Table Info

Table 1.

List of the main genetic variants associated with the histological spectrum of MAFLD

Variant	Gene	Function	Effect	Impact	Phenotype
rs738409 C > G	PNPLA3	Lipid remodeling	p.I148M	Loss-of-function	↑ MAFLD, NASH, fibrosis, HCC
rs58542926 C > T	TM6SF2	VLDL secretion	p.E167K	Loss-of-function	↑ MAFLD, NASH, fibrosis
rs641738 C > T	TMC4/MBOAT7	Lipid remodeling	p.G17E	Loss-of-function	↑ MAFLD, NASH, fibrosis, HCC
rs1260326 C > T	GCKR	Regulation of de novo lipogenesis	p.P446L	Loss-of-function	↑ MAFLD, NASH, fibrosis
rs72613567 T > TA	HSD17B13	Lipid remodeling	Truncated protein	Loss-of-function	↓ NASH, fibrosis, HCC
rs4841132 G > A	PPP1R3B	Glycogen synthesis	Non-coding	Gain-of-function	↓ MAFLD, fibrosis, HCC
rs1801278 A > C	IRS1	Insulin signaling	p.G972R	Loss-of-function	↑ Fibrosis
rs1044498 A > C	ENPP1	Insulin signaling	p.K121Q	Gain-of-function	↑ Fibrosis
rs2954021 G > A	TRIB1	Regulation of de novo lipogenesis	Non-coding	Gain-of-function	↑ MAFLD
rs12137855 C > T	LYPLAL1	Lipid metabolism	Intronic	Loss-of-function	↑ MAFLD
Several	APOB	VLDL secretion	Protein change	Loss-of-function	↑ MAFLD, NASH, fibrosis, HCC
Several	MTTP	VLDL secretion	Protein change	Loss-of-function	↑ MAFLD
rs236918 G > C	PCSK7	Membrane transferrin receptor shedding and regulation of circulating lipids	Intronic	Gain-of-function	↑ NASH, fibrosis
Several	PCSK9	LDL uptake	Protein change	Loss-of-function	No evidence of association with steatosis
Several	LIPA	Lipid remodeling	Protein change	LAL deficiency	↑ MAFLD, NASH, fibrosis
rs56225452 G > A	FATP5	FFAs uptake	Non-coding	Gain-of-function	↑ NASH, fibrosis
rs13412852 C > T	LPIN1	Lipid metabolism	Intronic	NA	↓ NASH, fibrosis
rs17618244 G > A	KLB	FGF19/FGFR4 pathway	R728Q	Loss-of-function	↓ NASH, fibrosis
rs4374383 G > A	MERTK	Innate immunity	Intronic	Loss-of-function	↓ Fibrosis
rs3750861 G > A	KLF6	HSCs activation	Splice variant IVS1-27G	Loss-of-function	↓ Fibrosis
Several	TERT	Telomere maintenance	Protein change	Loss-of-function	↑ Fibrosis, HCC
rs12979860 C > T	IL28B	Innate immunity	Alternative IFNL3/4 transcription	Loss-of-function	↓ NASH, Fibrosis
rs3480 A > G	FNDC5	HSCs activation	Non-coding	Loss-of-function	↓ Fibrosis
rs4880 C > T	SOD2	Mitochondrial antioxidant	p.A16V	Loss-of-function	↑ Fibrosis
rs695366 G > A	UCP2	Mitochondrial lipid metabolism Oxphos	-866 promoter variant	Gain-of-function	↓ NASH, fibrosis
rs2642438 G > A	MARC1	Mitochondrial detoxification	A165T	Loss-of-function	↓ MAFLD, NASH, fibrosis

NA: not applicable

Declarations

Author contributions

MM, ML and PD all took part in writing the manuscript, preparing figures and reading and approving the final draft. All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

The study was supported by the Ricerca Corrente Fondazione IRCCS Cà Granda and Ricerca Finalizzata Ministero della Salute RF-2013-02358319. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84. [DOI] [PubMed]

Eslam M, Sanyal AJ, George J. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology. 2020;158:1999–2014.e1. [DOI] [PubMed]

Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol. 2020;73:202–9. [DOI] [PubMed]

Cholankeril G, Wong RJ, Hu M, Perumpail RB, Yoo ER, Puri P, et al. Liver transplantation for nonalcoholic steatohepatitis in the US: temporal trends and outcomes. Dig Dis Sci. 2017;62:2915–22. [DOI] [PubMed]

Younossi ZM, Henry L, Bush H, Mishra A. Clinical and economic burden of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Clin Liver Dis. 2018;22:1–10. [DOI] [PubMed]

Day CP. From fat to inflammation. Gastroenterology. 2006;130:207–10. [DOI] [PubMed]

Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148:547–55. [DOI] [PubMed]

Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001;50:1844–50. [DOI] [PubMed]

Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015;62:S47–64. [DOI] [PubMed]

10.

Dongiovanni P, Valenti L. A nutrigenomic approach to non-alcoholic fatty liver disease. Int J Mol Sci. 2017;18:1534. [DOI]

11.

Meroni M, Longo M, Rustichelli A, Dongiovanni P. Nutrition and genetics in NAFLD: the perfect binomium. Int J Mol Sci. 2020;21:2986. [DOI]

12.

Dongiovanni P, Valenti L. Genetics of nonalcoholic fatty liver disease. Metabolism. 2016;65:1026–37. [DOI] [PubMed]

13.

Meroni M, Longo M, Erconi V, Valenti L, Gatti S, Fracanzani AL, et al. mir-101-3p downregulation promotes fibrogenesis by facilitating hepatic stellate cell transdifferentiation during insulin resistance. Nutrients. 2019;11:2597. [DOI]

14.

Dongiovanni P, Meroni M, Longo M, Fargion S, Fracanzani AL. miRNA signature in NAFLD: a turning point for a non-invasive diagnosis. Int J Mol Sci. 2018;19:3966. [DOI]

15.

Meroni M, Longo M, Dongiovanni P. Alcohol or gut microbiota: who is the guilty? Int J Mol Sci. 2019;20:4568. [DOI]

16.

Meroni M, Longo M, Dongiovanni P. The role of probiotics in nonalcoholic fatty liver disease: a new insight into therapeutic strategies. Nutrients. 2019;11:2642. [DOI]

17.

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;19:5219–38. [DOI] [PubMed] [PMC]

18.

