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Apical bulkheads accumulate as adaptive response to impaired bile flow in liver disease.

Abstract (Expand)

Hepatocytes form bile canaliculi that dynamically respond to the signalling activity of bile acids and bile flow. Little is known about their responses to intraluminal pressure. During embryonic … development, hepatocytes assemble apical bulkheads that increase the canalicular resistance to intraluminal pressure. Here, we investigate whether they also protect bile canaliculi against elevated pressure upon impaired bile flow in adult liver. Apical bulkheads accumulate upon bile flow obstruction in mouse models and patients with primary sclerosing cholangitis (PSC). Their loss under these conditions leads to abnormally dilated canaliculi, resembling liver cell rosettes described in other hepatic diseases. 3D reconstruction reveals that these structures are sections of cysts and tubes formed by hepatocytes. Mathematical modelling establishes that they positively correlate with canalicular pressure and occur in early PSC stages. Using primary hepatocytes and 3D organoids, we demonstrate that excessive canalicular pressure causes the loss of apical bulkheads and formation of rosettes. Our results suggest that apical bulkheads are a protective mechanism of hepatocytes against impaired bile flow, highlighting the role of canalicular pressure in liver diseases.

Authors: C. Mayer, S. Nehring, M. Kucken, U. Repnik, S. Seifert, A. Sljukic, J. Delpierre, H. Morales-Navarrete, S. Hinz, M. Brosch, B. Chung, T. Karlsen, M. Huch, Y. Kalaidzidis, L. Brusch, J. Hampe, C. Schafmayer, M. Zerial

Date Published: 31st Jul 2023

Publication Type: Journal

Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study

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Objective Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account …tors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. Design Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case–control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). Results Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10 −9 , OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10 −5 , OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10 −44 ). Conclusion This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.

Authors: Stephan Buch, Hamish Innes, Philipp Ludwig Lutz, Hans Dieter Nischalke, Jens U Marquardt, Janett Fischer, Karl Heinz Weiss, Jonas Rosendahl, Astrid Marot, Marcin Krawczyk, Markus Casper, Frank Lammert, Florian Eyer, Arndt Vogel, Silke Marhenke, Johann von Felden, Rohini Sharma, Stephen Rahul Atkinson, Andrew McQuillin, Jacob Nattermann, Clemens Schafmayer, Andre Franke, Christian Strassburg, Marcella Rietschel, Heidi Altmann, Stefan Sulk, Veera Raghavan Thangapandi, Mario Brosch, Carolin Lackner, Rudolf E Stauber, Ali Canbay, Alexander Link, Thomas Reiberger, Mattias Mandorfer, Georg Semmler, Bernhard Scheiner, Christian Datz, Stefano Romeo, Stefano Ginanni Corradini, William Lucien Irving, Joanne R Morling, Indra Neil Guha, Eleanor Barnes, M Azim Ansari, Jocelyn Quistrebert, Luca Valenti, Sascha A Müller, Marsha Yvonne Morgan, Jean-François Dufour, Jonel Trebicka, Thomas Berg, Pierre Deltenre, Sebastian Mueller, Jochen Hampe, Felix Stickel

Date Published: 5th Jan 2023

Publication Type: Journal

The rs429358 Locus in Apolipoprotein E Is Associated With Hepatocellular Carcinoma in Patients With Cirrhosis

Abstract (Expand)

The host genetic background for hepatocellular carcinoma (HCC) is incompletely understood. We aimed to determine if four germline genetic polymorphisms, rs429358 in apolipoprotein E ( APOE ), rs2642438 …rotein E ( APOE ), rs2642438 in mitochondrial amidoxime reducing component 1 ( MARC1 ), rs2792751 in glycerol‐3‐phosphate acyltransferase ( GPAM ), and rs187429064 in transmembrane 6 superfamily member 2 ( TM6SF2 ), previously associated with progressive alcohol‐related and nonalcoholic fatty liver disease, are also associated with HCC. Four HCC case‐control data sets were constructed, including two mixed etiology data sets (UK Biobank and FinnGen); one hepatitis C virus (HCV) cohort (STOP‐HCV), and one alcohol‐related HCC cohort (Dresden HCC). The frequency of each variant was compared between HCC cases and cirrhosis controls (i.e., patients with cirrhosis without HCC). Population controls were also considered. Odds ratios (ORs) associations were calculated using logistic regression, adjusting for age, sex, and principal components of genetic ancestry. Fixed‐effect meta‐analysis was used to determine the pooled effect size across all data sets. Across four case‐control data sets, 2,070 HCC cases, 4,121 cirrhosis controls, and 525,779 population controls were included. The rs429358:C allele ( APOE ) was significantly less frequent in HCC cases versus cirrhosis controls (OR, 0.71; 95% confidence interval [CI], 0.61‐0.84; P  = 2.9 × 10 −5 ). Rs187429064:G ( TM6SF2 ) was significantly more common in HCC cases versus cirrhosis controls and exhibited the strongest effect size (OR, 2.03; 95% CI, 1.45‐2.86; P  = 3.1 × 10 −6 ). In contrast, rs2792751:T ( GPAM ) was not associated with HCC (OR, 1.01; 95% CI, 0.90‐1.13; P  = 0.89), whereas rs2642438:A ( MARC1 ) narrowly missed statistical significance (OR, 0.91; 95% CI, 0.84‐1.00; P  = 0.043). Conclusion: This study associates carriage of rs429358:C ( APOE ) with a reduced risk of HCC in patients with cirrhosis. Conversely, carriage of rs187429064:G in TM6SF2 is associated with an increased risk of HCC in patients with cirrhosis.

