Genetik der nicht-alkoholischen Fettlebererkrankung

M. Krawczyk; F. Lammert

doi:10.1055/s-0037-1618951

Adipositas - Ursachen, Folgeerkrankungen, Therapie, Table of Contents

Adipositas - Ursachen, Folgeerkrankungen, Therapie 2017; 11(01): 09-12
DOI: 10.1055/s-0037-1618951

Übersichtsarbeit

Schattauer GmbH

Genetik der nicht-alkoholischen Fettlebererkrankung

Genetics of fatty liver disease

Authors

M. Krawczyk

¹Klinik für Innere Medizin II, Universität des Saarlandes, Universitätsklinikum des Saarlandes, Homburg

²Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warschau, Polen
F. Lammert

¹Klinik für Innere Medizin II, Universität des Saarlandes, Universitätsklinikum des Saarlandes, Homburg

Abstract

Zusammenfassung

Die nicht-alkoholische Fettlebererkrankung (NAFLD) gehört aktuell zu den häufigsten Leberkrankheiten in der Welt. Die wichtigsten exogenen Determinanten der NAFLD sind Übergewicht, Diabetes und metabolisches Syndrom. In den letzten Jahren konnte nachgewiesen werden, dass die Träger bestimmter Genvarianten nicht nur häufiger NAFLD entwickeln, sondern auch ein erhöhtes Risiko für eine fortschreitende Leberschädigung aufweisen. In Analysen sehr großer Patientenkohorten mit NAFLD konnten drei Polymorphismen, PNPLA3 p.I148M, TM6SF2 p.E167K und MBOAT7 rs641738, als sichere Risikofaktoren für die Entstehung einer Fettleber identifiziert werden. Diese Varianten sind auch mit Komplikationen der NAFLD, wie zum Beispiel Leberzirrhose und Leberkrebs, assoziiert. In dieser Übersicht werden ausgewählte Studien zu diesen Genpolymorphismen vorgestellt. Wir diskutieren ihre möglichen pathophysiologischen Mechanismen und stellen das Konzept einer genbasierten Leberkrankheit, PASH (PNPLA3-assoziierte Steatohepatitis), vor.

Summary

Non-alcoholic fatty liver disease (NAFLD) belongs to the most frequent liver disorders in the world. The exogenous risk factors for NAFLD (overweight, diabetes and metabolic syndrome) have been known for a long time. Recently it became apparent that individuals carrying specific gene variants might not only develop NAFLD more frequently but are also prone to progressive liver injury. Genomewide analyses of large cohorts of patients with NAFLD led to the identification of three prosteatotic (and profibrogenic) polymorphisms, i.e. PNPLA3 p.I148M, TM6SF2 p.E167K, and MBOAT7 rs641738. The presence of these variants also increases the risk of NAFLD complications such as liver cirrhosis and hepatocellular carcinoma. In this review, we present selected studies of each of these variants and briefly discuss their distinct functional mechanisms. Finally, we introduce the concept of PASH (PNPLA3-associated steatohepatitis) as novel genebased liver disease.