Dongiovanni P, Romeo S, Valenti L. Genetic factors in the pathogenesis of nonalcoholic fatty liver and steatohepatitis. Biomed Res Int. 2015;2015:460190. [DOI] [PubMed] [PMC]

19.

Schwimmer JB, Celedon MA, Lavine JE, Salem R, Campbell N, Schork NJ, et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology. 2009;136:1585–92. [DOI] [PubMed] [PMC]

20.

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;96:2957–61. [DOI] [PubMed]

21.

Makkonen J, Pietilainen 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;50:1035–42. [DOI] [PubMed]

22.

Loomba R, Schork N, Chen CH, Bettencourt R, Bhatt A, Ang B, et al. Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology. 2015;149:1784–93. [DOI] [PubMed] [PMC]

23.

Cui J, Chen CH, Lo MT, Schork N, Bettencourt R, Gonzalez MP, et al.; For The Genetics Of Nafld In Twins Consortium. Shared genetic effects between hepatic steatosis and fibrosis: a prospective twin study. Hepatology. 2016. 64:1547–58. [DOI] [PubMed] [PMC]

24.

Balakrishnan M, Kanwal F, El-Serag HB, Thrift AP. Acculturation and nonalcoholic fatty liver disease risk among hispanics of mexican origin: findings from the national health and nutrition examination survey. Clin Gastroenterol Hepatol. 2017;15:310–2. [DOI] [PubMed] [PMC]

25.

Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–95. [DOI] [PubMed]

26.

Fleischman MW, Budoff M, Zeb I, Li D, Foster T. NAFLD prevalence differs among hispanic subgroups: the multi-ethnic study of atherosclerosis. World J Gastroenterol. 2014;20:4987–93. [DOI] [PubMed] [PMC]

27.

Guerrero R, Vega GL, Grundy SM, Browning JD. Ethnic differences in hepatic steatosis: an insulin resistance paradox? Hepatology. 2009;49:791–801. [DOI] [PubMed] [PMC]

28.

Dongiovanni P, Stender S, Pietrelli A, Mancina RM, Cespiati A, Petta S, et al. Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver. J Intern Med. 2018;283:356–70. [DOI] [PubMed] [PMC]

29.

Di Costanzo A, Belardinilli F, Bailetti D, Sponziello M, D’Erasmo L, Polimeni L, et al. Evaluation of polygenic determinants of non-alcoholic fatty liver disease (NAFLD) by a candidate genes resequencing strategy. Sci Rep. 2018;8:3702. [DOI] [PubMed] [PMC]

30.

Krawczyk M, Bantel H, Rau M, Schattenberg JM, Grünhage F, Pathil A, et al. Could inherited predisposition drive non-obese fatty liver disease? Results from German tertiary referral centers. J Hum Genet. 2018;63:621–6. [DOI] [PubMed]

31.

Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461–5. [DOI] [PubMed] [PMC]

32.

Pingitore P, Dongiovanni P, Motta BM, Meroni M, Lepore SM, Mancina RM, et al. PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis. Hum Mol Genet. 2016;25:5212–22. [DOI] [PubMed] [PMC]

33.

Mondul A, Mancina RM, Merlo A, Dongiovanni P, Rametta R, Montalcini T, et al. PNPLA3 I148M variant influences circulating retinol in adults with nonalcoholic fatty liver disease or obesity. J Nutr. 2015;145:1687–91. [DOI] [PubMed] [PMC]

34.

Huang Y, He S, Li JZ, Seo YK, Osborne TF, Cohen JC, et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci U S A. 2010;107:7892–7. [DOI] [PubMed] [PMC]

35.

Baulande S, Lasnier F, Lucas M, Pairault J. Adiponutrin, a transmembrane protein corresponding to a novel dietary- and obesity-linked mRNA specifically expressed in the adipose lineage. J Biol Chem. 2001;276:33336–44. [DOI] [PubMed]

36.

Stender S, Kozlitina J, Nordestgaard BG, Tybjærg-Hansen A, Hobbs HH, Cohen JC. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat Genet. 2017;49:842–7. [DOI] [PubMed] [PMC]

37.

Santoro N, Kursawe R, D’Adamo E, Dykas DJ, Zhang CK, Bale AE, et al. A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology. 2010;52:1281–90. [DOI] [PubMed] [PMC]

38.

McGeoch LJ, Patel PR, Mann JP. PNPLA3: a determinant of response to low-fructose diet in nonalcoholic fatty liver disease. Gastroenterology. 2018;154:1207–8. [DOI] [PubMed]

39.

Fracanzani AL, Petta S, Lombardi R, Pisano G, Russello M, Consonni D, et al. Liver and cardiovascular damage in patients with lean nonalcoholic fatty liver disease, and association with visceral obesity. Clin Gastroenterol Hepatol. 2017;15:1604–11.e1. [DOI] [PubMed]

40.

Kumari M, Schoiswohl G, Chitraju C, Paar M, Cornaciu I, Rangrez AY, et al. Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab. 2012;15:691–702. [DOI] [PubMed] [PMC]

41.

Pingitore P, Pirazzi C, Mancina RM, Motta BM, Indiveri C, Pujia A, et al. Recombinant PNPLA3 protein shows triglyceride hydrolase activity and its I148M mutation results in loss of function. Biochim Biophys Acta. 2014;1841:574–80. [DOI] [PubMed]

42.

Dongiovanni P, Romeo S, Valenti L. Hepatocellular carcinoma in nonalcoholic fatty liver: role of environmental and genetic factors. World J Gastroenterol. 2014;20:12945–55. [DOI] [PubMed] [PMC]

43.

Basantani MK, Sitnick MT, Cai L, Brenner DS, Gardner NP, Li JZ, et al. Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. J Lipid Res. 2011;52:318–29. [DOI] [PubMed] [PMC]

44.

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;52:1134–42. [DOI] [PubMed] [PMC]

45.

Smagris E, BasuRay S, Li J, Huang Y, Lai KM, Gromada J, et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology. 2015;61:108–18. [DOI] [PubMed] [PMC]

46.

Lindén D, Ahnmark A, Pingitore P, Ciociola E, Ahlstedt I, Andréasson AC, et al. Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in Pnpla3 I148M knock-in mice. Mol Metab. 2019;22:49–61. [DOI] [PubMed] [PMC]

47.

