A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis

Nature Genetics

Volumn 47, Issue 12, 2015, Pages 1443-1448

  Buch, Stephan ^a   Stickel, Felix ^b   Trépo, Eric ^c,d   Way, Michael ^e   Herrmann, Alexander ^a   Nischalke, Hans Dieter ^f   Brosch, Mario ^a   Rosendahl, Jonas ^g   Berg, Thomas ^g   Ridinger, Monika ^h,i   Rietschel, Marcella ^j   McQuillin, Andrew ^e   Frank, Josef ^j   Kiefer, Falk ^j   Schreiber, Stefan ^k   Lieb, Wolfgang ^l   Soyka, Michael ^m   Semmo, Nasser ⁿ   Aigner, Elmar ^o   Datz, Christian ^o   Schmelz, Renate ^a   Brückner, Stefan ^a   Zeissig, Sebastian ^a   Stephan, Anna Magdalena ^a   Wodarz, Norbert ^h   Devière, Jacques ^c,d   Clumeck, Nicolas ^d   Sarrazin, Christoph ^p   Lammert, Frank ^q   Gustot, Thierry ^c,d   Deltenre, Pierre ^c,r,s   Völzke, Henry ^t   Lerch, Markus M ^t   Mayerle, Julia ^t   Eyer, Florian ^u   Schafmayer, Clemens ^k   Cichon, Sven ^v   Nöthen, Markus M ^f   Nothnagel, Michael ^w   Ellinghaus, David ^l   Huse, Klaus ^x   Franke, Andre ^l   Zopf, Steffen ^y   Hellerbrand, Claus ^z   Moreno, Christophe ^c,d   Franchimont, Denis ^c,d   Morgan, Marsha Y ^e   Hampe, Jochen ^a   more..

^a UNIVERSITY HOSPITAL CARL GUSTAV CARUS   (Germany)

^b UNIVERSITY HOSPITAL ZURICH   (Switzerland)

^c ERASME HOSPITAL   (Belgium)

^d UNIVERSITÉ LIBRE DE BRUXELLES   (Belgium)

^e UNIVERSITY COLLEGE LONDON   (United Kingdom)

^f UNIVERSITY OF BONN   (Germany)

^g UNIVERSITY HOSPITAL LEIPZIG   (Germany)

^h UNIVERSITY OF REGENSBURG   (Germany)

ⁱ Psychiatrische Dienste Aargau   (Switzerland)

^j UNIVERSITY OF HEIDELBERG   (Germany)

^k UNIVERSITY HOSPITAL SCHLESWIG HOLSTEIN   (Germany)

^l UNIVERSITY OF KIEL   (Germany)

^m UNIVERSITY OF MUNICH   (Germany)

ⁿ UNIVERSITY OF BERN   (Switzerland)

^o UNIVERSITY OF SALZBURG   (Austria)

^p UNIVERSITY HOSPITAL FRANKFURT   (Germany)

^q SAARLAND UNIVERSITY   (Germany)

^r Hospital de Jolimont   (Belgium)

^s LAUSANNE UNIVERSITY HOSPITAL   (Switzerland)

^t UNIVERSITY MEDICINE GREIFSWALD   (Germany)

^u TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^v UNIVERSITY HOSPITAL BASEL   (Switzerland)

^w UNIVERSITY OF COLOGNE   (Germany)

^x FRITZ LIPMANN INSTITUTE   (Germany)

^y UNIVERSITY HOSPITAL ERLANGEN   (Germany)

^z UNIVERSITY HOSPITAL REGENSBURG   (Germany)

more..

Author keywords

[No Author keywords available]

Indexed keywords

LIPID; ACYLTRANSFERASE; ADIPONUTRIN, HUMAN; GHRELIN O-ACYLTRANSFERASE, HUMAN; MEMBRANE PROTEIN; TM6SF2 PROTEIN, HUMAN; TRIACYLGLYCEROL LIPASE;

