Download PDF
Semin Liver Dis 2015; 35(03): 270-290
DOI: 10.1055/s-0035-1562947
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Genetics of Nonalcoholic Fatty Liver Disease: Spotlight on PNPLA3 and TM6SF2

Quentin M. Anstee
1   Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, United Kingdom
,
Christopher P. Day
1   Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, United Kingdom
› Author Affiliations
Further Information

Publication History

Publication Date:
17 September 2015 (online)

   Permissions and Reprints

Abstract

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum that spans simple steatosis, through nonalcoholic steatohepatitis (NASH) to fibrosis and ultimately cirrhosis. Nonalcoholic fatty liver disease is characterized by substantial interpatient variation in rate of progression and disease outcome: Although up to 25% of the general population are at risk of progressive disease, only a minority experience associated liver-related morbidity. Nonalcoholic fatty liver disease is considered a complex disease trait that occurs when environmental exposures act upon a susceptible polygenic background composed of multiple independent modifiers. Recent advances include the identification of PNPLA3 as a modifier of disease outcome across the full spectrum of NAFLD from steatosis to advanced fibrosis and hepatocellular carcinoma; and the discovery of TM6SF2 as a potential “master regulator” of metabolic syndrome outcome, determining not only risk of advanced liver disease, but also cardiovascular disease outcomes. In this article, the authors will review the field, discussing in detail the current status of research into these important genetic modifiers of NAFLD progression.

Keywords

nonalcoholic fatty liver disease - TM6SF2 - PNPLA3 - gene - steatohepatitis - fibrosis
 

  • References

  • 1 Anstee QM, McPherson S, Day CP. How big a problem is non-alcoholic fatty liver disease?. BMJ 2011; 343: d3897
    CrossrefPubMedGoogle Scholar
  • 2 Sanyal AJ ; American Gastroenterological Association. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 2002; 123 (5) 1705-1725
    CrossrefPubMedGoogle Scholar
  • 3 Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013; 10 (6) 330-344
    CrossrefPubMedGoogle Scholar
  • 4 Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010; 53 (2) 372-384
    CrossrefPubMedGoogle Scholar
  • 5 Das K, Das K, Mukherjee PS , et al. Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease. Hepatology 2010; 51 (5) 1593-1602
    CrossrefPubMedGoogle Scholar
  • 6 Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011; 141 (4) 1249-1253
    CrossrefPubMedGoogle Scholar
  • 7 Satapathy MBBS, Sanyal AJ. Epidemiology and natural history of nonalcoholic fatty liver Disease. Semin Liver Dis 2015; 35 (3) 221-235
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol 2015; 13 (4) 643-54.e1 , 9, quiz e39–e40
    CrossrefPubMedGoogle Scholar
  • 9 McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol 2015; 62 (5) 1148-1155
    CrossrefPubMedGoogle Scholar
  • 10 Angulo P. The natural history of NAFLD. In: Farrell G, McCulloch AJ, Day C, , eds. Non-Alcoholic Fatty Liver Disease: A Practical Guide. Hoboken, NJ: Wiley Blackwell Press; 2013: 37-45
    CrossrefGoogle Scholar
  • 11 Day CP. Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol 2002; 16 (5) 663-678
    CrossrefPubMedGoogle Scholar
  • 12 Anstee QM, Goldin RD. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol 2006; 87 (1) 1-16
    CrossrefPubMedGoogle Scholar
  • 13 Anstee QM, Daly AK, Day CP. Genetics of alcoholic and nonalcoholic fatty liver disease. Semin Liver Dis 2011; 31 (2) 128-146
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Anstee QM, Day CP. The genetics of NAFLD. Nat Rev Gastroenterol Hepatol 2013; 10 (11) 645-655
    CrossrefPubMedGoogle Scholar
  • 15 Hirschhorn JN, Gajdos ZK. Genome-wide association studies: results from the first few years and potential implications for clinical medicine. Annu Rev Med 2011; 62: 11-24
    CrossrefPubMedGoogle Scholar
  • 16 Altshuler D, Daly MJ, Lander ES. Genetic mapping in human disease. Science 2008; 322 (5903) 881-888
    CrossrefPubMedGoogle Scholar
  • 17 Willner IR, Waters B, Patil SR, Reuben A, Morelli J, Riely CA. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol 2001; 96 (10) 2957-2961
    CrossrefPubMedGoogle Scholar
  • 18 Struben VM, Hespenheide EE, Caldwell SH. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. Am J Med 2000; 108 (1) 9-13
    PubMedGoogle Scholar