Wang Y, Kory N, BasuRay S, Cohen JC, Hobbs HH. PNPLA3, CGI-58, and inhibition of hepatic triglyceride hydrolysis in mice. Hepatology. 2019;69:2427–41. [DOI] [PubMed] [PMC]

48.

Yang A, Mottillo EP, Mladenovic-Lucas L, Zhou L, Granneman JG. Dynamic interactions of ABHD5 with PNPLA3 regulate triacylglycerol metabolism in brown adipocytes. Nat Metab. 2019;1:560–9. [DOI] [PubMed] [PMC]

49.

BasuRay S, Smagris E, Cohen JC, Hobbs HH. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology. 2017;66:1111–24. [DOI] [PubMed] [PMC]

50.

Donati B, Motta BM, Pingitore P, Meroni M, Pietrelli A, Alisi A, et al. The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage. Hepatology. 2016;63:787–98. [DOI] [PubMed]

51.

BasuRay S, Wang Y, Smagris E, Cohen JC, Hobbs HH. Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis. Proc Natl Acad Sci U S A. 2019;116:9521–6. [DOI] [PubMed] [PMC]

52.

Negoita F, Blomdahl J, Wasserstrom S, Winberg ME, Osmark P, Larsson S, et al. PNPLA3 variant M148 causes resistance to starvation-mediated lipid droplet autophagy in human hepatocytes. J Cell Biochem. 2019;120:343–56. [DOI] [PubMed]

53.

Luukkonen PK, Nick A, Hölttä-Vuori M, Thiele C, Isokuortti E, Lallukka-Brück S, et al. Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids. JCI Insight. 2019;4:e127902. [DOI]

54.

Franko A, Merkel D, Kovarova M, Hoene M, Jaghutriz BA, Heni M, et al. Dissociation of fatty liver and insulin resistance in I148M PNPLA3 carriers: differences in diacylglycerol (DAG) FA18:1 lipid species as a possible explanation. Nutrients. 2018;10:1314. [DOI]

55.

Luukkonen PK, Zhou Y, Sädevirta S, Leivonen M, Arola J, Orešič M, et al. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J Hepatol. 2016;64:1167–75. [DOI] [PubMed]

56.

Qadri S, Lallukka-Brück S, Luukkonen PK, Zhou Y, Gastaldelli A, Orho-Melander M, et al. The PNPLA3-I148M variant increases polyunsaturated triglycerides in human adipose tissue. Liver Int. 2020;[Epub ahead of print]. [DOI]

57.

Bruschi FV, Claudel T, Tardelli M, Caligiuri A, Stulnig TM, Marra F, et al. The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells. Hepatology. 2017;65:1875–90. [DOI] [PubMed]

58.

Dongiovanni P, Donati B, Fares R, Lombardi R, Mancina RM, Romeo S, et al. PNPLA3 I148M polymorphism and progressive liver disease. World J Gastroenterol. 2013;19:6969–78. [DOI] [PubMed] [PMC]

59.

Valenti L, Motta BM, Soardo G, Iavarone M, Donati B, Sangiovanni A, et al. PNPLA3 I148M polymorphism, clinical presentation, and survival in patients with hepatocellular carcinoma. PLoS One. 2013;8:e75982. [DOI] [PubMed] [PMC]

60.

Pirazzi C, Valenti L, Motta BM, Pingitore P, Hedfalk K, Mancina RM, et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum Mol Genet. 2014;23:4077–85. [DOI] [PubMed] [PMC]

61.

Trepo E, Nahon P, Bontempi G, Valenti L, Falleti E, Nischalke HD, et al. Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: eidence from a meta-analysis of individual participant data. Hepatology. 2014;59:2170–7. [DOI] [PubMed]

62.

Carpino G, Pastori D. PNPLA3 variant and portal/periportal histological pattern in patients with biopsy-proven non-alcoholic fatty liver disease: a possible role for oxidative stress. Sci Rep. 2017;7:15756. [DOI] [PubMed] [PMC]

63.

Grimaudo S, Pipitone RM, Pennisi G, Celsa C, Cammà C, Di Marco V, et al. Association between PNPLA3 rs738409 C>G variant and liver-related outcomes in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2020;18:935–44.e3. [DOI] [PubMed]

64.

Valenti L, Rumi M, Galmozzi E, Aghemo A, Del Menico B, De Nicola S, et al. Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. Hepatology. 2011;53:791–9. [DOI] [PubMed]

65.

Guyot E, Sutton A, Rufat P, Laguillier C, Mansouri A, Moreau R, et al. PNPLA3 rs738409, hepatocellular carcinoma occurrence and risk model prediction in patients with cirrhosis. J Hepatol. 2013;58:312–8. [DOI] [PubMed]

66.

Mederacke YS, Kirstein MM, Großhennig A, Marhenke S, Metzler F, Manns MP, et al. The PNPLA3 rs738409 GG genotype is associated with poorer prognosis in 239 patients with autoimmune hepatitis. Aliment Pharmacol Ther. 2020;51:1160–8. [DOI] [PubMed]

67.

Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjaerg-Hansen A, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2014;46:352–6. [DOI] [PubMed] [PMC]

68.

Prill S, Caddeo A, Baselli G, Jamialahmadi O, Dongiovanni P, Rametta R, et al. The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids. Sci Rep. 2019;9:11585. [DOI] [PubMed] [PMC]

69.

Smagris E, Gilyard S, BasuRay S, Cohen JC, Hobbs HH. Inactivation of Tm6sf2, a gene defective in fatty liver disease, impairs lipidation but not secretion of very low density lipoproteins. J Biol Chem. 2016;291:10659–76. [DOI] [PubMed] [PMC]

70.

Fan Y, Lu H, Guo Y, Zhu T, Garcia-Barrio MT, Jiang Z, et al. Hepatic transmembrane 6 superfamily member 2 regulates cholesterol metabolism in mice. Gastroenterology. 2016;150:1208–18. [DOI] [PubMed] [PMC]

71.

Ruhanen H, Nidhina Haridas PA, Eskelinen EL, Eriksson O, Olkkonen VM, Käkelä R. Depletion of TM6SF2 disturbs membrane lipid composition and dynamics in HuH7 hepatoma cells. Biochim Biophys Acta Mol Cell Biol Lipids. 2017;1862:676–85. [DOI] [PubMed]

72.

Musso G, Cassader M, Paschetta E, Gambino R. TM6SF2 may drive postprandial lipoprotein cholesterol toxicity away from the vessel walls to the liver in NAFLD. J Hepatol. 2016;64:979–81. [DOI] [PubMed]

73.

