson, Georgios N. Dalekos, David Ellinghaus, Hanns-Ulrich Marschall, Rinse K. Weersma, Marco Marzioni, Olivier Chazouillères, Domenico Alvaro, Christian Rupp, Angela M. Cheung, Jimmy Z. Liu, Brian D. Juran, Michael P. Manns, Rudi Alberts, Bertus Eksteen, Tobias J. Weismüller, Graeme J.M. Alexander, Annarosa Floreani, Tobias Müller, Stefan Schreiber, Andre Franke, Elizabeth C. Goode, Henrike Lenzen, Arnau Vich Vila, Annika Bergquist, Kirsten Muri Boberg, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Graduate School, Pathology, Alberts, R, De Vries, E, Goode, E, Jiang, X, Sampaziotis, F, Rombouts, K, Böttcher, K, Folseraas, T, Weismüller, T, Mason, A, Wang, W, Alexander, G, Alvaro, D, Bergquist, A, Björkström, N, Beuers, U, Björnsson, E, Boberg, K, Bowlus, C, Bragazzi, M, Carbone, M, Chazouillères, O, Cheung, A, Dalekos, G, Eaton, J, Eksteen, B, Ellinghaus, D, Färkkilä, M, Festen, E, Floreani, A, Franceschet, I, Gotthardt, D, Hirschfield, G, Hoek, B, Holm, K, Hohenester, S, Hov, J, Imhann, F, Invernizzi, P, Juran, B, Lenzen, H, Lieb, W, Liu, J, Marschall, H, Marzioni, M, Melum, E, Milkiewicz, P, Müller, T, Pares, A, Rupp, C, Rust, C, Sandford, R, Schramm, C, Schreiber, S, Schrumpf, E, Silverberg, M, Srivastava, B, Sterneck, M, Teufel, A, Vallier, L, Verheij, J, Vila, A, Vries, B, Zachou, K, Chapman, R, Manns, M, Pinzani, M, Rushbrook, S, Lazaridis, K, Franke, A, Anderson, C, Karlsen, T, Ponsioen, C, Weersma, R, Centre of Excellence in Complex Disease Genetics, Doctoral Programme in Drug Research, Department of Medicine, Clinicum, Gastroenterologian yksikkö, HUS Abdominal Center, and Universitat de Barcelona

Subjects
Male, 0301 basic medicine, Oncology, Candidate gene, Cholangitis, medicine.medical_treatment, Medizin, Trasplantament hepàtic, Genome-wide association study, Kaplan-Meier Estimate, LIVER FIBROSIS, Liver transplantation, Bioinformatics, Sclerosing, Oral and gastrointestinal, Primary sclerosing cholangitis, genetics, liver transplantation, Cohort Studies, ACTIVATION, 0302 clinical medicine, MED/12 - GASTROENTEROLOGIA, MULTIPLE, 2.1 Biological and endogenous factors, EPIDEMIOLOGY, Aetiology, CIRRHOSIS, Bilious diseases and biliousness, Liver Disease, digestive, oral, and skin physiology, Gastroenterology, Single Nucleotide, Primary sclerosing cholangiti, Middle Aged, 3. Good health, ULCERATIVE-COLITIS, Disease Progression, Female, 030211 gastroenterology & hepatology, Adult, medicine.medical_specialty, Cholangitis, Sclerosing, Chronic Liver Disease and Cirrhosis, Clinical Sciences, Malalties del tracte biliar, Single-nucleotide polymorphism, HEPATIC STELLATE CELLS, Polymorphism, Single Nucleotide, International PSC Study Group, Article, Paediatrics and Reproductive Medicine, 03 medical and health sciences, Rare Diseases, Clinical Research, Internal medicine, Genetics, medicine, Humans, Polymorphism, GENOME-WIDE ASSOCIATION, Allele, Digestive Diseases - (Gallbladder), Survival analysis, Proportional Hazards Models, MALIGNANCY, The UK PSC Consortium, Transplantation, Gastroenterology & Hepatology, business.industry, Proportional hazards model, medicine.disease, RISK LOCI, Logistic Models, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, genetic, Hepatic transplantation, Thrombospondins, Digestive Diseases, business, Genètica
Abstract

ObjectivePrimary 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.DesignWe 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.ResultsWe identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). 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.ConclusionWe 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.

