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29 Publications visible to you, out of a total of 29

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OBJECTIVES: Variants in patatin-like phospholipase domain-containing 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), and membrane bound O-acyltransferase domain containingg 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

Abstract

Not specified

Authors: Ahmed Ghallab, Ute Hofmann, Selahaddin Sezgin, Nachiket Vartak, Reham Hassan, Ayham Zaza, Patricio Godoy, Kai Markus Schneider, Georgia Guenther, Yasser A Ahmed, Aya A Abbas, Verena Keitel, Lars Kuepfer, Steven Dooley, Frank Lammert, Christian Trautwein, Michael Spiteller, Dirk Drasdo, Alan F Hofmann, Peter L M Jansen, Jan G Hengstler, Raymond Reif

Date Published: 13th Aug 2018

Publication Type: Not specified

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

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

Abstract (Expand)

BACKGROUND/AIMS: Common genetic variations in vitamin D metabolism are associated with liver stiffness. Whether these genes are implicated in hepatic steatosis remains unclear. Here we aimed to analyse the association of common vitamin D pathway gene variants with liver steatosis. METHODS: Liver steatosis was assessed non-invasively in 241 patients with chronic liver conditions by controlled attenuation parameter (CAP). The following polymorphisms were genotyped using TaqMan assays: group-specific component (GC) rs7041, 7-dehydrocholesterol reductase (DHCR7) rs12785878, cytochrome P450 2R1 (CYP2R1) rs10741657, -vitamin D receptor (VDR) rs7974353. Chemiluminescence immunoassay determined serum 25-hydroxyvitamin D (25(OH) D) concentrations. RESULTS: Vitamin D deficiency (defined by 25(OH)D concentrations <20 ng/mL) occurred in 66% of patients. Median CAP was 296 (100-400) dB/m. Patients with advanced steatosis (CAP >/=280 dB/m) had significantly (p = 0.033) lower 25(OH)D levels as compared to patients with CAP <280 dB/m. Moreover, the rare allele [T] in GC rs7041 was significantly (p = 0.018) associated with higher 25(OH)D levels in patients with CAP <280 dB/m. However, GC, DHCR7, CYP2R1, and VDR polymorphisms were not related to liver steatosis and obesity traits. CONCLUSIONS: Higher CAP values are associated with low serum 25(OH)D concentrations but not with common vitamin D pathway gene variants.

Authors: M. Jamka, A. Arslanow, A. Bohner, M. Krawczyk, S. N. Weber, F. Grunhage, F. Lammert, C. S. Stokes

Date Published: 8th Mar 2018

Publication Type: Not specified

Abstract (Expand)

New technologies to generate, store and retrieve medical and research data are inducing a rapid change in clinical and translational research and health care. Systems medicine is the interdisciplinary approach wherein physicians and clinical investigators team up with experts from biology, biostatistics, informatics, mathematics and computational modeling to develop methods to use new and stored data to the benefit of the patient. We here provide a critical assessment of the opportunities and challenges arising out of systems approaches in medicine and from this provide a definition of what systems medicine entails. Based on our analysis of current developments in medicine and healthcare and associated research needs, we emphasize the role of systems medicine as a multilevel and multidisciplinary methodological framework for informed data acquisition and interdisciplinary data analysis to extract previously inaccessible knowledge for the benefit of patients.

Authors: R. Apweiler, T. Beissbarth, M. R. Berthold, N. Bluthgen, Y. Burmeister, O. Dammann, A. Deutsch, F. Feuerhake, A. Franke, J. Hasenauer, S. Hoffmann, T. Hofer, P. L. Jansen, L. Kaderali, U. Klingmuller, I. Koch, O. Kohlbacher, L. Kuepfer, F. Lammert, D. Maier, N. Pfeifer, N. Radde, M. Rehm, I. Roeder, J. Saez-Rodriguez, U. Sax, B. Schmeck, A. Schuppert, B. Seilheimer, F. J. Theis, J. Vera, O. Wolkenhauer

Date Published: 3rd Mar 2018

Publication Type: Not specified

Abstract (Expand)