Authors: Hamish Innes, Hans Dieter Nischalke, Indra Neil Guha, Karl Heinz Weiss, Will Irving, Daniel Gotthardt, Eleanor Barnes, Janett Fischer, M. Azim Ansari, Jonas Rosendahl, Shang‐Kuan Lin, Astrid Marot, Vincent Pedergnana, Markus Casper, Jennifer Benselin, Frank Lammert, John McLauchlan, Philip L. Lutz, Victoria Hamill, Sebastian Mueller, Joanne R. Morling, Georg Semmler, Florian Eyer, Johann von Felden, Alexander Link, Arndt Vogel, Jens U. Marquardt, Stefan Sulk, Jonel Trebicka, Luca Valenti, Christian Datz, Thomas Reiberger, Clemens Schafmayer, Thomas Berg, Pierre Deltenre, Jochen Hampe, Felix Stickel, Stephan Buch

Date Published: 2022

Publication Type: Journal

Non-alcoholic fatty liver disease Stratification by Liver Lipidomics

Abstract (Expand)

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic dysfunction leading to hepatic steatosis. However, NAFLD's global impact on the liver lipidome is poorly understood. Using high-resolution … shotgun mass spectrometry, we quantified the molar abundance of 316 species from 22 major lipid classes in liver biopsies of 365 patients, including non-steatotic patients with normal or excessive weight, patients diagnosed with NAFL (non-alcoholic fatty liver) or NASH (non-alcoholic steatohepatitis), and patients bearing common mutations of NAFLD-related protein factors. We confirmed the progressive accumulation of di- and tri- acylglycerols and cholesteryl esters in the liver of NAFL and NASH patients, while the bulk composition of glycerophospho- and sphingolipids remained unchanged. Further stratification by biclustering analysis identified sphingomyelin species comprising n24:2 fatty acid moieties as membrane lipid markers of NAFLD. Normalized relative abundance of sphingomyelins SM 43:3;2 and SM 43:1;2 containing n24:2 and n24:0 fatty acid moieties, respectively, showed opposite trends during NAFLD progression and distinguished NAFL and NASH lipidomes from the lipidome of non-steatoic livers. Together with several glycerophospholipids containing a C22:6 fatty acid moiety, these lipids serve as markers of early and advanced stages of NAFL.

Authors: Olga Vvedenskaya, Tim Daniel Rose, Oskar Knittelfelder, Alessandra Palladini, Judith Andrea Heidrun Wodke, Kai Schumann, Jacobo Miranda Ackerman, Yuting Wang, Canan Has, Mario Brosch, Veera Raghavan Thangapandi, Stephan Buch, Thomas Züllig, Jürgen Hartler, Harald C. Köfeler, Christoph Röcken, Ünal Coskun, Edda Klipp, Witigo von Schoenfels, Justus Gross, Clemens Schafmayer, Jochen Hampe, Josch Konstantin Pauling, Andrej Shevchenko

Date Published: 1st Aug 2021

Publication Type: Journal

rs641738C>T near MBOAT7 is associated with liver fat, ALT, and fibrosis in NAFLD: a meta-analysis.

Abstract (Expand)

BACKGROUND & AIMS: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in non-alcoholic fatty liver disease (NAFLD), however, … these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and characterize its role in the regulation of related metabolic phenotypes through meta-analysis. METHODS: We performed meta-analysis of studies with data on the association between rs641738C>T genotype and: liver fat, NAFLD histology, and serum ALT, lipids, or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed random effects meta-analysis using recessive, additive, and dominant genetic models. RESULTS: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI: 0.02 - 0.05], pz=4.8x10(-5)) and diagnosis of NAFLD (OR 1.17 [95% CI 1.05 - 1.3], pz=0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI: 1.03 - 1.45], pz=0.021) in Caucasian adults using a recessive model of inheritance (CC+CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz=0.002) and lower serum triglycerides (pz=1.5x10(-4)). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. CONCLUSION: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent.

Authors: K. Teo, K. W. M. Abeysekera, L. Adams, E. Aigner, Q. M. Anstee, J. M. Banales, R. Banerjee, P. Basu, T. Berg, P. Bhatnagar, S. Buch, A. Canbay, S. Caprio, A. Chatterjee, Y. D. Ida Chen, A. Chowdhury, A. K. Daly, C. Datz, D. de Gracia Hahn, J. K. DiStefano, J. Dong, A. Duret, C. Emdin, M. Fairey, G. S. Gerhard, X. Guo, J. Hampe, M. Hickman, L. Heintz, C. Hudert, H. Hunter, M. Kelly, J. Kozlitina, M. Krawczyk, F. Lammert, C. Langenberg, J. Lavine, L. Li, H. K. Lim, R. Loomba, P. K. Luukkonen, P. E. Melton, T. A. Mori, N. D. Palmer, C. A. Parisinos, S. G. Pillai, F. Qayyum, M. C. Reichert, S. Romeo, J. I. Rotter, Y. R. Im, N. Santoro, C. Schafmayer, E. K. Speliotes, S. Stender, F. Stickel, C. D. Still, P. Strnad, K. D. Taylor, A. Tybjaerg-Hansen, G. R. Umano, M. Utukuri, L. Valenti, L. E. Wagenknecht, N. J. Wareham, R. M. Watanabe, J. Wattacheril, H. Yaghootkar, H. Yki-Jarvinen, K. A. Young, J. P. Mann

Date Published: 31st Aug 2020

Publication Type: Journal

Loss of hepatic Mboat7 leads to liver fibrosis.

