Genetic variants in adult liver diseases

C. Dröge; D. Häussinger; V. Keitel

doi:10.1055/s-0035-1566903

Zeitschrift für Gastroenterologie, Table of Contents

Z Gastroenterol 2015; 53(12): 1436-1446
DOI: 10.1055/s-0035-1566903

Übersicht

Genetic variants in adult liver diseases

Genetische Varianten bei Lebererkrankungen im Erwachsenenalter

C. Dröge

,

D. Häussinger

,

V. Keitel

Abstract

In the last decades, understanding of genetic variants contributing to liver disease development has considerably improved through novel genotyping techniques. Genetic variants of single genes are known to be decisive for the development of monogenetic liver diseases of varying severity. Identification of genetic variants is an important part of the diagnostic process, e. g. the majority of patients with high iron [Fe] (HFE)-associated hemochromatosis carry the homozygous mutation p.C282Y. Detection of mutations in genes encoding hepatobiliary transport proteins like familial intrahepatic cholestasis 1 (FIC1), bile salt export pump (BSEP), or multidrug resistance protein 3 (MDR3) is the basis to differentiate various forms of intrahepatic cholestasis. Moreover, genetic variants in a variety of genes are known to act as disease modifiers and represent risk factors for disease progression and the development of cirrhosis or even hepatocellular carcinoma. Success of drug treatment or appearance of severe side effects can also be influenced by specific genetic variants. All these aspects underscore the increasing importance of genetic variants, which in the future may help to identify patients at risk for disease progression or help to guide treatment decisions. In the present overview, specific frequent genetic variants are summarized that play roles in monogenetic liver diseases, forms of intrahepatic cholestasis, gallstone development, fatty liver disease, drug-induced liver injury, and liver disease progression as well as hepatocellular carcinoma development.

Zusammenfassung

In den letzten Jahrzehnten hat sich das Verständnis von Lebererkrankungen mit Hilfe neuer Techniken erheblich verbessert. Genetische Varianten einzelner Gene sind für die Entwicklung monogenetischer Lebererkrankungen unterschiedlichen Schweregrads entscheidend. Die Identifizierung genetischer Varianten ist ein wichtiger Teil des Diagnostikprozesses, z. B. trägt die Mehrheit der Patienten mit high iron [Fe] (HFE)-assoziierter Hämochromatose die homozygote Mutation p.C282Y. Der Nachweis von Mutationen in Genen, die hepatobiliäre Transportproteine wie FIC1 (familial intrahepatic cholestasis 1), BSEP (bile salt export pump) oder MDR3 (multidrug resistance protein 3) kodieren, ist die Grundlage für die Diagnose verschiedener Formen intrahepatischer Cholestasen. Des Weiteren beeinflussen genetische Varianten in einer Vielzahl von Genen den Krankheitsverlauf unterschiedlicher Lebererkrankungen und stellen Risikofaktoren für die Entwicklung einer Leberzirrhose oder des hepatozellulären Karzinoms dar. Der Behandlungserfolg oder das Auftreten schwerer Nebenwirkungen kann ebenfalls durch spezifische genetische Varianten beeinflusst werden. All diese Aspekte verdeutlichen, dass die Einbeziehung genetischer Informationen im Bereich Diagnostik, Risikostratifizierung und Therapieentscheidung bei Patienten mit Lebererkrankungen in Zukunft weiter an Bedeutung gewinnen wird. In der vorliegenden Arbeit sind spezifische genetische Varianten zusammengefasst, die bei monogenetischen Lebererkrankungen, intrahepatischen Cholestasen, Gallensteinentwicklung, Fettleber, medikamentös-toxischer Leberschädigung, Leberzirrhose und hepatozellulärem Karzinom eine Rolle spielen.

