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1. Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ)

Author

Fromme, Malin, Hamesch, Karim, Schneider, Carolin V., Mandorfer, Mattias, Pons, Monica, Thorhauge, Katrine H., Pereira, Vitor, Sperl, Jan, Frankova, Sona, Reichert, Matthias C., Benini, Federica, Burbaum, Barbara, Kleinjans, Moritz, Amzou, Samira, Rademacher, Laura, Bewersdorf, Lisa, Verbeek, Jef, Nevens, Frederik, Genesca, Joan, Miravitlles, Marc, Nuñez, Alexa, Schaefer, Benedikt, Zoller, Heinz, Janciauskiene, Sabina, Waern, Johan, Oliveira, António, Maia, Luís, Simões, Carolina, Mahadeva, Ravi, Fraughen, Daniel D., Trauner, Michael, Krag, Aleksander, Lammert, Frank, Bals, Robert, Gaisa, Nadine T., Aigner, Elmar, Griffiths, William J., Denk, Helmut, Teumer, Alexander, McElvaney, Noel G., Turner, Alice M., Trautwein, Christian, and Strnad, Pavel

Published
2024
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2. TNF-related apoptosis-inducing ligand, interferon gamma-induced protein 10, and C-reactive protein in predicting the progression of SARS-CoV-2 infection: a prospective cohort study

Author

Tegethoff, Sina A., Danziger, Guy, Kühn, Dennis, Kimmer, Charlotte, Adams, Thomas, Heintz, Lena, Metz, Carlos, Reifenrath, Katharina, Angresius, Rebecca, Mang, Sebastian, Rixecker, Torben, Becker, André, Geisel, Jürgen, Jentgen, Christophe, Seiler, Frederik, Reichert, Matthias C., Fröhlich, Franziska, Meyer, Sascha, Rissland, Jürgen, Ewen, Sebastian, Wagenpfeil, Gudrun, Last, Katharina, Smola, Sigrun, Bals, Robert, Lammert, Frank, Becker, Sören L., Krawczyk, Marcin, Lepper, Philipp M., and Papan, Cihan

Published
2022
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4. Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation

Author

Hamesch, Karim, Mandorfer, Mattias, Pereira, Vítor M., Moeller, Linda S., Pons, Monica, Dolman, Grace E., Reichert, Matthias C., Schneider, Carolin V., Woditsch, Vivien, Voss, Jessica, Lindhauer, Cecilia, Fromme, Malin, Spivak, Igor, Guldiken, Nurdan, Zhou, Biaohuan, Arslanow, Anita, Schaefer, Benedikt, Zoller, Heinz, Aigner, Elmar, Reiberger, Thomas, Wetzel, Martin, Siegmund, Britta, Simões, Carolina, Gaspar, Rui, Maia, Luís, Costa, Dalila, Bento-Miranda, Mário, van Helden, Josef, Yagmur, Eray, Bzdok, Danilo, Stolk, Jan, Gleiber, Wolfgang, Knipel, Verena, Windisch, Wolfram, Mahadeva, Ravi, Bals, Robert, Koczulla, Rembert, Barrecheguren, Miriam, Miravitlles, Marc, Janciauskiene, Sabina, Stickel, Felix, Lammert, Frank, Liberal, Rodrigo, Genesca, Joan, Griffiths, William J., Trauner, Michael, Krag, Aleksander, Trautwein, Christian, and Strnad, Pavel

Published
2019
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5. Alpha-1 antitrypsin (AAT) augmentation and the liver phenotype of adults with AAT deficiency (genotype Pi*ZZ)

Author

Fromme, Malin, primary, Hamesch, Karim, additional, Schneider, Carolin V., additional, Mandorfer, Mattias, additional, Pons, Monica, additional, Thorhauge, Katrine, additional, Pereira, Vitor, additional, Sperl, Jan, additional, Frankova, Sona, additional, Reichert, Matthias C., additional, Benini, Federica, additional, Burbaum, Barbara, additional, Kleinjans, Moritz, additional, Amzou, Samira, additional, Rademacher, Laura, additional, Bewersdorf, Lisa, additional, Verbeek, Jef, additional, Nevens, Frederik, additional, Genesca, Joan, additional, Miravitlles, Marc, additional, Nuñez, Alexa, additional, Schaefer, Benedikt, additional, Zoller, Heinz, additional, Janciauskiene, Sabina, additional, Waern, Johan, additional, Oliveira, António, additional, Maia, Luís, additional, Simões, Carolina, additional, Mahadeva, Ravi, additional, Fraughen, Daniel D., additional, Trauner, Michael, additional, Krag, Aleksander, additional, Lammert, Frank, additional, Bals, Robert, additional, Gaisa, Nadine T., additional, Aigner, Elmar, additional, Griffiths, William J., additional, Denk, Helmut, additional, Teumer, Alexander, additional, McElvaney, Noel G., additional, Turner, Alice M., additional, Trautwein, Christian, additional, and Strnad, Pavel, additional

Published
2023
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6. Common variation in FAM155A is associated with diverticulitis but not diverticulosis

Author

Reichert, Matthias C., Kupcinskas, Juozas, Schulz, Antje, Schramm, Christoph, Weber, Susanne N., Krawczyk, Marcin, Jüngst, Christoph, Casper, Markus, Grünhage, Frank, Appenrodt, Beate, Zimmer, Vincent, Tamelis, Algimantas, Lukosiene, Jaune I., Pauziene, Neringa, Kiudelis, Gediminas, Jonaitis, Laimas, Goeser, Tobias, Malinowski, Maciej, Glanemann, Matthias, Kupcinskas, Limas, and Lammert, Frank

Published
2020
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13. rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

Author

Teo, Kevin, Abeysekera, Kushala WM, Adams, Leon, Aigner, Elmar, Anstee, Quentin M, Banales, Jesus M, Banerjee, Rajarshi, Basu, Priyadarshi, Berg, Thomas, Bhatnagar, Pallav, Buch, Stephan, Canbay, Ali, Caprio, Sonia, Chatterjee, Ankita, Ida Chen, Yii-Der, Chowdhury, Abhijit, Daly, Ann K, Datz, Christian, de Gracia Hahn, Dana, DiStefano, Johanna K, Dong, Jiawen, Duret, Amedine, EU-PNAFLD Investigators, Emdin, Connor, Fairey, Madison, Gerhard, Glenn S, GOLD Consortium, Guo, Xiuqing, Hampe, Jochen, Hickman, Matthew, Heintz, Lena, Hudert, Christian, Hunter, Harriet, Kelly, Matt, Kozlitina, Julia, Krawczyk, Marcin, Lammert, Frank, Langenberg, Claudia, Lavine, Joel, Li, Lin, Lim, Hong Kai, Loomba, Rohit, Luukkonen, Panu K, Melton, Phillip E, Mori, Trevor A, Palmer, Nicholette D, Parisinos, Constantinos A, Pillai, Sreekumar G, Qayyum, Faiza, Reichert, Matthias C, Romeo, Stefano, Rotter, Jerome I, Im, Yu Ri, Santoro, Nicola, Schafmayer, Clemens, Speliotes, Elizabeth K, Stender, Stefan, Stickel, Felix, Still, Christopher D, Strnad, Pavel, Taylor, Kent D, Tybjærg-Hansen, Anne, Umano, Giuseppina Rosaria, Utukuri, Mrudula, Valenti, Luca, Wagenknecht, Lynne E, Wareham, Nicholas J, Watanabe, Richard M, Wattacheril, Julia, Yaghootkar, Hanieh, Yki-Järvinen, Hannele, Young, Kendra A, Mann, Jake P, Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Mann, Jake [0000-0002-4711-9215], and Apollo - University of Cambridge Repository

