The genetics of NAFLD

Nature Reviews Gastroenterology and Hepatology

Volumn 10, Issue 11, 2013, Pages 645-655

  Anstee, Quentin M ^a   Day, Christopher P ^a  

^a NEWCASTLE UNIVERSITY   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANGIOTENSIN RECEPTOR; KRUPPEL LIKE FACTOR 6; MANGANESE SUPEROXIDE DISMUTASE; TRIACYLGLYCEROL;

ATGR1 GENE; CLINICAL CLASSIFICATION; DIZYGOTIC TWINS; EPIGENETICS; ETHNIC DIFFERENCE; FAMILIAL DISEASE; GCKR GENE; GENE; GENE FUNCTION; GENETIC ASSOCIATION; GENETIC RISK; GENETIC SUSCEPTIBILITY; GENETIC TRAIT; GENETIC VARIABILITY; GEOGRAPHIC DISTRIBUTION; HISTOPATHOLOGY; HUMAN; LIVER CIRRHOSIS; LIVER FIBROSIS; MONOZYGOTIC TWINS; NONALCOHOLIC FATTY LIVER; NONHUMAN; PATHOGENESIS; PEMT GENE; PHENOTYPIC VARIATION; PNPLA3 GENE; PREVALENCE; PRIORITY JOURNAL; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; SOD2 GENE; STEATOSIS;

DISEASE PROGRESSION; EPIGENOMICS; FATTY LIVER; GENOME-WIDE ASSOCIATION STUDY; HUMANS; LIPASE; MEMBRANE PROTEINS; SEVERITY OF ILLNESS INDEX;

EID: 84887319663     PISSN: 17595045     EISSN: 17595053     Source Type: Journal    
DOI: 10.1038/nrgastro.2013.182     Document Type: Review

References (183)

1. Anstee, Q. M., McPherson, S. & Day, C. P. How big a problem is non-alcoholic fatty liver disease? BMJ 343, d3897 (2011).
2. Sanyal, A. J. & American Gastroenterological Association. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 123, 1705-1725 (2002).
3. Anstee, Q. M., Targher, G. & Day, C. P. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat. Rev. Gastroenterol. Hepatol. 10, 330-344 (2013).
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. 53, 372-384 (2010).
5. Das, K. et al. Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease. Hepatology 51, 1593-1602 (2010).
6. Cobbold, J. F., Anstee, Q. M. & Taylor?Robinson, S. D. The importance of fatty liver disease in clinical practice. Proc. Nutr. Soc. 1-10 (2010).
7. 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. 43, 617-649 (2011).
8. Minervini, M. I. et al. Liver biopsy findings from healthy potential living liver donors: reasons for disqualification, silent diseases and correlation with liver injury tests. J. Hepatol. 50, 501-510 (2009).
9. Nadalin, S. et al. Preoperative donor liver biopsy for adult living donor liver transplantation: risks and benefits. Liver Transpl. 11, 980-986 (2005).
10. Tran, T. T. et al. Living donor liver transplantation: histological abnormalities found on liver biopsies of apparently healthy potential donors. J. Gastroenterol. Hepatol. 21, 381-383 (2006).
11. Ryan, C. K., Johnson, L. A., Germin, B. I. & Marcos, A. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation. Liver Transpl. 8, 1114-1122 (2002).
12. Browning, J. D. et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40, 1387-1395 (2004).
13. Szczepaniak, L. S. et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am. J. Physiol. Endocrinol. Metab. 288, E462-E468 (2005).
14. Bellentani, S., Bedogni, G., Miglioli, L. & Tiribelli, C. The epidemiology of fatty liver. Eur. J. Gastroenterol. Hepatol. 16, 1087-1093 (2004).
15. Argo, C. K. & Caldwell, S. H. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin. Liver Dis. 13, 511-531 (2009).
16. Targher, G. et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 30, 1212-1218 (2007).
17. Jimba, S. et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet. Med. 22, 1141-1145 (2005).
18. Williams, C. D. et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140, 124-131 (2011).
19. Williamson, R. M. et al. Prevalence of and risk factors for hepatic steatosis and nonalcoholic fatty liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes Care 34, 1139-1144 (2011).