Schlüsselwörter

monogenetisch - Polymorphismus - autosomal - Genotyp - Phänotyp - Krankheitsmodifikator

Key Words

monogenetic - single nucleotide polymorphism - autosomal - genotype - phenotype - disease modifier

Full Text

References

References
1 Andrews NC. Disorders of iron metabolism. N Engl J Med 1999; 341: 1986-1995
2 Chanprasert S, Scaglia F. Adult liver disorders caused by inborn errors of metabolism: review and update. Mol Genet Metab 2015; 114: 1-10
3 Ward DM, Kaplan J. Ferroportin-mediated iron transport: expression and regulation. Biochim Biophys Acta 2012; 1823: 1426-1433
4 Roy CN. An update on iron homeostasis: make new friends, but keep the old. Am J Med Sci 2013; 346: 413-419
5 Nemeth E, Tuttle MS, Powelson J et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004; 306: 2090-2093
6 EASL. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol 2010; 53: 3-22
7 Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology 2010; 139: 393-408 , 408 e391–392
8 Adams PC, Passmore L, Chakrabarti S et al. Liver diseases in the hemochromatosis and iron overload screening study. Clin Gastroenterol Hepatol 2006; 4: 918-923 ; quiz 807
9 Stickel F, Buch S, Zoller H et al. Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis. Hum Mol Genet 2014; 23: 3883-3890
10 Niederau C, Fischer R, Sonnenberg A et al. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 1985; 313: 1256-1262
11 Karlsen TH, Lammert F, Thompson RJ. Genetics of liver disease: From pathophysiology to clinical practice. J Hepatol 2015; 62: S6-S14
12 Ala A, Walker AP, Ashkan K et al. Wilson's disease. Lancet 2007; 369: 397-408
13 Bull PC, Thomas GR, Rommens JM et al. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet 1993; 5: 327-337
14 Ferenci P, Czlonkowska A et al. European Association for Study of L. EASL Clinical Practice Guidelines: Wilson's disease. Journal of hepatology 2012; 56: 671-685
15 Stattermayer AF, Traussnigg S, Dienes HP et al. Hepatic steatosis in Wilson disease – Role of copper and PNPLA3 mutations. J Hepatol 2015; 63: 156-163
16 Silverman EK, Sandhaus RA. Clinical practice. Alpha1-antitrypsin deficiency. N Engl J Med 2009; 360: 2749-2757
17 Greulich T, Vogelmeier CF. Alpha-1-antitrypsin deficiency: increasing awareness and improving diagnosis. Ther Adv Respir Dis 2015; pii: 1753465815602162. [Epub ahead of print]
18 Kelly E, Greene CM, Carroll TP et al. Alpha-1 antitrypsin deficiency. Respir Med 2010; 104: 763-772
19 Kidd VJ, Wallace RB, Itakura K et al. alpha 1-antitrypsin deficiency detection by direct analysis of the mutation in the gene. Nature 1983; 304: 230-234
20 Jeppsson JO. Amino acid substitution Glu leads to Lys alpha1-antitrypsin PiZ. FEBS Lett 1976; 65: 195-197
21 Perlmutter DH, Kay RM, Cole FS et al. The cellular defect in alpha 1-proteinase inhibitor (alpha 1-PI) deficiency is expressed in human monocytes and in Xenopus oocytes injected with human liver mRNA. Proceedings of the National Academy of Sciences of the United States of America 1985; 82: 6918-6921
22 Foreman RC, Judah JD, Colman A. Xenopus oocytes can synthesise but do not secrete the Z variant of human alpha 1-antitrypsin. FEBS Lett 1984; 168: 84-88
23 Blanco I, de Serres FJ, Fernandez-Bustillo E et al. Estimated numbers and prevalence of PI*S and PI*Z alleles of alpha1-antitrypsin deficiency in European countries. Eur Respir J 2006; 27: 77-84
24 Eriksson S, Carlson J, Velez R. Risk of cirrhosis and primary liver cancer in alpha 1-antitrypsin deficiency. N Engl J Med 1986; 314: 736-739
25 Antoury C, Lopez R, Zein N et al. Alpha-1 antitrypsin deficiency and the risk of hepatocellular carcinoma in end-stage liver disease. World J Hepatol 2015; 7: 1427-1432
26 Perlmutter DH. Autophagic disposal of the aggregation-prone protein that causes liver inflammation and carcinogenesis in alpha-1-antitrypsin deficiency. Cell Death Differ 2009; 16: 39-45