  • 19 Schwimmer JB, Celedon MA, Lavine JE , et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology 2009; 136 (5) 1585-1592
    CrossrefPubMedGoogle Scholar
  • 20 Makkonen J, Pietiläinen KH, Rissanen A, Kaprio J, Yki-Järvinen H. Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: a study in monozygotic and dizygotic twins. J Hepatol 2009; 50 (5) 1035-1042
    CrossrefPubMedGoogle Scholar
  • 21 Browning JD, Szczepaniak LS, Dobbins R , et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40 (6) 1387-1395
    CrossrefPubMedGoogle Scholar
  • 22 Browning JD, Kumar KS, Saboorian MH, Thiele DL. Ethnic differences in the prevalence of cryptogenic cirrhosis. Am J Gastroenterol 2004; 99 (2) 292-298
    CrossrefPubMedGoogle Scholar
  • 23 Guerrero R, Vega GL, Grundy SM, Browning JD. Ethnic differences in hepatic steatosis: an insulin resistance paradox?. Hepatology 2009; 49 (3) 791-801
    CrossrefPubMedGoogle Scholar
  • 24 Bambha K, Belt P, Abraham M , et al; Nonalcoholic Steatohepatitis Clinical Research Network Research Group. Ethnicity and nonalcoholic fatty liver disease. Hepatology 2012; 55 (3) 769-780
    CrossrefPubMedGoogle Scholar
  • 25 Szczepaniak LS, Nurenberg P, Leonard D , et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005; 288 (2) E462-E468
    CrossrefPubMedGoogle Scholar
  • 26 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
  • 27 Reich DE, Lander ES. On the allelic spectrum of human disease. Trends Genet 2001; 17 (9) 502-510
    CrossrefPubMedGoogle Scholar
  • 28 Wang WY, Barratt BJ, Clayton DG, Todd JA. Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 2005; 6 (2) 109-118
    CrossrefPubMedGoogle Scholar
  • 29 Pritchard JK. Are rare variants responsible for susceptibility to complex diseases?. Am J Hum Genet 2001; 69 (1) 124-137
    CrossrefPubMedGoogle Scholar
  • 30 Hindorff LA, Sethupathy P, Junkins HA , et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A 2009; 106 (23) 9362-9367
    CrossrefPubMedGoogle Scholar
  • 31 Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003; 33 (2) 177-182
    CrossrefPubMedGoogle Scholar
  • 32 Manolio TA, Collins FS, Cox NJ , et al. Finding the missing heritability of complex diseases. Nature 2009; 461 (7265) 747-753
    CrossrefPubMedGoogle Scholar
  • 33 Cardon LR, Bell JI. Association study designs for complex diseases. Nat Rev Genet 2001; 2 (2) 91-99
    CrossrefPubMedGoogle Scholar
  • 34 Hirschhorn JN. Genomewide association studies—illuminating biologic pathways. N Engl J Med 2009; 360 (17) 1699-1701
    CrossrefPubMedGoogle Scholar
  • 35 Manolio TA, Brooks LD, Collins FS. A HapMap harvest of insights into the genetics of common disease. J Clin Invest 2008; 118 (5) 1590-1605
    Google Scholar
  • 36 Hardy J, Singleton A. Genomewide association studies and human disease. N Engl J Med 2009; 360 (17) 1759-1768
    CrossrefPubMedGoogle Scholar
  • 37 Hirschhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005; 6 (2) 95-108
    PubMedGoogle Scholar
  • 38 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 (5) 1567-1576 , 1576.e1–1576.e6
    CrossrefPubMedGoogle Scholar
  • 39 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 (3) e1001324
    CrossrefPubMedGoogle Scholar
  • 40 Anstee QM, Darlay R, Leathart JB , et al. Genome-wide association analysis confirms importance of PNPLA3 and identifies novel variants associated with histologically progressive steatohepatitis in NAFLD. Hepatology 2012; 56: 265A-266A
    PubMedGoogle Scholar
  • 41 Kawaguchi T, Sumida Y, Umemura A , et al; Japan Study Group of Nonalcoholic Fatty Liver Disease; Takeshi Okanoue. Genetic polymorphisms of the human PNPLA3 gene are strongly associated with severity of non-alcoholic fatty liver disease in Japanese. PLoS ONE 2012; 7 (6) e38322
    CrossrefPubMedGoogle Scholar
  • 42 Feitosa MF, Wojczynski MK, North KE , et al. The ERLIN1-CHUK-CWF19L1 gene cluster influences liver fat deposition and hepatic inflammation in the NHLBI Family Heart Study. Atherosclerosis 2013; 228 (1) 175-180
    CrossrefPubMedGoogle Scholar
  • 43 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 (4) 352-356
    CrossrefPubMedGoogle Scholar
  • 44 DiStefano JK, Kingsley C, Craig Wood G , et al. Genome-wide analysis of hepatic lipid content in extreme obesity. Acta Diabetol 2015; 52 (2) 373-382
    CrossrefPubMedGoogle Scholar
  • 45 Victor RG, Haley RW, Willett DL , et al; Dallas Heart Study Investigators. The Dallas Heart Study: a population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health. Am J Cardiol 2004; 93 (12) 1473-1480