20. Hirschhorn, J. N. & Gajdos, Z. K. Genome-wide association studies: results from the first few years and potential implications for clinical medicine. Annu. Rev. Med. 62, 11-24 (2011).
21. Altshuler, D., Daly, M. J. & Lander, E. S. Genetic mapping in human disease. Science 322, 881-888 (2008).
22. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature 431, 931-945 (2004).
23. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860-921 (2001).
24. Manolio, T. A., Brooks, L. D. & Collins, F. S. A HapMap harvest of insights into the genetics of common disease. J. Clin. Invest. 118, 1590-1605 (2008).
25. International HapMap Consortium. The International HapMap Project. Nature 426, 789-796 (2003).
26. International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299-1320 (2005).
27. Frazer, K. A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851-861 (2007).
28. Reich, D. E. & Lander, E. S. On the allelic spectrum of human disease. Trends Genet. 17, 502-510 (2001).
29. Wang, W. Y., Barratt, B. J., Clayton, D. G. & Todd, J. A. Genome-wide association studies: theoretical and practical concerns. Nat. Rev. Genet. 6, 109-118 (2005).
30. Pritchard, J. K. Are rare variants responsible for susceptibility to complex diseases? Am. J. Hum. Genet. 69, 124-137 (2001).
31. Hindorff, L. A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA 106, 9362-9367 (2009).
32. Lohmueller, K. E., Pearce, C. L., Pike, M., Lander, E. S. & Hirschhorn, J. N. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat. Genet. 33, 177-182 (2003).
33. Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature 461, 747-753 (2009).
34. Cardon, L. R. & Bell, J. I. Association study designs for complex diseases. Nat. Rev. Genet. 2, 91-99 (2001).
35. Hirschhorn, J. N. Genomewide association studies-illuminating biologic pathways. N. Engl. J. Med. 360, 1699-1701 (2009).
36. Hardy, J. & Singleton, A. Genomewide association studies and human disease. N. Engl. J. Med. 360, 1759-1768 (2009).
37. Hirschhorn, J. N. & Daly, M. J. Genome-wide association studies for common diseases and complex traits. Nat. Rev. Genet. 6, 95-108 (2005).
38. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661-678 (2007).
39. McCarthy, M. I. & Hirschhorn, J. N. Genome-wide association studies: past, present and future. Hum. Mol. Genet. 17, R100-R101 (2008).
40. Yuan, X. et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am. J. Hum. Genet. 83, 520-528 (2008).
41. Chambers, J. C. et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat. Genet. 43, 1131-1138 (2011).
42. Anstee, Q. M., McPherson, S. & Day, C. P. How big a problem is non-alcoholic fatty liver disease? BMJ 343, d3897 (2011).
43. Sanyal, A. J. & American Gastroenterological Association. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 123, 1705-1725 (2002).
44. Anstee, Q. M., Targher, G. & Day, C. P. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat. Rev. Gastroenterol. Hepatol. 10, 330-344 (2013).
45. 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. 53, 372-384 (2010).
46. Das, K. et al. Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease. Hepatology 51, 1593-1602 (2010).
47. Cobbold J. F., Anstee, Q. M. & Taylor?Robinson, S. D. The importance of fatty liver disease in clinical practice. Proc. Nutr. Soc. 1-10 (2010)
48. 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. 43, 617-649 (2011).
49. Minervini, M. I. et al. Liver biopsy findings from healthy potential living liver donors: reasons for disqualification, silent diseases and correlation with liver injury tests. J. Hepatol. 50, 501-510 (2009).
50. Nadalin, S. et al. Preoperative donor liver biopsy for adult living donor liver transplantation: risks and benefits. Liver Transpl. 11, 980-986 (2005).
51. Tran, T. T. et al. Living donor liver transplantation: histological abnormalities found on liver biopsies of apparently healthy potential donors. J. Gastroenterol. Hepatol. 21, 381-383 (2006).
52. Ryan, C. K., Johnson, L. A., Germin, B. I. & Marcos, A. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation. Liver Transpl. 8, 1114-1122 (2002).