27 Rudnick DA, Liao Y, An JK et al. Analyses of hepatocellular proliferation in a mouse model of alpha-1-antitrypsin deficiency. Hepatology (Baltimore, Md) 2004; 39: 1048-1055
28 Hidvegi T, Ewing M, Hale P et al. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science 2010; 329: 229-232
29 Wilson AA, Ying L, Liesa M et al. Emergence of a stage-dependent human liver disease signature with directed differentiation of alpha-1 antitrypsin-deficient iPS cells. Stem Cell Reports 2015; 4: 873-885
30 Burrows JA, Willis LK, Perlmutter DH. Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z: A potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency. Proc Natl Acad Sci USA 2000; 97: 1796-1801
31 Hayashi H, Sugiyama Y. 4-phenylbutyrate enhances the cell surface expression and the transport capacity of wild-type and mutated bile salt export pumps. Hepatology 2007; 45: 1506-1516
32 Saheki T, Inoue K, Tushima A et al. Citrin deficiency and current treatment concepts. Mol Genet Metab 2010; 100 (Suppl. 01) S59-S64
33 Kobayashi K, Bang LuY, Xian LiM et al. Screening of nine SLC25A13 mutations: their frequency in patients with citrin deficiency and high carrier rates in Asian populations. Mol Genet Metab 2003; 80: 356-359
34 Kobayashi K, Sinasac DS, Iijima M et al. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet 1999; 22: 159-163
35 Saheki T, Kobayashi K. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J Hum Genet 2002; 47: 333-341
36 Dimmock D, Maranda B, Dionisi-Vici C et al. Citrin deficiency, a perplexing global disorder. Mol Genet Metab 2009; 96: 44-49
37 Erez A, Shchelochkov OA, Plon SE et al. Insights into the pathogenesis and treatment of cancer from inborn errors of metabolism. Am J Hum Genet 2011; 88: 402-421
38 Strassburg CP. Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). Best Pract Res Clin Gastroenterol 2010; 24: 555-571
39 Strassburg CP, Manns MP. Jaundice, genes and promoters. J Hepatol 2000; 33: 476-479
40 Bosma PJ, Chowdhury JR, Bakker C et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med 1995; 333: 1171-1175
41 Strassburg CP. Gilbert-Meulengracht's syndrome and pharmacogenetics: is jaundice just the tip of the iceberg?. Drug Metab Rev 2010; 42: 162-175
42 Kartenbeck J, Leuschner U, Mayer R et al. Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson syndrome. Hepatology 1996; 23: 1061-1066
43 Dubin IN, Johnson FB. Chronic idiopathic jaundice with unidentified pigment in liver cells; a new clinicopathologic entity with a report of 12 cases. Medicine (Baltimore) 1954; 33: 155-197
44 Nies AT, Keppler D. The apical conjugate efflux pump ABCC2 (MRP2). Pflugers Arch 2007; 453: 643-659
45 Kamisako T, Leier I, Cui Y et al. Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2. Hepatology 1999; 30: 485-490
46 Donner MG, Keppler D. Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver. Hepatology 2001; 34: 351-359
47 Keppler D, Kartenbeck J. The canalicular conjugate export pump encoded by the cmrp/cmoat gene. Prog Liver Dis 1996; 14: 55-67
48 Keitel V, Nies AT, Brom M et al. A common Dubin-Johnson syndrome mutation impairs protein maturation and transport activity of MRP2 (ABCC2). Am J Physiol Gastrointest Liver Physiol 2002; 284: G165-G174
49 Mor-Cohen R, Zivelin A, Rosenberg N et al. Identification and functional analysis of two novel mutations in the multidrug resistance protein 2 gene in Israeli patients with Dubin-Johnson syndrome. J Biol Chem 2001; 276: 36923-36930
50 Suzuki H, Sugiyama Y. Single nucleotide polymorphisms in multidrug resistance associated protein 2 (MRP2 / ABCC2): its impact on drug disposition. Adv Drug Deliv Rev 2002; 54: 1311-1331
51 Hulot JS, Villard E, Maguy A et al. A mutation in the drug transporter gene ABCC2 associated with impaired methotrexate elimination. Pharmacogenet Genomics 2005; 15: 277-285