    CrossrefPubMedGoogle Scholar
  • 46 Romeo S, Huang-Doran I, Baroni MG, Kotronen A. Unravelling the pathogenesis of fatty liver disease: patatin-like phospholipase domain-containing 3 protein. Curr Opin Lipidol 2010; 21 (3) 247-252
    CrossrefPubMedGoogle Scholar
  • 47 Gorden A, Yang R, Yerges-Armstrong LM , et al; GOLD Consortium. Genetic variation at NCAN locus is associated with inflammation and fibrosis in non-alcoholic fatty liver disease in morbid obesity. Hum Hered 2013; 75 (1) 34-43
    CrossrefPubMedGoogle Scholar
  • 48 Kathiresan S, Melander O, Guiducci C , et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 2008; 40 (2) 189-197
    CrossrefPubMedGoogle Scholar
  • 49 Teslovich TM, Musunuru K, Smith AV , et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010; 466 (7307) 707-713
    CrossrefPubMedGoogle Scholar
  • 50 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
    PubMedGoogle Scholar
  • 51 Kleiner DE, Brunt EM, Van Natta M , et al; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41 (6) 1313-1321
    CrossrefPubMedGoogle Scholar
  • 52 Ballestri S, Day CP, Daly AK. Polymorphism in the farnesyl diphosphate farnesyl transferase 1 gene and nonalcoholic fatty liver disease severity. Gastroenterology 2011; 140 (5) 1694-1695
    PubMedGoogle Scholar
  • 53 Kitamoto T, Kitamoto A, Yoneda M , et al. Genome-wide scan revealed that polymorphisms in the PNPLA3, SAMM50, and PARVB genes are associated with development and progression of nonalcoholic fatty liver disease in Japan. Hum Genet 2013; 132 (7) 783-792
    CrossrefPubMedGoogle Scholar
  • 54 Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 116 (6) 1413-1419
    CrossrefPubMedGoogle Scholar
  • 55 Mofrad P, Contos MJ, Haque M , et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 2003; 37 (6) 1286-1292
    CrossrefPubMedGoogle Scholar
  • 56 Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011; 34 (3) 274-285
    CrossrefPubMedGoogle Scholar
  • 57 Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011; 43 (8) 617-649
    CrossrefPubMedGoogle Scholar
  • 58 Yuan X, Waterworth D, Perry JR , et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet 2008; 83 (4) 520-528
    CrossrefPubMedGoogle Scholar
  • 59 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
  • 60 Aulchenko YS, Ripatti S, Lindqvist I , et al; ENGAGE Consortium. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 2009; 41 (1) 47-55
    CrossrefPubMedGoogle Scholar
  • 61 Willer CJ, Sanna S, Jackson AU , et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008; 40 (2) 161-169
    CrossrefPubMedGoogle Scholar
  • 62 Valenti L, Al-Serri A, Daly AK , et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2010; 51 (4) 1209-1217
    CrossrefPubMedGoogle Scholar
  • 63 Kotronen A, Johansson LE, Johansson LM , et al. A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans. Diabetologia 2009; 52 (6) 1056-1060
    CrossrefPubMedGoogle Scholar
  • 64 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
  • 65 Kantartzis K, Peter A, Machicao F , et al. Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene. Diabetes 2009; 58 (11) 2616-2623
    CrossrefPubMedGoogle Scholar
  • 66 Rotman Y, Koh C, Zmuda JM, Kleiner DE, Liang TJ ; NASH CRN. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 2010; 52 (3) 894-903
    CrossrefPubMedGoogle Scholar
  • 67 Romeo S, Sentinelli F, Cambuli VM , et al. The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life. J Hepatol 2010; 53 (2) 335-338
    CrossrefPubMedGoogle Scholar
  • 68 Valenti L, Alisi A, Galmozzi E , et al. I148M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease. Hepatology 2010; 52 (4) 1274-1280
    CrossrefPubMedGoogle Scholar
  • 69 Santoro N, Kursawe R, D'Adamo E , et al. A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology 2010; 52 (4) 1281-1290
    CrossrefPubMedGoogle Scholar
  • 70 Kollerits B, Coassin S, Kiechl S , et al. A common variant in the adiponutrin gene influences liver enzyme values. J Med Genet 2010; 47 (2) 116-119
    CrossrefPubMedGoogle Scholar
  • 71 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 (1) 104-111
    CrossrefPubMedGoogle Scholar
  • 72 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 (1) 139-146
    CrossrefPubMedGoogle Scholar
  • 73 El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132 (7) 2557-2576
    CrossrefPubMedGoogle Scholar
  • 74 Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis 2010; 42 (Suppl. 03) S206-S214