ADULT; AGE; ALCOHOL LIVER CIRRHOSIS; ALLELE; ARTICLE; BELGIUM; BODY MASS; CONTROLLED STUDY; FEMALE; GENDER; GENE; GENE LOCUS; GENETIC ASSOCIATION; GENETIC IDENTIFICATION; GENETIC RISK; GENOTYPE; GERMANY; HUMAN; LIPID METABOLISM; LIPOGENESIS; MAJOR CLINICAL STUDY; MALE; MARKER GENE; MBOAT7 GENE; NON INSULIN DEPENDENT DIABETES MELLITUS; PNPLA3 GENE; POPULATION RESEARCH; PRIORITY JOURNAL; TM6SF2 GENE; UNITED KINGDOM; AGED; CASE CONTROL STUDY; COMPARATIVE STUDY; GENETIC PREDISPOSITION; GENETICS; GENOME-WIDE ASSOCIATION STUDY; MIDDLE AGED; RISK FACTOR; SINGLE NUCLEOTIDE POLYMORPHISM;

ACYLTRANSFERASES; ADULT; AGED; CASE-CONTROL STUDIES; FEMALE; GENETIC PREDISPOSITION TO DISEASE; GENOME-WIDE ASSOCIATION STUDY; HUMANS; LIPASE; LIVER CIRRHOSIS, ALCOHOLIC; MALE; MEMBRANE PROTEINS; MIDDLE AGED; POLYMORPHISM, SINGLE NUCLEOTIDE; RISK FACTORS;

EID: 84949089603     PISSN: 10614036     EISSN: 15461718     Source Type: Journal    
DOI: 10.1038/ng.3417     Document Type: Article

References (50)