52 Izzedine H, Hulot JS, Villard E et al. Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy. J Infect Dis 2006; 194: 1481-1491
53 Kim WJ, Lee JH, Yi J et al. A nonsynonymous variation in MRP2 / ABCC2 is associated with neurological adverse drug reactions of carbamazepine in patients with epilepsy. Pharmacogenet Genomics 2010; 20: 249-256
54 Wojnowski L, Kulle B, Schirmer M et al. NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. Circulation 2005; 112: 3754-3762
55 Bhattacharyya AK, Connor WE. Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. J Clin Invest 1974; 53: 1033-1043
56 Berge KE, Tian H, Graf GA et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 2000; 290: 1771-1775
57 Lee MH, Lu K, Hazard S et al. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet 2001; 27: 79-83
58 Yu L, von Bergmann K, Lutjohann D et al. Selective sterol accumulation in ABCG5 / ABCG8-deficient mice. J Lipid Res 2004; 45: 301-307
59 Salen G, Shore V, Tint GS et al. Increased sitosterol absorption, decreased removal, and expanded body pools compensate for reduced cholesterol synthesis in sitosterolemia with xanthomatosis. J Lipid Res 1989; 30: 1319-1330
60 Lütjohann D, Bjorkhem I, Beil UF et al. Sterol absorption and sterol balance in phytosterolemia evaluated by deuterium-labeled sterols: effect of sitostanol treatment. J Lipid Res 1995; 36: 1763-1773
61 Solca C, Stanga Z, Pandit B et al. Sitosterolaemia in Switzerland: molecular genetics links the US Amish-Mennonites to their European roots. Clin Genet 2005; 68: 174-178
62 Miettinen TA, Klett EL, Gylling H et al. Liver transplantation in a patient with sitosterolemia and cirrhosis. Gastroenterology 2006; 130: 542-547
63 Horenstein RB, Mitchell BD, Post WS et al. The ABCG8 G574R variant, serum plant sterol levels, and cardiovascular disease risk in the Old Order Amish. Arterioscler Thromb Vasc Biol 2013; 33: 413-419
64 Klomp LW, Bull LN, Knisely AS et al. A missense mutation in FIC1 is associated with greenland familial cholestasis. Hepatology 2000; 32: 1337-1341
65 Chong JX, Ouwenga R, Anderson RL et al. A population-based study of autosomal-recessive disease-causing mutations in a founder population. Am J Hum Genet 2012; 91: 608-620
66 Maurice N, Perlmutter DH. Novel treatment strategies for liver disease due to alpha1-antitrypsin deficiency. Clin Transl Sci 2012; 5: 289-294
67 Bull LN, van Eijk MJ, Pawlikowska L et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet 1998; 18: 219-224
68 Klomp LW, Vargas JC, van Mil SW et al. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology 2004; 40: 27-38
69 van Mil SW, Van Der Woerd WL, Van Der Brugge G et al. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology 2004; 127: 379-384
70 Kubitz R, Häussinger D. Mutations of the bile salt export pump (BSEP) and multidrug-resistance protein 3 (MDR3). In: Häussinger D, Keitel V, Kubitz R, eds Hepatobliary transport in health and disease. Berlin: De Gruyter; 2012: 151-170
71 Pauli-Magnus C, Meier PJ, Stieger B. Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy. Semin Liver Dis 2010; 30: 147-159
72 Dixon PH, van Mil SW, Chambers J et al. Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. Gut 2009; 58: 537-544
73 Bull LN, Carlton VE, Stricker NL et al. Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): evidence for heterogeneity. Hepatology 1997; 26: 155-164
74 Rosmorduc O, Hermelin B, Poupon R. MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. Gastroenterology 2001; 120: 1459-1467
75 Van Mil SW, Milona A, Dixon PH et al. Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. Gastroenterology 2007; 133: 507-516
76 Admirand WH, Small DM. The physicochemical basis of cholesterol gallstone formation in man. J Clin Invest 1968; 47: 1043-1052