Non-alcoholic fatty liver disease (NAFLD) is frequent among obese individuals with metabolic syndrome. Variants PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 rs641738 are associated with higher liver fat contents. Here we analyzed 63 biopsied non-obese, non-diabetic patients with NAFLD (39 men, age: 20-72 years) recruited within the German NAFLD CSG program. The frequencies of the PNPLA3, TM6SF2 and MBOAT7 polymorphisms were compared with the remaining patients in the NAFLD CSG cohort and with a control population (n = 174). Serum CK18-M30 was measured by ELISA. In non-obese NAFLD patients, the frequency of the PNPLA3 p.I148M allele (74.6%), but not of the TM6SF2 or MBOAT7 polymorphisms, was significantly (P < 0.05) higher as compared to the other patients in the NAFLD CSG cohort (54.9%) or controls (40.2%). The presence of the minor PNPLA3 p.I148M risk allele increased the risk of developing NAFLD (OR = 3.29, P < 0.001) and was associated with higher steatosis, fibrosis, and serum CK18-M30 levels (all P < 0.05). According to the population attributable fraction (PAF), 49.8% of NAFLD cases could be eliminated if the PNPLA3 mutation was absent. The MBOAT7 polymorphism was more frequent (P = 0.019) in patients with severe hepatic steatosis. In conclusion, PNPLA3, and to a lesser extent, MBOAT7 variants are associated with NAFLD risk and modulate liver injury in non-obese patients without diabetes.

Authors: M. Krawczyk, H. Bantel, M. Rau, J. M. Schattenberg, F. Grunhage, A. Pathil, M. Demir, J. Kluwe, T. Boettler, S. N. Weber, A. Geier, F. Lammert

Date Published: 28th Feb 2018

Publication Type: Not specified

Abstract (Expand)

Background/Aims: Common genetic variations in vitamin D metabolism are associated with liver stiffness. Whether these genes are implicated in hepatic steatosis remains unclear. Here we aimed to analyse the association of common vitamin D pathway gene variants with liver steatosis. Methods: Liver steatosis was assessed non-invasively in 241 patients with chronic liver conditions by controlled attenuation parameter (CAP). The following polymorphisms were genotyped using TaqMan assays: group-specific component ( GC ) rs7041, 7-dehydrocholesterol reductase ( DHCR7 ) rs12785878, cytochrome P450 2R1 ( CYP2R1 ) rs10741657, vitamin D receptor ( VDR ) rs7974353. Chemiluminescence immunoassay determined serum 25-hydroxyvitamin D (25(OH) D) concentrations. Results: Vitamin D deficiency (defined by 25(OH)D concentrations <20 ng/mL) occurred in 66% of patients. Median CAP was 296 (100–400) dB/m. Patients with advanced steatosis (CAP ≥ 280 dB/m) had significantly ( p = 0.033) lower 25(OH)D levels as compared to patients with CAP <280 dB/m. Moreover, the rare allele [T] in GC rs7041 was significantly ( p = 0.018) associated with higher 25(OH)D levels in patients with CAP <280 dB/m. However, GC , DHCR7, CYP2R1 , and VDR polymorphisms were not related to liver steatosis and obesity traits. Conclusions: Higher CAP values are associated with low serum 25(OH)D concentrations but not with common vitamin D pathway gene variants.

Authors: Malgorzata Jamka, Anita Arslanow, Annika Bohner, Marcin Krawczyk, Susanne N. Weber, Frank Grünhage, Frank Lammert, Caroline S Stokes

Date Published: 7th Feb 2018

Publication Type: Not specified

Abstract (Expand)

Familial cholangiopathies are rare but potentially severe diseases. Their spectrum ranges from fairly benign conditions as, for example, benign recurrent intrahepatic cholestasis to low-phospholipid associated cholelithiasis and progressive familial intrahepatic cholestasis (PFIC). Many cholangiopathies such as primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) affect first the bile ducts ("ascending pathophysiology") but others, such as PFIC, start upstream in hepatocytes and cause progressive damage "descending" down the biliary tree and leading to end-stage liver disease. In recent years our understanding of cholestatic diseases has improved, since we have been able to pinpoint numerous disease-causing mutations that cause familial cholangiopathies. Accordingly, six PFIC subtypes (PFIC type 1-6) have now been defined. Given the availability of genotyping resources, these findings can be introduced in the diagnostic work-up of patients with peculiar cholestasis. In addition, functional studies have defined the pathophysiological consequences of some of the detected variants. Furthermore, ABCB4 variants do not only cause PFIC type 3 but confer an increased risk for chronic liver disease in general. In the near future these findings will serve to develop new therapeutic strategies for patients with liver diseases. Here we present the latest data on the genetic background of familial cholangiopathies and discuss their application in clinical practice for the differential diagnosis of cholestasis of unknown aetiology. As look in the future we present "system genetics" as a novel experimental tool for the study of cholangiopathies and disease-modifying genes. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Authors: M. C. Reichert, R. A. Hall, M. Krawczyk, F. Lammert

