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Felix Stickel, Stephan Buch, Hans Dieter Nischalke, Karl Heinz Weiss, Daniel Gotthardt, Janett Fischer, Jonas Rosendahl, Pierre Deltenre, Astrid Marot, Mona Elamly, Markus Casper, Frank Lammert, Andrew McQuillin, Steffen Zopf, Ulrich Spengler, Silke Marhenke, Martha M Kirstein, Arndt Vogel, Florian Eyer, Johann von Felden, Henning Wege, Thorsten Buch, Clemens Schafmayer, Felix Braun, Thomas Berg, Marsha Y Morgan, Jochen Hampe
OBJECTIVES: Variants in patatin-like phospholipase domain-containing 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), and membrane bound O-acyltransferase domain containing 7 (MBOAT7; rs641738) are risk factors for the development of alcohol-related cirrhosis. Within this population, PNPLA3 rs738409 is also an established risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to explore possible risk associations of TM6SF2 rs58542926 and MBOAT7 rs641738 with HCC...
March 13, 2018: American Journal of Gastroenterology
Jane I Grove, Prarthana Thiagarajan, Stuart Astbury, Rebecca Harris, Toby Delahooke, I Neil Guha, Guruprasad P Aithal
BACKGROUND & AIMS: Chronic liver disease presents a major global public health challenge. Stratification of asymptomatic, at-risk patients in primary care using non-invasive methods has the potential to address this by identifying those likely to progress. We therefore evaluated variant alleles at loci associated with non-alcoholic fatty liver disease (NAFLD) as genetic determinants of substantial liver injury in patients with disease risk factors. METHODS: Levels of serum procollagen III (PIIINP), an established fibrosis and steatohepatitis marker, were determined in 467 people who had type 2 diabetes and/or BMI>27...
March 1, 2018: Liver International: Official Journal of the International Association for the Study of the Liver
Yuya Seko, Kanji Yamaguchi, Yoshito Itoh
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. The development and progression of NAFLD are determined by environmental and genetic factors. The effect of genetic factors has been demonstrated by familial studies, twin studies and several cross-sectional studies. In the past 10 years, genome-wide association studies have revealed several single nucleotide polymorphisms (SNPs) associated with the pathology of NAFLD...
February 28, 2018: Clinical Journal of Gastroenterology
Alessia Di Costanzo, Francesca Belardinilli, Diego Bailetti, Marialuisa Sponziello, Laura D'Erasmo, Licia Polimeni, Francesco Baratta, Daniele Pastori, Fabrizio Ceci, Anna Montali, Gabriella Girelli, Bruna De Masi, Antonio Angeloni, Giuseppe Giannini, Maria Del Ben, Francesco Angelico, Marcello Arca
NAFLD is a polygenic condition but the individual and cumulative contribution of identified genes remains to be established. To get additional insight into the genetic architecture of NAFLD, GWAS-identified GCKR, PPP1R3B, NCAN, LYPLAL1 and TM6SF2 genes were resequenced by next generation sequencing in a cohort of 218 NAFLD subjects and 227 controls, where PNPLA3 rs738409 and MBOAT7 rs641738 genotypes were also obtained. A total of 168 sequence variants were detected and 47 were annotated as functional. When all functional variants within each gene were considered, only those in TM6SF2 accumulate in NAFLD subjects compared to controls (P = 0...
February 27, 2018: Scientific Reports
Giuseppina R Umano, Sonia Caprio, Anna Di Sessa, Naga Chalasani, Daniel J Dykas, Bridget Pierpont, Allen E Bale, Nicola Santoro
OBJECTIVES: Non alcoholic fatty liver disease (NAFLD) is a leading cause of liver damage in childhood, its occurrence is influenced by genetic and environmental factors. Recently, the rs626283 polymorphism in the MBOAT7 gene has been found to be associated with alcoholic liver disease and NAFLD in adults. METHODS: In a multiethnic cohort of obese children and adolescents we genotyped the rs626283 polymorphism in the MBOAT7 gene, evaluated insulin sensitivity by an oral glucose tolerance test, and measured the intra-hepatic fat content (HFF%) by magnetic resonance imaging...
February 27, 2018: American Journal of Gastroenterology
Marcin Krawczyk, Heike Bantel, Monika Rau, Jörn M Schattenberg, Frank Grünhage, Anita Pathil, Münevver Demir, Johannes Kluwe, Tobias Boettler, Susanne N Weber, Andreas Geier, Frank Lammert
Non-alcoholic fatty liver disease (NAFLD) is frequent among obese individuals with metabolic syndrome. Variants PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 rs641738 are associated with higher liver fat contents. Here we analyzed 63 biopsied non-obese, non-diabetic patients with NAFLD (39 men, age: 20-72 years) recruited within the German NAFLD CSG program. The frequencies of the PNPLA3, TM6SF2 and MBOAT7 polymorphisms were compared with the remaining patients in the NAFLD CSG cohort and with a control population (n = 174)...