77 Strautnieks SS, Kagalwalla AF, Tanner MS et al. Identification of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24. Am J Hum Genet 1997; 61: 630-633
78 Smit JJ, Schinkel AH, Mol CA et al. Tissue distribution of the human MDR3 P-glycoprotein. Lab Invest 1994; 71: 638-649
79 van Helvoort A, Smith AJ, Sprong H et al. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell 1996; 87: 507-517
80 Paulusma CC, de Waart DR, Kunne C et al. Activity of the bile salt export pump (ABCB11) is critically dependent on canalicular membrane cholesterol content. J Biol Chem 2009; 284: 9947-9954
81 Groen A, Romero MR, Kunne C et al. Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity. Gastroenterology 2011; 141: 1927-1937
82 Paulusma CC, Groen A, Kunne C et al. Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport. Hepatology 2006; 44: 195-204
83 Jansen PL, Müller M, Sturm E. Genes and cholestasis. Hepatology 2001; 34: 1067-1074
84 Carlton VE, Pawlikowska L, Bull LN. Molecular basis of intrahepatic cholestasis. Ann Med 2004; 36: 606-617
85 Knisely AS. Progressive familial intrahepatic cholestasis: an update. Pediatr Dev Pathol 2004; 7: 309-314
86 Pauli-Magnus C, Stieger B, Meier Y et al. Enterohepatic transport of bile salts and genetics of cholestasis. J Hepatol 2005; 43: 342-357
87 Davit-Spraul A, Gonzales E, Baussan C et al. Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis 2009; 4: 1
88 Kubitz R, Dröge C, Stindt J et al. The bile salt export pump (BSEP) in health and disease. Clin Res Hepatol Gastroenterol 2012; 36: 536-553
89 De Vree JM, Jacquemin E, Sturm E et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci USA 1998; 95: 282-287
90 Dixon PH, Weerasekera N, Linton KJ et al. Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. Hum Mol Genet 2000; 9: 1209-1217
91 Müllenbach R, Linton KJ, Wiltshire S et al. ABCB4 gene sequence variation in women with intrahepatic cholestasis of pregnancy. J Med Genet 2003; 40: e70
92 Müllenbach R, Bennett A, Tetlow N et al. ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy. Gut 2005; 54: 829-834
93 Dixon PH, Wadsworth CA, Chambers J et al. A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy. Am J Gastroenterol 2014; 109: 76-84
94 Painter JN, Savander M, Ropponen A et al. Sequence variation in the ATP8B1 gene and intrahepatic cholestasis of pregnancy. Eur J Hum Genet 2005; 13: 435-439
95 Pauli-Magnus C, Lang T, Meier Y et al. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. Pharmacogenetics 2004; 14: 91-102
96 Davit-Spraul A, Gonzales E, Baussan C et al. The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects. Semin Liver Dis 2010; 30: 134-146
97 Bacq Y, Gendrot C, Perrotin F et al. ABCB4 gene mutations and single-nucleotide polymorphisms in women with intrahepatic cholestasis of pregnancy. J Med Genet 2009; 46: 711-715
98 Kubitz R, Keitel V, Scheuring S et al. Benign recurrent intrahepatic cholestasis associated with mutations of the bile salt export pump. J Clin Gastroenterol 2006; 40: 171-175
99 Takahashi A, Hasegawa M, Sumazaki R et al. Gradual improvement of liver function after administration of ursodeoxycholic acid in an infant with a novel ABCB11 gene mutation with phenotypic continuum between BRIC2 and PFIC2. Eur J Gastroenterol Hepatol 2007; 19: 942-946
100 Stindt J, Ellinger P, Weissenberger K et al. A novel mutation within a transmembrane helix of the bile salt export pump (BSEP, ABCB11) with delayed development of cirrhosis. Liver Int 2013; 33: 1527-1535
101 Strautnieks SS, Byrne JA, Pawlikowska L et al. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology 2008; 134: 1203-1214
102 Pauli-Magnus C, Kerb R, Fattinger K et al. BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology 2004; 39: 779-791
103 Lang T, Haberl M, Jung D et al. Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11). Drug Metab Dispos 2006; 34: 1582-1599
