Frank Lammert

Publications of Frank Lammert

• Common genetic variation in vitamin D metabolism is associated with liver stiffness.

  Authors: Frank Grünhage, Katrin Hochrath, Marcin Krawczyk, Aksana Höblinger, Barbara Obermayer-Pietsch, Jürgen Geisel, Michael Trauner, Tilman Sauerbruch, Frank Lammert

  Hepatology (Baltimore, Md.). 05/2012;

  BACKGROUND: Recently, genome-wide studies identified genetic variants that affect serum 25-hydroxyvitamin D levels in healthy populations (rs12785878, near dehydrocholesterol reductase, DHCR7;BACKGROUND: Recently, genome-wide studies identified genetic variants that affect serum 25-hydroxyvitamin D levels in healthy populations (rs12785878, near dehydrocholesterol reductase, DHCR7; rs10741657, near CYP2R1; and rs7041, near vitamin D binding protein, GC). Since vitamin D deficiency is associated with advanced liver disease, we hypothesized that these variants are associated with 25(OH)-vitamin D levels and liver fibrosis. PATIENTS AND METHODS: Overall, 712 Caucasian patients with chronic liver diseases were included. Liver fibrosis was assessed by transient elastography (TE) and/or histology. Serum levels of 25(OH)-vitamin D were correlated with TE and fibrosis stages. Genotypes were determined using TaqMan assays and tested for association with vitamin D and liver stiffness. RESULTS: Serum 25(OH)-vitamin D levels were inversely correlated with liver stiffness and histology (p < 0.001). Homozygous carriers of the rare DHCR7 allele or the common CYP2R1 allele presented with reduced 25(OH)-vitamin D levels (p < 0.05). The variant rs12785878 in the DHCR7 locus was associated with liver stiffness in both patients with TE < 7.0 kPa and TE between 7.0 and 9.5 kPa. 25(OH)-vitamin D levels correlated with sunshine hours at time of inclusion (p < 0.001). CONCLUSIONS: Common variation in 25(OH)-vitamin D metabolism is associated with liver stiffness in patients presenting with low to moderately increased elasticity. Although the susceptible DHCR7 genotype confers small risk, we speculate that the observed stiffness differences indicate a stronger influence of 25(OH)-vitamin D on initiation rather than progression of hepatic fibrosis. (HEPATOLOGY 2012.).

• Nuclear receptor variants in liver disease.

  Authors: Roman Müllenbach, Susanne N Weber, Frank Lammert

  Journal of lipids. 01/2012; 2012:934707.

  This review aims to provide a snapshot of the actual state of knowledge on genetic variants of nuclear receptors (NR) involved in regulating important aspects of liver metabolism. It recapitulatesThis review aims to provide a snapshot of the actual state of knowledge on genetic variants of nuclear receptors (NR) involved in regulating important aspects of liver metabolism. It recapitulates recent evidence for the application of NR in genetic diagnosis of monogenic ("Mendelian") liver disease and their use in clinical diagnosis. Genetic analysis of multifactorial liver diseases such as viral hepatitis or fatty liver disease identifies key players in disease predisposition and progression. Evidence from these analyses points towards a role of NR polymorphisms in common diseases, linking regulatory networks to complex and variable phenotypes. The new insights into NR variants also offer perspectives and cautionary advice for their use as handles towards diagnosis and treatment.

• Phytosterol and cholesterol precursor levels indicate increased cholesterol excretion and biosynthesis in gallstone patients.

  Authors: Marcin Krawczyk, Dieter Lütjohann, Ramin Schirin-Sokhan, Luis Villarroel, Flavio Nervi, Fernando Pimentel, Frank Lammert, Juan Francisco Miquel

  Hepatology (Baltimore, Md.). 12/2011;