February 26, 2018: Journal of Human Genetics
Alessia Di Costanzo, Francesca Belardinilli, Diego Bailetti, Marialuisa Sponziello, Laura D'Erasmo, Licia Polimeni, Francesco Baratta, Maria Del Ben, Giuseppe Giannini, Francesco Angelico, Marcello Arca
No abstract text is available yet for this article.
August 2017: Atherosclerosis
Yu-Cheng Lin, Pi-Feng Chang, Mei-Hwei Chang, Yen-Hsuan Ni
BACKGROUND/AIMS: There are substantial genetic components contributing to the susceptibility of nonalcoholic NAFLD disease (NAFLD). It has recently been reported that the rs641738 C>T variant in the membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7) gene increased severity of NAFLD in adults of European descent. We aimed to test the hypothesis that MBOAT7 rs641738 variant would increase hepatic steatosis and hepatocellular injury in obese children. METHODS: A total of 831 obese children aged 7-15 years were recruited...
January 4, 2018: Liver International: Official Journal of the International Association for the Study of the Liver
P Dongiovanni, S Stender, A Pietrelli, R M Mancina, A Cespiati, S Petta, S Pelusi, P Pingitore, S Badiali, M Maggioni, V Mannisto, S Grimaudo, R M Pipitone, J Pihlajamaki, A Craxi, M Taube, L M S Carlsson, S Fargion, S Romeo, J Kozlitina, L Valenti
BACKGROUND AND AIMS: Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance. METHODS: We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at-risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population-based Dallas Heart Study (DHS)...
December 27, 2017: Journal of Internal Medicine
Caroline Manchiero, Arielle Karen da Silva Nunes, Mariana Carvalheiro Magri, Bianca Peixoto Dantas, Celso Carmo Mazza, Antonio Alci Barone, Fátima Mitiko Tengan
BACKGROUND: Prospective studies have shown that 80% of acute hepatitis C virus (HCV) cases progress to chronic infection; approximately 10-20% of patients with these conditions will develop liver cirrhosis within 2 to 3 decades, and 1-5% will develop liver cancer. Some studies have indicated that the rs738409 polymorphism of the PNPLA3 gene is associated with steatosis and the progression of advanced fibrosis. This study assessed the contribution of the PNPLA3 rs738409 polymorphism with regard to the steatosis and degree of liver fibrosis in Brazilian patients diagnosed with chronic hepatitis C...
December 19, 2017: BMC Infectious Diseases
Ting-Ting Li, Tao-Hua Li, Juan Peng, Bei He, Lu-Shan Liu, Dang-Heng Wei, Zhi-Sheng Jiang, Xi-Long Zheng, Zhi-Han Tang
Transmembrane 6 superfamily 2 (TM6SF2), a gene identified at the locus 19p12, has been recognized to regulate plasma lipids. Here, we provide an overview of the roles of TM6SF2 as a novel target for plasma lipid regulation. We first review the association of TM6SF2 variant with plasma lipid traits, cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). Then, we present an overview about the in vivo validation of TM6SF2 as a regulator of plasma lipid levels using mice, with overexpression or knockdown/knockout of TM6SF2...
December 1, 2017: Atherosclerosis
Bo Kyung Koo, Sae Kyung Joo, Donghee Kim, Jeong Mo Bae, Jeong Hwan Park, Jung Ho Kim, Won Kim
BACKGROUND AND AIM: We investigated the effects of PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7-TMC4 rs641738 variants on metabolic phenotypes and their combined effects on the histological severity of non-alcoholic fatty liver disease (NAFLD). METHODS: We genotyped rs738409, rs58542926, and rs641738 in biopsy-proven NAFLD patients (n = 416) and healthy controls (n = 109). Homeostasis model assessment of insulin resistance and adipose tissue insulin resistance were calculated...
November 29, 2017: Journal of Gastroenterology and Hepatology
S Pillai, S Duvvuru, P Bhatnagar, W Foster, M Farmen, S Shankar, C Harris, E Bastyr, B Hoogwerf, A Haupt
Basal insulin peglispro (BIL) is a novel insulin with hepato-preferential action. In phase 3 trials, BIL showed significantly improved glycemic control but higher levels of transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), triglycerides (TGs) and liver fat content (LFC) compared with insulin glargine (GL). As variants in PNPLA3 (I148M) and TM6SF2 (E167K) are associated with nonalcoholic fatty liver disease, we assessed these variants in type 2 diabetes (T2D) patients randomized to receive BIL (n=1822) or GL (n=1270) in three phase 3 trials...