104 Lammert F, Marschall HU, Glantz A et al. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol 2000; 33: 1012-1021
105 Müllenbach R, Lammert F. Hepatobiliary transport during pregnancy: Crosstalk between transporters and hormones. In: Häussinger D, Keitel V, Kubitz R, eds, Hepatobiliary transport in health and disease. Berlin: De Gruyter; 2012: 183-194
106 Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol 2009; 15: 2049-2066
107 de Pagter AG, Berge Henegouwen GP, Bokkel Huinink JA et al. Familial benign recurrent intrahepatic cholestasis. Interrelation with intrahepatic cholestasis of pregnancy and from oral contraceptives?. Gastroenterology 1976; 71: 202-207
108 Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol 2014; 124: 120-133
109 O'Donohue J, Williams R. Hormone replacement therapy in women with liver disease. Br J Obstet Gynaecol 1997; 104: 1-3
110 Wasmuth HE, Glantz A, Keppeler H et al. Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene. Gut 2007; 56: 265-270
111 Keitel V, Vogt C, Häussinger D et al. Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy. Gastroenterology 2006; 131: 624-629
112 Jacquemin E, Cresteil D, Manouvrier S et al. Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy. Lancet 1999; 353: 210-211
113 Savander M, Ropponen A, Avela K et al. Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy. Gut 2003; 52: 1025-1029
114 Sookoian S, Castano G, Burgueno A et al. Association of the multidrug-resistance-associated protein gene (ABCC2) variants with intrahepatic cholestasis of pregnancy. J Hepatol 2008; 48: 125-132
115 Ananthanarayanan M, Balasubramanian N, Makishima M et al. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem 2001; 276: 28857-28865
116 Huang L, Zhao A, Lew JL et al. Farnesoid X receptor activates transcription of the phospholipid pump MDR3. J Biol Chem 2003; 278: 51085-51090
117 Lammert F, Sauerbruch T. Mechanisms of disease: the genetic epidemiology of gallbladder stones. Nat Clin Pract Gastroenterol Hepatol 2005; 2: 423-433
118 Wittenburg H. Hereditary liver disease: gallstones. Best Pract Res Clin Gastroenterol 2010; 24: 747-756
119 Krawczyk M, Stokes CS, Lammert F. Genetics and treatment of bile duct stones: new approaches. Curr Opin Gastroenterol 2013; 29: 329-335
120 Katsika D, Grjibovski A, Einarsson C et al. Genetic and environmental influences on symptomatic gallstone disease: a Swedish study of 43141 twin pairs. Hepatology 2005; 41: 1138-1143
121 Klass DM, Lauer N, Hay B et al. Arg64 variant of the beta3-adrenergic receptor is associated with gallstone formation. Am J Gastroenterol 2007; 102: 2482-2487
122 Nakeeb A, Comuzzie AG, Martin L et al. Gallstones: genetics versus environment. Ann Surg 2002; 235: 842-849
123 Zimmer V, Lammert F. Role of genetics in diagnosis and therapy of acquired liver disease. Mol Aspects Med 2014; 37: 15-34
124 Buch S, Schafmayer C, Volzke H et al. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat Genet 2007; 39: 995-999
125 Grunhage F, Acalovschi M, Tirziu S et al. Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol. Hepatology 2007; 46: 793-801
126 Ko CW, Beresford SA, Schulte SJ et al. Incidence, natural history, and risk factors for biliary sludge and stones during pregnancy. Hepatology 2005; 41: 359-365
127 Tsimoyiannis EC, Antoniou NC, Tsaboulas C et al. Cholelithiasis during pregnancy and lactation. Prospective study. Eur J Surg 1994; 160: 627-631
128 Acalovschi M, Tirziu S, Chiorean E et al. Common variants of ABCB4 and ABCB11 and plasma lipid levels: a study in sib pairs with gallstones, and controls. Lipids 2009; 44: 521-526
129 Wittenburg H. Hepatobiliary transport and gallstone formation. In: Häussinger D, Keitel V, Kubitz R, eds, Hepatobiliary transport in health and disease. Berlin: De Gruyter; 2012: 195-205
