PNPLA3 I148M polymorphism and progressive liver disease

World Journal of Gastroenterology

Volumn 19, Issue 41, 2013, Pages 6969-6978

  Dongiovanni, Paola ^a   Donati, Benedetta ^a   Fares, Roberta ^a   Lombardi, Rosa ^a   Mancina, Rosellina Margherita ^b   Romeo, Stefano ^b,c   Valenti, Luca ^a  

^a UNIVERSITY OF MILAN   (Italy)

^b UNIVERSITY OF GOTHENBURG   (Sweden)

^c UNIVERSITY MAGNA GRAECIA OF CATANZARO   (Italy)

Author keywords

Alcoholic liver disease; Chronic hepatitis C virus hepatitis; Fibrogenesis; Genetics; Hepatocellular carcinoma; Liver disease; Nonalcoholic fatty liver disease; Patatin like phospholipase domain containing 3; Single nucleotide polymorphism; Steatosis

Indexed keywords

ISOLEUCINE; METHIONINE; PATATIN LIKE PHOSPHOLIPASE DOMAIN CONTAINING 3; PROTEIN; PROTEIN VARIANT; UNCLASSIFIED DRUG; PROTEIN DERIVATIVE;

ALCOHOL LIVER DISEASE; ALLELE; CLINICAL TRIAL (TOPIC); DISEASE ASSOCIATION; DISEASE COURSE; FATTY LIVER; FIBROGENESIS; GENE FREQUENCY; HEMOCHROMATOSIS; HUMAN; KUPFFER CELL; LIPID LIVER LEVEL; LIPID STORAGE; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER FIBROSIS; MUTATION; NONALCOHOLIC FATTY LIVER; PRIMARY SCLEROSING CHOLANGITIS; PROTEIN POLYMORPHISM; REVIEW; STELLATE CELL; GENETIC ASSOCIATION; GENETIC POLYMORPHISM; GENETIC PREDISPOSITION; HEPATITIS B; HEPATITIS C; LIVER DISEASE;

ALCOHOLIC LIVER DISEASE; CHRONIC HEPATITIS C VIRUS HEPATITIS; FIBROGENESIS; GENETICS; HEPATOCELLULAR CARCINOMA; LIVER DISEASE; NONALCOHOLIC FATTY LIVER DISEASE; PATATIN-LIKE PHOSPHOLIPASE DOMAIN-CONTAINING 3; SINGLE NUCLEOTIDE POLYMORPHISM; STEATOSIS;

CARCINOMA, HEPATOCELLULAR; CHOLANGITIS, SCLEROSING; DISEASE PROGRESSION; FATTY LIVER; FATTY LIVER, ALCOHOLIC; GENETIC PREDISPOSITION TO DISEASE; HEMOCHROMATOSIS; HEPATITIS B, CHRONIC; HEPATITIS C, CHRONIC; HUMANS; LIPASE; LIVER CIRRHOSIS; LIVER CIRRHOSIS, ALCOHOLIC; LIVER NEOPLASMS; MEMBRANE PROTEINS; PHENOTYPE; POLYMORPHISM, GENETIC; RISK FACTORS;

EID: 84887553152     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v19.i41.6969     Document Type: Review

References (97)