Published
2017
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47. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

Author

Christopher L. Bowlus, Sören Mucha, Piotr Milkiewicz, Jennifer G. Sambrook, Michael P. Manns, Peter R. Durie, Daniel J. Gaffney, Catalina Coltescu, Konstantinos N. Lazaridis, David Ellinghaus, Daniel Gotthardt, George F. Mells, Espen Melum, Joseph A. Odin, Mattias Laudes, Cisca Wijmenga, Kris V. Kowdley, Annarosa Floreani, Tejas S. Shah, Richard Sandford, Erik M. Schlicht, Kirsten Muri Boberg, Javier Gutierrez-Achury, Felix Braun, Martina Sterneck, Carl A. Anderson, Tom H. Karlsen, Andre Franke, Velimir A. Luketic, Brijesh Srivastava, Aliya Gulamhusein, Elizabeth C. Goode, Kelly Spiess, Gunnar Jacobs, Olivier Chazouillères, Wolfgang Lieb, Tobias Müller, Andreas Teufel, Trine Folseraas, Roger W. Chapman, Hanns-Ulrich Marschall, David J. Roberts, Christoph Schramm, Sun-Gou Ji, Albert Parés, Mariza de Andrade, Stefan Schreiber, Elizabeth J. Atkinson, Kimmo Kontula, Pietro Invernizzi, Simon M. Rushbrook, Luke Jostins, Carmel Moore, Naga Chalasani, Jimmy Z. Liu, Brian D. Juran, Willem H. Ouwehand, Graeme J.M. Alexander, John E. Eaton, Gideon M. Hirschfield, Natsuhiko Kumasaka, Martti Färkkilä, Annika Bergquist, Kapil B. Chopra, John Danesh, Bertus Eksteen, Tobias J. Weismüller, Rinse K. Weersma, Ulrich Beuers, Severine Vermeire, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Ji, S, Juran, B, Mucha, S, Folseraas, T, Jostins, L, Melum, E, Kumasaka, N, Atkinson, E, Schlicht, E, Liu, J, Shah, T, Gutierrez Achury, J, Boberg, K, Bergquist, A, Vermeire, S, Eksteen, B, Durie, P, Farkkila, M, Müller, T, Schramm, C, Sterneck, M, Weismüller, T, Gotthardt, D, Ellinghaus, D, Braun, F, Teufel, A, Laudes, M, Lieb, W, Jacobs, G, Beuers, U, Weersma, R, Wijmenga, C, Marschall, H, Milkiewicz, P, Pares, A, Kontula, K, Chazouillères, O, Invernizzi, P, Goode, E, Spiess, K, Moore, C, Sambrook, J, Ouwehand, W, Roberts, D, Danesh, J, Floreani, A, Gulamhusein, A, Eaton, J, Schreiber, S, Coltescu, C, Bowlus, C, Luketic, V, Odin, J, Chopra, K, Kowdley, K, Chalasani, N, Manns, M, Srivastava, B, Mells, G, Sandford, R, Alexander, G, Gaffney, D, Chapman, R, Hirschfield, G, de Andrade, M, Rushbrook, S, Franke, A, Karlsen, T, Lazaridis, K, Anderson, C, and Universitat de Barcelona