130 Hirobe-Jahn S, Harsch S, Renner O et al. Association of FXR gene variants with cholelithiasis. Clin Res Hepatol Gastroenterol 2015; 39: 68-79
131 Jiang ZY, Han TQ, Suo GJ et al. Polymorphisms at cholesterol 7alpha-hydroxylase, apolipoproteins B and E and low density lipoprotein receptor genes in patients with gallbladder stone disease. World J Gastroenterol 2004; 10: 1508-1512
132 Tönjes A, Wittenburg H, Halbritter J et al. Effects of SLC10A2 variant rs9514089 on gallstone risk and serum cholesterol levels- meta-analysis of three independent cohorts. BMC Med Genet 2011; 12: 149
133 Renner O, Harsch S, Schaeffeler E et al. A variant of the SLC10A2 gene encoding the apical sodium-dependent bile acid transporter is a risk factor for gallstone disease. PLoS One 2009; 4: e7321
134 Stieger B, Fattinger K, Madon J et al. Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology 2000; 118: 422-430
135 Roman ID, Fernandez-Moreno MD, Fueyo JA et al. Cyclosporin A Induced Internalization of the Bile Salt Export Pump in Isolated Rat Hepatocyte Couplets. Toxicol Sci 2003; 71: 276-281
136 Rosmorduc O, Poupon R. Low phospholipid associated cholelithiasis: association with mutation in the MDR3 / ABCB4 gene. Orphanet J Rare Dis 2007; 2: 29
137 Lancellotti S, Zaffanello M, Di Leo E et al. Pediatric gallstone disease in familial hypobetalipoproteinemia. J Hepatol 2005; 43: 188-191
138 Shen J, Arnett DK, Parnell LD et al. The effect of CYP7A1 polymorphisms on lipid responses to fenofibrate. J Cardiovasc Pharmacol 2012; 59: 254-259
139 Stender S, Frikke-Schmidt R, Nordestgaard BG et al. Extreme bilirubin levels as a causal risk factor for symptomatic gallstone disease. JAMA Intern Med 2013; 173: 1222-1228
140 Chitturi S, Farrell GC. Drug-induced liver disease. In: Schiff ER, Maddrey WC, Sorrell MF, eds Schiff's diseases of the liver. 11 ed. Chichester: John Wiley & Sons, Ltd; 2012: 703-783
141 Lee WM. Drug-induced hepatotoxicity. N Engl J Med 2003; 349: 474-485
142 Meier Y, Cavallaro M, Roos M et al. Incidence of drug-induced liver injury in medical inpatients. Eur J Clin Pharmacol 2005; 61: 135-143
143 Shapiro MA, Lewis JH. Causality assessment of drug-induced hepatotoxicity: promises and pitfalls. Clin Liver Dis 2007; 11: 477-505 , v
144 Lang C, Meier Y, Stieger B et al. Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury. Pharmacogenet Genomics 2007; 17: 47-60
145 Smith AJ, van Helvoort A, van Meer G et al. MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J Biol Chem 2000; 275: 23530-23539
146 Morgan RE, Trauner M, van Staden CJ et al. Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci 2010; 118: 485-500
147 Ogimura E, Sekine S, Horie T. Bile salt export pump inhibitors are associated with bile acid-dependent drug-induced toxicity in sandwich-cultured hepatocytes. Biochem Biophys Res Commun 2011; 416: 313-317
148 Daly AK, Aithal GP, Leathart JB et al. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 2007; 132: 272-281
149 Azuma J, Ohno M, Kubota R et al. NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: a randomized controlled trial for pharmacogenetics-based therapy. Eur J Clin Pharmacol 2013; 69: 1091-1101
150 Ho HT, Wang TH, Hsiong CH et al. The NAT2 tag SNP rs1495741 correlates with the susceptibility of antituberculosis drug-induced hepatotoxicity. Pharmacogenet Genomics 2013; 23: 200-207
151 Huang YS, Chern HD, Su WJ et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatology 2002; 35: 883-889
152 Zhou SF, Zhou ZW, Huang M. Polymorphisms of human cytochrome P450 2C9 and the functional relevance. Toxicology 2010; 278: 165-188
153 Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol 2010; 5: 145-171
154 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: 2005-2023
155 Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010; 51: 1820-1832
156 Byrne CD, Targher G. NAFLD: a multisystem disease. Journal of hepatology 2015; 62: S47-S64