53. Browning, J. D. et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40, 1387-1395 (2004).
54. Szczepaniak, L. S. et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am. J. Physiol. Endocrinol. Metab. 288, E462-E468 (2005).
55. Bellentani, S., Bedogni, G., Miglioli, L. & Tiribelli, C. The epidemiology of fatty liver. Eur. J. Gastroenterol. Hepatol. 16, 1087-1093 (2004).
56. Argo, C. K. & Caldwell, S. H. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin. Liver Dis. 13, 511-531 (2009).
57. Targher, G. et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 30, 1212-1218 (2007).
58. Jimba, S. et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet. Med. 22, 1141-1145 (2005).
59. Williams, C. D. et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140, 124-131 (2011).
60. Williamson, R. M. et al. Prevalence of and risk factors for hepatic steatosis and nonalcoholic fatty liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes Care 34, 1139-1144 (2011).
61. Hirschhorn, J. N. & Gajdos, Z. K. Genome-wide association studies: results from the first few years and potential implications for clinical medicine. Annu. Rev. Med. 62, 11-24 (2011).
62. Altshuler, D., Daly, M. J. & Lander, E. S. Genetic mapping in human disease. Science 322, 881-888 (2008).
63. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature 431, 931-945 (2004).
64. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860-921 (2001).
65. Manolio, T. A., Brooks, L. D. & Collins, F. S. A HapMap harvest of insights into the genetics of common disease. J. Clin. Invest. 118, 1590-1605 (2008).
66. International HapMap Consortium. The International HapMap Project. Nature 426, 789-796 (2003).
67. International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299-1320 (2005).
68. Frazer, K. A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851-861 (2007).
69. Reich, D. E. & Lander, E. S. On the allelic spectrum of human disease. Trends Genet. 17, 502-510 (2001).
70. Wang, W. Y., Barratt, B. J., Clayton, D. G. & Todd, J. A. Genome-wide association studies: theoretical and practical concerns. Nat. Rev. Genet. 6, 109-118 (2005).
71. Pritchard, J. K. Are rare variants responsible for susceptibility to complex diseases? Am. J. Hum. Genet. 69, 124-137 (2001).
72. Hindorff, L. A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA 106, 9362-9367 (2009).
73. Lohmueller, K. E., Pearce, C. L., Pike, M., Lander, E. S. & Hirschhorn, J. N. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat. Genet. 33, 177-182 (2003).
74. Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature 461, 747-753 (2009).
75. Cardon, L. R. & Bell, J. I. Association study designs for complex diseases. Nat. Rev. Genet. 2, 91-99 (2001).
76. Hirschhorn, J. N. Genomewide association studies-illuminating biologic pathways. N. Engl. J. Med. 360, 1699-1701 (2009).
77. Hardy, J. & Singleton, A. Genomewide association studies and human disease. N. Engl. J. Med. 360, 1759-1768 (2009).
78. Hirschhorn, J. N. & Daly, M. J. Genome-wide association studies for common diseases and complex traits. Nat. Rev. Genet. 6, 95-108 (2005).
79. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661-678 (2007).
80. McCarthy, M. I. & Hirschhorn, J. N. Genome-wide association studies: past, present and future. Hum. Mol. Genet. 17, R100-R101 (2008).
81. Yuan, X. et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am. J. Hum. Genet. 83, 520-528 (2008).
82. Chambers, J. C. et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat. Genet. 43, 1131-1138 (2011).
83. Daly, A. K. et al. HLA?B5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat. Genet. 41, 816-819 (2009).
84. Buch, S. et al. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat. Genet. 39, 995-999 (2007).
85. Hirschfield, G. M. et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N. Engl. J. Med. 360, 2544-2555 (2009).
86. Liu, X. et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat. Genet. 42, 658-660 (2010).
87. Mells, G. F. et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat. Genet. 43, 329-332 (2011).
88. Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461-1465 (2008).
89. Chalasani, N. et al. Genome-wide association study identifies variants associated with histologic features of nonalcoholic fatty liver disease. Gastroenterology 139, 1567-1576 (2010).