Subjects
0301 basic medicine, Genome-wide association study, VARIANTS, Bioinformatics, Gastroenterology, Inflammatory bowel disease, 0302 clinical medicine, Risk Factors, Gastroenterologia, education.field_of_study, digestive, oral, and skin physiology, REGIONS, Ulcerative colitis, Inflamació, 3. Good health, Malalties inflamatòries intestinals, ULCERATIVE-COLITIS, 030211 gastroenterology & hepatology, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Population, Cholangitis, Sclerosing, Locus (genetics), Biology, Inflammatory bowel diseases, digestive system, Polymorphism, Single Nucleotide, Article, Primary sclerosing cholangitis, 03 medical and health sciences, Internal medicine, REVEALS, Genetics, medicine, SNP, Humans, RNA, Messenger, Allele, TRANSCRIPTOME, education, METAANALYSIS, Alleles, Adaptor Proteins, Signal Transducing, Inflammation, medicine.disease, Inflammatory Bowel Diseases, digestive system diseases, 030104 developmental biology, PSORIATIC-ARTHRITIS, Colitis, Ulcerative, Genome-Wide Association Study
Abstract

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; similar to 75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (r(G)) between PSC and ulcerative colitis (UC) (r(G) = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (r(G) = 0.04) (P = 2.55 x 10(-15)). UC and CD were genetically more similar to each other (r(G) = 0.56) than either was to PSC (P

Published
2016

48. HLA haplotypes in primary sclerosing cholangitis patients of admixed and non-European ancestry

Author

E K K, Henriksen, M K, Viken, M, Wittig, K, Holm, T, Folseraas, S, Mucha, E, Melum, J R, Hov, K N, Lazaridis, B D, Juran, O, Chazouillères, M, Färkkilä, D N, Gotthardt, P, Invernizzi, M, Carbone, G M, Hirschfield, S M, Rushbrook, E, Goode, C Y, Ponsioen, R K, Weersma, B, Eksteen, K K, Yimam, S C, Gordon, D, Goldberg, L, Yu, C L, Bowlus, A, Franke, B A, Lie, T H, Karlsen, Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Henriksen, E, Viken, M, Wittig, M, Holm, K, Folseraas, T, Mucha, S, Melum, E, Hov, J, Lazaridis, K, Juran, B, Chazouillãres, O, Fã¤rkkilã¤, M, Gotthardt, D, Invernizzi, P, Carbone, M, Hirschfield, G, Rushbrook, S, Goode, E, Ponsioen, C, Weersma, R, Eksteen, B, Yimam, K, Gordon, S, Goldberg, D, Yu, L, Bowlus, C, Franke, A, Lie, B, and Karlsen, T

Subjects
endocrine system diseases, FEATURES, Cholangitis, Sclerosing, Immunology, LOCI, Gene Expression, Scandinavian and Nordic Countries, SUSCEPTIBILITY, Linkage Disequilibrium, White People, Article, DISEASE, ANTIGENS, Gene Frequency, PSC, human leukocyte antigen, immune system diseases, multi-ethnic, Ethnicity, Genetics, HLA-DQ beta-Chains, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Alleles, causative, RISK, ASSOCIATION, ALLELE, Haplotypes, ULCERATIVE-COLITIS, POPULATIONS, trans-ancestry, HLA-DRB1 Chains
Abstract

Primary sclerosing cholangitis (PSC) is strongly associated with several human leukocyte antigen (HLA) haplotypes. Due to extensive linkage disequilibrium and multiple polymorphic candidate genes in the HLA complex, identifying the alleles responsible for these associations has proven difficult. We aimed to evaluate whether studying populations of admixed or non-European descent could help in defining the causative HLA alleles. When assessing haplotypes carrying HLA-DRB1*13:01 (hypothesized to specifically increase the susceptibility to chronic cholangitis), we observed that every haplotype in the Scandinavian PSC population carried HLA-DQB1*06:03. In contrast, only 65% of HLA-DRB1*13:01 haplotypes in an admixed/non-European PSC population carried this allele, suggesting that further assessments of the PSC-associated haplotype HLA-DRB1*13:01-DQA1*01:03-DQB1*06:03 in admixed or multi-ethnic populations could aid in identifying the causative allele.