Schlüsselwörter

Adiponutrin - Fettleber - MBOAT7 - PNPLA3 - TM6SF2

Keywords

Adiponutrin - NAFLD - MBOAT7 - PNPLA3 - TM6SF2

Full Text

References

Literatur
1 Anstee QM, Seth D, Day CP. Genetic Factors That Affect Risk of Alcoholic and Nonalcoholic Fatty Liver Disease. Gastroenterology 2016; 150 (08) 1728-1744 e7.
2 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. Nat Genet 2015; 47 (12) 1443-1448.
3 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.
4 Cai T, Dufour JF, Muellhaupt B. et al/ Swiss Hepatitis C Cohort Study Group. Viral genotype-specific role of PNPLA3, PPARG, MTTP, and IL28B in hepatitis C virus-associated steatosis. J Hepatol 2011; 55 (03) 529-535.
5 Casper M, Krawczyk M, Behrmann I, Glanemann M, Lammert F. Variant PNPLA3 increases the HCC risk: prospective study in patients treated at the Saarland University Medical Center. Z Gastroenterol 2016; 54 (06) 585-586.
6 Giudice EM, Grandone A, Cirillo G, Santoro N, Amato A, Brienza C, Savarese P, Marzuillo P, Perrone L. The association of PNPLA3 variants with liver enzymes in childhood obesity is driven by the interaction with abdominal fat. PLoS One 2011; 06 (11) e27933.
7 Krawczyk M, Grünhage F, Zimmer V, Lammert F. Variant adiponutrin (PNPLA3) represents a common fibrosis risk gene: non-invasive elastographybased study in chronic liver disease. J Hepatol 2011; 55 (02) 299-306.
8 Krawczyk M, Portincasa P, Lammert F. PNPLA3-associated steatohepatitis: toward a gene-based classification of fatty liver disease. Semin Liver Dis 2013; 33 (04) 369-379.
9 Krawczyk M, Rau M, Schattenberg JM, Bantel H, Pathil A, Demir M, Kluwe J, Boettler T, Lammert F, Geier A. NAFLD Clinical Study Group. 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 (01) 247-255.
10 Liu YL, Patman GL, Leathart JB, Piguet AC, Burt AD, Dufour JF, Day CP, Daly AK, Reeves HL, Anstee QM. 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 (01) 75-81.
11 Loomba R, Schork N, Chen CH, Bettencourt R, Bhatt A, Ang B, Nguyen P, Hernandez C, Richards L, Salotti J, Lin S, Seki E, Nelson KE, Sirlin CB, Brenner D. Genetics of NAFLD in Twins Consortium. Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study. Gastroenterology 2015; 149 (07) 1784-1793.
12 Mancina RM, Dongiovanni P, Petta S. et al. The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent. Gastroenterology 2016; 150 (05) 1219-1230 e6.
13 Pingitore P, Pirazzi C, Mancina RM, Motta BM, Indiveri C, Pujia A, Montalcini T, Hedfalk K, Romeo S. Recombinant PNPLA3 protein shows triglyceride hydrolase activity and its I148M mutation results in loss of function. Biochim Biophys Acta 2014; 1841 (04) 574-580.
14 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 (06) 1742-1756.
15 Romeo S, Kozlitina J, Xing C, ertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40 (12) 1461-1465.
16 Salameh H, Hanayneh MA, Masadeh M, Naseemuddin M, Matin T, Erwin A, Singal AK. PNPLA3 as a Genetic Determinant of Risk for and Severity of Non-alcoholic Fatty Liver Disease Spectrum. J Clin Transl Hepatol 2016; 04 (03) 175-191.
17 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 (06) 846-856.
18 Smagris E, BasuRay S, Li J, Huang Y, Lai KM, Gromada J, Cohen JC, Hobbs HH. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 2015; 61 (01) 108-118.
19 Tai CM, Huang CK, Tu HP, Hwang JC, Chang CY, Yu ML. PNPLA3 genotype increases susceptibility of nonalcoholic steatohepatitis among obese patients with nonalcoholic fatty liver disease. Surg Obes Relat Dis 2015; 11 (04) 888-894.
20 Tian C, Stokowski RP, Kershenobich D, Ballinger DG, Hinds DA. Variant in PNPLA3 is associated with alcoholic liver disease. Nat Genet 2010; 42 (01) 21-23.
21 Trépo E, Gustot T, Degré D. et al. Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease. J Hepatol 2011; 55 (04) 906-912.
22 Trépo E, Guyot E, Ganne-Carrie N, Degre D, Gustot T, Franchimont D, Sutton A, Nahon P, Moreno C. PNPLA3 (rs738409 C>G) is a common risk variant associated with hepatocellular carcinoma in alcoholic cirrhosis. Hepatology 2012; 55 (04) 1307-1308.
23 Valenti L, Alisi A, Galmozzi E, Bartuli A, Del Menico B, Alterio A, Dongiovanni P, Fargion S, Nobili V. I148M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease. Hepatology 2010; 52 (04) 1274-1280.
24 Valenti L, Rumi M, Galmozzi E, Aghemo A, Del Menico B, De Nicola S, Dongiovanni P, Maggioni M, Fracanzani AL, Rametta R, Colombo M, Fargion S. Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. Hepatology 2011; 53 (03) 791-799.
25 Viganò M, Valenti L, Lampertico P. et al. Patatinlike phospholipase domain-containing 3 I148M affects liver steatosis in patients with chronic hepatitis B. Hepatology 2013; 58 (04) 1245-1252.
26 Viitasalo A, Pihlajamaki J, Lindi V, Atalay M, Kaminska D, Joro R, Lakka TA. Associations of I148M variant in PNPLA3 gene with plasma ALT levels during 2-year follow-up in normal weight and overweight children: the PANIC Study. Pediatr Obes 2015; 10 (02) 84-90.
27 Weber S, Grünhage F, Hall R, Lammert F. Genomweite Assoziationsstudien in der Hepatologie. Z Gastroenterol 2010; 48 (01) 56-64.
28 Weiss J, Rau M, Bantel H, Bock H, Demir M, Kluwe J, Krawczyk M, Pathil-Warth A, Schattenberg JM, Tacke F, Roeb E, Geier A. Klinische Studiengruppe NAFLD (NAFLD CSG). Erste Daten zur Versorgungssituation von Patienten mit nicht alkoholischer Fettlebererkrankung (NAFLD) in Deutschland – Eine Umfrage an universitären hepatologischen Zentren. Z Gastroenterol 2015; 53 (06) 562-567.