    CrossrefPubMedGoogle Scholar
  • 75 [Anonymous] European Association For The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56 (4) 908-943
    CrossrefPubMedGoogle Scholar
  • 76 Dyson J, Jaques B, Chattopadyhay D , et al. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J Hepatol 2014; 60 (1) 110-117
    CrossrefPubMedGoogle Scholar
  • 77 Hassan MM, Kaseb A, Etzel CJ , et al. Genetic variation in the PNPLA3 gene and hepatocellular carcinoma in USA: risk and prognosis prediction. Mol Carcinog 2013; 52 (Suppl. 01) E139-E147
    CrossrefPubMedGoogle Scholar
  • 78 Burza MA, Pirazzi C, Maglio C , et al. PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals. Dig Liver Dis 2012; 44 (12) 1037-1041
    CrossrefPubMedGoogle Scholar
  • 79 Guyot E, Sutton A, Rufat P , et al. PNPLA3 rs738409, hepatocellular carcinoma occurrence and risk model prediction in patients with cirrhosis. J Hepatol 2013; 58 (2) 312-318
    CrossrefPubMedGoogle Scholar
  • 80 Nischalke HD, Berger C, Luda C , et al. The PNPLA3 rs738409 148M/M genotype is a risk factor for liver cancer in alcoholic cirrhosis but shows no or weak association in hepatitis C cirrhosis. PLoS ONE 2011; 6 (11) e27087
    CrossrefPubMedGoogle Scholar
  • 81 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 (4) 1307-1308
    CrossrefPubMedGoogle Scholar
  • 82 Trepo E, Nahon P, Bontempi G , et al. Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: evidence from a meta-analysis of individual participant data. Hepatology 2014; 59 (6) 2170-2177
    CrossrefPubMedGoogle Scholar
  • 83 Valenti L, Rumi M, Galmozzi E , et al. Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. Hepatology 2011; 53 (3) 791-799
    CrossrefPubMedGoogle Scholar
  • 84 Falleti E, Fabris C, Cmet S , et al. PNPLA3 rs738409C/G polymorphism in cirrhosis: relationship with the aetiology of liver disease and hepatocellular carcinoma occurrence. Liver Int 2011; 31 (8) 1137-1143
    CrossrefPubMedGoogle Scholar
  • 85 Singal AG, Manjunath H, Yopp AC , et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol 2014; 109 (3) 325-334
    CrossrefPubMedGoogle Scholar
  • 86 Liu YL, Patman GL, Leathart JB , et al. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol 2014; 61 (1) 75-81
    CrossrefPubMedGoogle Scholar
  • 87 Krawczyk M, Stokes CS, Romeo S, Lammert F. HCC and liver disease risks in homozygous PNPLA3 p.I148M carriers approach monogenic inheritance. J Hepatol 2015; 62 (4) 980-981
    PubMedGoogle Scholar
  • 88 Anstee QM, Liu YL, Day CP, Reeves HL. Reply to: HCC and liver disease risk in homozygous PNPLA3 p.I148M carriers approach monogenic inheritance. J Hepatol 2015; 62 (4) 982-983
    CrossrefPubMedGoogle Scholar
  • 89 Zimmermann R, Strauss JG, Haemmerle G , et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 2004; 306 (5700) 1383-1386
    CrossrefPubMedGoogle Scholar
  • 90 Rydel TJ, Williams JM, Krieger E , et al. The crystal structure, mutagenesis, and activity studies reveal that patatin is a lipid acyl hydrolase with a Ser-Asp catalytic dyad. Biochemistry 2003; 42 (22) 6696-6708
    CrossrefPubMedGoogle Scholar
  • 91 He S, McPhaul C, Li JZ , et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem 2010; 285 (9) 6706-6715
    CrossrefPubMedGoogle Scholar
  • 92 Romeo S, Sentinelli F, Dash S , et al. Morbid obesity exposes the association between PNPLA3 I148M (rs738409) and indices of hepatic injury in individuals of European descent. Int J Obes 2010; 34 (1) 190-194
    CrossrefPubMedGoogle Scholar
  • 93 Speliotes EK, Butler JL, Palmer CD, Voight BF, Hirschhorn JN ; GIANT Consortium; MIGen Consortium; NASH CRN. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 2010; 52 (3) 904-912
    CrossrefPubMedGoogle Scholar
  • 94 Huang Y, Cohen JC, Hobbs HH. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease. J Biol Chem 2011; 286 (43) 37085-37093
    CrossrefPubMedGoogle Scholar
  • 95 Pirazzi C, Adiels M, Burza MA , et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J Hepatol 2012; 57 (6) 1276-1282
    CrossrefPubMedGoogle Scholar
  • 96 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
  • 97 Kumari M, Schoiswohl G, Chitraju C , et al. Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab 2012; 15 (5) 691-702
    CrossrefPubMedGoogle Scholar
  • 98 Huang Y, He S, Li JZ , et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci U S A 2010; 107 (17) 7892-7897
    CrossrefPubMedGoogle Scholar