Luukkonen PK, Zhou Y, Nidhina Haridas PA, Dwivedi OP, Hyötyläinen T, Ali A, et al. Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers with NAFLD. J Hepatol. 2017;67:128–36. [DOI] [PubMed]

74.

Li TT, Li TH, Peng J, He B, Liu LS, Wei DH, et al. TM6SF2: a novel target for plasma lipid regulation. Atherosclerosis. 2018;268:170–6. [DOI] [PubMed]

75.

Ehrhardt N, Doche ME, Chen S, Mao HZ, Walsh MT, Bedoya C, et al. Hepatic Tm6sf2 overexpression affects cellular ApoB-trafficking, plasma lipid levels, hepatic steatosis and atherosclerosis. Hum Mol Genet. 2017;26:2719–31. [DOI] [PubMed] [PMC]

76.

Mahdessian H, Taxiarchis A, Popov S, Silveira A, Franco-Cereceda A, Hamsten A, 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;111:8913–8. [DOI] [PubMed] [PMC]

77.

O’Hare EA, Yang R, Yerges-Armstrong LM, Sreenivasan U, McFarland R, Leitch CC, et al. TM6SF2 rs58542926 impacts lipid processing in liver and small intestine. Hepatology. 2017;65:1526–42. [DOI] [PubMed] [PMC]

78.

Mancina RM, Sentinelli F, Incani M, Bertoccini L, Russo C, Romeo S, et al. Transmembrane-6 superfamily member 2 (TM6SF2) E167K variant increases susceptibility to hepatic steatosis in obese children. Dig Liver Dis. 2016;48:100–1. [DOI] [PubMed]

79.

Goffredo M, Caprio S, Feldstein AE, D’Adamo E, Shaw MM, Pierpont B, et al. Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: a multiethnic study. Hepatology. 2016;63:117–25. [DOI] [PubMed] [PMC]

80.

Grandone A, Cozzolino D, Marzuillo P, Cirillo G, Di Sessa A, Ruggiero L, et al. TM6SF2 Glu167Lys polymorphism is associated with low levels of LDL-cholesterol and increased liver injury in obese children. Pediatr Obes. 2016;11:115–9. [DOI] [PubMed]

81.

Dongiovanni P, Petta S, Maglio C, Fracanzani AL, Pipitone R, Mozzi E, et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology. 2015;61:506–14. [DOI] [PubMed]

82.

Liu Z, Que S, Zhou L, Zheng S, Romeo S, Mardinoglu A, et al. The effect of the TM6SF2 E167K variant on liver steatosis and fibrosis in patients with chronic hepatitis C: a meta-analysis. Sci Rep. 2017;7:9273. [DOI] [PubMed] [PMC]

83.

Liu DJ, Peloso GM, Yu H, Butterworth AS, Wang X, Mahajan A, et al. Exome-wide association study of plasma lipids in > 300, 000 individuals. Nat Genet. 2017;49:1758–66. [DOI] [PubMed] [PMC]

84.

Holmen OL, Zhang H, Fan Y, Hovelson DH, Schmidt EM, Zhou W, et al. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat Genet. 2014;46:345–51. [DOI] [PubMed] [PMC]

85.

Chen LZ, Xia HHX, Xin YN, Lin ZH, Xuan SY. TM6SF2 E167K variant, a novel genetic susceptibility variant, contributing to nonalcoholic fatty liver disease. J Clin Transl Hepatol. 2015;3:265–70. [DOI] [PubMed] [PMC]

86.

Viitasalo A, Pihlajamäki J, Paananen J, Atalay M, Lindi V, Lakka TA. Associations of TM6SF2 167K allele with liver enzymes and lipid profile in children: the PANIC study. Pediatr Res. 2016;79:684–8. [DOI] [PubMed]

87.

Pirola CJ, Sookoian S. The dual and opposite role of the TM6SF2-rs58542926 variant in protecting against cardiovascular disease and conferring risk for nonalcoholic fatty liver: a meta-analysis. Hepatology. 2015;62:1742–56. [DOI] [PubMed]

88.

Sookoian S, Castaño GO, Scian R, Mallardi P, Fernández Gianotti T, Burgueño AL, et al. Genetic variation in transmembrane 6 superfamily member 2 and the risk of nonalcoholic fatty liver disease and histological disease severity. Hepatology. 2015;61:515–25. [DOI] [PubMed]

89.

Musso G, Cipolla U, Cassader M, Pinach S, Saba F, De Michieli F, et al. TM6SF2 rs58542926 variant affects postprandial lipoprotein metabolism and glucose homeostasis in NAFLD. J Lipid Res. 2017;58:1221–9. [DOI] [PubMed] [PMC]

90.

Chen F, Esmaili S, Rogers GB, Bugianesi E, Petta S, Marchesini G, et al. Lean NAFLD: a distinct entity shaped by differential metabolic adaptation. Hepatology. 2020;71:1213–27. [DOI] [PubMed]

91.

Liu YL, Reeves HL, Burt AD, Tiniakos D, McPherson S, Leathart JBS, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun. 2014;5:4309. [DOI] [PubMed] [PMC]

92.

Eslam M, Mangia A, Berg T, Chan HL, Irving WL, Dore GJ, et al. Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes. Hepatology. 2016;64:34–46. [DOI] [PubMed]

93.

Chen X, Zhou P, De L, Li B, Su S. The roles of transmembrane 6 superfamily member 2 rs58542926 polymorphism in chronic liver disease: a meta-analysis of 24, 147 subjects. Mol Genet Genomic Med. 2019;7:e824. [DOI] [PubMed] [PMC]

94.

Stickel F, Buch S, Nischalke HD, Weiss KH, Gotthardt D, Fischer J, et al. Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis. Am J Gastroenterol. 2018;113:1475–83. [DOI] [PubMed]

95.

Petta S, Maida M, Grimaudo S, Pipitone RM, Macaluso FS, Cabibi D, et al. TM6SF2 rs58542926 is not associated with steatosis and fibrosis in large cohort of patients with genotype 1 chronic hepatitis C. Liver Int. 2016;36:198–204. [DOI] [PubMed]

96.

Falleti E, Cussigh A, Cmet S, Fabris C, Toniutto P. PNPLA3 rs738409 and TM6SF2 rs58542926 variants increase the risk of hepatocellular carcinoma in alcoholic cirrhosis. Dig Liver Dis. 2016;48:69–75. [DOI] [PubMed]

97.

