Insights from Genome-Wide Association Analyses of Nonalcoholic Fatty Liver Disease

Bratati Kahali; Brian Halligan; Elizabeth K. Speliotes

doi:10.1055/s-0035-1567870

Seminars in Liver Disease, Inhaltsverzeichnis

Semin Liver Dis 2015; 35(04): 375-391
DOI: 10.1055/s-0035-1567870

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Insights from Genome-Wide Association Analyses of Nonalcoholic Fatty Liver Disease

Bratati Kahali

¹Division of Gastroenterology, Department of Internal Medicine, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan

,

Brian Halligan

¹Division of Gastroenterology, Department of Internal Medicine, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan

,

Elizabeth K. Speliotes

¹Division of Gastroenterology, Department of Internal Medicine, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan

› Institutsangaben

Abstract

Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis, which can progress to nonalcoholic steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma in the absence of excessive alcohol consumption. Nonalcoholic fatty liver disease will become the number one cause of liver disease worldwide by 2020. Nonalcoholic fatty liver disease is correlated albeit imperfectly with obesity and other metabolic diseases such as diabetes, hyperlipidemia, and cardiovascular disease, but exactly how having one of these diseases contributes to the development of other metabolic diseases is only now being elucidated. Development of NAFLD and related metabolic diseases is genetically influenced in the population, and recent genome-wide association studies (GWASs) have discovered genetic variants that associate with these diseases. These GWAS-associated variants cannot only help us to identify individuals at high risk of developing NAFLD, but also to better understand its pathophysiology so that we can develop more effective treatments for this disease and related metabolic diseases in the future.

Keywords

nonalcoholic liver disease - nonalcoholic steatohepatitis - gene - genetics - polymorphism