Subjects
Liver Cirrhosis, Diabetes, Membrane Proteins, Alanine Transaminase, ALSPAC, Fibrosis, Triglyceride, Polymorphism, Single Nucleotide, MBOAT7, Liver, Non-alcoholic Fatty Liver Disease, NAFLD, Drug Discovery, Humans, Genetic Predisposition to Disease, Acyltransferases
Abstract

BACKGROUND & AIMS: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in 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 to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. METHODS: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a 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 = 4.8×10-5) and diagnosis of NAFLD (odds ratio [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 = 1.5×10-4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. CONCLUSIONS: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. LAY SUMMARY: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.

Published
2021

14. Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality

Author

Schunk, Stefan J., Kleber, Marcus E., März, Winfried, Pang, Shichao, Zewinger, Stephen, Triem, Sarah, Ege, Philipp, Reichert, Matthias C., Krawczyk, Marcin, Weber, Susanne N., Jaumann, Isabella, Schmit, David, Sarakpi, Tamim, Wagenpfeil, Stefan, Kramann, Rafael, Boerwinkle, Eric, Ballantyne, Christie M., Grove, Megan L., Tragante, Vinicius, Pilbrow, Anna P., Richards, A. Mark, Cameron, Vicky A., Doughty, Robert N., Dubé, Marie-Pierre, Tardif, Jean-Claude, Feroz-Zada, Yassamin, Sun, Maxine, Liu, Chang, Ko, Yi-An, Quyyumi, Arshed A., Hartiala, Jaana A., Tang, W. H. Wilson, Hazen, Stanley L., Allayee, Hooman, McDonough, Caitrin W., Gong, Yan, Cooper-DeHoff, Rhonda M., Johnson, Julie A., Scholz, Markus, Teren, Andrej, Burkhardt, Ralph, Martinsson, Andreas, Smith, J. Gustav, Wallentin, Lars, James, Stefan K., Eriksson, Niclas, White, Harvey, Held, Claes, Waterworth, Dawn, Trompet, Stella, Jukema, J. Wouter, Ford, Ian, Stott, David J., Sattar, Naveed, Cresci, Sharon, Spertus, John A., Campbell, Hannah, Tierling, Sascha, Walter, Jörn, Ampofo, Emmanuel, Niemeyer, Barbara A., Lipp, Peter, Schunkert, Heribert, Böhm, Michael, Koenig, Wolfgang, Fliser, Danilo, Laufs, Ulrich, Speer, Thimoteus, Schunk, Stefan J., Kleber, Marcus E., März, Winfried, Pang, Shichao, Zewinger, Stephen, Triem, Sarah, Ege, Philipp, Reichert, Matthias C., Krawczyk, Marcin, Weber, Susanne N., Jaumann, Isabella, Schmit, David, Sarakpi, Tamim, Wagenpfeil, Stefan, Kramann, Rafael, Boerwinkle, Eric, Ballantyne, Christie M., Grove, Megan L., Tragante, Vinicius, Pilbrow, Anna P., Richards, A. Mark, Cameron, Vicky A., Doughty, Robert N., Dubé, Marie-Pierre, Tardif, Jean-Claude, Feroz-Zada, Yassamin, Sun, Maxine, Liu, Chang, Ko, Yi-An, Quyyumi, Arshed A., Hartiala, Jaana A., Tang, W. H. Wilson, Hazen, Stanley L., Allayee, Hooman, McDonough, Caitrin W., Gong, Yan, Cooper-DeHoff, Rhonda M., Johnson, Julie A., Scholz, Markus, Teren, Andrej, Burkhardt, Ralph, Martinsson, Andreas, Smith, J. Gustav, Wallentin, Lars, James, Stefan K., Eriksson, Niclas, White, Harvey, Held, Claes, Waterworth, Dawn, Trompet, Stella, Jukema, J. Wouter, Ford, Ian, Stott, David J., Sattar, Naveed, Cresci, Sharon, Spertus, John A., Campbell, Hannah, Tierling, Sascha, Walter, Jörn, Ampofo, Emmanuel, Niemeyer, Barbara A., Lipp, Peter, Schunkert, Heribert, Böhm, Michael, Koenig, Wolfgang, Fliser, Danilo, Laufs, Ulrich, and Speer, Thimoteus

Abstract

Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

Published
2021
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15. rs641738C>T nearMBOAT7is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