Yang J, Trépo E, Nahon P, Cao Q, Moreno C, Letouzé E, et al. PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases. 2019;144:533–44. [DOI]

98.

Raksayot M, Chuaypen N, Khlaiphuengsin A, Pinjaroen N, Treeprasertsuk S, Poovorawan Y, et al. Independent and additive effects of PNPLA3 and TM6SF2 polymorphisms on the development of non-B, non-C hepatocellular carcinoma. J Gastroenterol. 2019;54:427–36. [DOI] [PubMed]

99.

Stickel F, Moreno C, Hampe J, Morgan MY. The genetics of alcohol dependence and alcohol-related liver disease. J Hepatol. 2017;66:195–211. [DOI] [PubMed]

100.

Buch S, Stickel F, Trépo E, Way M, Herrmann A, Nischalke HD, et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat Genet. 2015;47:1443–8. [DOI] [PubMed]

101.

Mancina RM, Dongiovanni P, Petta S, Pingitore P, Meroni M, Rametta R, et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology. 2016;150:1219–30.e6. [DOI] [PubMed] [PMC]

102.

Luukkonen PK, Zhou Y, Hyötyläinen T, Leivonen M, Arola J, Orho-Melander M, et al. The MBOAT7 variant rs641738 alters hepatic phosphatidylinositols and increases severity of non-alcoholic fatty liver disease in humans. J Hepatol. 2016;65:1263–5. [DOI] [PubMed]

103.

Donati B, Dongiovanni P, Romeo S, Meroni M, McCain M, Miele L, et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci Rep. 2017;7:4492. [DOI] [PubMed] [PMC]

104.

Viitasalo A, Eloranta AM, Atalay M, Romeo S, Pihlajamaki J, Lakka TA. Association of MBOAT7 gene variant with plasma ALT levels in children: the PANIC study. Pediatr Res. 2016;80:651–5. [DOI] [PubMed]

105.

Di Sessa A, Umano GR, Cirillo G, Del Prete A, Iacomino R, Marzuillo P, et al. The membrane-bound O-acyltransferase7 rs641738 variant in pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2018;67:69–74. [DOI] [PubMed]

106.

Krawczyk M, Rau M, Schattenberg JM, Bantel H, Pathil A, Demir M, et al. Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study. J Lipid Res. 2017;58:247–55. [DOI] [PubMed] [PMC]

107.

Thabet K, Chan HLY, Petta S, Mangia A, Berg T, Boonstra A, et al. The membrane-bound O-acyltransferase domain-containing 7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B. Hepatology. 2017;65:1840–50. [DOI] [PubMed]

108.

Thabet K, Asimakopoulos A, Shojaei M, Romero-Gomez M, Mangia A, Irving WL, et al. MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C. Nat Commun. 2016;7:12757. [DOI] [PubMed] [PMC]

109.

Rahal HK, Tabibian JH. The MBOAT7 rs641738 variant in primary sclerosing cholangitis: a novel biomarker for prognostication. Clin Res Hepatol Gastroenterol. 2020;[Epub ahead of print]. [DOI]

110.

Freund C, Wahlers A, Begli NH, Leopold Y, Klöters-Plachky P, Mehrabi A, et al. The MBOAT7 rs641738 variant is associated with an improved outcome in primary sclerosing cholangitis. Clin Res Hepatol Gastroenterol. 2020;[Epub ahead of print]. [DOI]

111.

Xia Y, Huang CX, Li GY, Chen KH, Han L, Tang L, et al. Meta-analysis of the association between MBOAT7 rs641738, TM6SF2 rs58542926 and nonalcoholic fatty liver disease susceptibility. Clin Res Hepatol Gastroenterol. 2019;43:533–41. [DOI] [PubMed]

112.

Sookoian S, Flichman D, Garaycoechea ME, Gazzi C, Martino JS, Castaño GO, et al. Lack of evidence supporting a role of TMC4-rs641738 missense variant-MBOAT7-intergenic downstream variant-in the susceptibility to nonalcoholic fatty liver disease. Sci Rep. 2018;8:5097. [DOI] [PubMed] [PMC]

113.

Basyte-Bacevice V, Skieceviciene J, Valantiene I, Sumskiene J, Petrenkiene V, Kondrackiene J, et al. TM6SF2 and MBOAT7 gene variants in liver fibrosis and cirrhosis. Int J Mol Sci. 2019;20:1277. [DOI]

114.

Koo BK, Joo SK, Kim D, Bae JM, Park JH, Kim JH, et al. Additive effects of PNPLA3 and TM6SF2 on the histological severity of non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2018;33:1277–85. [DOI] [PubMed]

115.

Anstee QM, Darlay R, Cockell S, Meroni M, Govaere O, Tiniakos D, et al. Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort. J Hepatol. 2020;[Epub ahead of print]. [DOI]

116.

Teo K, Abeysekera KW, Adams L, Aigner E, Banales JM, Banerjee R, et al. rs641738C>T near MBOAT7 is positively associated with liver fat, ALT, and histological severity of NAFLD: a meta-analysis. medRxiv 19013623 [Preprint]. 2020 [cited 2020 Feb 9]. Available from: https://www.medrxiv.org/content/10.1101/19013623v3

117.

Zarini S, Hankin JA, Murphy RC, Gijón MA. Lysophospholipid acyltransferases and eicosanoid biosynthesis in zebrafish myeloid cells. Prostaglandins Other Lipid Mediat. 2014;113–115:52–61. [DOI]

118.

Meroni M, Dongiovanni P, Longo M, Carli F, Baselli G, Rametta R, et al. Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes. EBioMedicine. 2020;52:102658. [DOI] [PubMed] [PMC]

119.

Petta S, Miele L, Bugianesi E, Camma C, Rosso C, Boccia S, et al. Glucokinase regulatory protein gene polymorphism affects liver fibrosis in non-alcoholic fatty liver disease. PLoS One. 2014;9:e87523. [DOI] [PubMed] [PMC]

120.

Santoro N, Zhang CK, Zhao H, Pakstis AJ, Kim G, Kursawe R, et al. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology. 2012;55:781–9. [DOI] [PubMed] [PMC]

121.

Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011;7:e1001324. [DOI] [PubMed] [PMC]

122.