Volltext

Referenzen

References
1 Bellentani S, Marino M. Epidemiology and natural history of non-alcoholic fatty liver disease (NAFLD). Ann Hepatol 2009; 8 (Suppl. 01) S4-S8
2 Speliotes EK, Massaro JM, Hoffmann U , et al. Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: the Framingham Heart Study. Hepatology 2010; 51 (6) 1979-1987
3 Mellinger JL, Pencina KM, Massaro JM , et al. Hepatic steatosis and cardiovascular disease outcomes: An analysis of the Framingham Heart Study. J Hepatol 2015; 63 (2) 470-476
4 Hernaez R, McLean J, Lazo M , et al; Genetics of Obesity-Related Liver Disease (GOLD) Consortium. 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 (9) 1183-1190.e2
5 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
6 Williams CD, Stengel J, Asike MI , 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 2011; 140 (1) 124-131
7 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
8 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
9 Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 2003; 37 (5) 1202-1219
10 Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol 2013; 10 (11) 656-665
11 Duwaerts CC, Maher JJ. Mechanisms of liver injury in non-alcoholic steatohepatitis. Curr Hematol Rep 2014; 13 (2) 119-129
12 Ertle J, Dechene A, Sowa JP, Penndorf V, Herzer K, Kaiser J, Schlaak JF, Gerken G, Syn WK, Canbay A. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer 2011; 128 (10) 2436-2443
13 Paradis V, Zalinski S, Chelbi E , et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 2009; 49 (3) 851-859
14 Guzman G, Brunt EM, Petrovic LM, Chejfec G, Layden TJ, Cotler SJ. Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis?. Arch Pathol Lab Med 2008; 132 (11) 1761-1766
15 Lee SS, Park SH, Kim HJ , et al. Non-invasive assessment of hepatic steatosis: prospective comparison of the accuracy of imaging examinations. J Hepatol 2010; 52 (4) 579-585
16 Kunde SS, Lazenby AJ, Clements RH, Abrams GA. Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women. Hepatology 2005; 42 (3) 650-656
17 Schwimmer JB, Celedon MA, Lavine JE , et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology 2009; 136 (5) 1585-1592
18 Wagenknecht LE, Scherzinger AL, Stamm ER , et al. Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort. Obesity (Silver Spring) 2009; 17 (6) 1240-1246
19 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
20 Loomba R, Schork N, Chen CH , et al; Genetics of NAFLD in Twins Consortium. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology 2015;
21 Visscher PM, Hill WG, Wray NR. Heritability in the genomics era—concepts and misconceptions. Nat Rev Genet 2008; 9 (4) 255-266
22 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
23 Petta S, Valenti L, Marchesini G , et al. PNPLA3 GG genotype and carotid atherosclerosis in patients with non-alcoholic fatty liver disease. PLoS ONE 2013; 8 (9) e74089
24 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
25 Aravinthan A, Mells G, Allison M , et al. Gene polymorphisms of cellular senescence marker p21 and disease progression in non-alcohol-related fatty liver disease. Cell Cycle 2014; 13 (9) 1489-1494
26 Wang Y, Wang BF, Tong J, Chang B, Wang BY. USF-1 genetic polymorphisms confer a high risk of nonalcoholic fatty liver disease in Chinese population. Int J Clin Exp Med 2015; 8 (2) 2545-2553
27 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
28 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
29 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
30 Kozlitina J, Boerwinkle E, Cohen JC, Hobbs HH. Dissociation between APOC3 variants, hepatic triglyceride content and insulin resistance. Hepatology 2011; 53 (2) 467-474
31 Crosby J, Peloso GM, Auer PL , et al; TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014; 371 (1) 22-31
32 Garrett ME, Abdelmalek MF, Ashley-Koch A , et al. IL28B rs12979860 is not associated with histologic features of NAFLD in a cohort of Caucasian North American patients. J Hepatol 2013; 58 (2) 402-403
33 Petta S, Craxi A. Reply to: “IL28B rs12979860 is not associated with histologic features of NAFLD in a cohort of Caucasian North American patients”. J Hepatol 2013; 58 (2) 403-404
34 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
35 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
36 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
37 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
38 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
39 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
40 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
41 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
42 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
43 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
44 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
45 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 (6) 1883-1894
46 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
47 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
48 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