Author

Medicina, Medikuntza, Teo, Kevin, Abeysekera, Kushala W.M., Adams, Leon, Aigner, Elmar, Anstee, Quentin M., Bañales Asurmendi, Jesús María, Banerjee, Rajarshi, Basu, Priyadarshi, Berg, Thomas, Bhatnagar, Pallav, Buch, Stephan, Canbay, Ali, Caprio, Sonia, Chatterjee, Ankita, Chen, Yii-Der Ida, Chowdhury, Abhijit, Daly, Ann K., Datz, Christian, De Gracia Hahn, Dana, DiStefano, Johanna K., Dong, Jiawen, Duret, Amedine, EU-PNAFLD Investigators, Emdin, Connor, Fairey, Madison, Gerhard, Glenn S., GOLD Consortium, Guo, Xiuqing, Hampe, Jochen, Hickman, Matthew, Heintz, Lena, Hudert, Christian, Hunter, Harriet, Kelly, Matt, Kozlitina, Julia, Krawczyk, Marcin, Lammert, Frank, Langenberg, Claudia, Lavine, Joel, Li, Lin, Lim, Hong Kai, Loomba, Rohit, Luukkonen, Panu K., Melton, Phillip E., Mori, Trevor A., Palmer, Nicholette D., Parisinos, Constantinos A., Pillai, Sreekumar G., Qayyum, Faiza, Reichert, Matthias C., Romeo, Stefano, Rotter, Jerome I., Im, Yu Ri, Santoro, Nicola, Schafmayer, Clemens, Speliotes, Elizabeth K., Stender, Stefan, Stickel, Felix, Still, Christopher D., Strnad, Pavel, Taylor, Kent D., Tybjærg-Hansen, Anne, Umano, Giuseppina Rosaria, Utukuri, Mrudula, Valenti, Luca, Wagenknecht, Lynne E., Wareham, Nicholas J., Watanabe, Richard M., Wattacheril, Julia, Yaghootkar, Hanieh, Yki-Järvinen, Hannele, Young, Kendra A., Mann, Jake P., Medicina, Medikuntza, Teo, Kevin, Abeysekera, Kushala W.M., Adams, Leon, Aigner, Elmar, Anstee, Quentin M., Bañales Asurmendi, Jesús María, Banerjee, Rajarshi, Basu, Priyadarshi, Berg, Thomas, Bhatnagar, Pallav, Buch, Stephan, Canbay, Ali, Caprio, Sonia, Chatterjee, Ankita, Chen, Yii-Der Ida, Chowdhury, Abhijit, Daly, Ann K., Datz, Christian, De Gracia Hahn, Dana, DiStefano, Johanna K., Dong, Jiawen, Duret, Amedine, EU-PNAFLD Investigators, Emdin, Connor, Fairey, Madison, Gerhard, Glenn S., GOLD Consortium, Guo, Xiuqing, Hampe, Jochen, Hickman, Matthew, Heintz, Lena, Hudert, Christian, Hunter, Harriet, Kelly, Matt, Kozlitina, Julia, Krawczyk, Marcin, Lammert, Frank, Langenberg, Claudia, Lavine, Joel, Li, Lin, Lim, Hong Kai, Loomba, Rohit, Luukkonen, Panu K., Melton, Phillip E., Mori, Trevor A., Palmer, Nicholette D., Parisinos, Constantinos A., Pillai, Sreekumar G., Qayyum, Faiza, Reichert, Matthias C., Romeo, Stefano, Rotter, Jerome I., Im, Yu Ri, Santoro, Nicola, Schafmayer, Clemens, Speliotes, Elizabeth K., Stender, Stefan, Stickel, Felix, Still, Christopher D., Strnad, Pavel, Taylor, Kent D., Tybjærg-Hansen, Anne, Umano, Giuseppina Rosaria, Utukuri, Mrudula, Valenti, Luca, Wagenknecht, Lynne E., Wareham, Nicholas J., Watanabe, Richard M., Wattacheril, Julia, Yaghootkar, Hanieh, Yki-Järvinen, Hannele, Young, Kendra A., and Mann, Jake P.

Abstract

Background & Aims: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in 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 to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. Methods: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a 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], p(z) = 4.8x10(-5)) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], p(z) = 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], p(z) = 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 (p(z) = 0.002) and lower serum triglycerides (p(z) = 1.5x10(-4)). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. Conclusions: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. Lay summary: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes

Published
2021

17. Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency

Author

Fromme, Malin, primary, Schneider, Carolin V, additional, Pereira, Vitor, additional, Hamesch, Karim, additional, Pons, Monica, additional, Reichert, Matthias C, additional, Benini, Federica, additional, Ellis, Paul, additional, H Thorhauge, Katrine, additional, Mandorfer, Mattias, additional, Burbaum, Barbara, additional, Woditsch, Vivien, additional, Chorostowska-Wynimko, Joanna, additional, Verbeek, Jef, additional, Nevens, Frederik, additional, Genesca, Joan, additional, Miravitlles, Marc, additional, Nuñez, Alexa, additional, Schaefer, Benedikt, additional, Zoller, Heinz, additional, Janciauskiene, Sabina, additional, Abreu, Nélia, additional, Jasmins, Luís, additional, Gaspar, Rui, additional, Liberal, Rodrigo, additional, Macedo, Guilherme, additional, Mahadeva, Ravi, additional, Gomes, Catarina, additional, Schneider, Kai Markus, additional, Trauner, Michael, additional, Krag, Aleksander, additional, Gooptu, Bibek, additional, Thorburn, Douglas, additional, Marshall, Aileen, additional, Hurst, John R, additional, Lomas, David A, additional, Lammert, Frank, additional, Gaisa, Nadine T, additional, Clark, Virginia, additional, Griffiths, William, additional, Trautwein, Christian, additional, Turner, Alice M, additional, McElvaney, Noel G, additional, and Strnad, Pavel, additional

Published
2021
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18. Common variation in FAM155A is associated with diverticulitis but not diverticulosis

Author

Reichert, Matthias C; https://orcid.org/0000-0002-8192-0575, Kupcinskas, Juozas, Schulz, Antje, Schramm, Christoph; https://orcid.org/0000-0001-6752-0690, Weber, Susanne N, Krawczyk, Marcin, Jüngst, Christoph, Casper, Markus, Grünhage, Frank, Appenrodt, Beate, Zimmer, Vincent, Tamelis, Algimantas, Lukosiene, Jaune I, Pauziene, Neringa, Kiudelis, Gediminas, Jonaitis, Laimas, Goeser, Tobias, Malinowski, Maciej, Glanemann, Matthias, Kupcinskas, Limas, Lammert, Frank, Reichert, Matthias C; https://orcid.org/0000-0002-8192-0575, Kupcinskas, Juozas, Schulz, Antje, Schramm, Christoph; https://orcid.org/0000-0001-6752-0690, Weber, Susanne N, Krawczyk, Marcin, Jüngst, Christoph, Casper, Markus, Grünhage, Frank, Appenrodt, Beate, Zimmer, Vincent, Tamelis, Algimantas, Lukosiene, Jaune I, Pauziene, Neringa, Kiudelis, Gediminas, Jonaitis, Laimas, Goeser, Tobias, Malinowski, Maciej, Glanemann, Matthias, Kupcinskas, Limas, and Lammert, Frank

Abstract

Colonic diverticulosis is a very common condition. Many patients develop diverticulitis or other complications of diverticular disease. Recent genome-wide association studies (GWAS) consistently identified three major genetic susceptibility factors for both conditions, but did not discriminate diverticulititis and diverticulosis in particular due the limitations of registry-based approaches. Here, we aimed to confirm the role of the identified variants for diverticulosis and diverticulitis, respectively, within a well-phenotyped cohort of patients who underwent colonoscopy. Risk variants rs4662344 in Rho GTPase-activating protein 15 (ARHGAP15), rs7609897 in collagen-like tail subunit of asymmetric acetylcholinesterase (COLQ) and rs67153654 in family with sequence similarity 155 A (FAM155A) were genotyped in 1,332 patients. Diverticulosis was assessed by colonoscopy, and diverticulitis by imaging, clinical symptoms and inflammatory markers. Risk of diverticulosis and diverticulitis was analyzed in regression models adjusted for cofactors. Overall, the variant in FAM155A was associated with diverticulitis, but not diverticulosis, when controlling for age, BMI, alcohol consumption, and smoking status (OR$_{adjusted}$ 0.49 [95% CI 0.27-0.89], p = 0.002). Our results contribute to the assessment specific genetic variants identified in GWAS in the predisposition to the development of diverticulitis in patients with diverticulosis.