November 21, 2017: Pharmacogenomics Journal
Mohammed Eslam, Luca Valenti, Stefano Romeo
Non-alcoholic fatty liver disease (NAFLD) is now recognised as the most common liver disease worldwide. It encompasses a broad spectrum of conditions, from simple steatosis, through non-alcoholic steatohepatitis, to fibrosis and ultimately cirrhosis and hepatocellular carcinoma. A hallmark of NAFLD is the substantial inter-patient variation in disease progression. NAFLD is considered a complex disease trait such that interactions between the environment and a susceptible polygenic host background determine disease phenotype and influence progression...
February 2018: Journal of Hepatology
Dajiang J Liu, Gina M Peloso, Haojie Yu, Adam S Butterworth, Xiao Wang, Anubha Mahajan, Danish Saleheen, Connor Emdin, Dewan Alam, Alexessander Couto Alves, Philippe Amouyel, Emanuele Di Angelantonio, Dominique Arveiler, Themistocles L Assimes, Paul L Auer, Usman Baber, Christie M Ballantyne, Lia E Bang, Marianne Benn, Joshua C Bis, Michael Boehnke, Eric Boerwinkle, Jette Bork-Jensen, Erwin P Bottinger, Ivan Brandslund, Morris Brown, Fabio Busonero, Mark J Caulfield, John C Chambers, Daniel I Chasman, Y Eugene Chen, Yii-Der Ida Chen, Rajiv Chowdhury, Cramer Christensen, Audrey Y Chu, John M Connell, Francesco Cucca, L Adrienne Cupples, Scott M Damrauer, Gail Davies, Ian J Deary, George Dedoussis, Joshua C Denny, Anna Dominiczak, Marie-Pierre Dubé, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Aliki-Eleni Farmaki, Mary F Feitosa, Marco Ferrario, Jean Ferrieres, Ian Ford, Myriam Fornage, Paul W Franks, Timothy M Frayling, Ruth Frikke-Schmidt, Lars G Fritsche, Philippe Frossard, Valentin Fuster, Santhi K Ganesh, Wei Gao, Melissa E Garcia, Christian Gieger, Franco Giulianini, Mark O Goodarzi, Harald Grallert, Niels Grarup, Leif Groop, Megan L Grove, Vilmundur Gudnason, Torben Hansen, Tamara B Harris, Caroline Hayward, Joel N Hirschhorn, Oddgeir L Holmen, Jennifer Huffman, Yong Huo, Kristian Hveem, Sehrish Jabeen, Anne U Jackson, Johanna Jakobsdottir, Marjo-Riitta Jarvelin, Gorm B Jensen, Marit E Jørgensen, J Wouter Jukema, Johanne M Justesen, Pia R Kamstrup, Stavroula Kanoni, Fredrik Karpe, Frank Kee, Amit V Khera, Derek Klarin, Heikki A Koistinen, Jaspal S Kooner, Charles Kooperberg, Kari Kuulasmaa, Johanna Kuusisto, Markku Laakso, Timo Lakka, Claudia Langenberg, Anne Langsted, Lenore J Launer, Torsten Lauritzen, David C M Liewald, Li An Lin, Allan Linneberg, Ruth J F Loos, Yingchang Lu, Xiangfeng Lu, Reedik Mägi, Anders Malarstig, Ani Manichaikul, Alisa K Manning, Pekka Mäntyselkä, Eirini Marouli, Nicholas G D Masca, Andrea Maschio, James B Meigs, Olle Melander, Andres Metspalu, Andrew P Morris, Alanna C Morrison, Antonella Mulas, Martina Müller-Nurasyid, Patricia B Munroe, Matt J Neville, Jonas B Nielsen, Sune F Nielsen, Børge G Nordestgaard, Jose M Ordovas, Roxana Mehran, Christoper J O'Donnell, Marju Orho-Melander, Cliona M Molony, Pieter Muntendam, Sandosh Padmanabhan, Colin N A Palmer, Dorota Pasko, Aniruddh P Patel, Oluf Pedersen, Markus Perola, Annette Peters, Charlotta Pisinger, Giorgio Pistis, Ozren Polasek, Neil Poulter, Bruce M Psaty, Daniel J Rader, Asif Rasheed, Rainer Rauramaa, Dermot F Reilly, Alex P Reiner, Frida Renström, Stephen S Rich, Paul M Ridker, John D Rioux, Neil R Robertson, Dan M Roden, Jerome I Rotter, Igor Rudan, Veikko Salomaa, Nilesh J Samani, Serena Sanna, Naveed Sattar, Ellen M Schmidt, Robert A Scott, Peter Sever, Raquel S Sevilla, Christian M Shaffer, Xueling Sim, Suthesh Sivapalaratnam, Kerrin S Small, Albert V Smith, Blair H Smith, Sangeetha Somayajula, Lorraine Southam, Timothy D Spector, Elizabeth K Speliotes, John M Starr, Kathleen E Stirrups, Nathan Stitziel, Konstantin Strauch, Heather M Stringham, Praveen Surendran, Hayato Tada, Alan R Tall, Hua Tang, Jean-Claude Tardif, Kent D Taylor, Stella Trompet, Philip S Tsao, Jaakko Tuomilehto, Anne Tybjaerg-Hansen, Natalie R van Zuydam, Anette Varbo, Tibor V Varga, Jarmo Virtamo, Melanie Waldenberger, Nan Wang, Nick J Wareham, Helen R Warren, Peter E Weeke, Joshua Weinstock, Jennifer Wessel, James G Wilson, Peter W F Wilson, Ming Xu, Hanieh Yaghootkar, Robin Young, Eleftheria Zeggini, He Zhang, Neil S Zheng, Weihua Zhang, Yan Zhang, Wei Zhou, Yanhua Zhou, Magdalena Zoledziewska, Joanna M M Howson, John Danesh, Mark I McCarthy, Chad A Cowan, Goncalo Abecasis, Panos Deloukas, Kiran Musunuru, Cristen J Willer, Sekar Kathiresan