1. Dongiovanni P, Anstee QM, Valenti L. Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment. Curr Pharm Des 2013; 19: 5219-5238 [PMID: 23394097]
2. 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 [PMID: 21226609 DOI: 10.1146/annurev.med.091708.162036]
3. Valenti L, Dongiovanni P, Ginanni Corradini S, Burza MA, Romeo S. PNPLA3 I148M variant and hepatocellular carcinoma: a common genetic variant for a rare disease. Dig Liver Dis 2013; 45: 619-624 [PMID: 23333103 DOI: 10.1016/ j.dld.2012.12.006]
4. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40: 1461-1465 [PMID: 18820647 DOI: 10.1038/ng.257]
5. Yuan X, Waterworth D, Perry JR, Lim N, Song K, Chambers JC, Zhang W, Vollenweider P, Stirnadel H, Johnson T, Bergmann S, Beckmann ND, Li Y, Ferrucci L, Melzer D, Hernandez D, Singleton A, Scott J, Elliott P, Waeber G, Cardon L, Frayling TM, Kooner JS, Mooser V. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet 2008; 83: 520-528 [PMID: 18940312 DOI: 10.1016/j.ajhg.2008.09.012]
6. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50: 1844-1850 [PMID: 11473047]
7. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40: 1387-1395 [PMID: 15565570]
8. Bellentani S, Saccoccio G, Masutti F, Crocè LS, Brandi G, Sasso F, Cristanini G, Tiribelli C. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000; 132: 112-117 [PMID: 10644271]
9. Day CP. From fat to inflammation. Gastroenterology 2006; 130: 207-210 [PMID: 16401483]
10. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41: 1313-1321 [PMID: 15915461]
11. Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, Musso A, De Paolis P, Capussotti L, Salizzoni M, Rizzetto M. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002; 123: 134-140 [PMID: 12105842]
12. Musso G, Gambino R, Cassader M, Pagano G. Metaanalysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011; 43: 617-649 [PMID: 21039302 DOI: 10.3109/07853890.2010.518623]
13. Bugianesi E, Gastaldelli A, Vanni E, Gambino R, Cassader M, Baldi S, Ponti V, Pagano G, Ferrannini E, Rizzetto M. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 2005; 48: 634-642 [PMID: 15747110]
14. Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, Bhanot S, Monia BP, Li YX, Diehl AM. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 2007; 45: 1366-1374 [PMID: 17476695 DOI: 10.1002/hep.21655]
15. Korenblat KM, Fabbrini E, Mohammed BS, Klein S. Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology 2008; 134: 1369-1375 [PMID: 18355813]
16. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363: 1341-1350 [PMID: 20879883]
17. Dongiovanni P, Valenti L, Rametta R, Daly AK, Nobili V, Mozzi E, Leathart JB, Pietrobattista A, Burt AD, Maggioni M, Fracanzani AL, Lattuada E, Zappa MA, Roviaro G, Marchesini G, Day CP, Fargion S. 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: 267-273 [PMID: 20176643 DOI: 10.1136/ gut.2009.190801]
18. Valenti L, Fracanzani AL, Fargion S. The immunopathogenesis of alcoholic and nonalcoholic steatohepatitis: two triggers for one disease? Semin Immunopathol 2009; 31: 359-369 [PMID: 19440711 DOI: 10.1007/s00281-009-0152-9]
19. Lee YS, Jeong WI. Retinoic acids and hepatic stellate cells in liver disease. J Gastroenterol Hepatol 2012; 27 Suppl 2: 75-79 [PMID: 22320921]
20. Lee UE, Friedman SL. Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol 2011; 25: 195-206 [PMID: 21497738]
21. Schwimmer JB, Celedon MA, Lavine JE, Salem R, Campbell N, Schork NJ, Shiehmorteza M, Yokoo T, Chavez A, Middleton MS, Sirlin CB. Heritability of nonalcoholic fatty liver disease. Gastroenterology 2009; 136: 1585-1592 [PMID: 19208353 DOI: 10.1053/j.gastro.2009.01.050]