Published
2020

19. rs641738C>T near MBOAT7 promotes steatosis, NASH, fibrosis and hepatocellular carcinoma in non-alcoholic fatty liver disease: a meta-analysis

Author

Teo, Kevin, Abeysekera, Kushala WM, Adams, Leon, Aigner, Elmar, Banerjee, Rajarshi, Basu, Priyadarshi, Berg, Thomas, Bhatnagar, Pallav, Buch, Stephan, Canbay, Ali, Caprio, Sonia, Chatterjee, Ankita, Chen, Yii-Der Ida, Datz, Christian, de Gracia Hahn, Dana, DiStefano, Johanna K, Dong, Jiawen, Duret, Amedine, Emdin, Connor, Fairey, Madison, Gerhard, Glenn S, Guo, Xiuqing, Hampe, Jochen, Hickman, Matthew, Heintz, Lena, Hudert, Christian, Hunter, Harriet, Kelly, Matt, Kozlitina, Julia, Krawczyk, Marcin, Lammert, Frank, Langenberg, Claudia, Lavine, Joel, Lim, Hong Kai, Luukkonen, Panu, Melton, Philip E, Mori, Trevor A, Parisinos, Constantinos A, Pillai, Sreekumar G, Qayyum, Faiza, Reichert, Matthias C, Romeo, Stefano, Rotter, Jerome, Im, Yu Ri, Santoro, Nicola, Schafmayer, Clemens, Speliotes, Elizabeth K, Stender, Stefan, Stickel, Felix, Still, Christopher D, Strnad, Pavel, Taylor, Kent D, Tybjaerg-Hansen, Anne, Umano, Giuseppina Rosaria, Utukuri, Mrudula, Valenti, Luca, Wareham, Nicholas J, Wattacheril, Julia, Yki-Jarvinen, Hannele, and Mann, Jake P

Abstract

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. Therefore, we aimed to establish whether rs641738 is a risk factor for NAFLD through meta-analysis. Data from 134,015 participants (7,692 with liver biopsies and 50,680 with imaging) was included in the meta-analysis. The minor T-allele of rs641738C>T was associated with higher liver fat on CT/MRI using an additive genetic model (+0.05 standard deviations [95% CI: 0.01 - 0.09], p=0.025), and with an increased risk of NAFLD (per-allele OR: 1.08 [95% CI: 1.01 - 1.15]), nonalcoholic steatohepatitis (OR: 1.11 [95% CI: 1.02 - 1.21]), advanced fibrosis (OR: 1.14 [95% CI: 1.05 - 1.23]), and hepatocellular carcinoma (OR: 1.43 [95% CI: 1.22 - 1.67]) in adults with NAFLD. Sub-group analysis did not demonstrate a difference in Caucasians and non-Caucasians. Rs641738C>T was not associated with markers of insulin resistance but was associated with higher risk of stroke in the UK Biobank. These data validate rs641738C>T near MBOAT7 as a risk factor for the development, activity, and stage of NAFLD including hepatocellular carcinoma.

Published
2019
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20. rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

Author

Teo, Kevin, primary, Abeysekera, Kushala W.M., additional, Adams, Leon, additional, Aigner, Elmar, additional, Anstee, Quentin M., additional, Banales, Jesus M., additional, Banerjee, Rajarshi, additional, Basu, Priyadarshi, additional, Berg, Thomas, additional, Bhatnagar, Pallav, additional, Buch, Stephan, additional, Canbay, Ali, additional, Caprio, Sonia, additional, Chatterjee, Ankita, additional, Ida Chen, Yii-Der, additional, Chowdhury, Abhijit, additional, Daly, Ann K., additional, Datz, Christian, additional, de Gracia Hahn, Dana, additional, DiStefano, Johanna K., additional, Dong, Jiawen, additional, Duret, Amedine, additional, Emdin, Connor, additional, Fairey, Madison, additional, Gerhard, Glenn S., additional, Guo, Xiuqing, additional, Hampe, Jochen, additional, Hickman, Matthew, additional, Heintz, Lena, additional, Hudert, Christian, additional, Hunter, Harriet, additional, Kelly, Matt, additional, Kozlitina, Julia, additional, Krawczyk, Marcin, additional, Lammert, Frank, additional, Langenberg, Claudia, additional, Lavine, Joel, additional, Li, Lin, additional, Lim, Hong Kai, additional, Loomba, Rohit, additional, Luukkonen, Panu K., additional, Melton, Phillip E., additional, Mori, Trevor A., additional, Palmer, Nicholette D., additional, Parisinos, Constantinos A., additional, Pillai, Sreekumar G., additional, Qayyum, Faiza, additional, Reichert, Matthias C., additional, Romeo, Stefano, additional, Rotter, Jerome I., additional, Im, Yu Ri, additional, Santoro, Nicola, additional, Schafmayer, Clemens, additional, Speliotes, Elizabeth K., additional, Stender, Stefan, additional, Stickel, Felix, additional, Still, Christopher D., additional, Strnad, Pavel, additional, Taylor, Kent D., additional, Tybjærg-Hansen, Anne, additional, Umano, Giuseppina Rosaria, additional, Utukuri, Mrudula, additional, Valenti, Luca, additional, Wagenknecht, Lynne E., additional, Wareham, Nicholas J., additional, Watanabe, Richard M., additional, Wattacheril, Julia, additional, Yaghootkar, Hanieh, additional, Yki-Järvinen, Hannele, additional, Young, Kendra A., additional, Mann, Jake P., additional, Vreugdenhil, Anita, additional, Alisi, Anna, additional, Socha, Piotr, additional, Jańczyk, Wojciech, additional, Baumann, Ulrich, additional, Rajwal, Sanjay, additional, van Mourik, Indra, additional, Lacaille, Florence, additional, Dabbas, Myriam, additional, Kelly, Deirdre A., additional, Nobili, Valerio, additional, Eiriksdottir, Gudny, additional, Garcia, Melissa E., additional, Gudnason, Vilmundur, additional, Harris, Tamara B., additional, Kim, Lauren J., additional, Launer, Lenore J., additional, Nalls, Michael A., additional, Smith, Albert V., additional, Clark, Jeanne M., additional, Hernaez, Ruben, additional, Kao, W.H. Linda, additional, Mitchell, Braxton D., additional, Shuldiner, Alan R., additional, Yerges-Armstrong, Laura M., additional, Borecki, Ingrid B., additional, Carr, J. Jeffrey, additional, Feitosa, Mary F., additional, Wu, Jun, additional, Butler, Johannah L., additional, Fox, Caroline S., additional, Hirschhorn, Joel N., additional, Hoffmann, Udo, additional, Hwang, Shih-Jen, additional, Massaro, Joseph M., additional, O'Donnell, Christopher J., additional, Palmer, Cameron D., additional, and Sahani, Dushyant V., additional

Published
2021
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21. Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.