Raimondo A, Rees MG, Gloyn AL. Glucokinase regulatory protein: complexity at the crossroads of triglyceride and glucose metabolism. Curr Opin Lipidol. 2015;26:88–95. [DOI] [PubMed] [PMC]

123.

Beer NL, Tribble ND, McCulloch LJ, Roos C, Johnson PR, Orho-Melander M, 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;18:4081–8. [DOI] [PubMed] [PMC]

124.

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;55:661–3. [DOI] [PubMed]

125.

Santoro N, Caprio S, Pierpont B, Van Name M, Savoye M, Parks EJ. Hepatic de novo lipogenesis in obese youth is modulated by a common variant in the GCKR gene. J Clin Endocrinol Metab. 2015;100:E1125–32. [DOI] [PubMed] [PMC]

126.

Tan HL, Zain SM, Mohamed R, Rampal S, Chin KF, Basu RC, 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. 2014;49:1056–64. [DOI] [PubMed]

127.

Kawaguchi T, Shima T, Mizuno M, Mitsumoto Y, Umemura A, Kanbara Y, et al. Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers. PLoS One. 2018;13:e0185490. [DOI] [PubMed] [PMC]

128.

Kozian DH, Barthel A, Cousin E, Brunnhöfer R, Anderka O, März W, et al. Glucokinase-activating GCKR polymorphisms increase plasma levels of triglycerides and free fatty acids, but do not elevate cardiovascular risk in the ludwigshafen risk and cardiovascular health study. Horm Metab Res. 2010;42:502–6. [DOI] [PubMed]

129.

Abul-Husn NS, Cheng X, Li AH, Xin Y, Schurmann C, Stevis P, et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N Engl J Med. 2018;378:1096–106. [DOI] [PubMed] [PMC]

130.

Horiguchi Y, Araki M, Motojima K. 17beta-Hydroxysteroid dehydrogenase type 13 is a liver-specific lipid droplet-associated protein. Biochem Biophys Res Commun. 2008;370:235–8. [DOI] [PubMed]

131.

Su W, Wang Y, Jia X, Wu W, Li L, Tian X, et al. Comparative proteomic study reveals 17beta-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A. 2014;111:11437–42. [DOI] [PubMed] [PMC]

132.

Adam M, Heikelä H, Sobolewski C, Portius D, Mäki-Jouppila J, Mehmood A, et al. Hydroxysteroid (17β) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice. FASEB J. 2018;32:3434–47. [DOI] [PubMed]

133.

Kozlitina J, Stender S, Hobbs HH, Cohen JC. HSD17B13 and chronic liver disease in blacks and hispanics. N Engl J Med. 2018;379:1876–7. [DOI] [PubMed]

134.

Pirola CJ, Garaycoechea M, Flichman D, Arrese M, Martino JS, Gazzi C, et al. Splice variant rs72613567 prevents worst histologic outcomes in patients with nonalcoholic fatty liver disease. J Lipid Res. 2019;60:176–85. [DOI] [PubMed] [PMC]

135.

Gellert-Kristensen H, Nordestgaard BG, Tybjaerg-Hansen A, Stender S. High risk of fatty liver disease amplifies the alanine transaminase-lowering effect of a HSD17B13 variant. Hepatology. 2020;71:56–66. [DOI] [PubMed]

136.

Yang J, Trépo E, Nahon P, Cao Q, Moreno C, Letouzé E, et al. A 17-beta-hydroxysteroid dehydrogenase 13 variant protects from hepatocellular carcinoma development in alcoholic liver disease. Hepatology. 2019;70:231–40. [DOI] [PubMed]

137.

Luukkonen PK, Tukiainen T, Juuti A, Sammalkorpi H, Haridas PAN, Niemelä O, et al. Hydroxysteroid 17-β dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease. JCI Insight. 2020;5:e132158. [DOI]

138.

Stender S., et al. Relationship between Genetic Variation at PPP1R3B and Liver Glycogen and Triglyceride Levels. Hepatology, 2017. [DOI]

139.

Dongiovanni P, Meroni M, Mancina RM, Baselli G, Rametta R, Pelusi S, et al. Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nonalcoholic fatty liver disease. Hepatol Commun. 2018;2:666–75. [DOI] [PubMed] [PMC]

140.

Mehta MB, Shewale SV, Sequeira RN, Millar JS, Hand NJ, Rader DJ. Hepatic protein phosphatase 1 regulatory subunit 3B (Ppp1r3b) promotes hepatic glycogen synthesis and thereby regulates fasting energy homeostasis. J Biol Chem. 2017;292:10444–54. [DOI] [PubMed] [PMC]

141.

Dongiovanni P, Rametta R, Meroni M, Valenti L. The role of insulin resistance in nonalcoholic steatohepatitis and liver disease development--a potential therapeutic target? Expert Rev Gastroenterol Hepatol. 2016;10:229–42. [DOI] [PubMed]

142.

Dongiovanni P, Meroni M, Baselli GA, Bassani GA, Rametta R, Pietrelli A, et al. Insulin resistance promotes lysyl oxidase like 2 induction and fibrosis accumulation in non-alcoholic fatty liver disease. Clin Sci (Lond). 2017;131:1301–15. [DOI] [PubMed]

143.

Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149:389–97.e10. [DOI] [PubMed] [PMC]

144.

McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015;62:1148–55. [DOI] [PubMed]

145.

Pelusi S, Petta S, Rosso C, Borroni V, Fracanzani AL, Dongiovanni P, et al. Renin-angiotensin system inhibitors, type 2 diabetes and fibrosis progression: an observational study in patients with nonalcoholic fatty liver disease. PLoS One. 2016;11:e0163069. [DOI] [PubMed] [PMC]

146.

Dongiovanni P, Valenti L, Rametta R, Daly AK, Nobili V, Mozzi E, 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;59:267–73. [DOI] [PubMed]

147.

Kitamoto A, Kitamoto T, Nakamura T, Ogawa Y, Yoneda M, Hyogo H, et al. Association of polymorphisms in GCKR and TRIB1 with nonalcoholic fatty liver disease and metabolic syndrome traits. Endocr J. 2014;61:683–9. [DOI] [PubMed]

148.

Cefalù AB, Pirruccello JP, Noto D, Gabriel S, Valenti V, Gupta N, et al. A novel APOB mutation identified by exome sequencing cosegregates with steatosis, liver cancer, and hypocholesterolemia. Arterioscler Thromb Vasc Biol. 2013;33:2021–5. [DOI] [PubMed] [PMC]

149.