49 Kitamoto A, Kitamoto T, Nakamura T , et al. Association of polymorphisms in GCKR and TRIB1 with nonalcoholic fatty liver disease and metabolic syndrome traits. Endocr J 2014; 61 (7) 683-689
50 Ishizuka Y, Nakayama K, Ogawa A , et al; Jichi Medical University Promotion Team of Large-Scale Human Genome Bank for All over Japan. TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions. J Mol Endocrinol 2014; 52 (2) 145-158
51 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
52 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
53 Moritou Y, Ikeda F, Iwasaki Y , et al. Impact of comorbid hepatic steatosis on treatment of chronic hepatitis C in Japanese patients and the relationship with genetic polymorphism of IL28B, PNPLA3 and LDL receptor. Acta Med Okayama 2014; 68 (1) 17-22
54 Coppola N, Rosa Z, Cirillo G , et al. TM6SF2 E167K variant is associated with severe steatosis in chronic hepatitis C, regardless of PNPLA3 polymorphism. Liver Int 2015; 35 (8) 1959-1963
55 Zampino R, Coppola N, Cirillo G , et al. Patatin-like phospholipase domain-containing 3 I148M variant is associated with liver steatosis and fat distribution in chronic hepatitis B. Dig Dis Sci 2015; 60 (10) 3005-3010
56 Salameh H, Raff E, Erwin A , et al. PNPLA3 gene polymorphism is associated with predisposition to and severity of alcoholic liver disease. Am J Gastroenterol 2015; 110 (6) 846-856
57 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
58 Viganò M, Valenti L, Lampertico P , et al. Patatin-like phospholipase domain-containing 3 I148M affects liver steatosis in patients with chronic hepatitis B. Hepatology 2013; 58 (4) 1245-1252
59 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
60 Tong J, Guo J, Hu J, Hou S, Zhang Y, Li Q. Correlation between patatin-like phospholipase domain-containing protein 3 gene polymorphisms and liver cirrhosis in a Chinese Han population with chronic hepatitis B. Hepat Mon 2014; 14 (8) e18943
61 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
62 Trépo 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
63 Dunn W, O'Neil M, Zhao J , et al. Donor PNPLA3 rs738409 genotype affects fibrosis progression in liver transplantation for hepatitis C. Hepatology 2014; 59 (2) 453-460
64 O'Shea RS, Dasarathy S, McCullough AJ ; Practice Guideline Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology 2010; 51 (1) 307-328
65 Younossi ZM, Otgonsuren M, Henry L , et al. Association of non-alcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004-2009. Hepatology 2015;
66 Purohit V, Russo D, Coates PM. Role of fatty liver, dietary fatty acid supplements, and obesity in the progression of alcoholic liver disease: introduction and summary of the symposium. Alcohol 2004; 34 (1) 3-8
67 Chalasani N, Younossi Z, Lavine JE , et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012; 55 (6) 2005-2023
68 Naveau S, Giraud V, Borotto E, Aubert A, Capron F, Chaput JC. Excess weight risk factor for alcoholic liver disease. Hepatology 1997; 25 (1) 108-111
69 Raynard B, Balian A, Fallik D , et al. Risk factors of fibrosis in alcohol-induced liver disease. Hepatology 2002; 35 (3) 635-638
70 Rosen HR. Clinical practice. Chronic hepatitis C infection. N Engl J Med 2011; 364 (25) 2429-2438
71 Lee SH, Chung YH, Kim JA , et al. Histological characteristics predisposing to development of hepatocellular carcinoma in patients with chronic hepatitis B. J Clin Pathol 2011; 64 (7) 599-604
72 Lonardo A, Adinolfi LE, Restivo L , et al. Pathogenesis and significance of hepatitis C virus steatosis: an update on survival strategy of a successful pathogen. World J Gastroenterol 2014; 20 (23) 7089-7103
73 Dyal HK, Aguilar M, Bhuket T , et al. Concurrent obesity, diabetes, and steatosis increase risk of advanced fibrosis among HCV patients: a systematic review. Dig Dis Sci 2015; 60 (9) 2813-2824
74 Persico M, Iolascon A. Steatosis as a co-factor in chronic liver diseases. World J Gastroenterol 2010; 16 (10) 1171-1176
75 Wang CC, Tseng TC, Kao JH. Hepatitis B virus infection and metabolic syndrome: fact or fiction?. J Gastroenterol Hepatol 2015; 30 (1) 14-20
76 Lok AS, Everhart JE, Chung RT , et al; HALT-C Trial Group. Hepatic steatosis in hepatitis C: comparison of diabetic and nondiabetic patients in the hepatitis C antiviral long-term treatment against cirrhosis trial. Clin Gastroenterol Hepatol 2007; 5 (2) 245-254
77 Trépo E, Pradat P, Potthoff A , et al. Impact of patatin-like phospholipase-3 (rs738409 C>G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C. Hepatology 2011; 54 (1) 60-69
78 Petta S, Maida M, Grimaudo S , et al. TM6SF2 rs58542926 is not associated with steatosis and fibrosis in large cohort of patients with genotype 1 chronic hepatitis C. Liver Int 2015;
79 Rüeger S, Bochud PY, Dufour JF , et al. Impact of common risk factors of fibrosis progression in chronic hepatitis C. Gut 2015; 64 (10) 1605-1615
80 Yasui K, Kawaguchi T, Shima T , et al. Effect of PNPLA3 rs738409 variant (I148 M) on hepatic steatosis, necroinflammation, and fibrosis in Japanese patients with chronic hepatitis C. J Gastroenterol 2015; 50 (8) 887-893