  In hepatocytes and enterocytes sterol uptake and secretion is mediated by NPC1L1 and ABCG5/8 proteins, respectively. Whereas serum levels of phytosterols represent surrogate markers for intestinalIn hepatocytes and enterocytes sterol uptake and secretion is mediated by NPC1L1 and ABCG5/8 proteins, respectively. Whereas serum levels of phytosterols represent surrogate markers for intestinal cholesterol absorption, cholesterol precursors reflect cholesterol biosynthesis. Here we compare serum and biliary sterol levels in ethnically different populations of patients with gallstone disease (GSD) and stone-free controls to identify differences in cholesterol transport and synthesis between these groups. In this case-control study four cohorts were analyzed: 112 German patients with GSD and 152 controls; two distinct Chilean ethnic groups: Hispanics (100 GSD, 100 controls) and Amerindians (20 GSD, 20 controls); additionally an 8-year follow-up of 70 Hispanics was performed. Serum sterols were measured by GC-MS. Gallbladder bile sterol levels were analyzed in cholesterol GSD and controls (n=17 each). Common ABCG5/8 variants were genotyped. Comparison of serum sterols showed lower levels of phytosterols and higher levels of cholesterol precursors in GSD patients than in controls. The ratios of phytosterols to cholesterol precursors were lower in GSD patients, whereas biliary phytosterol and cholesterol concentrations were elevated as compared to controls. In the follow-up study, serum phytosterol levels were significantly lower even before GSD were detectable by ultrasound. An ethnic gradient in the ratios of phytosterols to cholesterol precursors was apparent (Germans > Hispanics > Amerindians). ABCG5/8 variants did not fully explain the sterol metabolic trait of GSD in any of the cohorts. Conclusions: Individuals predisposed to GSD display increased biliary output of cholesterol in the setting of relatively low intestinal cholesterol absorption, indicating enhanced whole body sterol clearance. This metabolic trait precedes gallstone formation and is a feature of ethnic groups at higher risk of cholesterol GSD. (HEPATOLOGY 2011.).

• The CXCL1 rs4074 A allele is associated with enhanced CXCL1 responses to TLR2 ligands and predisposes to cirrhosis in HCV genotype 1-infected Caucasian patients.

  Authors: Hans Dieter Nischalke, Cordula Berger, Carolin Luda, Tobias Müller, Thomas Berg, Martin Coenen, Benjamin Krämer, Christian Körner, Jonel Trebicka, Frank Grünhage, Frank Lammert, Jacob Nattermann, Tilman Sauerbruch, Ulrich Spengler

  Journal of hepatology. 12/2011;

  BACKGROUND & AIMS: CXCL1 is a ligand for CXC chemokine-receptor 2 expressed on hepatic stellate cells (HSC). Thus, CXCL1 might contribute to HSC activation and fibrogenesis. Here, we investigatedBACKGROUND & AIMS: CXCL1 is a ligand for CXC chemokine-receptor 2 expressed on hepatic stellate cells (HSC). Thus, CXCL1 might contribute to HSC activation and fibrogenesis. Here, we investigated whether the CXCL1 rs4074 polymorphism affects CXCL1 expression and progression of chronic hepatitis C virus (HCV) infection towards cirrhosis. METHODS: The study involved 237 patients with chronic HCV genotype 1 infection (75 with cirrhosis) and 342 healthy controls. The CXCL1 rs4074 polymorphism was determined by a LightSNiP assay on the LightCycler system. CXCL1 serum levels and induction in response to HCV proteins were studied by ELISA. RESULTS: Distributions of CXCL1 genotypes (GG/GA/AA) matched the Hardy-Weinberg equilibrium in all subgroups (HCV-associated cirrhosis: 29.3%/54.7%/16.0%; non-cirrhotic HCV infection: 45.1%/44.4%/10.5%, healthy controls: 46.2%/40.9%/12.9%). HCV-infected cirrhotic patients had a significantly greater CXCL1 rs4074 A allele frequency (43.3%) than patients without cirrhosis (32.7%, OR=1.573, p=0.03) and healthy controls (33.3%, OR=1.529, p=0.02). In vitro carriers of the A allele produced greater amounts of CXCL1 in response to TLR2-ligands including HCV core and NS3, and HCV-infected carriers of the CXCL1 rs4074 A allele had higher CXCL1 serum levels than those with the G/G genotype. Moreover, multivariate Cox-regression analysis confirmed age and the presence of a CXCL1 rs4074 A allele as risk factors for cirrhosis. CONCLUSIONS: Enhanced production of CXCL1 in response to HCV antigens in carriers of the rs4074 A allele together with its increased frequency in cirrhotic patients with hepatitis C suggest the CXCL1 rs4074 A allele as a genetic risk factor for cirrhosis progression in hepatitis C.

