Download PDF
Semin Liver Dis 2019; 39(02): 124-140
DOI: 10.1055/s-0039-1679920
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Genetics of Nonalcoholic Fatty Liver Disease: From Pathogenesis to Therapeutics

Silvia Sookoian
1   Institute of Medical Research A Lanari, School of Medicine, University of Buenos Aires, Ciudad Autonoma de Buenos Aires (C1427ARN), Argentina
2   Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires (C1427ARN), Argentina
,
Carlos J. Pirola
1   Institute of Medical Research A Lanari, School of Medicine, University of Buenos Aires, Ciudad Autonoma de Buenos Aires (C1427ARN), Argentina
3   Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autonoma de Buenos Aires (C1427ARN), Argentina
› Author Affiliations FundingAgencia Nacional de Promoción Científica y Tecnológica, Fondo para la Investigación Científica y Tecnológica (Fon-CyT) (PICT 2014-0432 and PICT 2015-0551 to S.S. and PICT 2014-1816 and PICT 2016-0135 to C.J.P.).
Further Information

Publication History

Publication Date:
25 March 2019 (online)

   Permissions and Reprints

Abstract

Here, the authors review the remarkable genetic discoveries that have illuminated the biology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). The authors integrate genes associated with NAFLD and NASH into regulatory pathways to elucidate the disease pathogenesis. They review the evidence for molecular mediators of chronic liver damage, which suggests that convergent pathophenotypes, including inflammation and fibrosis, share common genetic modifiers. They further demonstrate that genes involved in the genetic susceptibility of NAFLD and NASH participate in cross-phenotype associations with diseases of the metabolic syndrome, including type 2 diabetes, obesity, and cardiovascular disease. However, immune-related loci associated with NAFLD and NASH exhibit some level of pleiotropy influencing disparate phenotypes, such as premature birth or sepsis. They finally focus on the translation of current genetic knowledge of NAFLD and NASH toward precision medicine. They provide evidence of genetic findings that can be leveraged to identify therapeutic targets.

Keywords

genetics - PNPLA3 - TM6SF2 - STAT3 - GCKR - HSD17B13 - GWAS - NASH - systems biology - druggability

Note

The authors apologize to the colleagues whose works could not be cited owing to manuscript length limitations.


 

  • References

  • 1 Brunt EM, Wong VW, Nobili V. , et al. Nonalcoholic fatty liver disease. Nat Rev Dis Primers 2015; 1: 15080
    CrossrefPubMedGoogle Scholar
  • 2 Palmer ND, Musani SK, Yerges-Armstrong LM. , et al. Characterization of European ancestry nonalcoholic fatty liver disease-associated variants in individuals of African and Hispanic descent. Hepatology 2013; 58 (03) 966-975
    CrossrefPubMedGoogle Scholar
  • 3 Speliotes EK, Yerges-Armstrong LM, Wu J. , et al; NASH CRN; GIANT Consortium; MAGIC Investigators; GOLD Consortium. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 2011; 7 (03) e1001324
    CrossrefPubMedGoogle Scholar
  • 4 Schwimmer JB, Celedon MA, Lavine JE. , et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology 2009; 136 (05) 1585-1592
    CrossrefPubMedGoogle Scholar
  • 5 Wagenknecht LE, Scherzinger AL, Stamm ER. , et al. Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort. Obesity (Silver Spring) 2009; 17 (06) 1240-1246
    CrossrefPubMedGoogle Scholar