157 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; [Epub ahead of print]
158 Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science 2011; 332: 1519-1523
159 Schwimmer JB, Celedon MA, Lavine JE et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology 2009; 136: 1585-1592
160 Romeo S, Kozlitina J, Xing C et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40: 1461-1465
161 Tian C, Stokowski RP, Kershenobich D et al. Variant in PNPLA3 is associated with alcoholic liver disease. Nat Genet 2010; 42: 21-23
162 Stickel F, Buch S, Lau K et al. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians. Hepatology 2011; 53: 86-95
163 Krawczyk M, Stokes CS, Romeo S et al. HCC and liver disease risks in homozygous PNPLA3p.I148M carriers approach monogenic inheritance. J Hepatol 2015; 62: 980-981
164 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: 75-81
165 Krawczyk M, Portincasa P, Lammert F. PNPLA3-associated steatohepatitis: toward a gene-based classification of fatty liver disease. Semin Liver Dis 2013; 33: 369-379
166 Sookoian S, Castano GO, Scian R et al. Genetic variation in transmembrane 6 superfamily member 2 and the risk of nonalcoholic fatty liver disease and histological disease severity. Hepatology 2015; 61: 515-525
167 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: 352-356
168 Pirola CJ, Sookoian S. The dual and opposite role of the TM6SF2-rs58542926 Variant in Protecting against Cardiovascular Disease and Conferring Risk for Non-alcoholic fatty liver: A meta-analysis. Hepatology 2015; [Epub ahead of print]
169 Zhou YJ, Zhang ZS, Nie YQ et al. Association of adiponectin gene variation with progression of non-alcoholic fatty liver disease: a 4 year follow-up survey. J Dig Dis 2015;
170 Petersen KF, Dufour S, Hariri A et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med 2010; 362: 1082-1089
171 Speliotes EK, Yerges-Armstrong LM, Wu J 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
172 EASL-EORTC. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908-943
173 Reynolds WF, Chang E, Douer D et al. An allelic association implicates myeloperoxidase in the etiology of acute promyelocytic leukemia. Blood 1997; 90: 2730-2737
174 Piedrafita FJ, Molander RB, Vansant G et al. An Alu element in the myeloperoxidase promoter contains a composite SP1-thyroid hormone-retinoic acid response element. J Biol Chem 1996; 271: 14412-14420
175 Nahon P, Sutton A, Rufat P et al. A variant in myeloperoxidase promoter hastens the emergence of hepatocellular carcinoma in patients with HCV-related cirrhosis. J Hepatol 2012; 56: 426-432
176 Nahon P, Sutton A, Rufat P et al. Myeloperoxidase and superoxide dismutase 2 polymorphisms comodulate the risk of hepatocellular carcinoma and death in alcoholic cirrhosis. Hepatology 2009; 50: 1484-1493
177 Kumar V, Kato N, Urabe Y et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet 2011; 43: 455-458
178 Lo PH, Urabe Y, Kumar V et al. Identification of a functional variant in the MICA promoter which regulates MICA expression and increases HCV-related hepatocellular carcinoma risk. PLoS One 2013; 8: e61279
179 Trepo E, Nahon P, Bontempi G et al. Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data. Hepatology 2014; 59: 2170-2177
180 Caldwell S. Cryptogenic cirrhosis: what are we missing?. Curr Gastroenterol Rep 2010; 12: 40-48
181 Krawczyk M, Grunhage F, Zimmer V et al. Variant adiponutrin (PNPLA3) represents a common fibrosis risk gene: non-invasive elastography-based study in chronic liver disease. J Hepatol 2011; 55: 299-306
182 Kubitz R, Bode J, Erhardt A et al. Cholestatic liver diseases from child to adult: the diversity of MDR3 disease. Z Gastroenterol 2011; 49: 728-736
183 Gotthardt D, Runz H, Keitel V et al. A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults. Hepatology 2008; 48: 1157-1166