90. Speliotes, E. K. et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 7, e1001324 (2011).
91. Kamatani, Y. et al. A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nat. Genet. 41, 591-595 (2009).
92. Ge, D. et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461, 399-401 (2009).
93. Suppiah, V. et al. IL28B is associated with response to chronic hepatitis C interferon-? and ribavirin therapy. Nat. Genet. 41, 1100-1104 (2009).
94. Miele, L. et al. The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease. Gastroenterology 135, 282-291 (2008).
95. Anstee, Q. M. et al. Genome-wide association analysis confirms importance of PNPLA3 and identifies novel variants associated with histologically progressive fibrosing steatohepatitis in NAFLD [abstract 146]. Hepatology 56 (Suppl. 1), 265A (2012).
96. Kawaguchi, T. et al. Genetic polymorphisms of the human PNPLA3 gene are strongly associated with severity of non-alcoholic fatty liver disease in Japanese. PLoS ONE 7, e38322 (2012).
97. Feitosa, M. F. et al. The ERLIN1-CHUK-CWF19L1 gene cluster influences liver fat deposition and hepatic inflammation in the NHLBI Family Heart Study. Atherosclerosis 228, 175-180 (2013).
98. Victor, R. G. et al. The Dallas Heart Study: a population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health. Am. J. Cardiol. 93, 1473-1480 (2004).
99. Cobbold, J. F. et al. Phenotyping murine models of non-alcoholic fatty liver disease through metabolic profiling of intact liver tissue. Clin. Sci. (Lond.) 116, 403-413 (2009).
100. Siegelman, E. S. & Rosen, M. A. Imaging of hepatic steatosis. Semin. Liver Dis. 21, 71-80 (2001).
101. Romeo, S., Huang-Doran, I., Baroni, M. G. & Kotronen, A. Unravelling the pathogenesis of fatty liver disease: patatin-like phospholipase domain-containing 3 protein. Curr. Opin. Lipidol. 21, 247-252 (2010).
102. Gorden, A. et al. Genetic variation at NCAN locus is associated with inflammation and fibrosis in non-alcoholic fatty liver disease in morbid obesity. Hum. Hered. 75, 34-43 (2013).
103. Kathiresan, S. et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 40, 189-197 (2008).
104. Teslovich, T. M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707-713 (2010).
105. Kleiner, D. E. et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41, 1313-1321 (2005).
106. Ballestri, S., Day, C. P. & Daly, A. K. Polymorphism in the farnesyl diphosphate farnesyl transferase 1 gene and nonalcoholic fatty liver disease severity. Gastroenterology 140, 1694-1695 (2011).
107. Kitamoto, T. 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. 132, 783-792 (2013).
108. Matteoni, C. A. et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 116, 1413-1419 (1999).
109. Saadeh, S. et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 123, 745-750 (2002).
110. Schwenzer, N. F. et al. Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. J. Hepatol. 51, 433-445 (2009).
111. Dasarathy, S. et al. Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study. J. Hepatol. 51, 1061-1067 (2009).
112. Mofrad, P. et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 37, 1286-1292 (2003).
113. Vernon, G., Baranova, A. & Younossi, Z. M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment. Pharmacol. Ther. 34, 274-285 (2011).
114. Armstrong, M. J. et al. Presence and severity of non-alcoholic fatty liver disease in a large prospective primary care cohort. J. Hepatol. 56, 234-240 (2012).
115. Aulchenko, Y. S. et al. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat. Genet. 41, 47-55 (2009).
116. Willer, C. J. et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 40, 161-169 (2008).
117. Valenti, L. et al. Homozygosity for the patatin-like phospholipase?3/ adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 51, 1209-1217 (2010).
118. Kotronen, A. et al. A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans. Diabetologia 52, 1056-1060 (2009).
119. Sookoian, S. et al. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J. Lipid Res. 50, 2111-2116 (2009).
120. Kantartzis, K. et al. Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene. Diabetes 58, 2616-2623 (2009).
121. Rotman, Y., Koh, C., Zmuda, J. M., Kleiner, D. E. & Liang, T. J. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 52, 894-903 (2010).