  • 99 Wilson PA, Gardner SD, Lambie NM, Commans SA, Crowther DJ. Characterization of the human patatin-like phospholipase family. J Lipid Res 2006; 47 (9) 1940-1949
    CrossrefPubMedGoogle Scholar
  • 100 Hoekstra M, Li Z, Kruijt JK, Van Eck M, Van Berkel TJ, Kuiper J. The expression level of non-alcoholic fatty liver disease-related gene PNPLA3 in hepatocytes is highly influenced by hepatic lipid status. J Hepatol 2010; 52 (2) 244-251
    CrossrefPubMedGoogle Scholar
  • 101 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
  • 102 Chen W, Chang B, Li L, Chan L. Patatin-like phospholipase domain-containing 3/adiponutrin deficiency in mice is not associated with fatty liver disease. Hepatology 2010; 52 (3) 1134-1142
    CrossrefPubMedGoogle Scholar
  • 103 Basantani MK, Sitnick MT, Cai L , et al. Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. J Lipid Res 2011; 52 (2) 318-329
    CrossrefPubMedGoogle Scholar
  • 104 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
  • 105 Smagris E, BasuRay S, Li J , et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 2015; 61 (1) 108-118
    CrossrefPubMedGoogle Scholar
  • 106 Pirazzi C, Valenti L, Motta BM , et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum Mol Genet 2014; 23 (15) 4077-4085
    CrossrefPubMedGoogle Scholar
  • 107 Dongiovanni P, Petta S, Maglio C , et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 2015; 61 (2) 506-514
    CrossrefPubMedGoogle Scholar
  • 108 Wong VW, Wong GL, Tse CH, Chan HL. Prevalence of the TM6SF2 variant and non-alcoholic fatty liver disease in Chinese. J Hepatol 2014; 61 (3) 708-709
    CrossrefPubMedGoogle Scholar
  • 109 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 (2) 515-525
    CrossrefPubMedGoogle Scholar
  • 110 Wang X, Liu Z, Peng Z, Liu W. The TM6SF2 rs58542926 T allele is significantly associated with non-alcoholic fatty liver disease in Chinese. J Hepatol 2015; 62 (6) 1438-1439
    CrossrefPubMedGoogle Scholar
  • 111 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 (3) 966-975
    CrossrefPubMedGoogle Scholar
  • 112 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
  • 113 Carim-Todd L, Escarceller M, Estivill X, Sumoy L. Cloning of the novel gene TM6SF1 reveals conservation of clusters of paralogous genes between human chromosomes 15q24—>q26 and 19p13.3—>p12. Cytogenet Cell Genet 2000; 90 (3-4) 255-260
    CrossrefPubMedGoogle Scholar
  • 114 Surakka I, Horikoshi M, Mägi R , et al; ENGAGE Consortium. The impact of low-frequency and rare variants on lipid levels. Nat Genet 2015; 47 (6) 589-597
    CrossrefPubMedGoogle Scholar
  • 115 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 (4) 345-351
    CrossrefPubMedGoogle Scholar
  • 116 Zhou Y, Llauradó G, Orešič M, Hyötyläinen T, Orho-Melander M, Yki-Järvinen H. Circulating triacylglycerol signatures and insulin sensitivity in NAFLD associated with the E167K variant in TM6SF2. J Hepatol 2015; 62 (3) 657-663
    PubMedGoogle Scholar
  • 117 Kahali B, Liu YL, Daly AK, Day CP, Anstee QM, Speliotes EK. TM6SF2: catch-22 in the fight against nonalcoholic fatty liver disease and cardiovascular disease?. Gastroenterology 2015; 148 (4) 679-684
    CrossrefPubMedGoogle Scholar
  • 118 Yamaguchi K, Yang L, McCall S , et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 2007; 45 (6) 1366-1374
    CrossrefPubMedGoogle Scholar
  • 119 Malhi H, Gores GJ, Lemasters JJ. Apoptosis and necrosis in the liver: a tale of two deaths?. Hepatology 2006; 43 (2) (Suppl. 01) S31-S44
    CrossrefPubMedGoogle Scholar
  • 120 Anstee QM, Concas D, Kudo H , et al. Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis. J Hepatol 2010; 53 (3) 542-550
    CrossrefPubMedGoogle Scholar
  • 121 Farrell GC, Larter CZ, Hou JY , et al. Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression. J Gastroenterol Hepatol 2009; 24 (3) 443-452
    CrossrefPubMedGoogle Scholar
  • 122 Iredale JP. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest 2007; 117 (3) 539-548
    CrossrefPubMedGoogle Scholar
  • 123 Spielman RS, Ewens WJ. The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet 1996; 59 (5) 983-989
    PubMedGoogle Scholar
  • 124 Namikawa C, Shu-Ping Z, Vyselaar JR , et al. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. J Hepatol 2004; 40 (5) 781-786
    CrossrefPubMedGoogle Scholar
  • 125 Al-Serri A, Anstee QM, Valenti L , et al. The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case-control and intra-familial allele association studies. J Hepatol 2012; 56 (2) 448-454
    CrossrefPubMedGoogle Scholar