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD...
December 2017: Nature Genetics
Govardhan Bale, Avanthi Urmila Steffie, Vishnubhotla Venkata Ravi Kanth, Padaki Nagaraja Rao, Mithun Sharma, Mitnala Sasikala, Duvvur Nageshwar Reddy
AIM: To validate the association of variants in PNPLA3 (rs2281135) and TM6SF2 (rs58542926) genes with ultrasound detected non-alcoholic fatty liver disease (NAFLD). METHODS: A total of 503 individuals with and without fatty infiltration were recruited. Fatty infiltration was confirmed based on ultrasound findings. Anthropometric data and blood samples were collected from the study group. DNA was isolated from peripheral blood, quality and quantity was assessed by gel electrophoresis and spectrophotometer respectively...
September 18, 2017: World Journal of Hepatology
Lingbo Kong, Yu Lu, Siyu Zhang, Yuemin Nan, Liang Qiao
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. The nutrients play important roles in the development and progression of NAFLD. High-calorie diet, especially the diet rich in saturated fatty acids and cholesterol, as well as sugary drinks with high fructose content, induces hepatic steatosis and triggers progression of steatohepatitis, fibrosis, and even hepatocellular carcinoma. Disordered micronutrient status and gut microbiota are also involved in the pathogenesis of NAFLD...
September 2017: Discovery Medicine
Supichaya Boonvisut, Ken Yoshida, Kazuhiro Nakayama, Kazuhisa Watanabe, Hiroshi Miyashita, Sadahiko Iwamoto
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a disorder characterized by excessive fat deposits in hepatocytes without excessive alcohol intake. NAFLD is influenced by genetic factors, and the heritability has been estimated at 0.35 to 0.6 by twin studies. We explored rare variants in known NAFLD-associated genes to investigate whether these rare variants are involved in the susceptibility to NAFLD. METHODS: The target genes for re-sequencing were PNPLA3, TM6SF2, and MTTP...
September 26, 2017: Lipids in Health and Disease
Zhengtao Liu, Shuping Que, Lin Zhou, Shusen Zheng, Stefano Romeo, Adil Mardinoglu, Luca Valenti
The impact of Transmembrane 6 superfamily member 2 (TM6SF2) E167K variant, which causes hepatocellular fat retention by altering lipoprotein secretion, on liver damage and metabolic traits in chronic hepatitis C patients is still debated. We performed a systematic review and meta-analysis to clarify this relationship. Four studies with a total of 4325 patients were included. The risk of histologically-determined advanced steatosis, fibrosis, and cirrhosis (but not of severe inflammation) were increased in carriers of the TM6SF2 variant (P < 0...
August 24, 2017: Scientific Reports
Melania Manco
Over the last decade, the understanding of the association between insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD) has dramatically evolved. There is clear understanding that carriers of some common genetic variants, i.e., the patatin-like phospholipase domain-containing 3 (PNPLA3) or the transmembrane 6 superfamily member 2 (TM6SF2) are at risk of developing severe forms of NAFLD even in the presence of reduced or absent IR. In contrast, there are obese patients with "metabolic" (non-genetically driven) NAFLD who present severe IR...
August 14, 2017: Children
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