Author

Fromme, Malin, Schneider, Carolin V., Pereira, Vitor, Hamesch, Karim, Pons, Monica, Reichert, Matthias C., Benini, Federica, Ellis, Paul, Thorhauge, Katrine H., Mandorfer, Mattias, Burbaum, Barbara, Woditsch, Vivien, Chorostowska-Wynimko, Joanna, Verbeek, Jef, Nevens, Frederik, Genesca, Joan, Miravitlles, Marc, Nuñez, Alexa, Schaefer, Benedikt, and Zoller, Heinz

Subjects
FATTY liver, TYPE 2 diabetes, TRYPSIN inhibitors, MEDICAL personnel
Published
2022
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22. Clinical, histological, and biochemical liver phenotype of European adults with heterozygous alpha-1 antitrypsin deficiency (Pi*MZ genotype)

Author

Hamesch, Karim, primary, Heimes, Carolin Victoria, additional, Gross, Annika, additional, Mandorfer, Mattias, additional, Moeller, Linda S., additional, Pereira, Vítor, additional, Delgado, Monica Pons, additional, Kuca, Pawel, additional, Reichert, Matthias C., additional, Benini, Federica, additional, Lurje, Georg, additional, Genesca, Joan, additional, Lammert, Frank, additional, Krag, Aleksander, additional, Trauner, Michael, additional, Teumer, Alexander, additional, Gaisa, Nadine, additional, Denk, Helmut, additional, Trautwein, Christian, additional, Aigner, Elmar, additional, and Strnad, Pavel, additional

Published
2020
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23. Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers

Author

Schneider, Carolin V., primary, Hamesch, Karim, additional, Gross, Annika, additional, Mandorfer, Mattias, additional, Moeller, Linda S., additional, Pereira, Vitor, additional, Pons, Monica, additional, Kuca, Pawel, additional, Reichert, Matthias C., additional, Benini, Federica, additional, Burbaum, Barbara, additional, Voss, Jessica, additional, Gutberlet, Marla, additional, Woditsch, Vivien, additional, Lindhauer, Cecilia, additional, Fromme, Malin, additional, Kümpers, Julia, additional, Bewersdorf, Lisa, additional, Schaefer, Benedikt, additional, Eslam, Mohammed, additional, Bals, Robert, additional, Janciauskiene, Sabina, additional, Carvão, Joana, additional, Neureiter, Daniel, additional, Zhou, Biaohuan, additional, Wöran, Katharina, additional, Bantel, Heike, additional, Geier, Andreas, additional, Dirrichs, Timm, additional, Stickel, Felix, additional, Teumer, Alexander, additional, Verbeek, Jef, additional, Nevens, Frederik, additional, Govaere, Olivier, additional, Krawczyk, Marcin, additional, Roskams, Tania, additional, Haybaeck, Johannes, additional, Lurje, Georg, additional, Chorostowska-Wynimko, Joanna, additional, Genesca, Joan, additional, Reiberger, Thomas, additional, Lammert, Frank, additional, Krag, Aleksander, additional, George, Jacob, additional, Anstee, Quentin M., additional, Trauner, Michael, additional, Datz, Christian, additional, Gaisa, Nadine T., additional, Denk, Helmut, additional, Trautwein, Christian, additional, Aigner, Elmar, additional, and Strnad, Pavel, additional

Published
2020
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24. Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Author

Schafmayer, Clemens, Harrison, James William, Buch, Stephan, Lange, Christina, Reichert, Matthias C., Hofer, Philipp, Cossais, François, Kupcinskas, Juozas, von Schönfels, Witigo, Schniewind, Bodo, Kruis, Wolfgang, Tepel, Jürgen, Zobel, Myrko, Rosendahl, Jonas, Jacobi, Thorsten, Walther-Berends, Andreas, Schroeder, Michael, Vogel, Ilka, Sergeev, Petr, Boedeker, Hans, Hinrichsen, Holger, Volk, Andreas, Erk, Jens-Uwe, Burmeister, Greta, Hendricks, Alexander, Hinz, Sebastian, Wolff, Sebastian, Böttner, Martina, Wood, Andrew R., Tyrrell, Jessica, Beaumont, Robin N., Langheinrich, Melanie, Kucharzik, Torsten, Brezina, Stefanie, Huber-Schönauer, Ursula, Pietsch, Leonora, Noack, Laura Sophie, Brosch, Mario, Herrmann, Alexander, Thangapandi, Raghavan Veera, Schimming, Hans Wolfgang, Zeissig, Sebastian, Palm, Stefan, Focke, Gerd, Andreasson, Anna, Schmidt, Peter T., Weitz, Juergen, Krawczak, Michael, Völzke, Henry, Leeb, Gernot, Michl, Patrick, Lieb, Wolfgang, Grützmann, Robert, Franke, Andre, Lammert, Frank, Becker, Thomas, Kupcinskas, Limas, D'Amato, Mauro, Wedel, Thilo, Datz, Christian, Gsur, Andrea, Weedon, Michael N., Hampe, Jochen, Schafmayer, Clemens, Harrison, James William, Buch, Stephan, Lange, Christina, Reichert, Matthias C., Hofer, Philipp, Cossais, François, Kupcinskas, Juozas, von Schönfels, Witigo, Schniewind, Bodo, Kruis, Wolfgang, Tepel, Jürgen, Zobel, Myrko, Rosendahl, Jonas, Jacobi, Thorsten, Walther-Berends, Andreas, Schroeder, Michael, Vogel, Ilka, Sergeev, Petr, Boedeker, Hans, Hinrichsen, Holger, Volk, Andreas, Erk, Jens-Uwe, Burmeister, Greta, Hendricks, Alexander, Hinz, Sebastian, Wolff, Sebastian, Böttner, Martina, Wood, Andrew R., Tyrrell, Jessica, Beaumont, Robin N., Langheinrich, Melanie, Kucharzik, Torsten, Brezina, Stefanie, Huber-Schönauer, Ursula, Pietsch, Leonora, Noack, Laura Sophie, Brosch, Mario, Herrmann, Alexander, Thangapandi, Raghavan Veera, Schimming, Hans Wolfgang, Zeissig, Sebastian, Palm, Stefan, Focke, Gerd, Andreasson, Anna, Schmidt, Peter T., Weitz, Juergen, Krawczak, Michael, Völzke, Henry, Leeb, Gernot, Michl, Patrick, Lieb, Wolfgang, Grützmann, Robert, Franke, Andre, Lammert, Frank, Becker, Thomas, Kupcinskas, Limas, D'Amato, Mauro, Wedel, Thilo, Datz, Christian, Gsur, Andrea, Weedon, Michael N., and Hampe, Jochen

Abstract

Objective Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. Design Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. Results We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p< 0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3x10-10 and 0.002 (OR allelic = 1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). Conclusion I n silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

Published
2019
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25. Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