Abstract (Expand)

OBJECTIVE: The rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty … liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD. DESIGN: Mice with hepatocyte-specific deletion of MBOAT7 (Mboat7(Deltahep)) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies. RESULTS: Allelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7(Deltahep) mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7(Deltahep) mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7(Deltahep) livers and human rs641738TT carriers were similar. CONCLUSION: Mboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.

Authors: V. R. Thangapandi, O. Knittelfelder, M. Brosch, E. Patsenker, O. Vvedenskaya, S. Buch, S. Hinz, A. Hendricks, M. Nati, A. Herrmann, D. R. Rekhade, T. Berg, M. Matz-Soja, K. Huse, E. Klipp, J. K. Pauling, J. A. Wodke, J. Miranda Ackerman, M. V. Bonin, E. Aigner, C. Datz, W. von Schonfels, S. Nehring, S. Zeissig, C. Rocken, A. Dahl, T. Chavakis, F. Stickel, A. Shevchenko, C. Schafmayer, J. Hampe, P. Subramanian

Date Published: 26th Jun 2020

Publication Type: Journal

Three-dimensional spatially resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression.

Abstract (Expand)

Early disease diagnosis is key to the effective treatment of diseases. Histopathological analysis of human biopsies is the gold standard to diagnose tissue alterations. However, this approach has low … resolution and overlooks 3D (three-dimensional) structural changes resulting from functional alterations. Here, we applied multiphoton imaging, 3D digital reconstructions and computational simulations to generate spatially resolved geometrical and functional models of human liver tissue at different stages of non-alcoholic fatty liver disease (NAFLD). We identified a set of morphometric cellular and tissue parameters correlated with disease progression, and discover profound topological defects in the 3D bile canalicular (BC) network. Personalized biliary fluid dynamic simulations predicted an increased pericentral biliary pressure and micro-cholestasis, consistent with elevated cholestatic biomarkers in patients' sera. Our spatially resolved models of human liver tissue can contribute to high-definition medicine by identifying quantitative multiparametric cellular and tissue signatures to define disease progression and provide new insights into NAFLD pathophysiology.

Authors: F. Segovia-Miranda, H. Morales-Navarrete, M. Kucken, V. Moser, S. Seifert, U. Repnik, F. Rost, M. Brosch, A. Hendricks, S. Hinz, C. Rocken, D. Lutjohann, Y. Kalaidzidis, C. Schafmayer, L. Brusch, J. Hampe, M. Zerial

Date Published: 2nd Dec 2019

Publication Type: Not specified

Mutual Zonated Interactions of Wnt and Hh Signaling Are Orchestrating the Metabolism of the Adult Liver in Mice and Human

Abstract (Expand)

The Hedgehog (Hh) and Wnt/β-Catenin (Wnt) cascades are morphogen pathways whose pronounced influence on adult liver metabolism has been identified in recent years. How both pathways communicate and … control liver metabolic functions are largely unknown. Detecting core components of Wnt and Hh signaling and mathematical modeling showed that both pathways in healthy liver act largely complementary to each other in the pericentral (Wnt) and the periportal zone (Hh) and communicate mainly by mutual repression. The Wnt/Hh module inversely controls the spatiotemporal operation of various liver metabolic pathways, as revealed by transcriptome, proteome, and metabolome analyses. Shifting the balance to Wnt (activation) or Hh (inhibition) causes pericentralization and periportalization of liver functions, respectively. Thus, homeostasis of the Wnt/Hh module is essential for maintaining proper liver metabolism and to avoid the development of certain metabolic diseases. With caution due to minor species-specific differences, these conclusions may hold for human liver as well.

Authors: Erik Kolbe, Susanne Aleithe, Christiane Rennert, Luise Spormann, Fritzi Ott, David Meierhofer, Robert Gajowski, Claus Stöpel, Stefan Hoehme, Michael Kücken, Lutz Brusch, Michael Seifert, Witigo von Schoenfels, Clemens Schafmayer, Mario Brosch, Ute Hofmann, Georg Damm, Daniel Seehofer, Jochen Hampe, Rolf Gebhardt, Madlen Matz-Soja

Date Published: 1st Dec 2019

Publication Type: Not specified

Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers.

Abstract (Expand)

BACKGROUND AND AIMS: Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular … carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. APPROACH AND RESULTS: Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 x 10(-6) ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 x 10(-4) ), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 x 10(-26) ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 x 10(-23) ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (ORallelic , 0.75; 95% CI, 0.64-0.87; P = 1.72 x 10(-4) ). CONCLUSIONS: Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.