Pelusi S, Baselli G, Pietrelli A, Dongiovanni P, Donati B, McCain MV, et al. Rare pathogenic variants predispose to hepatocellular carcinoma in nonalcoholic fatty liver disease. Sci Rep. 2019;9:3682. [DOI] [PubMed] [PMC]

150.

Di Filippo M, Moulin P, Roy P, Samson-Bouma ME, Collardeau-Frachon S, Chebel-Dumont S, et al. Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. J Hepatol. 2014;61:891–902. [DOI] [PubMed]

151.

Petersen KF, Dufour S, Hariri A, Nelson-Williams C, Foo JN, Zhang XM, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med. 2010;362:1082–9. [DOI] [PubMed] [PMC]

152.

Kozlitina J, Boerwinkle E, Cohen JC, Hobbs HH. Dissociation between APOC3 variants, hepatic triglyceride content and insulin resistance. Hepatology. 2011;53:467–74. [DOI] [PubMed] [PMC]

153.

Valenti L, Nobili V, Al-Serri A, Rametta R, Leathart JB, Zappa MA, et al. The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage independently of PNPLA3 I148M genotype in patients with nonalcoholic fatty liver. J Hepatol. 2011;55:1409–14. [DOI] [PubMed]

154.

Dongiovanni P, Meroni M, Baselli G, Mancina RM, Ruscica M, Longo M, et al. PCSK7 gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients. J Lipid Res. 2019;60:1144–53. [DOI] [PubMed] [PMC]

155.

Huang T, Huang J, Qi Q, Li Y, Bray GA, Rood J, et al. PCSK7 genotype modifies effect of a weight-loss diet on 2-year changes of insulin resistance: the POUNDS LOST trial. Diabetes Care. 2015;38:439–44. [DOI] [PubMed] [PMC]

156.

Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37:161–5. [DOI] [PubMed]

157.

Ruscica M, Ferri N, Macchi C, Meroni M, Lanti C, Ricci C, et al. Liver fat accumulation is associated with circulating PCSK9. Ann Med. 2016;48:384–91. [DOI] [PubMed]

158.

Trinder M, Francis GA, Brunham LR. Association of monogenic vs. polygenic hypercholesterolemia with risk of atherosclerotic cardiovascular disease. JAMA Cardiol. 2020;[Epub ahead of print]. [DOI]

159.

Costet P, Cariou B, Lambert G, Lalanne F, Lardeux B, Jarnoux AL, et al. Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c. J Biol Chem. 2006;281:6211–8. [DOI] [PubMed]

160.

Kotowski IK, Pertsemlidis A, Luke A, Cooper RS, Vega GL, Cohen JC, et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet. 2006;78:410–22. [DOI] [PubMed] [PMC]

161.

Gomaraschi M, Fracanzani AL, Dongiovanni P, Pavanello C, Giorgio E, Da Dalt L, et al. Lipid accumulation impairs lysosomal acid lipase activity in hepatocytes: evidence in NAFLD patients and cell cultures. Biochim Biophys Acta Mol Cell Biol Lipids. 2019;1864:158523. [DOI] [PubMed]

162.

Reiner Ž, Guardamagna O, Nair D, Soran H, Hovingh K, Bertolini S, et al. Lysosomal acid lipase deficiency--an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis. 2014;235:21–30. [DOI] [PubMed]

163.

Auinger A, Valenti L, Pfeuffer M, Helwig U, Herrmann J, Fracanzani AL, et al. A promoter polymorphism in the liver-specific fatty acid transport protein 5 is associated with features of the metabolic syndrome and steatosis. Horm Metab Res. 2010;42:854–9. [DOI] [PubMed]

164.

Valenti L, Motta BM, Alisi A, Sartorelli R, Buonaiuto G, Dongiovanni P, et al. LPIN1 rs13412852 polymorphism in pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2012;54:588–93. [DOI] [PubMed]

165.

Marra F, Bertolani C. Adipokines in liver diseases. Hepatology. 2009;50:957–69. [DOI] [PubMed]

166.

Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49:1877–87. [DOI] [PubMed]

167.

Bilzer M, Roggel F, Gerbes AL. Role of Kupffer cells in host defense and liver disease. Liver Int. 2006;26:1175–86. [DOI] [PubMed]

168.

Eslam M, McLeod D, Kelaeng KS, Mangia A, Berg T, Thabet K, et al. IFN-λ3, not IFN-λ4, likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis. Nat Genet. 2017;49:795–800. [DOI] [PubMed]

169.

Petta S, Grimaudo S, Cammà C, Cabibi D, Di Marco V, Licata G, et al. IL28B and PNPLA3 polymorphisms affect histological liver damage in patients with non-alcoholic fatty liver disease. J Hepatol. 2012;56:1356–62. [DOI] [PubMed]

170.

Eslam M, Hashem AM, Leung R, Romero-Gomez M, Berg T, Dore GJ, et al. Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease. Nat Commun. 2015;6:6422. [DOI] [PubMed] [PMC]

171.

Eslam M, Hashem AM, Romero-Gomez M, Berg T, Dore GJ, Mangia A, et al. FibroGENE: a gene-based model for staging liver fibrosis. J Hepatol. 2016;64:390–8. [DOI] [PubMed]

172.

Petta S, Valenti L, Tuttolomondo A, Dongiovanni P, Pipitone RM, Cammà C, et al. Interferon lambda 4 rs368234815 TT>δG variant is associated with liver damage in patients with nonalcoholic fatty liver disease. Hepatology. 2017;66:1885–93. [DOI] [PubMed]

173.

Petta S, Valenti L, Svegliati-Baroni G, Ruscica M, Pipitone RM, Dongiovanni P, et al. Fibronectin type III domain-containing protein 5 rs3480 A>G polymorphism, irisin, and liver fibrosis in patients with nonalcoholic fatty liver disease. J Clin Endocrinol Metab. 2017;102:2660–9. [DOI] [PubMed]

174.

Metwally M, Bayoumi A, Romero-Gomez M, Thabet K, John M, Adams LA, et al. A polymorphism in the Irisin-encoding gene (FNDC5) associates with hepatic steatosis by differential miRNA binding to the 3’UTR. J Hepatol. 2019;70:494–500. [DOI] [PubMed]

175.