  • 126 Dong H, Wang J, Li C , et al. The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population. J Hepatol 2007; 46 (5) 915-920
    CrossrefPubMedGoogle Scholar
  • 127 Song J, da Costa KA, Fischer LM , et al. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). FASEB J 2005; 19 (10) 1266-1271
    CrossrefPubMedGoogle Scholar
  • 128 Wang L, Athinarayanan S, Jiang G, Chalasani N, Zhang M, Liu W. Fatty acid desaturase 1 gene polymorphisms control human hepatic lipid composition. Hepatology 2015; 61 (1) 119-128
    CrossrefPubMedGoogle Scholar
  • 129 Narla G, Difeo A, Reeves HL , et al. A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk. Cancer Res 2005; 65 (4) 1213-1222
    CrossrefPubMedGoogle Scholar
  • 130 Miele L, Beale G, Patman G , et al. The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease. Gastroenterology 2008; 135 (1) 282-291.e1
    CrossrefPubMedGoogle Scholar
  • 131 Anstee QM, Darlay R, Leathart J , et al. A candidate-gene approach to validation of genetic modifier associations using a large cohort with histologically characterised non-alcoholic fatty liver disease. J Hepatol 2013; 58: S46
    PubMedGoogle Scholar
  • 132 Perttilä J, Huaman-Samanez C, Caron S , et al. PNPLA3 is regulated by glucose in human hepatocytes, and its I148M mutant slows down triglyceride hydrolysis. Am J Physiol Endocrinol Metab 2012; 302 (9) E1063-E1069
    CrossrefPubMedGoogle Scholar
  • 133 Grarup N, Urhammer SA, Ek J , et al. Studies of the relationship between the ENPP1 K121Q polymorphism and type 2 diabetes, insulin resistance and obesity in 7,333 Danish white subjects. Diabetologia 2006; 49 (9) 2097-2104
    CrossrefPubMedGoogle Scholar
  • 134 McGettrick AJ, Feener EP, Kahn CR. Human insulin receptor substrate-1 (IRS-1) polymorphism G972R causes IRS-1 to associate with the insulin receptor and inhibit receptor autophosphorylation. J Biol Chem 2005; 280 (8) 6441-6446
    CrossrefPubMedGoogle Scholar
  • 135 Dongiovanni P, Valenti L, Rametta R , et al. Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease. Gut 2010; 59 (2) 267-273
    CrossrefPubMedGoogle Scholar
  • 136 Petta S, Miele L, Bugianesi E , et al. Glucokinase regulatory protein gene polymorphism affects liver fibrosis in non-alcoholic fatty liver disease. PLoS ONE 2014; 9 (2) e87523
    CrossrefPubMedGoogle Scholar
  • 137 Vazquez-Chantada M, Gonzalez-Lahera A, Martinez-Arranz I , et al. Solute carrier family 2 member 1 is involved in the development of nonalcoholic fatty liver disease. Hepatology 2013; 57 (2) 505-514
    CrossrefPubMedGoogle Scholar
  • 138 Musso G, Gambino R, Pacini G, Pagano G, Durazzo M, Cassader M. Transcription factor 7-like 2 polymorphism modulates glucose and lipid homeostasis, adipokine profile, and hepatocyte apoptosis in NASH. Hepatology 2009; 49 (2) 426-435
    CrossrefPubMedGoogle Scholar
  • 139 Tönjes A, Scholz M, Loeffler M, Stumvoll M. Association of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma with pre-diabetic phenotypes: meta-analysis of 57 studies on nondiabetic individuals. Diabetes Care 2006; 29 (11) 2489-2497
    CrossrefPubMedGoogle Scholar
  • 140 Gawrieh S, Marion MC, Komorowski R , et al. Genetic variation in the peroxisome proliferator activated receptor-gamma gene is associated with histologically advanced NAFLD. Dig Dis Sci 2012; 57 (4) 952-957
    CrossrefPubMedGoogle Scholar
  • 141 Rey JW, Noetel A, Hardt A , et al. Pro12Ala polymorphism of the peroxisome proliferator-activated receptor γ2 in patients with fatty liver diseases. World J Gastroenterol 2010; 16 (46) 5830-5837
    CrossrefPubMedGoogle Scholar
  • 142 Dongiovanni P, Rametta R, Fracanzani AL , et al. Lack of association between peroxisome proliferator-activated receptors alpha and gamma2 polymorphisms and progressive liver damage in patients with non-alcoholic fatty liver disease: a case control study. BMC Gastroenterol 2010; 10: 102
    CrossrefPubMedGoogle Scholar
  • 143 Hirsch D, Stahl A, Lodish HF. A family of fatty acid transporters conserved from mycobacterium to man. Proc Natl Acad Sci U S A 1998; 95 (15) 8625-8629
    CrossrefPubMedGoogle Scholar
  • 144 Doege H, Grimm D, Falcon A , et al. Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia. J Biol Chem 2008; 283 (32) 22186-22192
    CrossrefPubMedGoogle Scholar
  • 145 Auinger A, Valenti L, Pfeuffer M , et al. A promoter polymorphism in the liver-specific fatty acid transport protein 5 is associated with features of the metabolic syndrome and steatosis. Horm Metab Res 2010; 42 (12) 854-859
    Article in Thieme ConnectPubMedGoogle Scholar