Authors: F. Stickel, P. Lutz, S. Buch, H. D. Nischalke, I. Silva, V. Rausch, J. Fischer, K. H. Weiss, D. Gotthardt, J. Rosendahl, A. Marot, M. Elamly, M. Krawczyk, M. Casper, F. Lammert, T. W. M. Buckley, A. McQuillin, U. Spengler, F. Eyer, A. Vogel, S. Marhenke, J. von Felden, H. Wege, R. Sharma, S. Atkinson, A. Franke, S. Nehring, V. Moser, C. Schafmayer, L. Spahr, C. Lackner, R. E. Stauber, A. Canbay, A. Link, L. Valenti, J. I. Grove, G. P. Aithal, J. U. Marquardt, W. Fateen, S. Zopf, J. F. Dufour, J. Trebicka, C. Datz, P. Deltenre, S. Mueller, T. Berg, J. Hampe, M. Y. Morgan

Date Published: 21st Oct 2019

Publication Type: Journal

Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control

Abstract

Not specified

Authors: Mario Brosch, Kathrin Kattler, Alexander Herrmann, Witigo von Schönfels, Karl Nordström, Daniel Seehofer, Georg Damm, Thomas Becker, Sebastian Zeissig, Sophie Nehring, Fabian Reichel, Vincent Moser, Raghavan Veera Thangapandi, Felix Stickel, Gustavo Baretton, Christoph Röcken, Michael Muders, Madlen Matz-Soja, Michael Krawczak, Gilles Gasparoni, Hella Hartmann, Andreas Dahl, Clemens Schafmayer, Jörn Walter, Jochen Hampe

Date Published: 1st Dec 2018

Publication Type: Not specified

Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control

Abstract (Expand)

A deeper epigenomic understanding of spatial organization of cells in human tissues is an important challenge. Here we report the first combined positional analysis of transcriptomes and methylomes … across three micro-dissected zones (pericentral, intermediate and periportal) of human liver. We identify pronounced anti-correlated transcriptional and methylation gradients including a core of 271 genes controlling zonated metabolic and morphogen networks and observe a prominent porto-central gradient of DNA methylation at binding sites of 46 transcription factors. The gradient includes an epigenetic and transcriptional Wnt signature supporting the concept of a pericentral hepatocyte regeneration pathway under steady-state conditions. While donors with non-alcoholic fatty liver disease show consistent gene expression differences corresponding to the severity of the disease across all zones, the relative zonated gene expression and DNA methylation patterns remain unchanged. Overall our data provide a wealth of new positional insights into zonal networks controlled by epigenetic and transcriptional gradients in human liver.

Authors: Mario Brosch, Kathrin Kattler, Alexander Herrmann, Witigo von Schönfels, Karl Nordström, Daniel Seehofer, Georg Damm, Thomas Becker, Sebastian Zeissig, Sophie Nehring, Fabian Reichel, Vincent Moser, Raghavan Veera Thangapandi, Felix Stickel, Gustavo Baretton, Christoph Röcken, Michael Muders, Madlen Matz-Soja, Michael Krawczak, Gilles Gasparoni, Hella Hartmann, Andreas Dahl, Clemens Schafmayer, Jörn Walter, Jochen Hampe

Date Published: 1st Dec 2018

Publication Type: Not specified

Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis

Abstract (Expand)

OBJECTIVES: Variants in patatin-like phospholipase domain-containing 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), and membrane bound O-acyltransferase domain containing …g 7 (MBOAT7; rs641738) are risk factors for the development of alcohol-related cirrhosis. Within this population, PNPLA3 rs738409 is also an established risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to explore possible risk associations of TM6SF2 rs58542926 and MBOAT7 rs641738 with HCC. METHODS: Risk variants in PNPLA3, TM6SF2, and MBOAT7 were genotyped in 751 cases with alcohol-related cirrhosis and HCC and in 1165 controls with alcohol-related cirrhosis without HCC. Association with the risk of developing HCC was analyzed using multivariate logistic regression. RESULTS: The development of HCC was independently associated with PNPLA3 rs738409 (ORadjusted 1.84 [95% CI 1.55-2.18], p = 1.85 × 10-12) and TM6SF2 rs58542926 (ORadjusted 1.66 [1.30-2.13], p = 5.13 × 10-05), using an additive model, and controlling the sex, age, body mass index, and type 2 diabetes mellitus; the risk associated with carriage of MBOAT7 rs641738 (ORadjusted 1.04 [0.88-1.24], p = 0.61) was not significant. The population-attributable fractions were 43.5% for PNPLA3 rs738409, 11.5% for TM6SF2 rs58542926, and 49.9% for the carriage of both the variants combined. CONCLUSIONS: Carriage of TM6SF2 rs58542926 is an additional risk factor for the development of HCC in people with alcohol-related cirrhosis. Carriage of both PNPLA3 rs738409 and TM6SF2 rs58542926 accounts for half of the attributable risk for HCC in this population. Genotyping will allow for more precise HCC risk-stratification of patients with alcohol-related cirrhosis, and genotype-guided screening algorithms would optimize patient care.