• Effects of SLC10A2 variant rs9514089 on gallstone risk and serum cholesterol levels- meta-analysis of three independent cohorts.

  Authors: Anke Tönjes, Henning Wittenburg, Jan Halbritter, Olga Renner, Simone Harsch, Eduard F Stange, Frank Lammert, Michael Stumvoll, Peter Kovacs

  BMC medical genetics. 11/2011; 12:149.

  Recently, a single nucleotide polymorphism (SNP) rs9514089 in SLC10A2 (apical sodium-dependent bile acid transporter gene) has been identified as a susceptibility variant for cholelithiasis inRecently, a single nucleotide polymorphism (SNP) rs9514089 in SLC10A2 (apical sodium-dependent bile acid transporter gene) has been identified as a susceptibility variant for cholelithiasis in humans. Here we assessed the effects of rs9514089 on gallstone risk and related phenotypes of the metabolic syndrome in the self-contained population of Sorbs (183 cases with gallstones/826 controls). Furthermore, we performed a meta-analysis for effects of rs9514089 on susceptibility for cholelithiasis in three independent cohorts (Stuttgart: 56 cases/71 controls, Aachen: 184 cases/184 controls and Sorbs). There was no significant association of rs9514089 with gallstone risk, serum lipid parameters and BMI in the Sorbs and in the meta-analysis of all three cohorts (p > 0.05). There was an effect trend in the subgroup of lean subjects but based on different effect directions in the three cohorts there was no significant association in the meta-analysis. We were not able to replicate the effect of rs9514089 on gallstone risk in the Sorbs. Further analyses in larger cohorts are required to finally assess the role of genetic variants in SLC10A2 in human gallstone development and lipid metabolism.

• Parenchyma-preserving hepatic resection for colorectal liver metastases.

  Authors: Maximilian von Heesen, Jochen Schuld, Jens Sperling, Frank Grünhage, Frank Lammert, Sven Richter, Martin K Schilling, Otto Kollmar

  Langenbeck's archives of surgery / Deutsche Gesellschaft für Chirurgie. 11/2011; 397(3):383-95.

  Hepatic resection of colorectal liver metastases is the only curative treatment option. As clinical and experimental data indicate that the extent of liver resection correlates with growth ofHepatic resection of colorectal liver metastases is the only curative treatment option. As clinical and experimental data indicate that the extent of liver resection correlates with growth of residual metastases, the present study analyzes the potential benefit of a parenchyma-preserving liver surgery approach. Data from a prospectively maintained database of patients undergoing liver resection for colorectal metastases were reviewed. Evaluation of outcome was performed using the Kaplan-Meier method. Correlations were calculated between clinical-pathological variables. One hundred sixty-three patients underwent 198 liver resections for colorectal metastases: 26 major hepatectomies, 65 minor anatomical resections, 78 non-anatomical resections, as well as 29 combinations of minor anatomical and non-anatomical procedures. Overall 1-, 3-, and 5-year survival was 93%, 62%, and 40%, respectively. Patients with repeated liver resections had a 5-year survival of 27%. Interestingly, large dissection areas were associated with a significant reduction of the 5-year survival rate (33%). Five-year survival after major hepatectomy was not significantly reduced. For colorectal liver metastases, minor resections offer a prolonged survival compared to major hepatectomies. As patients with stage IV colorectal disease are candidates for repeat resections, preservation of hepatic parenchyma is of increasing importance in the setting of multi-modal and repeated therapy approaches.

• Pancreatic cancer risk variant ABO rs505922 in patients with cholangiocarcinoma.

  Authors: Marcin Krawczyk, Florentina Mihalache, Aksana Höblinger, Monica Acalovschi, Frank Lammert, Vincent Zimmer

  World journal of gastroenterology : WJG. 11/2011; 17(41):4640-2.