  • 6 Loomba R, Schork N, Chen CH. , et al; Genetics of NAFLD in Twins Consortium. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology 2015; 149 (07) 1784-1793
    CrossrefPubMedGoogle Scholar
  • 7 Tarnoki AD, Tarnoki DL, Bata P. , et al. Heritability of non-alcoholic fatty liver disease and association with abnormal vascular parameters: a twin study. Liver Int 2012; 32 (08) 1287-1293
    CrossrefPubMedGoogle Scholar
  • 8 Sookoian S, Pirola CJ. The genetic epidemiology of nonalcoholic fatty liver disease: toward a personalized medicine. Clin Liver Dis 2012; 16 (03) 467-485
    CrossrefPubMedGoogle Scholar
  • 9 Hernaez R. Genetic factors associated with the presence and progression of nonalcoholic fatty liver disease: a narrative review. Gastroenterol Hepatol 2012; 35 (01) 32-41
    CrossrefPubMedGoogle Scholar
  • 10 Sookoian S, Pirola CJ. Genetic predisposition in nonalcoholic fatty liver disease. Clin Mol Hepatol 2017; 23 (01) 1-12
    CrossrefPubMedGoogle Scholar
  • 11 Romeo S, Kozlitina J, Xing C. , et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40 (12) 1461-1465
    CrossrefPubMedGoogle Scholar
  • 12 Kozlitina J, Smagris E, Stender S. , et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2014; 46 (04) 352-356
    CrossrefPubMedGoogle Scholar
  • 13 Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 2011; 53 (06) 1883-1894
    CrossrefPubMedGoogle Scholar
  • 14 Pirola CJ, Sookoian S. The dual and opposite role of the TM6SF2-rs58542926 variant in protecting against cardiovascular disease and conferring risk for nonalcoholic fatty liver: a meta-analysis. Hepatology 2015; 62 (06) 1742-1756
    CrossrefPubMedGoogle Scholar
  • 15 Zain SM, Mohamed Z, Mohamed R. Common variant in the glucokinase regulatory gene rs780094 and risk of nonalcoholic fatty liver disease: a meta-analysis. J Gastroenterol Hepatol 2015; 30 (01) 21-27
    CrossrefPubMedGoogle Scholar
  • 16 Sookoian S, Castaño GO, Burgueño AL, Gianotti TF, Rosselli MS, Pirola CJ. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J Lipid Res 2009; 50 (10) 2111-2116
    CrossrefPubMedGoogle Scholar
  • 17 Liu YL, Reeves HL, Burt AD. , et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun 2014; 5: 4309
    CrossrefPubMedGoogle Scholar
  • 18 Dongiovanni P, Petta S, Maglio C. , et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 2015; 61 (02) 506-514
    CrossrefPubMedGoogle Scholar
  • 19 Mancina RM, Dongiovanni P, Petta S. , et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology 2016; 150 (05) 1219-1230.e6
    CrossrefPubMedGoogle Scholar
  • 20 Kawaguchi T, Shima T, Mizuno M. , et al. Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers. PLoS One 2018; 13 (01) e0185490
    CrossrefPubMedGoogle Scholar
  • 21 Koo BK, Joo SK, Kim D. , et al. Additive effects of PNPLA3 and TM6SF2 on the histological severity of non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2018; 33 (06) 1277-1285
    CrossrefPubMedGoogle Scholar
  • 22 Sookoian S, Flichman D, Garaycoechea ME. , et al. Lack of evidence supporting a role of TMC4-rs641738 missense variant-MBOAT7- intergenic downstream variant-in the susceptibility to nonalcoholic fatty liver disease. Sci Rep 2018; 8 (01) 5097
    CrossrefPubMedGoogle Scholar
  • 23 Abul-Husn NS, Cheng X, Li AH. , et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med 2018; 378 (12) 1096-1106
    CrossrefPubMedGoogle Scholar