Authors: Felix Stickel, Stephan Buch, Hans Dieter Nischalke, Karl Heinz Weiss, Daniel Gotthardt, Janett Fischer, Jonas Rosendahl, Astrid Marot, Mona Elamly, Markus Casper, Frank Lammert, Andrew McQuillin, Steffen Zopf, Ulrich Spengler, Silke Marhenke, Martha M. Kirstein, Arndt Vogel, Florian Eyer, Johann von Felden, Henning Wege, Thorsten Buch, Clemens Schafmayer, Felix Braun, Pierre Deltenre, Thomas Berg, Marsha Y. Morgan, Jochen Hampe

Date Published: 1st Oct 2018

Publication Type: Not specified

Histologic improvement of NAFLD in patients with obesity after bariatric surgery based on standardized NAS (NAFLD activity score).

Abstract (Expand)

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in industrialized countries. Nonalcoholic steatohepatitis is the fastest growing cause for liver failure. … Bariatric surgery represents a treatment option for NAFLD with an established effect on liver histology. OBJECTIVES: We aimed to assess the impact of bariatric surgery on standardized liver histology using the NAFLD activity score. SETTING: Retrospective comparison of metabolic data before and after bariatric surgery and comparison of sleeve gastrectomy and Roux-en-Y gastric bypass. The study was performed in an academic center, the university hospital Schleswig-Holstein in Kiel, Germany. METHODS: Between 2009 and 2012, bariatric surgery was performed in 257 patients according to the national guidelines, and a liver biopsy was obtained in 150 of these patients during surgery. A follow-up biopsy was available in 53 of these patients at a median of 192 days. Liver histology was analyzed using the NAFLD activity score. In this subgroup of 53 patients an analysis of the metabolic improvement after bariatric surgery and a comparative analysis between the 2 different operative procedures was performed. RESULTS: The study cohort showed improvement of preoperative pathologic liver histology findings after operative procedures took place. Both surgery methods improved the NAFLD activity score significantly, all improvement -2.0 (confidence interval -2.5 to -1.0; P < .001); Roux-en-Y gastric bypass, improvement -1.0 (confidence interval -2.0 to -.0; P=.038); sleeve gastrectomy, improvement -2.5 (confidence interval -3.5 to -1.5; P < .001). No differences were found with regard to histologic recovery between gastric bypass and sleeve gastrectomy (P = .22). CONCLUSIONS: Bariatric surgery significantly improves NAFLD.

Authors: W. von Schonfels, J. H. Beckmann, M. Ahrens, A. Hendricks, C. Rocken, S. Szymczak, J. Hampe, C. Schafmayer

Date Published: 28th Aug 2018

Publication Type: Not specified

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

Abstract (Expand)

OBJECTIVE: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of … the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. DESIGN: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed. RESULTS: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). CONCLUSION: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.

Authors: P. Strnad, S. Buch, K. Hamesch, J. Fischer, J. Rosendahl, R. Schmelz, S. Brueckner, M. Brosch, C. V. Heimes, V. Woditsch, D. Scholten, H. D. Nischalke, S. Janciauskiene, M. Mandorfer, M. Trauner, M. J. Way, A. McQuillin, M. C. Reichert, M. Krawczyk, M. Casper, F. Lammert, F. Braun, W. von Schonfels, S. Hinz, G. Burmeister, C. Hellerbrand, A. Teufel, A. Feldman, J. M. Schattenberg, H. Bantel, A. Pathil, M. Demir, J. Kluwe, T. Boettler, M. Ridinger, N. Wodarz, M. Soyka, M. Rietschel, F. Kiefer, T. Weber, S. Marhenke, A. Vogel, H. Hinrichsen, A. Canbay, M. Schlattjan, K. Sosnowsky, C. Sarrazin, J. von Felden, A. Geier, P. Deltenre, B. Sipos, C. Schafmayer, M. Nothnagel, E. Aigner, C. Datz, F. Stickel, M. Y. Morgan, J. Hampe, T. Berg, C. Trautwein

Date Published: 3rd Aug 2018

Publication Type: Journal

Evolutionary Distance Predicts Recurrence After Liver Transplantation in Multifocal Hepatocellular Carcinoma.

Abstract (Expand)

BACKGROUND: Liver transplantation (LTx) is a potentially curative treatment option for hepatocellular carcinoma (HCC) in cirrhosis. However, patients, where HCC is already a systemic disease, LTx may … be individually harmful and has a negative impact on donor organ usage. Thus, there is a need for improved selection criteria beyond nodule morphology to select patients with a favorable outcome for LTx in multifocal HCC. Evolutionary distance measured from genome-wide single-nucleotide polymorphism data between tumor nodules and the cirrhotic liver may be a prognostic marker of survival after LTx for multifocal HCC. METHODS: In a retrospective multicenter study, clinical data and formalin-fixed paraffin-embedded specimens of the liver and 2 tumor nodules were obtained from explants of 30 patients in the discovery and 180 patients in the replication cohort. DNA was extracted from formalin-fixed paraffin-embedded specimens followed by genome wide single-nucleotide polymorphism genotyping. RESULTS: Genotype quality criteria allowed for analysis of 8 patients in the discovery and 17 patients in the replication set. DNA concentrations of a total of 25 patients fulfilled the quality criteria and were included in the analysis. Both, in the discovery (P = 0.04) and in the replication data sets (P = 0.01), evolutionary distance was associated with the risk of recurrence of HCC after transplantation (combined P = 0.0002). In a univariate analysis, evolutionary distance (P = 7.4 x 10) and microvascular invasion (P = 1.31 x 10) were significantly associated with survival in a Cox regression analysis. CONCLUSIONS: Evolutionary distance allows for the determination of a high-risk group of recurrence if preoperative liver biopsy is considered.