81 Valenti L, Aghemo A, Stättermayer AF , et al. Implications of PNPLA3 polymorphism in chronic hepatitis C patients receiving peginterferon plus ribavirin. Aliment Pharmacol Ther 2012; 35 (12) 1434-1442
82 Clark PJ, Thompson AJ, Zhu Q , et al. The association of genetic variants with hepatic steatosis in patients with genotype 1 chronic hepatitis C infection. Dig Dis Sci 2012; 57 (8) 2213-2221
83 Milano M, Aghemo A, Mancina RM , et al. Transmembrane 6 superfamily member 2 gene E167K variant impacts on steatosis and liver damage in chronic hepatitis C patients. Hepatology 2015; 62 (1) 111-117
84 do O NT, Eurich D, Trautwein C, Neuhaus P, Neumann UP, Wasmuth HE. The common I148 M variant of PNPLA3 does not predict fibrosis progression after liver transplantation for hepatitis C. Hepatology 2011; 54 (4) 1483-1484
85 Finkenstedt A, Auer C, Glodny B , et al. Patatin-like phospholipase domain-containing protein 3 rs738409-G in recipients of liver transplants is a risk factor for graft steatosis. Clin Gastroenterol Hepatol 2013; 11 (12) 1667-1672
86 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
87 Corradini SG, Burza MA, Molinaro A, Romeo S. Patatin-like phospholipase domain containing 3 sequence variant and hepatocellular carcinoma. Hepatology 2011; 53 (5) 1776 , author reply 1777
88 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
89 Hamza H, Cao J, Li X, Zhao S. In vivo study of hepatitis B vaccine effects on inflammation and metabolism gene expression. Mol Biol Rep 2012; 39 (3) 3225-3233
90 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
91 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
92 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
93 [Anonymous] Human Protein Atlas . Available at: http://www.proteinatlas.org/ENSG00000100344-PNPLA3/tissue . Accessed August 30, 2015
94 Tian L, McClafferty H, Knaus HG, Ruth P, Shipston MJ. Distinct acyl protein transferases and thioesterases control surface expression of calcium-activated potassium channels. J Biol Chem 2012; 287 (18) 14718-14725
95 Bian Y, Song C, Cheng K , et al. An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics 2014; 96: 253-262
96 Gerhard DS, Wagner L, Feingold EA , et al; MGC Project Team. The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res 2004; 14 (10B): 2121-2127
97 Ota T, Suzuki Y, Nishikawa T , et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet 2004; 36 (1) 40-45
98 Doherty MJ, Moorhead G, Morrice N, Cohen P, Cohen PT. Amino acid sequence and expression of the hepatic glycogen-binding (GL)-subunit of protein phosphatase-1. FEBS Lett 1995; 375 (3) 294-298
99 Browne GJ, Delibegovic M, Keppens S, Stalmans W, Cohen PT. The level of the glycogen targetting regulatory subunit R5 of protein phosphatase 1 is decreased in the livers of insulin-dependent diabetic rats and starved rats. Biochem J 2001; 360 (Pt 2) 449-459
100 Gasa R, Jensen PB, Berman HK, Brady MJ, DePaoli-Roach AA, Newgard CB. Distinctive regulatory and metabolic properties of glycogen-targeting subunits of protein phosphatase-1 (PTG, GL, GM/RGl) expressed in hepatocytes. J Biol Chem 2000; 275 (34) 26396-26403
101 Munro S, Cuthbertson DJ, Cunningham J, Sales M, Cohen PT. Human skeletal muscle expresses a glycogen-targeting subunit of PP1 that is identical to the insulin-sensitive glycogen-targeting subunit G(L) of liver. Diabetes 2002; 51 (3) 591-598
102 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
103 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
104 Choi JM, Seo MH, Kyeong HH, Kim E, Kim HS. Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase. Proc Natl Acad Sci U S A 2013; 110 (25) 10171-10176
105 Jin L, Guo T, Li Z , et al. Role of glucokinase in the subcellular localization of glucokinase regulatory protein. Int J Mol Sci 2015; 16 (4) 7377-7393
106 Hayward BE, Dunlop N, Intody S , et al. Organization of the human glucokinase regulator gene GCKR. Genomics 1998; 49 (1) 137-142
107 Kiss-Toth E, Bagstaff SM, Sung HY , et al. Human tribbles, a protein family controlling mitogen-activated protein kinase cascades. J Biol Chem 2004; 279 (41) 42703-42708
108 GeneCards. PNPLA3 gene (protein coding). . Available at: http://www.genecards.org/cgi-bin/carddisp.pl?gene=PNPLA3 . Accessed 09/15/15
109 Kumari M, Schoiswohl G, Chitraju C , et al. Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab 2012; 15 (5) 691-702
110 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
111 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
112 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
113 GeneCards. TRIB1 gene (protein coding). Available at: http://www.genecards.org/cgi-bin/carddisp.pl?gene=TRIB1&keywords=TRIB1 . Accessed 09/15/15
114 Makishima S, Boonvisut S, Ishizuka Y, Watanabe K, Nakayama K, Iwamoto S. Sin3A-associated protein, 18 kDa, a novel binding partner of TRIB1, regulates MTTP expression. J Lipid Res 2015; 56 (6) 1145-1152