  • 24 Sookoian S, Flichman D, Scian R. , et al. Mitochondrial genome architecture in non-alcoholic fatty liver disease. J Pathol 2016; 240 (04) 437-449
    CrossrefPubMedGoogle Scholar
  • 25 Sookoian S, Rosselli MS, Gemma C. , et al. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter. Hepatology 2010; 52 (06) 1992-2000
    CrossrefPubMedGoogle Scholar
  • 26 Sunny NE, Parks EJ, Browning JD, Burgess SC. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab 2011; 14 (06) 804-810
    CrossrefPubMedGoogle Scholar
  • 27 Koliaki C, Szendroedi J, Kaul K. , et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab 2015; 21 (05) 739-746
    CrossrefPubMedGoogle Scholar
  • 28 Pirola CJ, Fernández Gianotti T, Castaño GO. , et al. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut 2015; 64 (05) 800-812
    CrossrefPubMedGoogle Scholar
  • 29 Sookoian S, Rohr C, Salatino A. , et al. Genetic variation in long noncoding RNAs and the risk of nonalcoholic fatty liver disease. Oncotarget 2017; 8 (14) 22917-22926
    CrossrefPubMedGoogle Scholar
  • 30 Chalasani N, Guo X, Loomba R. , et al; Nonalcoholic Steatohepatitis Clinical Research Network. Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease. Gastroenterology 2010; 139 (05) 1567-1576 , 1576.e1–1576.e6
    CrossrefPubMedGoogle Scholar
  • 31 Stender S, Kozlitina J, Nordestgaard BG, Tybjærg-Hansen A, Hobbs HH, Cohen JC. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat Genet 2017; 49 (06) 842-847
    CrossrefPubMedGoogle Scholar
  • 32 Boonvisut S, Yoshida K, Nakayama K, Watanabe K, Miyashita H, Iwamoto S. Identification of deleterious rare variants in MTTP, PNPLA3, and TM6SF2 in Japanese males and association studies with NAFLD. Lipids Health Dis 2017; 16 (01) 183
    CrossrefPubMedGoogle Scholar
  • 33 Pirola CJ, Flichman D, Dopazo H. , et al. A rare nonsense mutation in the glucokinase regulator gene is associated with a rapidly progressive clinical form of nonalcoholic steatohepatitis. Hepatol Commun 2018; 2 (09) 1030-1036
    CrossrefPubMedGoogle Scholar
  • 34 Ahrens M, Ammerpohl O, von Schönfels W. , et al. DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. Cell Metab 2013; 18 (02) 296-302
    CrossrefPubMedGoogle Scholar
  • 35 Kitamoto T, Kitamoto A, Ogawa Y. , et al. Targeted-bisulfite sequence analysis of the methylation of CpG islands in genes encoding PNPLA3, SAMM50, and PARVB of patients with non-alcoholic fatty liver disease. J Hepatol 2015; 63 (02) 494-502
    CrossrefPubMedGoogle Scholar
  • 36 Murphy SK, Yang H, Moylan CA. , et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology 2013; 145 (05) 1076-1087
    CrossrefPubMedGoogle Scholar
  • 37 Pirola CJ, Scian R, Gianotti TF. , et al. Epigenetic modifications in the biology of nonalcoholic fatty liver disease: the role of DNA hydroxymethylation and TET proteins. Medicine (Baltimore) 2015; 94 (36) e1480
    PubMedGoogle Scholar
  • 38 Zeybel M, Hardy T, Robinson SM. , et al. Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease. Clin Epigenetics 2015; 7: 25
    CrossrefPubMedGoogle Scholar
  • 39 Pirola CJ, Gianotti TF, Burgueño AL. , et al. Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut 2013; 62 (09) 1356-1363
    CrossrefPubMedGoogle Scholar
  • 40 Mitsche MA, Hobbs HH, Cohen JC. Patatin-like phospholipase domain-containing protein 3 promotes transfer of essential fatty acids from triglycerides to phospholipids in hepatic lipid droplets. J Biol Chem 2018; 293 (18) 6958-6968