Date Published: 2nd Aug 2017

Publication Type: Journal

Abstract (Expand)

Understanding the dynamics of human liver metabolism is fundamental for effective diagnosis and treatment of liver diseases in general and the metabolism of drugs in particular. This knowledge can be obtained with systems biology/medicine approaches that account for the complexity of hepatic responses and their systemic consequences in other organs. Computational modelling can reveal hidden principles of the system by classification of individual components, analysing their interactions and simulating the effects that are difficult to investigate experimentally. Herein we review the state-of-the-art computational models that describe liver dynamics from the metabolic, gene regulatory and signal transduction perspectives. We focus especially on large-scale liver models described either by genome scale metabolic networks (GSMN) or object-oriented approach. We also discuss the benefits and limitations of each modelling approach and their value for clinical applications in diagnosis, therapy and prevention of liver diseases as well as precision medicine in hepatology. This article is protected by copyright. All rights reserved.

Authors: T. Cvitanovic, M. C. Reichert, M. Moskon, M. Mraz, F. Lammert, D. Rozman

Date Published: 19th May 2017

Publication Type: Not specified

Abstract (Expand)

Latest data suggest that placental growth factor (PLGF), growth differentiation factor-15 (GDF-15) and hepatic growth factor (HGF) are involved in hepatic fibrogenesis. Diagnostic performance of these markers for non-invasive liver fibrosis prediction was evaluated based on liver histology and stiffness. In total 834 patients were recruited. Receiver-operating-characteristics were used to define cut-offs for markers correlating to fibrosis stages. Odds-ratios were calculated for the presence/absence of fibrosis/cirrhosis and confirmed in the sub-group of patients phenotyped by elastography only. Logistic and uni- and multivariate regression analyses were used to test for association of markers with liver fibrosis stages and for independent prediction of liver histology and stiffness. Marker concentrations correlated significantly (P<0.001) with histology and stiffness. Cut-offs for liver fibrosis (>/=F2) were PLGF = 20.20 pg/ml, GDF15 = 1582.76 pg/ml and HGF = 2598.00 pg/ml. Logistic regression confirmed an increase of ORs from 3.6 over 33.0 to 108.4 with incremental (1-3) markers positive for increased liver stiffness (>/=12.8kPa; all P<0.05). Subgroup analysis revealed associations with advanced fibrosis for HCV (three markers positive: OR = 59.9, CI 23.4-153.4, P<0.001) and non-HCV patients (three markers positive: OR = 144, CI 59-3383, P<0.001). Overall, serum markers identified additional 50% of patients at risk for advanced fibrosis presenting with low elastography results. In conclusion, this novel combination of markers reflects the presence of significant liver fibrosis detected by elastography and histology and may also identify patients at risk presenting with low elastography values.

Authors: M. Krawczyk, S. Zimmermann, G. Hess, R. Holz, M. Dauer, J. Raedle, F. Lammert, F. Grunhage

Date Published: 17th Mar 2017

Publication Type: Not specified

Abstract (Expand)

In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending course of the disease process. The first and early lesions are in "downstream" bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)-mediated toxic injury of the "upstream" liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom-poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%-60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more "tailored" use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium-dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis-suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti-inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor-ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end-stage disease. These are arguments to consider a step-wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage-defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (Hepatology 2017;65:722-738).

Authors: P. L. Jansen, A. Ghallab, N. Vartak, R. Reif, F. G. Schaap, J. Hampe, J. G. Hengstler

Date Published: 17th Feb 2017

Publication Type: Not specified

Abstract

Not specified

Authors: Zhe Shen, Yan Liu, Bedair Dewidar, Junhao Hu, Ogyi Park, Teng Feng, Chengfu Xu, Chaohui Yu, Qi Li, Christoph Meyer, Iryna Ilkavets, Alexandra Müller, Carolin Stump-Guthier, Stefan Munker, Roman Liebe, Vincent Zimmer, Frank Lammert, Peter R. Mertens, Hai Li, Peter ten Dijke, Hellmut G. Augustin, Jun Li, Bin Gao, Matthias P. Ebert, Steven Dooley, Youming Li, Hong-Lei Weng

Date Published: 1st Jul 2016

Publication Type: Not specified

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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