122. Romeo, S. et al. The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life. J. Hepatol. 53, 335-338 (2010).
123. Valenti, L. et al. I148M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease. Hepatology 52, 1274-1280 (2010).
124. Santoro, N. 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 52, 1281-1290 (2010).
125. Kollerits, B. et al. A common variant in the adiponutrin gene influences liver enzyme values. J. Med. Genet. 47, 116-119 (2010).
126. Liu, Y.?L. et al. Carriage of PNPLA3 I148M is associated with an increased risk of non-alcoholic fatty liver diesease associated hepatocellular carcinoma [abstract 1275]. J. Hepatol. 58, S516 (2013).
127. Hassan M. M. et al. Genetic variation in the PNPLA3 gene and hepatocellular carcinoma in USA: risk and prognosis prediction. Mol. Carcinog. http://dx.doi.org/10.1002/mc.22057.
128. Zimmermann, R. et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306, 1383-1386 (2004).
129. Rydel, T. J. et al. The crystal structure, mutagenesis, and activity studies reveal that patatin is a lipid acyl hydrolase with a Ser-Asp catalytic dyad. Biochemistry 42, 6696-6708 (2003).
130. He, S. et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J. Biol. Chem. 285, 6706-6715 (2010).
131. Romeo, 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. (Lond.) 34, 190-194 (2010).
132. Speliotes, E. K., Butler, J. L., Palmer, C. D., Voight, B. F. & Hirschhorn, J. N. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 52, 904-912 (2010).
133. Huang, Y., Cohen, J. C. & Hobbs, H. H. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease. J. Biol. Chem. 286, 37085-37093 (2011).
134. Pirazzi, C. et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J. Hepatol. 57, 1276-1282 (2012).
135. Jenkins, C. M. et al. 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. 279, 48968-48975 (2004).
136. Kumari, M. et al. Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab. 15, 691-702 (2012).
137. Huang, Y. et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc. Natl Acad. Sci. USA 107, 7892-7897 (2010).
138. Wilson, P. A., Gardner, S. D., Lambie, N. M., Commans, S. A. & Crowther, D. J. Characterization of the human patatin-like phospholipase family. J. Lipid Res. 47, 1940-1949 (2006).
139. Hoekstra, M. et al. The expression level of non-alcoholic fatty liver disease-related gene PNPLA3 in hepatocytes is highly influenced by hepatic lipid status. J. Hepatol. 52, 244-251 (2010).
140. Lake, A. C. et al. Expression, regulation, and triglyceride hydrolase activity of adiponutrin family members. J. Lipid Res. 46, 2477-2487 (2005).
141. 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 52, 1134-1142 (2010).
142. Basantani, M. K. et al. Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. J. Lipid Res. 52, 318-329 (2011).
143. Li, J. Z. et al. Chronic overexpression of PNPLA3 I148M in mouse liver causes hepatic steatosis. J. Clin. Invest. 122, 4130-4144 (2012).
144. Wree, A. et al. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat. Rev. Gastroenterol. Hepatol. http://dx.doi.org/10.1038/ nrgastro.2013.149.
145. Anstee, Q. M. & Goldin, R. D. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int. J. Exp. Pathol. 87, 1-16 (2006).
146. Yamaguchi, K. et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 45, 1366-1374 (2007).
147. Malhi, H., Gores, G. J. & Lemasters, J. J. Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology 43, S31-S44 (2006).
148. Anstee, Q. M. et al. Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis. J. Hepatol. 53, 542-550 (2010).
149. Farrell, G. C. et al. Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression. J. Gastroenterol. Hepatol. 24, 443-452 (2009).
150. Iredale, J. P. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J. Clin. Invest. 117, 539-548 (2007).
151. Spielman, R. S. & Ewens, W. J. The TDT and other family-based tests for linkage disequilibrium and association. Am. J. Hum. Genet. 59, 983-989 (1996).
152. Tan, H. L. et al. Association of glucokinase regulatory gene polymorphisms with risk and severity of non-alcoholic fatty liver disease: an interaction study with adiponutrin gene. J. Gastroenterol. http://dx.doi.org/10. 1007/s00535-013-0850-x.