    CrossrefPubMedGoogle Scholar
  • 41 BasuRay S, Smagris E, Cohen JC, Hobbs HH. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 2017; 66 (04) 1111-1124
    CrossrefPubMedGoogle Scholar
  • 42 Smagris E, BasuRay S, Li J. , et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 2015; 61 (01) 108-118
    CrossrefPubMedGoogle Scholar
  • 43 Li JZ, Huang Y, Karaman R. , et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest 2012; 122 (11) 4130-4144
    CrossrefPubMedGoogle Scholar
  • 44 Mahdessian H, Taxiarchis A, Popov S. , et al. TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content. Proc Natl Acad Sci U S A 2014; 111 (24) 8913-8918
    CrossrefPubMedGoogle Scholar
  • 45 Smagris E, Gilyard S, BasuRay S, Cohen JC, Hobbs HH. Inactivation of Tm6sf2, a gene defective in fatty liver disease, impairs lipidation but not secretion of very low density lipoproteins. J Biol Chem 2016; 291 (20) 10659-10676
    CrossrefPubMedGoogle Scholar
  • 46 Anstee QM, Daly AK, Day CP. Genetics of alcoholic and nonalcoholic fatty liver disease. Semin Liver Dis 2011; 31 (02) 128-146
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Hernaez R, Yeung E, Clark JM, Kowdley KV, Brancati FL, Kao WH. Hemochromatosis gene and nonalcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 2011; 55 (05) 1079-1085
    CrossrefPubMedGoogle Scholar
  • 48 Kahali B, Halligan B, Speliotes EK. Insights from genome-wide association analyses of nonalcoholic fatty liver disease. Semin Liver Dis 2015; 35 (04) 375-391
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Sookoian S, Pirola CJ. Systems biology elucidates common pathogenic mechanisms between nonalcoholic and alcoholic-fatty liver disease. PLoS One 2013; 8 (03) e58895
    CrossrefPubMedGoogle Scholar
  • 50 Gao B, Tsukamoto H. Inflammation in alcoholic and nonalcoholic fatty liver disease: friend or foe?. Gastroenterology 2016; 150 (08) 1704-1709
    CrossrefPubMedGoogle Scholar
  • 51 Goossens N, Hoshida Y. Is hepatocellular cancer the same disease in alcoholic and nonalcoholic fatty liver diseases?. Gastroenterology 2016; 150 (08) 1710-1717
    CrossrefPubMedGoogle Scholar
  • 52 Greuter T, Malhi H, Gores GJ, Shah VH. Therapeutic opportunities for alcoholic steatohepatitis and nonalcoholic steatohepatitis: exploiting similarities and differences in pathogenesis. JCI Insight 2017; 2 (17) 2
    PubMedGoogle Scholar
  • 53 Sookoian S, Pirola CJ. Genetic determinants of acquired cholestasis: a systems biology approach. Front Biosci (Landmark Ed) 2012; 17: 206-220
    CrossrefPubMedGoogle Scholar
  • 54 Hirschfield GM, Chapman RW, Karlsen TH, Lammert F, Lazaridis KN, Mason AL. The genetics of complex cholestatic disorders. Gastroenterology 2013; 144 (07) 1357-1374
    CrossrefPubMedGoogle Scholar
  • 55 Reichert MC, Hall RA, Krawczyk M, Lammert F. Genetic determinants of cholangiopathies: molecular and systems genetics. Biochim Biophys Acta Mol Basis Dis 2018; 1864 (4 Pt B): 1484-1490
    CrossrefPubMedGoogle Scholar
  • 56 Sookoian S, Flichman D, Garaycoechea ME, San Martino J, Castaño GO, Pirola CJ. Metastasis-associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune-mediated liver damage. Hepatol Commun 2018; 2 (06) 654-665
    CrossrefPubMedGoogle Scholar
  • 57 Stickel F, Buch S, Lau K. , et al. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in Caucasians. Hepatology 2011; 53 (01) 86-95