Author

Strnad, Pavel, Buch, Stephan, Hamesch, Karim, Fischer, Janett, Rosendahl, Jonas, Schmelz, Renate, Brueckner, Stefan, Brosch, Mario, Heimes, Carolin V., Woditsch, Vivien, Scholten, David, Nischalke, Hans Dieter, Janciauskiene, Sabina, Mandorfer, Mattias, Trauner, Michael, Way, Michael J., McQuillin, Andrew, Reichert, Matthias C., Krawczyk, Marcin, Casper, Markus, Lammert, Frank, von Schoenfels, Witigo, Hinz, Sebastian, Burmeister, Greta, Hellerbrand, Claus, Teufel, Andreas, Feldman, Alexandra, Schattenberg, Joern M., Bantel, Heike, Pathil, Anita, Demir, Muenevver, Kluwe, Johannes, Boettler, Tobias, Ridinger, Monika, Wodarz, Norbert, Soyka, Michael, Rietschel, Marcella, Kiefer, Falk, Weber, Thomas, Marhenke, Silke, Vogel, Arndt, Hinrichsen, Holger, Canbay, Ali, Schlattjan, Martin, Sosnowsky, Katharina, Sarrazin, Christoph, von Felden, Johann, Geier, Andreas, Deltenre, Pierre, Sipos, Bence, Schafmayer, Clemens, Nothnagel, Michael, Aigner, Elmar, Datz, Christian, Stickel, Felix, Morgan, Marsha Yvonne, Hampe, Jochen, Berg, Thomas, Trautwein, Christian, Strnad, Pavel, Buch, Stephan, Hamesch, Karim, Fischer, Janett, Rosendahl, Jonas, Schmelz, Renate, Brueckner, Stefan, Brosch, Mario, Heimes, Carolin V., Woditsch, Vivien, Scholten, David, Nischalke, Hans Dieter, Janciauskiene, Sabina, Mandorfer, Mattias, Trauner, Michael, Way, Michael J., McQuillin, Andrew, Reichert, Matthias C., Krawczyk, Marcin, Casper, Markus, Lammert, Frank, von Schoenfels, Witigo, Hinz, Sebastian, Burmeister, Greta, Hellerbrand, Claus, Teufel, Andreas, Feldman, Alexandra, Schattenberg, Joern M., Bantel, Heike, Pathil, Anita, Demir, Muenevver, Kluwe, Johannes, Boettler, Tobias, Ridinger, Monika, Wodarz, Norbert, Soyka, Michael, Rietschel, Marcella, Kiefer, Falk, Weber, Thomas, Marhenke, Silke, Vogel, Arndt, Hinrichsen, Holger, Canbay, Ali, Schlattjan, Martin, Sosnowsky, Katharina, Sarrazin, Christoph, von Felden, Johann, Geier, Andreas, Deltenre, Pierre, Sipos, Bence, Schafmayer, Clemens, Nothnagel, Michael, Aigner, Elmar, Datz, Christian, Stickel, Felix, Morgan, Marsha Yvonne, Hampe, Jochen, Berg, Thomas, and Trautwein, Christian

Abstract

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 T he 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 NAFLDrelated cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). Conclusion T he 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.

Published
2019

26. Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.

Author

Schunk, Stefan J, Kleber, Marcus E, März, Winfried, Pang, Shichao, Zewinger, Stephen, Triem, Sarah, Ege, Philipp, Reichert, Matthias C, Krawczyk, Marcin, Weber, Susanne N, Jaumann, Isabella, Schmit, David, Sarakpi, Tamim, Wagenpfeil, Stefan, Kramann, Rafael, Boerwinkle, Eric, Ballantyne, Christie M, Grove, Megan L, Tragante, Vinicius, and Pilbrow, Anna P

Subjects
INFLAMMATION, CARDIOVASCULAR diseases, ATHEROSCLEROSIS, ANIMAL models in research, MONOCYTES
Abstract

Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target. [ABSTRACT FROM AUTHOR]

Published
2021
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27. Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms

Author

Schafmayer, Clemens, primary, Harrison, James William, additional, Buch, Stephan, additional, Lange, Christina, additional, Reichert, Matthias C, additional, Hofer, Philipp, additional, Cossais, François, additional, Kupcinskas, Juozas, additional, von Schönfels, Witigo, additional, Schniewind, Bodo, additional, Kruis, Wolfgang, additional, Tepel, Jürgen, additional, Zobel, Myrko, additional, Rosendahl, Jonas, additional, Jacobi, Thorsten, additional, Walther-Berends, Andreas, additional, Schroeder, Michael, additional, Vogel, Ilka, additional, Sergeev, Petr, additional, Boedeker, Hans, additional, Hinrichsen, Holger, additional, Volk, Andreas, additional, Erk, Jens-Uwe, additional, Burmeister, Greta, additional, Hendricks, Alexander, additional, Hinz, Sebastian, additional, Wolff, Sebastian, additional, Böttner, Martina, additional, Wood, Andrew R, additional, Tyrrell, Jessica, additional, Beaumont, Robin N, additional, Langheinrich, Melanie, additional, Kucharzik, Torsten, additional, Brezina, Stefanie, additional, Huber-Schönauer, Ursula, additional, Pietsch, Leonora, additional, Noack, Laura Sophie, additional, Brosch, Mario, additional, Herrmann, Alexander, additional, Thangapandi, Raghavan Veera, additional, Schimming, Hans Wolfgang, additional, Zeissig, Sebastian, additional, Palm, Stefan, additional, Focke, Gerd, additional, Andreasson, Anna, additional, Schmidt, Peter T, additional, Weitz, Juergen, additional, Krawczak, Michael, additional, Völzke, Henry, additional, Leeb, Gernot, additional, Michl, Patrick, additional, Lieb, Wolfgang, additional, Grützmann, Robert, additional, Franke, Andre, additional, Lammert, Frank, additional, Becker, Thomas, additional, Kupcinskas, Limas, additional, D’Amato, Mauro, additional, Wedel, Thilo, additional, Datz, Christian, additional, Gsur, Andrea, additional, Weedon, Michael N, additional, and Hampe, Jochen, additional

Published
2019
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28. Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