  The aim of this study was to investigate an association between the development of cholangiocarcinoma (CCA) and the ABO variant rs505922 (known to increase pancreatic cancer risk) in a large cohortThe aim of this study was to investigate an association between the development of cholangiocarcinoma (CCA) and the ABO variant rs505922 (known to increase pancreatic cancer risk) in a large cohort of European individuals with CCA. In total, 180 individuals with CCA and 350 CCA-free controls were included. The ABO variant rs505922 was genotyped using a polymerase chain reaction-based assay. Association between this single nucleotide polymorphism (SNP) and CCA was tested in contingency tables. Neither allele distributions nor association tests and regression analysis provided evidence for an increased risk of CCA among carriers of the ABO variant (all P > 0.05). Nevertheless, we documented a deviation from Hardy-Weinberg equilibrium in the entire CCA cohort (P = 0.028) and for patients with intrahepatic (P = 0.037) but not extrahepatic tumor localization (P > 0.05). The association tests did not provide evidence for a prominent role of the investigated SNP in the genetic risk of CCA. However, Hardy-Weinberg disequilibrium in the entire cohort and the intrahepatic CCA subgroup warrants future studies investigating a potential CCA risk modulation by individual blood groups.

• Endoscopic resection of a large duodenal hamartoma related to SMAD4-associated juvenile polyposis/hereditary hemorrhagic teleangiectasia syndrome.

  Authors: Vincent Zimmer, Rainer Grobholz, Frank Lammert, Jochen Raedle

  The American journal of gastroenterology. 11/2011; 106(11):2047-8.

• Expression of the megalin C-terminal fragment by macrophages during liver fibrogenesis in mice.

  Authors: Ursula Pieper-Fürst, Rabea Hall, Sebastian Huss, Katrin Hochrath, Hans-Peter Fischer, Frank Tacke, Ralf Weiskirchen, Frank Lammert

  Biochimica et biophysica acta. 09/2011; 1812(12):1640-8.

  The low-density-lipoprotein receptor megalin (LRP2, gp330) is strongly expressed in the kidney, where it is responsible for the resorption of metabolites from primary urine. One of the main ligandsThe low-density-lipoprotein receptor megalin (LRP2, gp330) is strongly expressed in the kidney, where it is responsible for the resorption of metabolites from primary urine. One of the main ligands is the complex of retinol and retinol binding protein. Megalin has been hypothesized to be part of the retinol storage system in liver. Considering the role of hepatic stellate cells in retinol storage and fibrogenesis we investigated mouse strains that developed different degrees of fibrosis after challenge with CCl(4). Immunoblotting revealed the invariable expression of the megalin C-terminal fragment independent of liver damage in all strains. However, only a specific cell population in centrilobular areas of fibrotic livers from DBA/2J mice, which were most susceptible for CCl(4)-induced fibrogenesis in our study, was stained using megalin-specific antibodies. Double immunostaining indicated that a subset of hepatic macrophages might represent the megalin-expressing cells in fibrotic liver. Fluorescence activated cell sorting based isolation of hepatic macrophages and megalin specific expression analysis demonstrated the transcription of the whole megalin gene in liver macrophages. We argue that megalin might exhibit a proinflammatory effect by the uptake of retinoids in recruited monocytes, which thereby differentiate to liver macrophages and potentiate fibrogenesis by the release of proinflammatory mediators. Otherwise, megalin might be activated in macrophages during advanced fibrogenesis and act as a negative regulator of proinflammatory genes.

• Metastatic lobular breast cancer presenting as gastric linitis plastica.

  Authors: Monica Rusticeanu, Michael Schuster, Simona L Moga, Erich-Franz Solomayer, Rainer M Bohle, Frank Lammert, Vincent Zimmer

  The American journal of medicine. 07/2011; 124(7):e5-6.

• Invasion of a fundoplication sleeve by esophageal squamous-cell carcinoma.

  Authors: Vincent Zimmer, Jens Kraemer, Arno Buecker, Martin K Schilling, Frank Lammert, Markus Menges

  Gastrointestinal cancer research : GCR. 05/2011; 4(3):109-10.