    CrossrefPubMedGoogle Scholar
  • 58 Chamorro AJ, Torres JL, Mirón-Canelo JA, González-Sarmiento R, Laso FJ, Marcos M. Systematic review with meta-analysis: the I148M variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is significantly associated with alcoholic liver cirrhosis. Aliment Pharmacol Ther 2014; 40 (06) 571-581
    CrossrefPubMedGoogle Scholar
  • 59 Buch S, Stickel F, Trépo E. , et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat Genet 2015; 47 (12) 1443-1448
    CrossrefPubMedGoogle Scholar
  • 60 Trepo E, Guyot E, Ganne-Carrie N. , et al. PNPLA3 (rs738409 C>G) is a common risk variant associated with hepatocellular carcinoma in alcoholic cirrhosis. Hepatology 2012; 55 (04) 1307-1308
    CrossrefPubMedGoogle Scholar
  • 61 Stickel F, Buch S, Nischalke HD. , et al. Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis. Am J Gastroenterol 2018; 113 (07) 1099
    CrossrefPubMedGoogle Scholar
  • 62 Salameh H, Raff E, Erwin A. , et al. PNPLA3 gene polymorphism is associated with predisposition to and severity of alcoholic liver disease. Am J Gastroenterol 2015; 110 (06) 846-856
    CrossrefPubMedGoogle Scholar
  • 63 Atkinson SR, Way MJ, McQuillin A, Morgan MY, Thursz MR. Homozygosity for rs738409:G in PNPLA3 is associated with increased mortality following an episode of severe alcoholic hepatitis. J Hepatol 2017; 67 (01) 120-127
    CrossrefPubMedGoogle Scholar
  • 64 Salameh H, Hanayneh MA, Masadeh M. , et al. PNPLA3 as a genetic determinant of risk for and severity of non-alcoholic fatty liver disease spectrum. J Clin Transl Hepatol 2016; 4 (03) 175-191
    PubMedGoogle Scholar
  • 65 Bruschi FV, Claudel T, Tardelli M. , et al. The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells. Hepatology 2017; 65 (06) 1875-1890
    CrossrefPubMedGoogle Scholar
  • 66 Jenkins CM, Mancuso DJ, Yan W, Sims HF, Gibson B, Gross RW. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J Biol Chem 2004; 279 (47) 48968-48975
    CrossrefPubMedGoogle Scholar
  • 67 Lake AC, Sun Y, Li JL. , et al. Expression, regulation, and triglyceride hydrolase activity of Adiponutrin family members. J Lipid Res 2005; 46 (11) 2477-2487
    CrossrefPubMedGoogle Scholar
  • 68 Pingitore P, Dongiovanni P, Motta BM. , et al. PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis. Hum Mol Genet 2016; 25 (23) 5212-5222
    PubMedGoogle Scholar
  • 69 Min HK, Sookoian S, Pirola CJ, Cheng J, Mirshahi F, Sanyal AJ. Metabolic profiling reveals that PNPLA3 induces widespread effects on metabolism beyond triacylglycerol remodeling in Huh-7 hepatoma cells. Am J Physiol Gastrointest Liver Physiol 2014; 307 (01) G66-G76
    CrossrefPubMedGoogle Scholar
  • 70 Sookoian S, Castaño GO, Pirola CJ. PNPLA3 I148M variant is associated with metabolic stress-response phenotype in patients with nonalcoholic fatty liver disease. Hepatology 2015; 61 (05) 1769
    CrossrefPubMedGoogle Scholar
  • 71 Pirola CJ, Garaycoechea M, Flichman D. , et al. Splice variant rs72613567 prevents worst histologic outcomes in patients with nonalcoholic fatty liver disease. J Lipid Res 2019; 60 (01) 176-185
    CrossrefPubMedGoogle Scholar
  • 72 Ma Y, Belyaeva OV, Brown PM. , et al. HSD17B13 is a hepatic retinol dehydrogenase associated with histological features of non-alcoholic fatty liver disease. Hepatology. 2018. doi: 10.1002/hep.30350. [Epub ahead of print]