Authors: N. Heits, M. Brosch, A. Herrmann, R. Behrens, C. Rocken, H. Schrem, A. Kaltenborn, J. Klempnauer, H. H. Kreipe, B. Reichert, C. Lenschow, C. Wilms, T. Vogel, H. Wolters, E. Wardelmann, D. Seehofer, S. Buch, S. Zeissig, S. Pannach, N. Raschzok, M. Dietel, W. von Schoenfels, S. Hinz, A. Teufel, M. Evert, A. Franke, T. Becker, F. Braun, J. Hampe, C. Schafmayer

Date Published: 12th Jul 2018

Publication Type: Not specified

Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis.

Abstract (Expand)

OBJECTIVES: Variants in patatin-like phospholipase domain-containing 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), and membrane bound O-acyltransferase domain containing … 7 (MBOAT7; rs641738) are risk factors for the development of alcohol-related cirrhosis. Within this population, PNPLA3 rs738409 is also an established risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to explore possible risk associations of TM6SF2 rs58542926 and MBOAT7 rs641738 with HCC. METHODS: Risk variants in PNPLA3, TM6SF2, and MBOAT7 were genotyped in 751 cases with alcohol-related cirrhosis and HCC and in 1165 controls with alcohol-related cirrhosis without HCC. Association with the risk of developing HCC was analyzed using multivariate logistic regression. RESULTS: The development of HCC was independently associated with PNPLA3 rs738409 (ORadjusted 1.84 [95% CI 1.55-2.18], p = 1.85 x 10(-12)) and TM6SF2 rs58542926 (ORadjusted 1.66 [1.30-2.13], p = 5.13 x 10(-05)), using an additive model, and controlling the sex, age, body mass index, and type 2 diabetes mellitus; the risk associated with carriage of MBOAT7 rs641738 (ORadjusted 1.04 [0.88-1.24], p = 0.61) was not significant. The population-attributable fractions were 43.5% for PNPLA3 rs738409, 11.5% for TM6SF2 rs58542926, and 49.9% for the carriage of both the variants combined. CONCLUSIONS: Carriage of TM6SF2 rs58542926 is an additional risk factor for the development of HCC in people with alcohol-related cirrhosis. Carriage of both PNPLA3 rs738409 and TM6SF2 rs58542926 accounts for half of the attributable risk for HCC in this population. Genotyping will allow for more precise HCC risk-stratification of patients with alcohol-related cirrhosis, and genotype-guided screening algorithms would optimize patient care.

Authors: F. Stickel, S. Buch, H. D. Nischalke, K. H. Weiss, D. Gotthardt, J. Fischer, J. Rosendahl, A. Marot, M. Elamly, M. Casper, F. Lammert, A. McQuillin, S. Zopf, U. Spengler, S. Marhenke, M. M. Kirstein, A. Vogel, F. Eyer, J. von Felden, H. Wege, T. Buch, C. Schafmayer, F. Braun, P. Deltenre, T. Berg, M. Y. Morgan, J. Hampe

Date Published: 15th Mar 2018

Publication Type: Journal

Electrosurgical liver resection has a superior regeneration outcome as compared to en-bloc ligation in a novel model of partial hepatectomy in mice

Abstract (Expand)

Background: The extent of resection and the frequency of liver surgery have increased over the past decades, enabled by improved haemostasis provided by electrosurgical liver dissection. Because extensive … liver surgery is still associated with lethal complications, further optimisation of the technique and a better molecular understanding of hepatic wound healing and regeneration are needed. Systematic studies and a mouse model reflecting the clinical reality of liver surgery are lacking. Methods: We performed liver resection in mice with a monopolar electrocautery device in comparison to the classical en-bloc ligation method. Regeneration was assessed using liver weight and BrDU immunohistochemistry after sacrifice and non-invasively using micro computed tomography (µCT). Results: Mortality in the electrosurgical model was similar to the ligation method given an identical extent of resection. Regeneration of liver proceeded significantly faster in the electrosurgical group: Liver weight was 25.6% higher at sacrifice after 168h (p=0.0003). Concordantly, both µCT analysis (22.6% higher liver volume at 168h, p=0.008) and BrDU staining (71.4% higher proliferation at 72h, p=0.0005) indicated superior regeneration of liver after electrosurgical partial hepatectomy. Conclusions: The mode of liver resection has a profound impact on regeneration and should be studied molecularly using the presented novel model of electrosurgical liver resection.