• Dissecting the genetic heterogeneity of gallbladder stone formation.

  Authors: Marcin Krawczyk, David Q-H Wang, Piero Portincasa, Frank Lammert

  Seminars in liver disease. 05/2011; 31(2):157-72.

  Gallstone disease affects almost 20% of individuals in Westernized countries. As its incidence in the developing countries is rising considerably, currently, it is the second most commonGallstone disease affects almost 20% of individuals in Westernized countries. As its incidence in the developing countries is rising considerably, currently, it is the second most common gastroenterological condition worldwide. Gallstone formation is driven by an interaction between genetic and environmental risk factors. Previous studies have demonstrated that the genetic background accounts for ~25% of the total disease risk. Linkage and case-control studies of candidate genes and recent genome-wide studies have identified multiple lithogenic genes, in particular the hepatocanalicular cholesterol transporter ABCG5/G8 and the bilirubin conjugating enzyme UGT1A1, as major genetic determinants of gallstones in humans. In this review, we summarize the recent findings related to the genetics of cholelithiasis, update the "inventory" of human lithogenic genes, and relate the genetic studies to the pathobiologic background of the disease. In closing, future applications of genetic testing for gallstone carriers and asymptomatic family members are addressed.

• Cancer risk in chronic hepatitis B: Do genome-wide association studies hit the mark?

  Authors: Markus Casper, Frank Grünhage, Frank Lammert

  Hepatology (Baltimore, Md.). 04/2011; 53(4):1390-2.

  To identify susceptibility variants for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we conducted a genome-wide association study by genotyping 440,794 SNPs in 355 chronic HBVTo identify susceptibility variants for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we conducted a genome-wide association study by genotyping 440,794 SNPs in 355 chronic HBV carriers with HCC and 360 chronic HBV carriers without HCC, all of Chinese ancestry. We identified one intronic SNP (rs17401966) in KIF1B on chromosome 1p36.22 that was highly associated with HBV-related HCC and confirmed this association in five additional independent samples, consisting of 1,962 individuals with HCC, 1,430 control subjects and 159 family trios. Across the six studies, the association with rs17401966 was highly statistically significant (joint odds ratio = 0.61, P = 1.7 × 10(-18) ). In addition to KIF1B, the association region tagged two other plausible causative genes, UBE4B and PGD. Our findings provide evidence that the 1p36.22 locus confers susceptibility to HBV-related HCC, and suggest that KIF1B-, UBE4B- or PGD-related pathways might be involved in the pathogenesis of this malignancy.

• Genetics and epigenetics in the fibrogenic evolution of chronic liver diseases.

  Authors: Vincent Zimmer, Frank Lammert

  Best practice & research. Clinical gastroenterology. 04/2011; 25(2):269-80.

  Recent years have seen unprecedented progress in the identification and characterization of genetic information related to chronic liver diseases (CLDs). However, despite the conceptual benefit inRecent years have seen unprecedented progress in the identification and characterization of genetic information related to chronic liver diseases (CLDs). However, despite the conceptual benefit in early recognition of at-risk populations amenable to pre-emptive treatment and/or surveillance strategies, recent genomic research in the field has placed focus on unravelling the genetic architecture of disease susceptibility, while data on genetic markers anticipating an accelerated fibrogenesis in an individual are still limited. Likewise, sequence variation assigning rapid fibrogenic evolution common to CLDs irrespective of etiology are poorly defined aside from PNPLA3 (adiponutrin) as a prominent exception. The emerging field of epigenetics in hepatology has mostly been studied under the perspective of gene regulation, less so as a heritable alteration in gene activity. In this article we will critically discuss recent findings in genomic hepatology with special focus on the (epi)genetic contribution to the fibrogenic evolution of CLDs.

• Multiple complicated gallbladder disease.

  Authors: Vincent Zimmer, Jochen Raedle, Rainer Grobholz, Alexander Massmann, Martin K Schilling, Frank Lammert

  Journal of gastrointestinal and liver diseases : JGLD. 03/2011; 20(1):98-9.