Published
2017

49. Characterization of animal models for primary sclerosing cholangitis (PSC)

Author

Carolin Lackner, Verena Keitel, Peter Fickert, Michael Manns, Gideon M. Hirschfield, Michael Trauner, Bertus Eksteen, Christoph Schramm, Tom H. Karlsen, Hanns-Ulrich Marschall, Arthur Kaser, Chantal Housset, Ulrich Beuers, Mario Strazzabosco, Espen Melum, Marion J. Pollheimer, Fickert, P, Pollheimer, M, Beuers, U, Lackner, C, Hirschfield, G, Housset, C, Keitel, V, Schramm, C, Marschall, H, Karlsen, T, Melum, E, Kaser, A, Eksteen, B, Strazzabosco, M, Manns, M, and Trauner, M

Subjects
Biliary fibrosis, medicine.medical_specialty, medicine.medical_treatment, Cholangitis, Sclerosing, Bile acid, Liver transplantation, Inflammatory bowel disease, Gastroenterology, Article, Primary sclerosing cholangitis, Cholestasis, MED/12 - GASTROENTEROLOGIA, Internal medicine, medicine, Animals, Humans, Animal model, Intensive care medicine, Anti-neutrophil cytoplasmic antibody, Hepatology, business.industry, Cholangiopathie, Cholestatic liver disease, Primary sclerosing cholangiti, medicine.disease, Ulcerative colitis, Bile acids, Disease Models, Animal, Biliary fibrosi, Position paper, business, Cholangiopathies
Abstract

SummaryPrimary sclerosing cholangitis (PSC) is a chronic cholangiopathy characterized by biliary fibrosis, development of cholestasis and end stage liver disease, high risk of malignancy, and frequent need for liver transplantation. The poor understanding of its pathogenesis is also reflected in the lack of effective medical treatment. Well-characterized animal models are utterly needed to develop novel pathogenetic concepts and study new treatment strategies. Currently there is no consensus on how to evaluate and characterize potential PSC models, which makes direct comparison of experimental results and effective exchange of study material between research groups difficult. The International Primary Sclerosing Cholangitis Study Group (IPSCSG) has therefore summarized these key issues in a position paper proposing standard requirements for the study of animal models of PSC.

Published
2014

50. Outcome of Liver Retransplantation in Patients With Primary Sclerosing Cholangitis.

Author

Molinaro A, Engesæter LK, Jorns C, Nordin A, Rasmussen A, Line PD, Pall V, Ericzon BG, Bennet W, Hov JR, and Melum E

Subjects
Humans, Male, Female, Adult, Middle Aged, Treatment Outcome, Registries, Scandinavian and Nordic Countries epidemiology, Retrospective Studies, Cholangitis, Sclerosing surgery, Cholangitis, Sclerosing mortality, Cholangitis, Sclerosing complications, Liver Transplantation adverse effects, Liver Transplantation mortality, Reoperation, Graft Survival, Recurrence
Abstract

Background and Aims: Primary sclerosing cholangitis (PSC) is among the most common indications for liver transplantation in the Nordic countries and with an increasing trend in Europe and North America. Due to post-transplant complications and high prevalence of disease recurrence this group is at risk of requiring retransplantation (re-LTX). Results from re-LTX for PSC are not extensively studied and there is a lack of knowledge regarding prognosis after re-LTX in this population., Methods: Graft and patient survival after re-LTX for patients with PSC and a comparable comparison group from the Nordic liver transplant registry were analysed. One-hundred and eighty-five patients with PSC and 208 patients in the comparison group were included., Results: The graft and patient survival were better for patients with PSC compared to the comparison group (p < 0.001). Re-LTX for recurrence of PSC (rPSC) compared to other aetiologies had similar and better outcomes for graft and patient survival (p = 0.093 and p = 0.023, respectively). Moreover, re-LTX for rPSC compared to the comparison group had a lower 30-day and 5-year mortality (p < 0.001 and p = 0.041, respectively)., Conclusion: Outcomes after retransplantation for PSC were similar or better compared to the comparison group. Retransplantation represents a treatment option with the potential for excellent outcomes in patients with PSC and should be considered in transplanted PSC patients with graft failure., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Published
2025
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