153. Namikawa, C. et al. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. J. Hepatol. 40, 781-786 (2004).
154. Al-Serri, A. et al. The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case-control and intra-familial allele association studies. J. Hepatol. 56, 448-454 (2012).
155. Dong, H. et al. The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population. J. Hepatol. 46, 915-920 (2007).
156. Song, J. et al. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). FASEB J. 19, 1266-1271 (2005).
157. Yoneda, M. et al. Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease. Liver Int. 29, 1078-1085 (2009).
158. Zain, S. M. 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 8, e58538 (2013).
159. Narla, G. 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. 65, 1213-1222 (2005).
160. Beer, N. L. et al. The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum. Mol. Genet. 18, 4081-4088 (2009).
161. Santoro, N. et al. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 55, 781-789 (2011).
162. 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 55, 661-663 (2012).
163. Ratziu, V. et al. Zf9, a Kruppel-like transcription factor up-regulated in vivo during early hepatic fibrosis. Proc. Natl Acad. Sci. USA 95, 9500-9505 (1998).
164. Starkel, P. et al. Oxidative stress, KLF6 and transforming growth factor-beta up-regulation differentiate non-alcoholic steatohepatitis progressing to fibrosis from uncomplicated steatosis in rats. J. Hepatol. 39, 538-546 (2003).
165. Bechmann, L. P. et al. Glucokinase links Kruppel-like factor 6 to the regulation of hepatic insulin sensitivity in nonalcoholic fatty liver disease. Hepatology 55, 1083-1093 (2012).
166. Oakley, F. et al. Angiotensin II activates I.B kinase phosphorylation of RelA at Ser536 to promote myofibroblast survival and liver fibrosis. Gastroenterology 136, 2334-2344 (2009).
167. Dixon, J. B. et al. Pro-fibrotic polymorphisms predictive of advanced liver fibrosis in the severely obese. J. Hepatol. 39, 967-971 (2003).
168. Yokohama, S. et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 40, 1222-1225 (2004).
169. Ginsberg, H. N. et al. Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. J. Clin. Invest. 78, 1287-1295 (1986).
170. Petersen, K. F. et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N. Engl. J. Med. 362, 1082-1089 (2010).
171. Kozlitina, J., Boerwinkle, E., Cohen, J. C. & Hobbs, H. H. Dissociation between APOC3 variants, hepatic triglyceride content and insulin resistance. Hepatology 53, 467-474 (2011).
172. Valenti, L. et al. The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage in patients with nonalcoholic fatty liver. J. Hepatol. 55, 1409-1414 (2012).
173. Verrijken A. 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) http://dx.doi.org/10.1002/oby.20366.
174. Sentinelli, F. 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. 10, 93 (2011).
175. Zeybel, M. et al. Multigenerational epigenetic adaptation of the hepatic wound-healing response. Nat. Med. 18, 1369-1377 (2012).
176. Willner, I. R. et al. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am. J. Gastroenterol. 96, 2957-2961 (2001).
177. Struben, V. M., Hespenheide, E. E. & Caldwell, S. H. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. Am. J. Med. 108, 9-13 (2000).
178. Schwimmer, J. B. et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology 136, 1585-1592 (2009).
179. Makkonen, J., Pietilainen, K. H., Rissanen, A., Kaprio, J. & Yki-Jarvinen, 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. 50, 1035-1042 (2009).
180. Browning, J. D., Kumar, K. S., Saboorian, M. H. & Thiele, D. L. Ethnic differences in the prevalence of cryptogenic cirrhosis. Am. J. Gastroenterol. 99, 292-298 (2004).
181. Guerrero, R., Vega, G. L., Grundy, S. M. & Browning, J. D. Ethnic differences in hepatic steatosis: an insulin resistance paradox? Hepatology 49, 791-801 (2009).
182. Bambha, K. et al. Ethnicity and nonalcoholic fatty liver disease. Hepatology 55, 769-780 (2012).
183. Perttila, J. et al. PNPLA3 is regulated by glucose in human hepatocytes, and its I148M mutant slows down triglyceride hydrolysis. Am. J. Phys. Endo. Met. 302, E1063-E1069 (2012).