    PubMedGoogle Scholar
  • 73 Chambers JC, Zhang W, Sehmi J. , et al; Alcohol Genome-wide Association (AlcGen) Consortium; Diabetes Genetics Replication and Meta-analyses (DIAGRAM+) Study; Genetic Investigation of Anthropometric Traits (GIANT) Consortium; Global Lipids Genetics Consortium; Genetics of Liver Disease (GOLD) Consortium; International Consortium for Blood Pressure (ICBP-GWAS); Meta-analyses of Glucose and Insulin-Related Traits Consortium (MAGIC). Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet 2011; 43 (11) 1131-1138
    CrossrefPubMedGoogle Scholar
  • 74 Sookoian S, Castaño GO, Burgueño AL, Gianotti TF, Rosselli MS, Pirola CJ. The nuclear receptor PXR gene variants are associated with liver injury in nonalcoholic fatty liver disease. Pharmacogenet Genomics 2010; 20 (01) 1-8
    CrossrefPubMedGoogle Scholar
  • 75 Wang YM, Chai SC, Brewer CT, Chen T. Pregnane X receptor and drug-induced liver injury. Expert Opin Drug Metab Toxicol 2014; 10 (11) 1521-1532
    CrossrefPubMedGoogle Scholar
  • 76 Feder JN, Gnirke A, Thomas W. , et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996; 13 (04) 399-408
    CrossrefPubMedGoogle Scholar
  • 77 Nahon P, Sutton A, Rufat P. , et al. Liver iron, HFE gene mutations, and hepatocellular carcinoma occurrence in patients with cirrhosis. Gastroenterology 2008; 134 (01) 102-110
    CrossrefPubMedGoogle Scholar
  • 78 George DK, Goldwurm S, MacDonald GA. , et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998; 114 (02) 311-318
    CrossrefPubMedGoogle Scholar
  • 79 Nelson JE, Bhattacharya R, Lindor KD. , et al. HFE C282Y mutations are associated with advanced hepatic fibrosis in Caucasians with nonalcoholic steatohepatitis. Hepatology 2007; 46 (03) 723-729
    CrossrefPubMedGoogle Scholar
  • 80 Chappell S, Hadzic N, Stockley R, Guetta-Baranes T, Morgan K, Kalsheker N. A polymorphism of the alpha1-antitrypsin gene represents a risk factor for liver disease. Hepatology 2008; 47 (01) 127-132
    PubMedGoogle Scholar
  • 81 Strnad P, Buch S, Hamesch K. , et al. Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis. Gut 2018; gutjnl-2018-316228
    PubMedGoogle Scholar
  • 82 Stearns FW. One hundred years of pleiotropy: a retrospective. Genetics 2010; 186 (03) 767-773
    PubMedGoogle Scholar
  • 83 Pickrell JK, Berisa T, Liu JZ, Ségurel L, Tung JY, Hinds DA. Detection and interpretation of shared genetic influences on 42 human traits. Nat Genet 2016; 48 (07) 709-717
    CrossrefPubMedGoogle Scholar
  • 84 Sivakumaran S, Agakov F, Theodoratou E. , et al. Abundant pleiotropy in human complex diseases and traits. Am J Hum Genet 2011; 89 (05) 607-618
    CrossrefPubMedGoogle Scholar
  • 85 Chesmore K, Bartlett J, Williams SM. The ubiquity of pleiotropy in human disease. Hum Genet 2018; 137 (01) 39-44
    CrossrefPubMedGoogle Scholar
  • 86 Sookoian S, Pirola CJ. Nonalcoholic fatty liver disease and metabolic syndrome: Shared genetic basis of pathogenesis. Hepatology 2016; 64 (05) 1417-1420
    CrossrefPubMedGoogle Scholar
  • 87 Iwata M, Maeda S, Kamura Y. , et al. Genetic risk score constructed using 14 susceptibility alleles for type 2 diabetes is associated with the early onset of diabetes and may predict the future requirement of insulin injections among Japanese individuals. Diabetes Care 2012; 35 (08) 1763-1770
    CrossrefPubMedGoogle Scholar