Authors: W. von Schonfels, Clemens Schafmayer, Jochen Hampe

Date Published: 27th Jan 2018

Publication Type: Not specified

Translational learning from clinical studies predicts drug pharmacokinetics across patient populations

Abstract

Not specified

Authors: Markus Krauss, Ute Hofmann, Clemens Schafmayer, Svitlana Igel, Jan Schlender, Christian Mueller, Mario Brosch, Witigo von Schoenfels, Wiebke Erhart, Andreas Schuppert, Michael Block, Elke Schaeffeler, Gabriele Boehmer, Linus Goerlitz, Jan Hoecker, Joerg Lippert, Reinhold Kerb, Jochen Hampe, Lars Kuepfer, Matthias Schwab

Date Published: 1st Dec 2017

Publication Type: Not specified

Translational learning from clinical studies predicts drug pharmacokinetics across patient populations.

Abstract (Expand)

Early indication of late-stage failure of novel candidate drugs could be facilitated by continuous integration, assessment, and transfer of knowledge acquired along pharmaceutical development programs. … We here present a translational systems pharmacology workflow that combines drug cocktail probing in a specifically designed clinical study, physiologically based pharmacokinetic modeling, and Bayesian statistics to identify and transfer (patho-)physiological and drug-specific knowledge across distinct patient populations. Our work builds on two clinical investigations, one with 103 healthy volunteers and one with 79 diseased patients from which we systematically derived physiological information from pharmacokinetic data for a reference probe drug (midazolam) at the single-patient level. Taking into account the acquired knowledge describing (patho-)physiological alterations in the patient cohort allowed the successful prediction of the population pharmacokinetics of a second, candidate probe drug (torsemide) in the patient population. In addition, we identified significant relations of the acquired physiological processes to patient metadata from liver biopsies. The presented prototypical systems pharmacology approach is a proof of concept for model-based translation across different stages of pharmaceutical development programs. Applied consistently, it has the potential to systematically improve predictivity of pharmacokinetic simulations by incorporating the results of clinical trials and translating them to subsequent studies.

Authors: M. Krauss, U. Hofmann, C. Schafmayer, S. Igel, J. Schlender, C. Mueller, M. Brosch, W. von Schoenfels, W. Erhart, A. Schuppert, M. Block, E. Schaeffeler, G. Boehmer, L. Goerlitz, J. Hoecker, J. Lippert, R. Kerb, J. Hampe, L. Kuepfer, M. Schwab

Date Published: 27th Jun 2017

Publication Type: Not specified

Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

Abstract (Expand)

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. … Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 x 10(-7), range P = 9.2 x 10(-8) to 6.0 x 10(-46); n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 x 10(-6), range P = 5.5 x 10(-6) to 6.1 x 10(-35), n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 x 10(-54)). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.

Authors: S. Wahl, A. Drong, B. Lehne, M. Loh, W. R. Scott, S. Kunze, P. C. Tsai, J. S. Ried, W. Zhang, Y. Yang, S. Tan, G. Fiorito, L. Franke, S. Guarrera, S. Kasela, J. Kriebel, R. C. Richmond, M. Adamo, U. Afzal, M. Ala-Korpela, B. Albetti, O. Ammerpohl, J. F. Apperley, M. Beekman, P. A. Bertazzi, S. L. Black, C. Blancher, M. J. Bonder, M. Brosch, M. Carstensen-Kirberg, A. J. de Craen, S. de Lusignan, A. Dehghan, M. Elkalaawy, K. Fischer, O. H. Franco, T. R. Gaunt, J. Hampe, M. Hashemi, A. Isaacs, A. Jenkinson, S. Jha, N. Kato, V. Krogh, M. Laffan, C. Meisinger, T. Meitinger, Z. Y. Mok, V. Motta, H. K. Ng, Z. Nikolakopoulou, G. Nteliopoulos, S. Panico, N. Pervjakova, H. Prokisch, W. Rathmann, M. Roden, F. Rota, M. A. Rozario, J. K. Sandling, C. Schafmayer, K. Schramm, R. Siebert, P. E. Slagboom, P. Soininen, L. Stolk, K. Strauch, E. S. Tai, L. Tarantini, B. Thorand, E. F. Tigchelaar, R. Tumino, A. G. Uitterlinden, C. van Duijn, J. B. van Meurs, P. Vineis, A. R. Wickremasinghe, C. Wijmenga, T. P. Yang, W. Yuan, A. Zhernakova, R. L. Batterham, G. D. Smith, P. Deloukas, B. T. Heijmans, C. Herder, A. Hofman, C. M. Lindgren, L. Milani, P. van der Harst, A. Peters, T. Illig, C. L. Relton, M. Waldenberger, M. R. Jarvelin, V. Bollati, R. Soong, T. D. Spector, J. Scott, M. I. McCarthy, P. Elliott, J. T. Bell, G. Matullo, C. Gieger, J. S. Kooner, H. Grallert, J. C. Chambers

Date Published: 21st Dec 2016

Publication Type: Not specified

NAFLD is associated with methylation shifts with relevance for the expression of genes involved in lipoprotein particle composition.