22. Guerrero R, Vega GL, Grundy SM, Browning JD. Ethnic differences in hepatic steatosis: an insulin resistance paradox? Hepatology 2009; 49: 791-801 [PMID: 19105205 DOI: 10.1002/ hep.22726]
23. Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011; 140: 124-131 [PMID: 20858492 DOI: 10.1053/j.gastro.2010.09.038]
24. Struben VM, Hespenheide EE, Caldwell SH. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. Am J Med 2000; 108: 9-13 [PMID: 11059435]
25. 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: 2957-2961 [PMID: 11693332]
26. 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: 1035-1042 [PMID: 19303161 DOI: 10.1016/ j.jhep.2008.12]
27. Bathum L, Petersen HC, Rosholm JU, Hyltoft Petersen P, Vaupel J, Christensen K. Evidence for a substantial genetic influence on biochemical liver function tests: results from a population-based Danish twin study. Clin Chem 2001; 47: 81-87 [PMID: 11148181]
28. Hernaez R, McLean J, Lazo M, Brancati FL, Hirschhorn JN, Borecki IB, Harris TB, Nguyen T, Kamel IR, Bonekamp S, Eberhardt MS, Clark JM, Kao WH, Speliotes EK. Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the third national health and nutrition examination survey. Clin Gastroenterol Hepatol 2013; 11: 1183-1190. e2 [PMID: 23416328 DOI: 10.1016/j.cgh.2013.02.011]
29. Kotronen A, Johansson LE, Johansson LM, Roos C, Westerbacka J, Hamsten A, Bergholm R, Arkkila P, Arola J, Kiviluoto T, Fisher RM, Ehrenborg E, Orho-Melander M, Ridderstråle M, Groop L, Yki-Järvinen H. A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans. Diabetologia 2009; 52: 1056-1060 [PMID: 19224197 DOI: 10.1007/s00125-009-1285-z]
30. 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: 2111-2116 [PMID: 19738004 DOI: 10.1194/jlr.P900013-JLR200]
31. Valenti L, Al-Serri A, Daly AK, Galmozzi E, Rametta R, Dongiovanni P, Nobili V, Mozzi E, Roviaro G, Vanni E, Bugianesi E, Maggioni M, Fracanzani AL, Fargion S, Day CP. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2010; 51: 1209-1217 [PMID: 20373368]
32. Romeo S, Sentinelli F, Dash S, Yeo GS, Savage DB, Leonetti F, Capoccia D, Incani M, Maglio C, Iacovino M, O'Rahilly S, Baroni MG. Morbid obesity exposes the association between PNPLA3 I148M (rs738409) and indices of hepatic injury in individuals of European descent. Int J Obes (Lond) 2010; 34: 190-194 [PMID: 19844213]
33. Romeo S, Sentinelli F, Cambuli VM, Incani M, Congiu T, Matta V, Pilia S, Huang-Doran I, Cossu E, Loche S, Baroni MG. The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life. J Hepatol 2010; 53: 335-338 [PMID: 20546964 DOI: 10.1016/j.jhep.2010.02.034]
34. Rotman Y, Koh C, Zmuda JM, Kleiner DE, Liang TJ. 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: 894-903 [PMID: 20684021 DOI: 10.1002/hep.23759]
35. Speliotes EK, Butler JL, Palmer CD, Voight BF, Hirschhorn JN. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 2010; 52: 904-912 [PMID: 20648472]
36. 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: 1883-1894 [PMID: 21381068 DOI: 10.1002/hep.24283]
37. Nobili V, Svegliati-Baroni G, Alisi A, Miele L, Valenti L, Vajro P. A 360-degree overview of paediatric NAFLD: recent insights. J Hepatol 2013; 58: 1218-1229 [PMID: 23238106 DOI: 10.1016/j.jhep.2012.12.003]
38. Kitamoto T, Kitamoto A, Yoneda M, Hyogo H, Ochi H, Nakamura T, Teranishi H, Mizusawa S, Ueno T, Chayama K, Nakajima A, Nakao K, Sekine A, Hotta K. Genomewide 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: 783-792 [PMID: 23535911 DOI: 10.1007/s00439-013-1294-3]
39. Peng XE, Wu YL, Lin SW, Lu QQ, Hu ZJ, Lin X. Genetic variants in PNPLA3 and risk of non-alcoholic fatty liver disease in a Han Chinese population. PLoS One 2012; 7: e50256 [PMID: 23226254]