Gorden A, Yang R, Yerges-Armstrong LM, Ryan KA, Speliotes E, Borecki IB, et al. Genetic variation at NCAN locus is associated with inflammation and fibrosis in non-alcoholic fatty liver disease in morbid obesity. Hum Hered. 2013;75:34–43. [DOI] [PubMed] [PMC]

176.

Cai W, Weng DH, Yan P, Lin YT, Dong ZH, Mailamuguliet al. Genetic polymorphisms associated with nonalcoholic fatty liver disease in Uyghur population: a case-control study and meta-analysis. Lipids Health Dis. 2019;18:14. [DOI] [PubMed] [PMC]

177.

Cicione C, Degirolamo C, Moschetta A. Emerging role of fibroblast growth factors 15/19 and 21 as metabolic integrators in the liver. Hepatology. 2012;56:2404–11. [DOI] [PubMed]

178.

Dongiovanni P, Crudele A, Panera N, Romito I, Meroni M, De Stefanis C, et al. beta-Klotho gene variation is associated with liver damage in children with NAFLD. J Hepatol. 2020;72:411–9. [DOI] [PubMed]

179.

Petta S, Valenti L, Marra F, Grimaudo S, Tripodo C, Bugianesi E, et al. MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease. J Hepatol. 2016;64:682–90. [DOI] [PubMed]

180.

Rüeger S, Bochud PY, Dufour JF, Müllhaupt B, Semela D, Heim MH, et al. Impact of common risk factors of fibrosis progression in chronic hepatitis C. Gut. 2015;64:1605–15. [DOI] [PubMed]

181.

Cai B, Dongiovanni P, Corey KE, Wang X, Shmarakov IO, Zheng Z, et al. Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis. Cell Metab. 2020;31:406–21.e7. [DOI] [PubMed] [PMC]

182.

Miele L, Beale G, Patman G, Nobili V, Leathart J, Grieco A, et al. The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease. Gastroenterology. 2008;135:282–91.e1. [DOI] [PubMed] [PMC]

183.

Rametta R, Meroni M, Dongiovanni P. From environment to genome and back: a lesson from HFE mutations. Int J Mol Sci. 2020;21:3505. [DOI]

184.

Aravinthan A, Mells G, Allison M, Leathart J, Kotronen A, Yki-Jarvinen H, et al. Gene polymorphisms of cellular senescence marker p21 and disease progression in non-alcohol-related fatty liver disease. Cell Cycle. 2014;13:1489–94. [DOI] [PubMed] [PMC]

185.

Calado RT, Regal JA, Kleiner DE, Schrump DS, Peterson NR, Pons V, et al. A spectrum of severe familial liver disorders associate with telomerase mutations. PLoS One. 2009;4:e7926. [DOI] [PubMed] [PMC]

186.

Pessayre D, Fromenty B. NASH: a mitochondrial disease. J Hepatol. 2005;42:928–40. [DOI] [PubMed]

187.

Mansouri A, Gattolliat CH, Asselah T. Mitochondrial dysfunction and signaling in chronic liver diseases. Gastroenterology. 2018;155:629–47. [DOI] [PubMed]

188.

Al-Serri A, Anstee QM, Valenti L, Nobili V, Leathart JB, Dongiovanni P, et al. The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case-control and intra-familial allele association studies. J Hepatol. 2012;56:448–54. [DOI] [PubMed]

189.

Namikawa C, Shu-Ping Z, Vyselaar JR, Nozaki Y, Nemoto Y, Ono M, et al. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. J Hepatol. 2004;40:781–6. [DOI] [PubMed]

190.

Serviddio G, Bellanti F, Tamborra R, Rollo T, Capitanio N, Romano AD, et al. Uncoupling protein-2 (UCP2) induces mitochondrial proton leak and increases susceptibility of non-alcoholic steatohepatitis (NASH) liver to ischaemia-reperfusion injury. Gut. 2008;57:957–65. [DOI] [PubMed]

191.

Fares R, Petta S, Lombardi R, Grimaudo S, Dongiovanni P, Pipitone R, et al. The UCP2 -866 G>A promoter region polymorphism is associated with nonalcoholic steatohepatitis. Liver Int. 2015;35:1574–80. [DOI] [PubMed]

192.

Aller R, De Luis DA, Izaola O, González Sagrado M, Conde R, Alvarez T, et al. Role of -55CT polymorphism of UCP3 gene on non alcoholic fatty liver disease and insulin resistance in patients with obesity. Nutr Hosp. 2010;25:572–6. [PubMed]

193.

Dong C, Della-Morte D, Wang L, Cabral D, Beecham A, McClendon MS, et al. Association of the sirtuin and mitochondrial uncoupling protein genes with carotid plaque. PLoS One. 2011;6:e27157. [DOI] [PubMed] [PMC]

194.

Emdin CA, Haas ME, Khera AV, Aragam K, Chaffin M, Klarin D, et al. A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease. PLoS Genet. 2020;16:e1008629. [DOI] [PubMed] [PMC]

195.

Trépo E, Valenti L. Update on NAFLD genetics: from new variants to the clinic. J Hepatol. 2020;72:1196–209. [DOI] [PubMed]

196.

Di Costanzo A, Pacifico L, Chiesa C, Perla FM, Ceci F, Angeloni A, et al. Genetic and metabolic predictors of hepatic fat content in a cohort of Italian children with obesity. Pediatr Res. 2019;85:671–7. [DOI] [PubMed] [PMC]

197.

Suomela E, Oikonen M, Pitkänen N, Ahola-Olli A, Virtanen J, Parkkola R, et al. Childhood predictors of adult fatty liver. The cardiovascular risk in young finns study. J Hepatol. 2016;65:784–90. [DOI] [PubMed]

198.

Chen L, Du S, Lu L, Lin Z, Jin W, Hu D, et al. The additive effects of the TM6SF2 E167K and PNPLA3 I148M polymorphisms on lipid metabolism. Oncotarget. 2017;8:74209–16. [DOI] [PubMed] [PMC]

199.

Gellert-Kristensen H, Richardson TG, Davey Smith G, Nordestgaard BG, Tybjaerg-Hansen A, Stender S. Combined effect of PNPLA3, TM6SF2, and HSD17B13 variants on risk of cirrhosis and hepatocellular carcinoma in the general population. Hepatology. 2020;[Epub ahead of print]. [DOI]

200.

Eslam M, George J. Genetic Insights for Drug Development in NAFLD. Trends Pharmacol Sci. 2019;40:506–16. [DOI] [PMC]