Abstract (Expand)

Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides, cholesterol and toxic free fatty acids and is related to low vitamin D levels. In an analysis of specific … gene sets we elucidate to what extent NAFLD associates to epigenetic and related transcriptional changes in gene networks regulating lipid, energy and vitamin D balance. Two gene clusters responsible for lipid homeostasis (74 genes) and vitamin D and energy balance (31 genes) were investigated with regard to average epigenetic shifts within the first 1500bp next to the transcriptional start site. Three cohorts from two published genome wide driven studies that used a microarray approach were investigated including altogether 103 NAFLD and 75 liver healthy subjects. In the first two steps associations between NAFLD abundance, strength of fibrosis and methylation were investigated in two cohorts by multiple linear regression analyses, correcting for important clinical and demographic parameters. Methylation associated strength of transcription in genes showing significant NAFLD related methylation changes were studied in a third step using a third cohort and applying Pearson's correlation and robust linear regression analyses. 41 genes in gene cluster 1 and 14 genes in cluster 2 were significantly differentially methylated in dependency of NAFLD and hepatic fibrosis. We detect new genes significantly changed in methylation, including APO family members (lipid transport), NPC1L1, STARD (cholesterol transport) and GRHL (energy homeostasis). Our results allow novel insights into the hepatic epigenetic regulation of genes important for lipid and vitamin D balance in NAFLD.

Authors: J. Mwinyi, A. E. Bostrom, C. Pisanu, S. K. Murphy, W. Erhart, C. Schafmayer, J. Hampe, C. Moylan, H. B. Schioth

Date Published: 18th Dec 2016

Publication Type: Not specified

Comparison of Gene Expression Patterns Between Mouse Models of Nonalcoholic Fatty Liver Disease and Liver Tissues From Patients.

Abstract (Expand)

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in industrialized countries. Mouse models of NAFLD have been used in studies of pathogenesis … and treatment, and have certain features of the human disease. We performed a systematic transcriptome-wide analysis of liver tissues from patients at different stages of NAFLD progression (ranging from healthy obese individuals to those with steatosis), as well as rodent models of NAFLD, to identify those that most closely resemble human disease progression in terms of gene expression patterns. METHODS: We performed a systematic evaluation of genome-wide messenger RNA expression using liver tissues collected from mice fed a standard chow diet (controls) and 9 mouse models of NAFLD: mice on a high-fat diet (with or without fructose), mice on a Western-type diet, mice on a methionine- and choline-deficient diet, mice on a high-fat diet given streptozotocin, and mice with disruption of Pten in hepatocytes. We compared gene expression patterns with those of liver tissues from 25 patients with nonalcoholic steatohepatitis (NASH), 27 patients with NAFLD, 15 healthy obese individuals, and 39 healthy nonobese individuals (controls). Liver samples were obtained from patients undergoing liver biopsy for suspected NAFLD or NASH, or during liver or bariatric surgeries. Data sets were analyzed using the limma R-package. Overlap of functional profiles was analyzed by gene set enrichment analysis profiles. RESULTS: We found differences between human and mouse transcriptomes to be significantly larger than differences between disease stages or models. Of the 65 genes with significantly altered expression in patients with NASH and 177 genes with significantly altered expression in patients with NAFLD, compared with controls, only 1-18 of these genes also differed significantly in expression between mouse models of NAFLD and control mice. However, expression of genes that regulate pathways associated with the development of NAFLD were altered in some mouse models (such as pathways associated with lipid metabolism). On a pathway level, gene expression patterns in livers of mice on the high-fat diet were associated more closely with human fatty liver disease than other models. CONCLUSIONS: In comparing gene expression profiles between liver tissues from different mouse models of NAFLD and patients with different stages of NAFLD, we found very little overlap. Our data set is available for studies of pathways that contribute to the development of NASH and NAFLD and selection of the most applicable mouse models (http://www.nash-profiler.com).

Authors: A. Teufel, T. Itzel, W. Erhart, M. Brosch, X. Y. Wang, Y. O. Kim, W. von Schonfels, A. Herrmann, S. Bruckner, F. Stickel, J. F. Dufour, T. Chavakis, C. Hellerbrand, R. Spang, T. Maass, T. Becker, S. Schreiber, C. Schafmayer, D. Schuppan, J. Hampe

Date Published: 19th Jun 2016

Publication Type: Not specified

A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis.

Abstract (Expand)

Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related … cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 x 10(-9)) and TM6SF2 (P = 7.89 x 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 x 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.

Authors: S. Buch, F. Stickel, E. Trepo, M. Way, A. Herrmann, H. D. Nischalke, M. Brosch, J. Rosendahl, T. Berg, M. Ridinger, M. Rietschel, A. McQuillin, J. Frank, F. Kiefer, S. Schreiber, W. Lieb, M. Soyka, N. Semmo, E. Aigner, C. Datz, R. Schmelz, S. Bruckner, S. Zeissig, A. M. Stephan, N. Wodarz, J. Deviere, N. Clumeck, C. Sarrazin, F. Lammert, T. Gustot, P. Deltenre, H. Volzke, M. M. Lerch, J. Mayerle, F. Eyer, C. Schafmayer, S. Cichon, M. M. Nothen, M. Nothnagel, D. Ellinghaus, K. Huse, A. Franke, S. Zopf, C. Hellerbrand, C. Moreno, D. Franchimont, M. Y. Morgan, J. Hampe

Date Published: 21st Oct 2015

Publication Type: Journal

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