40. Hotta K, Yoneda M, Hyogo H, Ochi H, Mizusawa S, Ueno T, Chayama K, Nakajima A, Nakao K, Sekine A. Association of the rs738409 polymorphism in PNPLA3 with liver damage and the development of nonalcoholic fatty liver disease. BMC Med Genet 2010; 11: 172 [PMID: 21176169 DOI: 10.1186 /1471-2350-11-172]
41. Lin YC, Chang PF, Hu FC, Yang WS, Chang MH, Ni YH. A common variant in the PNPLA3 gene is a risk factor for nonalcoholic fatty liver disease in obese Taiwanese children. J Pediatr 2011; 158: 740-744 [PMID: 21168155 DOI: 10.1016/ j.jpeds.2010.11.016]
42. Giudice EM, Grandone A, Cirillo G, Santoro N, Amato A, Brienza C, Savarese P, Marzuillo P, Perrone L. The association of PNPLA3 variants with liver enzymes in childhood obesity is driven by the interaction with abdominal fat. PLoS One 2011; 6: e27933 [PMID: 22140488]
43. Davis JN, Lê KA, Walker RW, Vikman S, Spruijt-Metz D, Weigensberg MJ, Allayee H, Goran MI. Increased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption. Am J Clin Nutr 2010; 92: 1522-1527 [PMID: 20962157 DOI: 10.3945/ajcn.2010.30185]
44. Santoro N, Savoye M, Kim G, Marotto K, Shaw MM, Pierpont B, Caprio S. Hepatic fat accumulation is modulated by the interaction between the rs738409 variant in the PNPLA3 gene and the dietary omega6/omega3 PUFA intake. PLoS One 2012; 7: e37827 [PMID: 22629460]
45. Santoro N, Zhang CK, Zhao H, Pakstis AJ, Kim G, Kursawe R, Dykas DJ, Bale AE, Giannini C, Pierpont B, Shaw MM, Groop L, Caprio S. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 2012; 55: 781-789 [PMID: 22105854 DOI: 10.1002/hep.24806]
46. Valenti L, Alisi A, Nobili V. Unraveling the genetics of fatty liver in obese children: additive effect of P446L GCKR and I148M PNPLA3 polymorphisms. Hepatology 2012; 55: 661-663 [PMID: 22281838 DOI: 10.1002/hep.25617]
47. Sevastianova K, Santos A, Kotronen A, Hakkarainen A, Makkonen J, Silander K, Peltonen M, Romeo S, Lundbom J, Lundbom N, Olkkonen VM, Gylling H, Fielding BA, Rissanen A, Yki-Järvinen H. Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans. Am J Clin Nutr 2012; 96: 727-734 [PMID: 22952180 DOI: 10.3945/ajcn.112.038695]
48. He S, McPhaul C, Li JZ, Garuti R, Kinch L, Grishin NV, Cohen JC, Hobbs HH. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem 2010; 285: 6706-6715 [PMID: 20034933 DOI: 10.1074/jbc.M109.064501]
49. Huang Y, He S, Li JZ, Seo YK, Osborne TF, Cohen JC, Hobbs HH. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci USA 2010; 107: 7892-7897 [PMID: 20385813 DOI: 10.1073/pnas.1003585107]
50. Pirazzi C, Adiels M, Burza MA, Mancina RM, Levin M, Ståhlman M, Taskinen MR, Orho-Melander M, Perman J, Pujia A, Andersson L, Maglio C, Montalcini T, Wiklund O, Borén J, Romeo S. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J Hepatol 2012; 57: 1276-1282 [PMID: 22878467 DOI: 10.1016/ j.jhep.2012.07.030]
51. Kumari M, Schoiswohl G, Chitraju C, Paar M, Cornaciu I, Rangrez AY, Wongsiriroj N, Nagy HM, Ivanova PT, Scott SA, Knittelfelder O, Rechberger GN, Birner-Gruenberger R, Eder S, Brown HA, Haemmerle G, Oberer M, Lass A, Kershaw EE, Zimmermann R, Zechner R. Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab 2012; 15: 691-702 [PMID: 22560221 DOI: 10.1016/j.cmet.2012.04.008]
52. Basantani MK, Sitnick MT, Cai L, Brenner DS, Gardner NP, Li JZ, Schoiswohl G, Yang K, Kumari M, Gross RW, Zechner R, Kershaw EE. Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. J Lipid Res 2011; 52: 318-329 [PMID: 21068004 DOI: 10.1194/jlr. M011205]
53. Li JZ, Huang Y, Karaman R, Ivanova PT, Brown HA, Roddy T, Castro-Perez J, Cohen JC, Hobbs HH. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest 2012; 122: 4130-4144 [PMID: 23023705 DOI: 10.1172/JCI65179]