115 Burkhardt R, Toh SA, Lagor WR , et al. Trib1 is a lipid- and myocardial infarction-associated gene that regulates hepatic lipogenesis and VLDL production in mice. J Clin Invest 2010; 120 (12) 4410-4414
116 Dugast E, Kiss-Toth E, Soulillou JP, Brouard S, Ashton-Chess J. The Tribbles-1 protein in humans: roles and functions in health and disease. Curr Mol Med 2013; 13 (1) 80-85
117 Akira S, Misawa T, Satoh T, Saitoh T. Macrophages control innate inflammation. Diabetes Obes Metab 2013; 15 (Suppl. 03) 10-18
118 GeneCards. GCKR gene (protein coding). . Available at: http://www.genecards.org/cgi-bin/carddisp.pl?gene=GCKR&keywords=gckr . Accessed 09/15/15
119 Shiota C, Coffey J, Grimsby J, Grippo JF, Magnuson MA. Nuclear import of hepatic glucokinase depends upon glucokinase regulatory protein, whereas export is due to a nuclear export signal sequence in glucokinase. J Biol Chem 1999; 274 (52) 37125-37130
120 Jetton TL, Shiota M, Knobel SM, Piston DW, Cherrington AD, Magnuson MA. Substrate-induced nuclear export and peripheral compartmentalization of hepatic glucokinase correlates with glycogen deposition. Int J Exp Diabetes Res 2001; 2 (3) 173-186
121 Bechmann LP, Hannivoort RA, Gerken G, Hotamisligil GS, Trauner M, Canbay A. The interaction of hepatic lipid and glucose metabolism in liver diseases. J Hepatol 2012; 56 (4) 952-964
122 Beer NL, Tribble ND, McCulloch LJ , 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 2009; 18 (21) 4081-4088
123 GeneCards. TM6SF2 gene (protein coding). . Available at: http://www.genecards.org/cgi-bin/carddisp.pl?gene=TM6SF2&keywords=TM6SF2 . Accessed 09/15/15
124 GeneCards. PPP1R3B gene (Protein Coding). Available at: http://www.genecards.org/cgi-bin/carddisp.pl?gene=PPP1R3B&keywords=pPP1R3B . Accessed 09/15/15
125 Johnson LN. Glycogen phosphorylase: control by phosphorylation and allosteric effectors. FASEB J 1992; 6 (6) 2274-2282
126 Weber G, Cantero A. Behavior of enzymes involved in glucose-6-phosphate utilization during 6-day fasting; study of hepatic glucose-6-phosphatase, phosphohexoseisomerase and phosphoglucomutase. Exp Cell Res 1958; 14 (3) 596-607
127 GeneCards. LYPLAL1 gene (Protein Coding). Available at: http://www.genecards.org/cgi-bin/carddisp.pl?gene=LYPLAL1&keywords=LYPLAL1 . Accessed 09/15/15
128 Bürger M, Zimmermann TJ, Kondoh Y , et al. Crystal structure of the predicted phospholipase LYPLAL1 reveals unexpected functional plasticity despite close relationship to acyl protein thioesterases. J Lipid Res 2012; 53 (1) 43-50
129 Rocks O, Peyker A, Kahms M , et al. An acylation cycle regulates localization and activity of palmitoylated Ras isoforms. Science 2005; 307 (5716) 1746-1752
130 Steinberg GR, Kemp BE, Watt MJ. Adipocyte triglyceride lipase expression in human obesity. Am J Physiol Endocrinol Metab 2007; 293 (4) E958-E964
131 Wei X, Song H, Semenkovich CF. Insulin-regulated protein palmitoylation impacts endothelial cell function. Arterioscler Thromb Vasc Biol 2014; 34 (2) 346-354
132 Kotronen A, Peltonen M, Hakkarainen A , et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology 2009; 137 (3) 865-872
133 León-Mimila P, Vega-Badillo J, Gutiérrez-Vidal R , et al. A genetic risk score is associated with hepatic triglyceride content and non-alcoholic steatohepatitis in Mexicans with morbid obesity. Exp Mol Pathol 2015; 98 (2) 178-183
134 Giudice EM, Grandone A, Cirillo G , et al. The association of PNPLA3 variants with liver enzymes in childhood obesity is driven by the interaction with abdominal fat. PLoS ONE 2011; 6 (11) e27933
135 Graff M, North KE, Franceschini N , et al. PNPLA3 gene-by-visceral adipose tissue volume interaction and the pathogenesis of fatty liver disease: the NHLBI family heart study. Int J Obes 2013; 37 (3) 432-438
136 Tian C, Stokowski RP, Kershenobich D, Ballinger DG, Hinds DA. Variant in PNPLA3 is associated with alcoholic liver disease. Nat Genet 2010; 42 (1) 21-23
137 Valenti L, Maggioni P, Piperno A , et al. Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis. World J Gastroenterol 2012; 18 (22) 2813-2820
138 Davis JN, Lê KA, Walker RW , et al. 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 (6) 1522-1527
139 Nobili V, Liccardo D, Bedogni G , et al. Influence of dietary pattern, physical activity, and I148M PNPLA3 on steatosis severity in at-risk adolescents. Genes Nutr 2014; 9 (3) 392
140 Sevastianova K, Santos A, Kotronen A , et al. Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans. Am J Clin Nutr 2012; 96 (4) 727-734
141 Santoro N, Savoye M, Kim G , et al. 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 (5) e37827
142 Nobili V, Bedogni G, Donati B, Alisi A, Valenti L. The I148M variant of PNPLA3 reduces the response to docosahexaenoic acid in children with non-alcoholic fatty liver disease. J Med Food 2013; 16 (10) 957-960
143 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
144 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
145 Buch S, Stickel F, Trépo E , et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nature Genet 2015. Available at http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3417.html . Accessed October 19, 2015