  • 146 Reue K, Zhang P. The lipin protein family: dual roles in lipid biosynthesis and gene expression. FEBS Lett 2008; 582 (1) 90-96
    CrossrefPubMedGoogle Scholar
  • 147 Reue K. The lipin family: mutations and metabolism. Curr Opin Lipidol 2009; 20 (3) 165-170
    CrossrefPubMedGoogle Scholar
  • 148 Wiedmann S, Fischer M, Koehler M , et al. Genetic variants within the LPIN1 gene, encoding lipin, are influencing phenotypes of the metabolic syndrome in humans. Diabetes 2008; 57 (1) 209-217
    CrossrefPubMedGoogle Scholar
  • 149 Burgdorf KS, Sandholt CH, Sparsø T , et al. Studies of association between LPIN1 variants and common metabolic phenotypes among 17,538 Danes. Eur J Endocrinol 2010; 163 (1) 81-87
    CrossrefPubMedGoogle Scholar
  • 150 Fawcett KA, Grimsey N, Loos RJ , et al. Evaluating the role of LPIN1 variation in insulin resistance, body weight, and human lipodystrophy in U.K. Populations. Diabetes 2008; 57 (9) 2527-2533
    CrossrefPubMedGoogle Scholar
  • 151 Valenti L, Motta BM, Alisi A , et al. LPIN1 rs13412852 polymorphism in pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 2012; 54 (5) 588-593
    CrossrefPubMedGoogle Scholar
  • 152 Zhang B, Xie W, Krasowski MD. PXR: a xenobiotic receptor of diverse function implicated in pharmacogenetics. Pharmacogenomics 2008; 9 (11) 1695-1709
    CrossrefPubMedGoogle Scholar
  • 153 Zhou J, Zhai Y, Mu Y , et al. A novel pregnane X receptor-mediated and sterol regulatory element-binding protein-independent lipogenic pathway. J Biol Chem 2006; 281 (21) 15013-15020
    CrossrefPubMedGoogle Scholar
  • 154 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 (1) 1-8
    CrossrefPubMedGoogle Scholar
  • 155 Kim H, Haluzik M, Asghar Z , et al. Peroxisome proliferator-activated receptor-alpha agonist treatment in a transgenic model of type 2 diabetes reverses the lipotoxic state and improves glucose homeostasis. Diabetes 2003; 52 (7) 1770-1778
    CrossrefPubMedGoogle Scholar
  • 156 Chen S, Li Y, Li S, Yu C. A Val227Ala substitution in the peroxisome proliferator activated receptor alpha (PPAR alpha) gene associated with non-alcoholic fatty liver disease and decreased waist circumference and waist-to-hip ratio. J Gastroenterol Hepatol 2008; 23 (9) 1415-1418
    CrossrefPubMedGoogle Scholar
  • 157 Yamakawa-Kobayashi K, Ishiguro H, Arinami T, Miyazaki R, Hamaguchi H. A Val227Ala polymorphism in the peroxisome proliferator activated receptor alpha (PPARalpha) gene is associated with variations in serum lipid levels. J Med Genet 2002; 39 (3) 189-191
    CrossrefPubMedGoogle Scholar
  • 158 Lonardo A, Lombardini S, Scaglioni F , et al. Hepatic steatosis and insulin resistance: does etiology make a difference?. J Hepatol 2006; 44 (1) 190-196
    CrossrefPubMedGoogle Scholar
  • 159 Bernard S, Touzet S, Personne I , et al. Association between microsomal triglyceride transfer protein gene polymorphism and the biological features of liver steatosis in patients with type II diabetes. Diabetologia 2000; 43 (8) 995-999
    CrossrefPubMedGoogle Scholar
  • 160 Oliveira CP, Stefano JT, Cavaleiro AM , et al. Association of polymorphisms of glutamate-cystein ligase and microsomal triglyceride transfer protein genes in non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2010; 25 (2) 357-361
    CrossrefPubMedGoogle Scholar
  • 161 Petersen KF, Dufour S, Hariri A , et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med 2010; 362 (12) 1082-1089
    CrossrefPubMedGoogle Scholar
  • 162 Kozlitina J, Boerwinkle E, Cohen JC, Hobbs HH. Dissociation between APOC3 variants, hepatic triglyceride content and insulin resistance. Hepatology 2011; 53 (2) 467-474
    CrossrefPubMedGoogle Scholar
  • 163 Sentinelli F, Romeo S, Maglio C , et al. Lack of effect of apolipoprotein C3 polymorphisms on indices of liver steatosis, lipid profile and insulin resistance in obese Southern Europeans. Lipids Health Dis 2011; 10: 93
    CrossrefPubMedGoogle Scholar
  • 164 Valenti L, Nobili V, Al-Serri A , et al. The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage independently of PNPLA3 I148M genotype in patients with nonalcoholic fatty liver. J Hepatol 2011; 55 (6) 1409-1414
    CrossrefPubMedGoogle Scholar
  • 165 Verrijken A, Beckers S, Francque S , et al. A gene variant of PNPLA3, but not of APOC3, is associated with histological parameters of NAFLD in an obese population. Obesity (Silver Spring) 2013; 21 (10) 2138-2145
    CrossrefPubMedGoogle Scholar