54. Kumashiro N, Yoshimura T, Cantley JL, Majumdar SK, Guebre-Egziabher F, Kursawe R, Vatner DF, Fat I, Kahn M, Erion DM, Zhang XM, Zhang D, Manchem VP, Bhanot S, Gerhard GS, Petersen KF, Cline GW, Samuel VT, Shulman GI. Role of patatin-like phospholipase domain-containing 3 on lipid-induced hepatic steatosis and insulin resistance in rats. Hepatology 2013; 57: 1763-1772 [PMID: 23175050 DOI: 10.1002/hep.26170]
55. 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: 1134-1142 [PMID: 20648554 DOI: 10.1002/hep.23812]
56. Santoro N, Kursawe R, D'Adamo E, Dykas DJ, Zhang CK, Bale AE, Calí AM, Narayan D, Shaw MM, Pierpont B, Savoye M, Lartaud D, Eldrich S, Cushman SW, Zhao H, Shulman GI, Caprio S. 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: 1281-1290 [PMID: 20803499]
57. Valenti L, Rametta R, Ruscica M, Dongiovanni P, Steffani L, Motta BM, Canavesi E, Fracanzani AL, Mozzi E, Roviaro G, Magni P, Fargion S. The I148M PNPLA3 polymorphism influences serum adiponectin in patients with fatty liver and healthy controls. BMC Gastroenterol 2012; 12: 111 [PMID: 22898488 DOI: 10.1186/1471-230X-12-111]
58. Chalasani N, Wilson L, Kleiner DE, Cummings OW, Brunt EM, Unalp A. Relationship of steatosis grade and zonal location to histological features of steatohepatitis in adult patients with non-alcoholic fatty liver disease. J Hepatol 2008; 48: 829-834 [PMID: 18321606 DOI: 10.1016/j.jhep.2008.01.016]
59. Valenti L, Alisi A, Galmozzi E, Bartuli A, Del Menico B, Alterio A, Dongiovanni P, Fargion S, Nobili V. I148M patatinlike phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease. Hepatology 2010; 52: 1274-1280 [PMID: 20648474]
60. Tian C, Stokowski RP, Kershenobich D, Ballinger DG, Hinds DA. Variant in PNPLA3 is associated with alcoholic liver disease. Nat Genet 2010; 42: 21-23 [PMID: 19946271 DOI: 10.1038/ng.488]
61. Stickel F, Buch S, Lau K, Meyer zu Schwabedissen H, Berg T, Ridinger M, Rietschel M, Schafmayer C, Braun F, Hinrichsen H, Günther R, Arlt A, Seeger M, Müller S, Seitz HK, Soyka M, Lerch M, Lammert F, Sarrazin C, Kubitz R, Häussinger D, Hellerbrand C, Bröring D, Schreiber S, Kiefer F, Spanagel R, Mann K, Datz C, Krawczak M, Wodarz N, Völzke H, Hampe J. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians. Hepatology 2011; 53: 86-95 [PMID: 21254164]
62. Stickel F, Hampe J. Genetic determinants of alcoholic liver disease. Gut 2012; 61: 150-159 [PMID: 22110053 DOI: 10.1136/gutjnl-2011-301239]
63. Burza MA, Molinaro A, Attilia ML, Rotondo C, Attilia F, Ceccanti M, Ferri F, Maldarelli F, Maffongelli A, De Santis A, Attili AF, Romeo S, Ginanni Corradini S. PNPLA3 I148M (rs738409) genetic variant and age at onset of at-risk alcohol consumption are independent risk factors for alcoholic cirrhosis. Liv Int 2013; in press.
64. Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol 2013; 58: 593-608 [PMID: 23419824 DOI: 10.1016/j.jhep.2012.12.005]
65. Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001; 33: 1358-1364 [PMID: 11391523]
66. Akuta N, Suzuki F, Tsubota A, Suzuki Y, Someya T, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H. Efficacy of interferon monotherapy to 394 consecutive naive cases infected with hepatitis C virus genotype 2a in Japan: therapy efficacy as consequence of tripartite interaction of viral, host and interferon treatment-related factors. J Hepatol 2002; 37: 831-836 [PMID: 12445425]
67. Rubbia-Brandt L, Quadri R, Abid K, Giostra E, Malé PJ, Mentha G, Spahr L, Zarski JP, Borisch B, Hadengue A, Negro F. Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J Hepatol 2000; 33: 106-115 [PMID: 10905593]
68. Westin J, Nordlinder H, Lagging M, Norkrans G, Wejstål R. Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients. J Hepatol 2002; 37: 837-842 [PMID: 12445426]