• Genetics in liver disease: new concepts.

  Authors: Vincent Zimmer, Frank Lammert

  Current opinion in gastroenterology. 03/2011; 27(3):231-9.

  Recent advancements in genotyping technology have contributed to an accelerated dissemination of information on sequence variation associated with hepatobiliary diseases and/or quantitativeRecent advancements in genotyping technology have contributed to an accelerated dissemination of information on sequence variation associated with hepatobiliary diseases and/or quantitative traits. Since the first genome-wide association study (GWAS) on genetic gallstone risk in 2007, a total of more than 25 GWAS related to the field have been reported. The identification of the IL-28B genotype as a critical host factor of natural and treatment-related outcomes in hepatitis C virus infection opens the avenue of personalized medicine and individual risk assessment by genetic information. By contrast, the second recent top-hit variant adiponutrin (PNPLA3) associated with liver fat content and fibrosis progression illustrates the potential of GWAS to identify novel pathobiological pathways. Another emerging research topic is in the designation of genetic markers for specific cirrhosis-related complications, such as spontaneous bacterial peritonitis (NOD2) and hepatic encephalopathy (glutaminase), of potential future relevance in prioritizing patients for preemptive treatment strategies. In this article we critically discuss new concepts in the genetics of hepatobiliary diseases with a special focus on the advantages and limitations of the GWAS approach. An update on relevant recent GWAS and selected candidate gene study data will be given.

• Genetics of liver injury and fibrosis.

  Authors: Susanne N Weber, Frank Lammert

  Alcoholism, clinical and experimental research. 02/2011; 35(5):800-3.

  Genetic risk factors play critical roles in liver injury and fibrosis, since both initiation and progression of chronic liver diseases differ between individuals challenged by identical environmentalGenetic risk factors play critical roles in liver injury and fibrosis, since both initiation and progression of chronic liver diseases differ between individuals challenged by identical environmental factors. Recently genomewide association studies have identified specific novel risk genes for (non-alcoholic) fatty liver disease (adiponutrin), viral hepatitis (interleukin 28B), and chronic cholestatic diseases (interleukin 12). Here, we summarize these studies and provide an inventory of the susceptibility genes. In the future, risk assessment of complex liver diseases might be based on polygenic risk scores or even gene networks. Complimentary to study in humans, experimental crosses of inbred mouse strains contribute to the genetic dissection of gene-gene interaction and gene-environment interactions. The results of these genomewide studies in mice and men might open new avenues for the prevention and treatment of chronic liver injury and the regression of liver fibrosis.

• One less ulcer, one extra pylorus.

  Authors: Vincent Zimmer, Marc Dauer, Frank Lammert

  Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 01/2011; 43(7):e13.

• A stomach carpeted red.

  Authors: Vincent Zimmer, Frank Grünhage, Bernhard Jüngling, Jens Kraemer, Rainer M Bohle, Frank Lammert

  Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 01/2011; 43(4):334-5.

• An update on genetic analysis of cholestatic liver diseases: digging deeper.

  Authors: Roman Müllenbach, Frank Lammert

  Digestive diseases (Basel, Switzerland). 01/2011; 29(1):72-7.

  Investigations into the molecular mechanisms of cholestasis have revealed intricate and intriguing details of bile salt metabolism as well as its regulatory mechanisms in health and disease.Investigations into the molecular mechanisms of cholestasis have revealed intricate and intriguing details of bile salt metabolism as well as its regulatory mechanisms in health and disease. Extensive studies on genotype-phenotype correlations in monogenic diseases, such as progressive familial and benign recurrent intrahepatic cholestasis, facilitate diagnostics and improve the risk assessment of hepatobiliary transporter gene variants in bile transport pathophysiology. While the comparatively easy targets in monogenic cholestasis have been identified for some time now, progress in complex liver disease is rather laborious but steady. Genome-wide association scans are the next step in gathering information about common contributors towards polygenic (multifactorial) cholestatic diseases. New determinants of bile salt metabolism affecting feedback loops within the liver or the enterohepatic circulation are presently under investigation for their contribution towards complex cholestatic syndromes.