1. Kim, W.R., Brown, R.S., Terrault, N.A. & El-Serag, H. Burden of liver disease in the United States: summary of a workshop. Hepatology 36, 227-242 (2002).
2. Rehm, J., Samokhvalov, A.V. & Shield, K.D. Global burden of alcoholic liver diseases. J. Hepatol. 59, 160-168 (2013).
3. Burra, P. et al. Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR (European Liver Transplant Registry). Am. J. Transplant. 10, 138-148 (2010).
4. Teli, M.R., Day, C.P., Burt, A.D., Bennett, M.K. & James, O.F. Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver. Lancet 346, 987-990 (1995).
5. Hrubec, Z. & Omenn, G.S. Evidence of genetic predisposition to alcoholic cirrhosis and psychosis: twin concordances for alcoholism and its biological end points by zygosity among male veterans. Alcohol. Clin. Exp. Res. 5, 207-215 (1981).
6. Reed, T., Page, W.F., Viken, R.J. & Christian, J.C. Genetic predisposition to organ-specific endpoints of alcoholism. Alcohol. Clin. Exp. Res. 20, 1528-1533 (1996).
7. Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461-1465 (2008).
8. Tian, C., Stokowski, R.P., Kershenobich, D., Ballinger, D.G. & Hinds, D.A. Variant in PNPLA3 is associated with alcoholic liver disease. Nat. Genet. 42, 21-23 (2010).
9. Stickel, F. et al. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in Caucasians. Hepatology 53, 86-95 (2011).
10. Pirazzi, C. et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum. Mol. Genet. 23, 4077-4085 (2014).
11. Smagris, E. et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 61, 108-118 (2015).
12. Treutlein, J. et al. A genome-wide association study of alcohol dependence. Arch. Gen. Psychiatry 66, 773-784 (2009).
13. Howie, B.N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).
14. Innocenti, F. et al. Identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue. PLoS Genet. 7, e1002078 (2011).
15. Chamorro, A.-J. et al. Systematic review with meta-analysis: the I148M variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is significantly associated with alcoholic liver cirrhosis. Aliment. Pharmacol. Ther. 40, 571-581 (2014).
16. Salameh, H. et al. PNPLA3 gene polymorphism is associated with predisposition to and severity of alcoholic liver disease. Am. J. Gastroenterol. 110, 846-856 (2015).
17. Kozlitina, J. et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 46, 352-356 (2014).
18. Patin, E. et al. Genome-wide association study identifies variants associated with progression of liver fibrosis from HCV infection. Gastroenterology 143, 1244-1252 (2012).
19. Buch, S. et al. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat. Genet. 39, 995-999 (2007).
20. Mells, G.F. et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat. Genet. 43, 329-332 (2011).
21. Melum, E. et al. Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci. Nat. Genet. 43, 17-19 (2011).
22. Daly, A.K. et al. HLA-B∗5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat. Genet. 41, 816-819 (2009).
23. Bierut, L.J. et al. A genome-wide association study of alcohol dependence. Proc. Natl. Acad. Sci. USA 107, 5082-5087 (2010).
24. Han, S. et al. Integrating GWASs and human protein interaction networks identifies a gene subnetwork underlying alcohol dependence. Am. J. Hum. Genet. 93, 1027-1034 (2013).
25. Treutlein, J. et al. Genome-wide association study of alcohol dependence. Arch. Gen. Psychiatry 66, 773-784 (2009).
26. Edenberg, H.J. & Foroud, T. Genetics and alcoholism. Nat. Rev. Gastroenterol. Hepatol. 10, 487-494 (2013).
27. Zintzaras, E., Stefanidis, I., Santos, M. & Vidal, F. Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease? Hepatology 43, 352-361 (2006).
28. He, S. et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J. Biol. Chem. 285, 6706-6715 (2010).
29. Gijón, M.A., Riekhof, W.R., Zarini, S., Murphy, R.C. & Voelker, D.R. Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils. J. Biol. Chem. 283, 30235-30245 (2008).
30. Yamashita, A. et al. Reverse reaction of lysophosphatidylinositol acyltransferase. Functional reconstitution of coenzyme A-dependent transacylation system. J. Biol. Chem. 278, 30382-30393 (2003).
31. Moreno-Navarrete, J.M. et al. The l-α-lysophosphatidylinositol/GPR55 system and its potential role in human obesity. Diabetes 61, 281-291 (2012).
32. Tam, J. et al. Endocannabinoids in liver disease. Hepatology 53, 346-355 (2011).
33. Patsenker, E. et al. Cannabinoid receptor type I modulates alcohol-induced liver fibrosis. Mol. Med. 17, 1285-1294 (2011).
34. Liu, Y.-L. et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat. Commun. 5, 4309 (2014).
35. Dongiovanni, P. et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61, 506-514 (2015).
36. Speliotes, E.K. et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 7, e1001324 (2011).
37. Nischalke, H.D. et al. A common polymorphism in the NCAN gene is associated with hepatocellular carcinoma in alcoholic liver disease. J. Hepatol. 61, 1073-1079 (2014).
38. Di Martino, V., Sheppard, F. & Vanlemmens, C. Early liver transplantation for severe alcoholic hepatitis. N. Engl. J. Med. 366, 478-479 (2012).
39. Vanlemmens, C. et al. Immediate listing for liver transplantation versus standard care for Child-Pugh stage B alcoholic cirrhosis: a randomized trial. Ann. Intern. Med. 150, 153-161 (2009).
40. Pruim, R.J. et al. Locus Zoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336-2337 (2010).
41. Higgins, J.P.T. & Thompson, S.G. Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539-1558 (2002).
42. Way, M. et al. Genetic variants in or near ADH1B and ADH1C affect susceptibility to alcohol dependence in a British and Irish population. Addict Biol. 20, 594-604 (2015).
43. Trépo, E. et al. Marked 25-hydroxyvitamin D deficiency is associated with poor prognosis in patients with alcoholic liver disease. J. Hepatol. 59, 344-350 (2013).
44. Ishak, K.G., Zimmerman, H.J. & Ray, M.B. Alcoholic liver disease: pathologic, pathogenetic and clinical aspects. Alcohol. Clin. Exp. Res. 15, 45-66 (1991).
45. Nguyen-Khac, E. et al. Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with seven non-invasive laboratory tests. Aliment. Pharmacol. Ther. 28, 1188-1198 (2008).
46. Browning, B.L. & Yu, Z. Simultaneous genotype calling and haplotype phasing improves genotype accuracy and reduces false-positive associations for genome-wide association studies. Am. J. Hum. Genet. 85, 847-861 (2009).
47. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904-909 (2006).
48. Roshyara, N.R. & Scholz, M. fcGENE: a versatile tool for processing and transforming SNP datasets. PLoS ONE 9, e97589 (2014).
49. Sinnott, J.A. & Kraft, P. Artifact due to differential error when cases and controls are imputed from different platforms. Hum. Genet. 131, 111-119 (2012).
50. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661-678 (2007).