  • 88 Holmen OL, Zhang H, Fan Y. , et al. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat Genet 2014; 46 (04) 345-351
    CrossrefPubMedGoogle Scholar
  • 89 Sookoian S, Castaño GO, Scian R. , et al. Genetic variation in transmembrane 6 superfamily member 2 and the risk of nonalcoholic fatty liver disease and histological disease severity. Hepatology 2015; 61 (02) 515-525
    CrossrefPubMedGoogle Scholar
  • 90 Andrade-Navarro MA, Fontaine JF. Gene Set to Diseases (GS2D): disease enrichment analysis on human gene sets with literature data. Genom Comput Biol 2016; 2 (01) e33
    PubMedGoogle Scholar
  • 91 Rowe GC, Jiang A, Arany Z. PGC-1 coactivators in cardiac development and disease. Circ Res 2010; 107 (07) 825-838
    CrossrefPubMedGoogle Scholar
  • 92 Lai CQ, Tucker KL, Parnell LD. , et al. PPARGC1A variation associated with DNA damage, diabetes, and cardiovascular diseases: the Boston Puerto Rican Health Study. Diabetes 2008; 57 (04) 809-816
    CrossrefPubMedGoogle Scholar
  • 93 Turek FW, Joshu C, Kohsaka A. , et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 2005; 308 (5724): 1043-1045
    CrossrefPubMedGoogle Scholar
  • 94 Scott EM, Carter AM, Grant PJ. Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man. Int J Obes 2008; 32 (04) 658-662
    CrossrefPubMedGoogle Scholar
  • 95 Sookoian S, Gemma C, Gianotti TF, Burgueño A, Castaño G, Pirola CJ. Genetic variants of Clock transcription factor are associated with individual susceptibility to obesity. Am J Clin Nutr 2008; 87 (06) 1606-1615
    CrossrefPubMedGoogle Scholar
  • 96 Sookoian S, Castaño G, Gemma C, Gianotti TF, Pirola CJ. Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease. World J Gastroenterol 2007; 13 (31) 4242-4248
    CrossrefPubMedGoogle Scholar
  • 97 Kotronen A, Peltonen M, Hakkarainen A. , et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology 2009; 137 (03) 865-872
    CrossrefPubMedGoogle Scholar
  • 98 Wood GC, Chu X, Argyropoulos G. , et al. A multi-component classifier for nonalcoholic fatty liver disease (NAFLD) based on genomic, proteomic, and phenomic data domains. Sci Rep 2017; 7: 43238
    CrossrefPubMedGoogle Scholar
  • 99 Zhou Y, Orešič M, Leivonen M. , et al. Noninvasive detection of nonalcoholic steatohepatitis using clinical markers and circulating levels of lipids and metabolites. Clin Gastroenterol Hepatol 2016; 14 (10) 1463-1472.e6
    CrossrefPubMedGoogle Scholar
  • 100 Nobili V, Donati B, Panera N. , et al. A 4-polymorphism risk score predicts steatohepatitis in children with nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 2014; 58 (05) 632-636
    CrossrefPubMedGoogle Scholar
  • 101 Sevastianova K, Kotronen A, Gastaldelli A. , et al. Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss-induced decrease in liver fat in humans. Am J Clin Nutr 2011; 94 (01) 104-111
    CrossrefPubMedGoogle Scholar
  • 102 Shen J, Wong GL, Chan HL. , et al. PNPLA3 gene polymorphism and response to lifestyle modification in patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol 2015; 30 (01) 139-146
    CrossrefPubMedGoogle Scholar
  • 103 Krawczyk M, Jiménez-Agüero R, Alustiza JM. , et al. PNPLA3 p.I148M variant is associated with greater reduction of liver fat content after bariatric surgery. Surg Obes Relat Dis 2016; 12 (10) 1838-1846
    CrossrefPubMedGoogle Scholar