  • 166 Utermann G, Hees M, Steinmetz A. Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man. Nature 1977; 269 (5629) 604-607
    CrossrefPubMedGoogle Scholar
  • 167 Demirag MD, Onen HI, Karaoguz MY , et al. Apolipoprotein E gene polymorphism in nonalcoholic fatty liver disease. Dig Dis Sci 2007; 52 (12) 3399-3403
    CrossrefPubMedGoogle Scholar
  • 168 Sazci A, Akpinar G, Aygun C, Ergul E, Senturk O, Hulagu S. Association of apolipoprotein E polymorphisms in patients with non-alcoholic steatohepatitis. Dig Dis Sci 2008; 53 (12) 3218-3224
    CrossrefPubMedGoogle Scholar
  • 169 George DK, Goldwurm S, MacDonald GA , et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998; 114 (2) 311-318
    CrossrefPubMedGoogle Scholar
  • 170 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 (3) 723-729
    CrossrefPubMedGoogle Scholar
  • 171 Bugianesi E, Manzini P, D'Antico S , et al. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology 2004; 39 (1) 179-187
    CrossrefPubMedGoogle Scholar
  • 172 Valenti L, Fracanzani AL, Bugianesi E , et al. HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology 2010; 138 (3) 905-912
    CrossrefPubMedGoogle Scholar
  • 173 Raszeja-Wyszomirska J, Kurzawski G, Lawniczak M, Miezynska-Kurtycz J, Lubinski J. Nonalcoholic fatty liver disease and HFE gene mutations: a Polish study. World J Gastroenterol 2010; 16 (20) 2531-2536
    CrossrefPubMedGoogle Scholar
  • 174 Ellervik C, Birgens H, Tybjaerg-Hansen A, Nordestgaard BG. Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls. Hepatology 2007; 46 (4) 1071-1080
    CrossrefPubMedGoogle Scholar
  • 175 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 (5) 1079-1085
    CrossrefPubMedGoogle Scholar
  • 176 Buch S, Schafmayer C, Völzke H , et al. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat Genet 2007; 39 (8) 995-999
    CrossrefPubMedGoogle Scholar
  • 177 Sookoian S, Castaño G, Gianotti TF, Gemma C, Pirola CJ. Polymorphisms of MRP2 (ABCC2) are associated with susceptibility to nonalcoholic fatty liver disease. J Nutr Biochem 2009; 20 (10) 765-770
    CrossrefPubMedGoogle Scholar
  • 178 Spruss A, Kanuri G, Wagnerberger S, Haub S, Bischoff SC, Bergheim I. Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology 2009; 50 (4) 1094-1104
    CrossrefPubMedGoogle Scholar
  • 179 Guo J, Loke J, Zheng F , et al. Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses. Hepatology 2009; 49 (3) 960-968
    CrossrefPubMedGoogle Scholar
  • 180 Huang H, Shiffman ML, Friedman S , et al. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology 2007; 46 (2) 297-306
    CrossrefPubMedGoogle Scholar
  • 181 Day CP, Leathart J, McTernan P , et al. Genetic evidence for a role of gut flora in the pathogenesis of NASH in humans. Hepatology 2006; 44 (Suppl. 01) 261A
    PubMedGoogle Scholar
  • 182 Baldini M, Lohman IC, Halonen M, Erickson RP, Holt PG, Martinez FD. A Polymorphism* in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 1999; 20 (5) 976-983
    CrossrefPubMedGoogle Scholar
  • 183 Valenti L, Fracanzani AL, Dongiovanni P , et al. Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease. Gastroenterology 2002; 122 (2) 274-280
    CrossrefPubMedGoogle Scholar
  • 184 Tokushige K, Takakura M, Tsuchiya-Matsushita N, Taniai M, Hashimoto E, Shiratori K. Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis. J Hepatol 2007; 46 (6) 1104-1110
    CrossrefPubMedGoogle Scholar
  • 185 Carulli L, Canedi I, Rondinella S , et al. Genetic polymorphisms in non-alcoholic fatty liver disease: interleukin-6-174G/C polymorphism is associated with non-alcoholic steatohepatitis. Dig Liver Dis 2009; 41 (11) 823-828
    CrossrefPubMedGoogle Scholar
  • 186 Eslam M, Hashem AM, Leung R , et al; International Hepatitis C Genetics Consortium (IHCGC). Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease. Nat Commun 2015; 6: 6422
    CrossrefPubMedGoogle Scholar
  • 187 Yoneda M, Hotta K, Nozaki Y , et al. Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease. Liver Int 2009; 29 (7) 1078-1085
    CrossrefPubMedGoogle Scholar
  • 188 Zain SM, Mohamed Z, Mahadeva S , et al. Susceptibility and gene interaction study of the angiotensin II type 1 receptor (AGTR1) gene polymorphisms with non-alcoholic fatty liver disease in a multi-ethnic population. PLoS ONE 2013; 8 (3) e58538
    CrossrefPubMedGoogle Scholar
  • 189 Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O'Donnell CJ, de Bakker PI. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 2008; 24 (24) 2938-2939
    CrossrefPubMedGoogle Scholar