69. Bassendine MF, Sheridan DA, Felmlee DJ, Bridge SH, Toms GL, Neely RD. HCV and the hepatic lipid pathway as a potential treatment target. J Hepatol 2011; 55: 1428-1440 [PMID: 21718665 DOI: 10.1016/j.jhep.2011.06.004]
70. Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Host-and disease-specific factors affecting steatosis in chronic hepatitis C. J Hepatol 1998; 29: 198-206 [PMID: 9722200]
71. Monto A, Alonzo J, Watson JJ, Grunfeld C, Wright TL. Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcohol. Hepatology 2002; 36: 729-736 [PMID: 12198667]
72. Kumar D, Farrell GC, Fung C, George J. Hepatitis C virus genotype 3 is cytopathic to hepatocytes: Reversal of hepatic steatosis after sustained therapeutic response. Hepatology 2002; 36: 1266-1272 [PMID: 12395339]
73. Lerat H, Honda M, Beard MR, Loesch K, Sun J, Yang Y, Okuda M, Gosert R, Xiao SY, Weinman SA, Lemon SM. Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology 2002; 122: 352-365 [PMID: 11832450]
74. Cai T, Dufour JF, Muellhaupt B, Gerlach T, Heim M, Moradpour D, Cerny A, Malinverni R, Kaddai V, Bochud M, Negro F, Bochud PY. Viral genotype-specific role of PNPLA3, PPARG, MTTP, and IL28B in hepatitis C virus-associated steatosis. J Hepatol 2011; 55: 529-535 [PMID: 21236304 DOI: 10.1016/j.jhep.2010.12.020]
75. Valenti L, Rumi M, Galmozzi E, Aghemo A, Del Menico B, De Nicola S, Dongiovanni P, Maggioni M, Fracanzani AL, Rametta R, Colombo M, Fargion S. Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. Hepatology 2011; 53: 791-799 [PMID: 21319195]
76. Müller T, Buch S, Berg T, Hampe J, Stickel F. Distinct, alcohol-modulated effects of PNPLA3 genotype on progression of chronic hepatitis C. J Hepatol 2011; 55: 732-733 [PMID: 21316406 DOI: 10.1016/j.jhep.2011.01.025]
77. Trépo E, Pradat P, Potthoff A, Momozawa Y, Quertinmont E, Gustot T, Lemmers A, Berthillon P, Amininejad L, Chevallier M, Schlué J, Kreipe H, Devière J, Manns M, Trépo C, Sninsky J, Wedemeyer H, Franchimont D, Moreno C. Impact of patatin-like phospholipase-3 (rs738409 C > G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C. Hepatology 2011; 54: 60-69 [PMID: 21488075]
78. Cefalù AB, Pirruccello JP, Noto D, Gabriel S, Valenti V, Gupta N, Spina R, Tarugi P, Kathiresan S, Averna MR. A novel APOB mutation identified by exome sequencing cosegregates with steatosis, liver cancer, and hypocholesterolemia. Arterioscler Thromb Vasc Biol 2013; 33: 2021-2025 [PMID: 23723369 DOI: 10.1161/ATVBAHA.112.301101]
79. Valenti L, Aghemo A, Stättermayer AF, Maggioni P, De Nicola S, Motta BM, Rumi MG, Dongiovanni P, Ferenci P, Colombo M, Fargion S. Implications of PNPLA3 polymorphism in chronic hepatitis C patients receiving peginterferon plus ribavirin. Aliment Pharmacol Ther 2012; 35: 1434-1442 [PMID: 22530607 DOI: 10.1111/j.1365-2036.2012.05109.x]
80. Valenti L, Colombo M, Fargion S. Modulation of the effect of PNPLA3 I148M mutation on steatosis and liver damage by alcohol intake in patients with chronic hepatitis C. J Hepatol 2011; 55: 1470-1471; author reply 1471-1472 [PMID: 22100032 DOI: 10.1016/j.jhep.2011.04.032]
81. Valenti L, Aghemo A, Stättermayer AF. Interaction between IL28B and PNPLA3 genotypes in the pathogenesis of steatosis in chronic hepatitis C non genotype-3 patients. J Hepatol 2012; 56: 1209-110; author reply 1209-1210 [PMID: 22230871]
82. Valenti L, Alisi A, Nobili V. 148M PNPLA3 variant and progressive liver disease: a new paradigm in hepatology. Hepatology 2012; 56: 1883-1889 [PMID: 23012712]
83. Rembeck K, Maglio C, Lagging M, Christensen PB, Färkkilä M, Langeland N, Buhl MR, Pedersen C, Mørch K, Norkrans G, Hellstrand K, Lindh M, Pirazzi C, Burza MA, Romeo S, Westin J. PNPLA 3 I148M genetic variant associates with insulin resistance and baseline viral load in HCV genotype 2 but not in genotype 3 infection. BMC Med Genet 2012; 13: 82 [PMID: 22978414 DOI: 10.1186/1471-2350-13-82]
