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23 Publications visible to you, out of a total of 23
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

Pathophysiology and Management of Alcoholic Liver Disease: Update 2016.

Abstract (Expand)

Alcoholic liver disease (ALD) is a leading cause of cirrhosis, liver cancer, and acute and chronic liver failure and as such causes significant morbidity and mortality. While alcohol consumption is … slightly decreasing in several European countries, it is rising in others and remains high in many countries around the world. The pathophysiology of ALD is still incompletely understood but relates largely to the direct toxic effects of alcohol and its main intermediate, acetaldehyde. Recently, novel putative mechanisms have been identified in systematic scans covering the entire human genome and raise new hypotheses on previously unknown pathways. The latter also identify host genetic risk factors for significant liver injury, which may help design prognostic risk scores. The diagnosis of ALD is relatively easy with a panel of well-evaluated tests and only rarely requires a liver biopsy. Treatment of ALD is difficult and grounded in abstinence as the pivotal therapeutic goal; once cirrhosis is established, treatment largely resembles that of other etiologies of advanced liver damage. Liver transplantation is a sound option for carefully selected patients with cirrhosis and alcoholic hepatitis because relapse rates are low and prognosis is comparable to other etiologies. Still, many countries are restrictive in allocating donor livers for ALD patients. Overall, few therapeutic options exist for severe ALD. However, there is good evidence of benefit for only corticosteroids in severe alcoholic hepatitis, while most other efforts are of limited efficacy. Considering the immense burden of ALD worldwide, efforts of medical professionals and industry partners to develop targeted therapies in ALF has been disappointingly low.

Authors: F. Stickel, C. Datz, J. Hampe, R. Bataller

Date Published: 15th Mar 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

The genetics of alcohol dependence and alcohol-related liver disease.

Abstract (Expand)

The susceptibility to developing alcohol dependence and significant alcohol-related liver injury is determined by a number of constitutional, environmental and genetic factors, although the nature and … level of interplay between them remains unclear. The familiality and heritability of alcohol dependence is well-documented but, to date, no strong candidate genes conferring increased risk have emerged, although variants in alcohol dehydrogenase and acetaldehyde dehydrogenase have been shown to confer protection, predominantly in individuals of East Asian ancestry. Population contamination with confounders such as drug co-dependence and psychiatric and physical co-morbidity may explain the essentially negative genome-wide association studies in this disorder. The familiality and hereditability of alcohol-related cirrhosis is not as well-documented but three strong candidate genes PNPLA3, TM6SF2 and MBOAT7, have been identified. The mechanisms by which variants in these genes confer risk and the nature of the functional interplay between them remains to be determined but, when elucidated, will undoubtedly increase our understanding of the pathophysiology of this disease. The way in which this genetic information could potentially inform patient management has yet to be determined and tested.

Authors: F. Stickel, C. Moreno, J. Hampe, M. Y. Morgan

Date Published: 27th Aug 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 targeted analysis reveals relevant shifts in the methylation and transcription of genes responsible for bile acid homeostasis and drug metabolism in non-alcoholic fatty liver disease.

Abstract (Expand)

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is associated with a high risk for liver cirrhosis and cancer. Recent studies demonstrate that NAFLD significantly impacts on the genome wide … methylation and expression reporting top hit genes to be associated with e.g. diabetes mellitus. In a targeted analysis we specifically investigate to what extent NAFLD is associated with methylation and transcriptional changes in gene networks responsible for drug metabolism (DM) and bile acid (BA) homeostasis, which may trigger liver and system toxic events. METHODS: We performed a systematic analysis of 73 genes responsible for BA homeostasis and DM based on liver derived methylation and expression data from three cohort studies including 103 NAFLD and 75 non-NAFLD patients. Using multiple linear regression models, we detected methylation differences in proximity to the transcriptional start site of these genes in two NAFLD cohorts and correlated the methylation of significantly changed CpG sites to transcriptional expression in a third cohort using robust multiple linear regression approaches. RESULTS: We detected 64 genes involved in BA homeostasis and DM to be significantly differentially methylated. In 26 of these genes, methylation significantly correlated with RNA expression, detecting i.e. genes such as CYP27A1, OSTa, and SLC27A5 (BA homeostasis), and SLCO2B1, SLC47A1, and several UGT and CYP genes (DM) to be NAFLD dependently modulated. CONCLUSIONS: NAFLD is associated with significant shifts in the methylation of key genes responsible for BA and DM that are associated with transcriptional modulations. These findings have implications for BA composition, BA regulated metabolic pathways and for drug safety and efficacy.

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

Date Published: 14th 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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