Author

Strnad, Pavel, primary, Buch, Stephan, additional, Hamesch, Karim, additional, Fischer, Janett, additional, Rosendahl, Jonas, additional, Schmelz, Renate, additional, Brueckner, Stefan, additional, Brosch, Mario, additional, Heimes, Carolin V, additional, Woditsch, Vivien, additional, Scholten, David, additional, Nischalke, Hans Dieter, additional, Janciauskiene, Sabina, additional, Mandorfer, Mattias, additional, Trauner, Michael, additional, Way, Michael J, additional, McQuillin, Andrew, additional, Reichert, Matthias C, additional, Krawczyk, Marcin, additional, Casper, Markus, additional, Lammert, Frank, additional, Braun, Felix, additional, von Schönfels, Witigo, additional, Hinz, Sebastian, additional, Burmeister, Greta, additional, Hellerbrand, Claus, additional, Teufel, Andreas, additional, Feldman, Alexandra, additional, Schattenberg, Joern M, additional, Bantel, Heike, additional, Pathil, Anita, additional, Demir, Muenevver, additional, Kluwe, Johannes, additional, Boettler, Tobias, additional, Ridinger, Monika, additional, Wodarz, Norbert, additional, Soyka, Michael, additional, Rietschel, Marcella, additional, Kiefer, Falk, additional, Weber, Thomas, additional, Marhenke, Silke, additional, Vogel, Arndt, additional, Hinrichsen, Holger, additional, Canbay, Ali, additional, Schlattjan, Martin, additional, Sosnowsky, Katharina, additional, Sarrazin, Christoph, additional, von Felden, Johann, additional, Geier, Andreas, additional, Deltenre, Pierre, additional, Sipos, Bence, additional, Schafmayer, Clemens, additional, Nothnagel, Michael, additional, Aigner, Elmar, additional, Datz, Christian, additional, Stickel, Felix, additional, Morgan, Marsha Yvonne, additional, Hampe, Jochen, additional, Berg, Thomas, additional, and Trautwein, Christian, additional

Published
2018
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30. NOD2 gene variants confer risk for secondary sclerosing cholangitis in critically ill patients

Author

Jüngst, Christoph, primary, Stadlbauer, Vanessa, additional, Reichert, Matthias C., additional, Zimmer, Vincent, additional, Weber, Susanne N., additional, Ofner-Ziegenfuß, Lisa, additional, Voigtländer, Torsten, additional, Spindelböck, Walter, additional, Fickert, Peter, additional, Kirchner, Gabriele I., additional, Lammert, Frank, additional, Lankisch, Tim O., additional, and Krawczyk, Marcin, additional

Published
2017
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33. Liver phenotype of adults with alpha-1 antitrypsin deficiency in the UK Biobank and in an international, multi-center cohort

Author

Malin Fromme, Carolin Victoria Schneider, Vitor Pereira, Karim Hamesch, Monica Pons Delgado, Reichert, Matthias C., Federica Benini, Paul Ellis, Katrine Holtz Thorhauge, Mattias Mandorfer, Barbara Burbaum, Vivien Woditsch, Joanna Chorostowska-Wynimko, Jef Verbeek, Frederik Nevens, Joan Genesca, Marc Miravitlles, Alexa Nunez, Benedikt Schaefer, Heinz Zoller, Sabina Janciauskiene, Nelia Abreu, Luis Jasmins, Rui Gaspar, Catarina Gomes, Kai Markus Schneider, Michael Trauner, Aleksander Krag, Bibek Gooptu, Douglas Thorburn, Aileen Marshall, Hurst, John R., David Lomas, Frank Lammert, Nadine Gaisa, Virginia Clark, Griffiths Bill, Christian Trautwein, Alice Turner, Mcelvaney, Noel G., and Pavel Strnad

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

Author

Teo, Kevin, Abeysekera, Kushala WM, Adams, Leon, Aigner, Elmar, Anstee, Quentin M, Banales, Jesus M, Banerjee, Rajarshi, Basu, Priyadarshi, Berg, Thomas, Bhatnagar, Pallav, Buch, Stephan, Canbay, Ali, Caprio, Sonia, Chatterjee, Ankita, Ida Chen, Yii-Der, Chowdhury, Abhijit, Daly, Ann K, Datz, Christian, De Gracia Hahn, Dana, DiStefano, Johanna K, Dong, Jiawen, Duret, Amedine, EU-PNAFLD Investigators, Emdin, Connor, Fairey, Madison, Gerhard, Glenn S, GOLD Consortium, Guo, Xiuqing, Hampe, Jochen, Hickman, Matthew, Heintz, Lena, Hudert, Christian, Hunter, Harriet, Kelly, Matt, Kozlitina, Julia, Krawczyk, Marcin, Lammert, Frank, Langenberg, Claudia, Lavine, Joel, Li, Lin, Lim, Hong Kai, Loomba, Rohit, Luukkonen, Panu K, Melton, Phillip E, Mori, Trevor A, Palmer, Nicholette D, Parisinos, Constantinos A, Pillai, Sreekumar G, Qayyum, Faiza, Reichert, Matthias C, Romeo, Stefano, Rotter, Jerome I, Im, Yu Ri, Santoro, Nicola, Schafmayer, Clemens, Speliotes, Elizabeth K, Stender, Stefan, Stickel, Felix, Still, Christopher D, Strnad, Pavel, Taylor, Kent D, Tybjærg-Hansen, Anne, Umano, Giuseppina Rosaria, Utukuri, Mrudula, Valenti, Luca, Wagenknecht, Lynne E, Wareham, Nicholas J, Watanabe, Richard M, Wattacheril, Julia, Yaghootkar, Hanieh, Yki-Järvinen, Hannele, Young, Kendra A, and Mann, Jake P

Subjects
Liver Cirrhosis, Diabetes, Membrane Proteins, Alanine Transaminase, ALSPAC, Fibrosis, Triglyceride, Polymorphism, Single Nucleotide, 3. Good health, MBOAT7, Liver, Non-alcoholic Fatty Liver Disease, NAFLD, Drug Discovery, Humans, Genetic Predisposition to Disease, Acyltransferases
Abstract

BACKGROUND & AIMS: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in 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 to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. METHODS: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a 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 = 4.8×10-5) and diagnosis of NAFLD (odds ratio [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 = 1.5×10-4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. CONCLUSIONS: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. LAY SUMMARY: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.

35. Recurrent Pancreatitis Caused by a Huge Intraluminal Duodenal Diverticulum.

Author

Reichert, Matthias C., Bittenbring, Jörg T., Fries, Peter, Zimmer, Vincent, Lammert, Frank, and Dauer, Marc

Subjects
*DIVERTICULUM, *ABDOMINAL pain, *BACKACHE, *PANCREATITIS diagnosis, *DUODENOSCOPY
Abstract

The article presents a case of a 35-year-old man who was presented with abdominal pain extending to the back. It says that a huge diverticulum adjacent to the Vater's papilla was revealed by duodenoscopy. Furthermore, it notes that the possibility of an intraluminal duodenal diverticulum should be considered in the diagnosis of acute pancreatitis.