84. European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012; 57: 167-185 [PMID: 22436845 DOI: 10.1016/j.jhep.2012.02.010]
85. Park SH, Kim DJ, Lee HY. Insulin resistance is not associated with histologic severity in nondiabetic, noncirrhotic patients with chronic hepatitis B virus infection. Am J Gastroenterol 2009; 104: 1135-1139 [PMID: 19319126]
86. Petta S, Cammà C, Di Marco V, Macaluso FS, Maida M, Pizzolanti G, Belmonte B, Cabibi D, Di Stefano R, Ferraro D, Guarnotta C, Venezia G, Craxì A. Hepatic steatosis and insulin resistance are associated with severe fibrosis in patients with chronic hepatitis caused by HBV or HCV infection. Liver Int 2011; 31: 507-515 [PMID: 21382161 DOI: 10.1111/ j.1478-3231.2011.02453.x]
87. Wong VW, Wong GL, Yu J, Choi PC, Chan AW, Chan HY, Chu ES, Cheng AS, Chim AM, Chan FK, Sung JJ, Chan HL. Interaction of adipokines and hepatitis B virus on histological liver injury in the Chinese. Am J Gastroenterol 2010; 105: 132-138 [PMID: 19809411 DOI: 10.1038/ajg.2009.560]
88. Wong GL, Wong VW, Choi PC, Chan AW, Chim AM, Yiu KK, Chan HY, Chan FK, Sung JJ, Chan HL. Metabolic syndrome increases the risk of liver cirrhosis in chronic hepatitis B. Gut 2009; 58: 111-117 [PMID: 18832522 DOI: 10.1136/ gut.2008.157735]
89. Viganò M, Valenti L, Lampertico P, Facchetti F, Motta BM, D'Ambrosio R, Romagnoli S, Dongiovanni P, Donati B, Fargion S, Colombo M. Patatin-like phospholipase domain-containing 3 I148M affects liver steatosis in patients with chronic hepatitis B. Hepatology 2013; 58: 1245-1252 [PMID: 23564580]
90. Gualdi R, Casalgrandi G, Montosi G, Ventura E, Pietrangelo A. Excess iron into hepatocytes is required for activation of collagen type I gene during experimental siderosis. Gastroenterology 1994; 107: 1118-1124 [PMID: 7926461]
91. Pietrangelo A. Hereditary hemochromatosis--a new look at an old disease. N Engl J Med 2004; 350: 2383-2397 [PMID: 15175440]
92. Wood MJ, Powell LW, Ramm GA. Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis. Blood 2008; 111: 4456-4462 [PMID: 18316631 DOI: 10.1182/blood-2007-11-122374]
93. Valenti L, Maggioni P, Piperno A, Rametta R, Pelucchi S, Mariani R, Dongiovanni P, Fracanzani AL, Fargion S. Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis. World J Gastroenterol 2012; 18: 2813-2820 [PMID: 22719190 DOI: 10.3748/wjg.v18.i22.2813]
94. Friedrich K, Rupp C, Hov JR, Steinebrunner N, Weiss KH, Stiehl A, Brune M, Schaefer PK, Schemmer P, Sauer P, Schirmacher P, Runz H, Karlsen TH, Stremmel W, Gotthardt DN. A frequent PNPLA3 variant is a sex specific disease modifier in PSC patients with bile duct stenosis. PLoS One 2013; 8: e58734 [PMID: 23505555 DOI: 10.1371/journal. pone.0058734]
95. Trepo E, Guyot E, Ganne-Carrie N, Degre D, Gustot T, Franchimont D, Sutton A, Nahon P, Moreno C. PNPLA3 (rs738409 C > G) is a common risk variant associated with hepatocellular carcinoma in alcoholic cirrhosis. Hepatol-ogy 2012; 55: 1307-1308 [PMID: 22162034 DOI: 10.1002/ hep.25518]
96. Falleti E, Fabris C, Cmet S, Cussigh A, Bitetto D, Fontanini E, Fornasiere E, Bignulin S, Fumolo E, Bignulin E, Pirisi M, Toniutto P. PNPLA3 rs738409C/G polymorphism in cirrhosis: relationship with the aetiology of liver disease and hepatocellular carcinoma occurrence. Liver Int 2011; 31: 1137-1143 [PMID: 21745286]
97. Burza MA, Pirazzi C, Maglio C, Sjöholm K, Mancina RM, Svensson PA, Jacobson P, Adiels M, Baroni MG, Borén J, Ginanni Corradini S, Montalcini T, Sjöström L, Carlsson LM, Romeo S. PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals. Dig Liver Dis 2012; 44: 1037-1041 [PMID: 22704398]