  • 104 Finkenstedt A, Auer C, Glodny B. , et al. Patatin-like phospholipase domain-containing protein 3 rs738409-G in recipients of liver transplants is a risk factor for graft steatosis. Clin Gastroenterol Hepatol 2013; 11 (12) 1667-1672
    CrossrefPubMedGoogle Scholar
  • 105 Kim H, Lee KW, Lee K. , et al. Effect of PNPLA3 I148M polymorphism on histologically proven non-alcoholic fatty liver disease in liver transplant recipients. Hepatol Res 2018; 48 (03) E162-E171
    CrossrefPubMedGoogle Scholar
  • 106 Sookoian S, Arrese M, Pirola CJ. Genetics meets therapy? Exome-wide association study reveals a loss-of-function variant in HSD17B13 (17-beta-hydroxysteroid dehydrogenase 13) that protects patients from liver damage and NAFLD-progression. Hepatology 2019; 69 (02) 907-910
    CrossrefPubMedGoogle Scholar
  • 107 Konerman MA, Jones JC, Harrison SA. Pharmacotherapy for NASH: current and emerging. J Hepatol 2018; 68 (02) 362-375
    CrossrefPubMedGoogle Scholar
  • 108 Chalasani N, Younossi Z, Lavine JE. , et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018; 67 (01) 328-357
    CrossrefPubMedGoogle Scholar
  • 109 Sanyal AJ, Chalasani N, Kowdley KV. , et al; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362 (18) 1675-1685
    CrossrefPubMedGoogle Scholar
  • 110 Ratziu V, Harrison SA, Francque S. , et al; GOLDEN-505 Investigator Study Group. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016; 150 (05) 1147-1159.e5
    CrossrefPubMedGoogle Scholar
  • 111 Sookoian S, Pirola CJ. Elafibranor for the treatment of NAFLD: one pill, two molecular targets and multiple effects in a complex phenotype. Ann Hepatol 2016; 15 (04) 604-609
    PubMedGoogle Scholar
  • 112 Bulusu KC, Tym JE, Coker EA, Schierz AC, Al-Lazikani B. canSAR: updated cancer research and drug discovery knowledgebase. Nucleic Acids Res 2014; 42 (Database issue): D1040-D1047
    CrossrefPubMedGoogle Scholar
  • 113 Sookoian S, Castaño G, Gianotti TF, Gemma C, Rosselli MS, Pirola CJ. Genetic variants in STAT3 are associated with nonalcoholic fatty liver disease. Cytokine 2008; 44 (01) 201-206
    CrossrefPubMedGoogle Scholar
  • 114 Jung KH, Yoo W, Stevenson HL. , et al. Multifunctional effects of a small-molecule STAT3 inhibitor on NASH and hepatocellular carcinoma in mice. Clin Cancer Res 2017; 23 (18) 5537-5546
    CrossrefPubMedGoogle Scholar
  • 115 Xiang DM, Sun W, Ning BF. , et al. The HLF/IL-6/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis. Gut 2018; 67 (09) 1704-1715
    CrossrefPubMedGoogle Scholar
  • 116 Min HK, Mirshahi F, Verdianelli A. , et al. Activation of the GP130-STAT3 axis and its potential implications in nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol 2015; 308 (09) G794-G803
    CrossrefPubMedGoogle Scholar
  • 117 Caussy C, Hsu C, Lo MT. , et al; Genetics of NAFLD in Twins Consortium. Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD. Hepatology 2018 Doi: 10.1002/hep.29892
    PubMedGoogle Scholar
  • 118 Puri P, Sanyal AJ. The intestinal microbiome in nonalcoholic fatty liver disease. Clin Liver Dis 2018; 22 (01) 121-132
    CrossrefPubMedGoogle Scholar
  • 119 Przulj N. Biological network comparison using graphlet degree distribution. Bioinformatics 2007; 23 (02) e177-e183
    CrossrefPubMedGoogle Scholar
  • 120 Mi H, Huang X, Muruganujan A. , et al. PANTHER version 11: expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements. Nucleic Acids Res 2017; 45 (D1): D183-D189
    CrossrefPubMedGoogle Scholar