Published
2012

36. Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency

Author

Alice M Turner, David A. Lomas, Alexa Nuñez, Sabina Janciauskiene, William J.H. Griffiths, Christian Trautwein, Joan Genescà, Michael Trauner, John R. Hurst, Jef Verbeek, Matthias C. Reichert, Guilherme Macedo, Ravi Mahadeva, Mònica Pons, Aleksander Krag, Rui Gaspar, V Pereira, Heinz Zoller, Catarina Gomes, Mattias Mandorfer, Barbara Burbaum, Frank Lammert, V Woditsch, Paul Ellis, Aileen Marshall, Douglas Thorburn, Nadine T. Gaisa, Karim Hamesch, Joanna Chorostowska-Wynimko, Luís Jasmins, Malin Fromme, Rodrigo Liberal, Pavel Strnad, Frederik Nevens, Noel G. McElvaney, Marc Miravitlles, Virginia Clark, Bibek Gooptu, Benedikt Schaefer, Katrine Holtz Thorhauge, Carolin V. Schneider, Nelia Abreu, Kai Markus Schneider, Federica Benini, Fromme, Malin [0000-0003-0382-5705], Hamesch, Karim [0000-0002-1702-2746], Reichert, Matthias C [0000-0002-8192-0575], Mandorfer, Mattias [0000-0003-2330-0017], Gaspar, Rui [0000-0003-0332-3844], Trauner, Michael [0000-0002-1275-6425], Krag, Aleksander [0000-0002-9598-4932], Gooptu, Bibek [0000-0002-5223-1121], Hurst, John R [0000-0002-7246-6040], Lomas, David A [0000-0003-2339-6979], Strnad, Pavel [0000-0002-7122-6379], and Apollo - University of Cambridge Repository

Subjects
Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Cirrhosis, liver cirrhosis, liver, Gastroenterology, Cohort Studies, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Cholelithiasis, Fibrosis, alpha 1-Antitrypsin Deficiency, Internal medicine, Diabetes mellitus, Genotype, Prevalence, medicine, Humans, cancer, Aged, Alpha 1-antitrypsin deficiency, business.industry, Liver Neoplasms, fibrosis, Cancer, Gallstones, Middle Aged, medicine.disease, United Kingdom, Phenotype, 030228 respiratory system, Case-Control Studies, Female, 030211 gastroenterology & hepatology, business
Abstract

ObjectiveAlpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the ‘Pi*Z’ variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous ‘Pi*Z’ carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common ‘Pi*S’ variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD.DesignBaseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption.ResultsAmong UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8–53.7)) and primary liver cancer (aOR=44.5 (10.8–183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2–2.2)) and cholelithiasis (aOR=1.3 (1.2–1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1–8.2)) and primary liver cancer (aOR=6.6 (1.6–26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis.ConclusionOur study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

Published
2022

37. Common variation in FAM155A is associated with diverticulitis but not diverticulosis

Author

JI Lukosiene, Juozas Kupcinskas, Neringa Pauziene, Limas Kupčinskas, Susanne N. Weber, Frank Lammert, Christoph Jüngst, Antje Schulz, Frank Grünhage, Marcin Krawczyk, Beate Appenrodt, Christoph Schramm, Matthias Glanemann, Vincent Zimmer, Gediminas Kiudelis, Algimantas Tamelis, Markus Casper, Tobias Goeser, Maciej Malinowski, Matthias C. Reichert, Laimas Virginijus Jonaitis, University of Zurich, and Reichert, Matthias C

Subjects
0301 basic medicine, Male, Colonoscopy, Muscle Proteins, lcsh:Medicine, Genome-wide association study, Gastroenterology, Diverticulitis, Colonic, Cohort Studies, 0302 clinical medicine, Risk Factors, Germany, lcsh:Science, Multidisciplinary, medicine.diagnostic_test, GTPase-Activating Proteins, Diverticulitis, Middle Aged, Diverticulosis, 10219 Clinic for Gastroenterology and Hepatology, Cohort, Diverticular disease, Acetylcholinesterase, 030211 gastroenterology & hepatology, Female, Collagen, medicine.medical_specialty, Genetic predisposition to disease, 610 Medicine & health, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Internal medicine, medicine, Genetic predisposition, Diverticulosis, Colonic, Humans, Colonic diseases, Genetic Association Studies, Genetic association, Aged, 1000 Multidisciplinary, business.industry, lcsh:R, Membrane Proteins, Lithuania, medicine.disease, 030104 developmental biology, lcsh:Q, business, Genome-Wide Association Study
Abstract

Colonic diverticulosis is a very common condition. Many patients develop diverticulitis or other complications of diverticular disease. Recent genome-wide association studies (GWAS) consistently identified three major genetic susceptibility factors for both conditions, but did not discriminate diverticulititis and diverticulosis in particular due the limitations of registry-based approaches. Here, we aimed to confirm the role of the identified variants for diverticulosis and diverticulitis, respectively, within a well-phenotyped cohort of patients who underwent colonoscopy. Risk variants rs4662344 in Rho GTPase-activating protein 15 (ARHGAP15), rs7609897 in collagen-like tail subunit of asymmetric acetylcholinesterase (COLQ) and rs67153654 in family with sequence similarity 155 A (FAM155A) were genotyped in 1,332 patients. Diverticulosis was assessed by colonoscopy, and diverticulitis by imaging, clinical symptoms and inflammatory markers. Risk of diverticulosis and diverticulitis was analyzed in regression models adjusted for cofactors. Overall, the variant in FAM155A was associated with diverticulitis, but not diverticulosis, when controlling for age, BMI, alcohol consumption, and smoking status (ORadjusted 0.49 [95% CI 0.27–0.89], p = 0.002). Our results contribute to the assessment specific genetic variants identified in GWAS in the predisposition to the development of diverticulitis in patients with diverticulosis.

Published
2020

38. FRI297 - Clinical, histological, and biochemical liver phenotype of European adults with heterozygous alpha-1 antitrypsin deficiency (Pi*MZ genotype).

Author

Hamesch, Karim, Heimes, Carolin Victoria, Gross, Annika, Mandorfer, Mattias, Moeller, Linda S., Pereira, Vítor, Delgado, Monica Pons, Kuca, Pawel, Reichert, Matthias C., Benini, Federica, Lurje, Georg, Genesca, Joan, Lammert, Frank, Krag, Aleksander, Trauner, Michael, Teumer, Alexander, Gaisa, Nadine, Denk, Helmut, Trautwein, Christian, and Aigner, Elmar

Subjects
*LIVER, *GENOTYPES, *PHENOTYPES, *ADULTS
Published
2020
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39. Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

Author

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

Subjects
Age Distribution, Austria, Biopsy, Needle, Case-Control Studies, Confidence Intervals, Female, Genetic Carrier Screening, Genetic Variation, Germany, Humans, Immunohistochemistry, Incidence, Liver Cirrhosis, Alcoholic epidemiology, Liver Cirrhosis, Alcoholic pathology, Male, Non-alcoholic Fatty Liver Disease epidemiology, Non-alcoholic Fatty Liver Disease genetics, Non-alcoholic Fatty Liver Disease pathology, Odds Ratio, Polymorphism, Single Nucleotide, Prognosis, Risk Assessment, Sex Distribution, Genetic Predisposition to Disease epidemiology, Heterozygote, Liver Cirrhosis, Alcoholic genetics, alpha 1-Antitrypsin genetics
Abstract

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2019
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