A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease

English version

Autoři: Connor A. Emdin ^aff001; Mary E. Haas ^aff001; Amit V. Khera ^aff001; Krishna Aragam ^aff001; Mark Chaffin ^aff003; Derek Klarin ^aff003; George Hindy ^aff003; Lan Jiang ^aff004; Wei-Qi Wei ^aff004; Qiping Feng ^aff005; Juha Karjalainen ^aff003; Aki Havulinna ^aff006; Tuomo Kiiskinen ^aff006; Alexander Bick ^aff003; Diego Ardissino ^aff007; James G. Wilson ^aff009; Heribert Schunkert ^aff010; Ruth McPherson ^aff011; Hugh Watkins ^aff012; Roberto Elosua ^aff014; Matthew J. Bown ^aff017; Nilesh J. Samani ^aff017; Usman Baber ^aff018; Jeanette Erdmann ^aff019; Namrata Gupta ^aff003; John Danesh ^aff021; Danish Saleheen ^aff024; Kyong-Mi Chang ^aff026; Marijana Vujkovic ^aff026; Ben Voight ^aff026; Scott Damrauer ^aff026; Julie Lynch ^aff026; David Kaplan ^aff026; Marina Serper ^aff026; Philip Tsao ^aff027; ; Josep Mercader ^aff001; Craig Hanis ^aff028; Mark Daly ^aff006; Joshua Denny ^aff004; Stacey Gabriel ^aff003; Sekar Kathiresan ^aff002
Působiště autorů: Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America ^aff001; Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America ^aff002; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America ^aff003; Departments of Biomedical Informatics, Vanderbilt University, Vanderbilt, Tennessee, United States of America ^aff004; Departments of Medicine, Vanderbilt University, Vanderbilt, Tennessee, United States of America ^aff005; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI, Helsinki, Finland ^aff006; Division of Cardiology, Azienda Ospedaliero–Universitaria di Parma, Parma, Italy ^aff007; Associazione per lo Studio Della Trombosi in Cardiologia, Pavia, Italy ^aff008; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, United States of America ^aff009; Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany ^aff010; University of Ottawa Heart Institute, Ottawa, Ontario, Canada ^aff011; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom ^aff012; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom ^aff013; Cardiovascular Epidemiology and Genetics, Hospital del Mar Research Institute, Barcelona, Spain ^aff014; CIBER Enfermedades Cardiovasculares (CIBERCV), Barcelona, Spain ^aff015; Facultat de Medicina, Universitat de Vic-Central de Cataluña, Vic, Spain ^aff016; Department of Cardiovascular Sciences, University of Leicester, and NIHR Leicester Biomedical Research Centre, Leicester, United Kingdom ^aff017; The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America ^aff018; Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany ^aff019; DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany ^aff020; Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom ^aff021; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom ^aff022; National Institute of Health Research Blood and Transplant; Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom ^aff023; Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America ^aff024; Center for Non-Communicable Diseases, Karachi, Pakistan ^aff025; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America ^aff026; Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America ^aff027; Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America ^aff028; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America ^aff029; Verve Therapeutics, Boston, Massachusetts, United States of America ^aff030
Vyšlo v časopise: A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease. PLoS Genet 16(4): e32767. doi:10.1371/journal.pgen.1008629
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008629

Souhrn

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10⁻¹¹). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10⁻⁴³), alkaline phosphatase (-0.025 SD, 1.2*10⁻³⁷), total cholesterol (-0.030 SD, p = 1.9*10⁻³⁶) and LDL cholesterol (-0.027 SD, p = 5.1*10⁻³⁰) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.

Klíčová slova:

Alcoholics – Alleles – Cirrhosis – Consortia – Coronary heart disease – Fatty liver – Cholesterol – Liver diseases

Zdroje

1. Plenge RM, Scolnick EM, Altshuler D. Validating therapeutic targets through human genetics. Nat Rev Drug Discov. 2013;12 : 581–594. doi: 10.1038/nrd4051 23868113

2. King EA, Davis JW, Degner JF. Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval. Marchini J, editor. Genet PLoS. 2019;15: e1008489. doi: 10.1371/journal.pgen.1008489 31830040

3. Dewey FE, Gusarova V, Dunbar RL, O'Dushlaine C, Schurmann C, Gottesman O, et al. Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. N Engl J Med. Massachusetts Medical Society; 2017;377 : 211–221. doi: 10.1056/NEJMoa1612790 28538136

4. Gusarova V, O'Dushlaine C, Teslovich TM, Benotti PN, Mirshahi T, Gottesman O, et al. Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes. Nat Commun. Nature Publishing Group; 2018;9 : 2252–11. doi: 10.1038/s41467-018-04611-z 29899519

5. Khetarpal SA, Zeng X, Millar JS, Vitali C, Somasundara AVH, Zanoni P, et al. A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels. Nat Med. Nature Publishing Group; 2017;23 : 1086–1094. doi: 10.1038/nm.4390 28825717

6. Stitziel NO, Khera AV, Wang X, Bierhals AJ, Vourakis AC, Sperry AE, et al. ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. J Am Coll Cardiol. 2017;69 : 2054–2063. doi: 10.1016/j.jacc.2017.02.030 28385496

7. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu, European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. Journal of hepatology. 2018. pp. 406–460. doi: 10.1016/j.jhep.2018.03.024 29653741

8. Schuppan D, Afdhal NH. Liver cirrhosis. Lancet. 2008;371 : 838–851. doi: 10.1016/S0140-6736(08)60383-9 18328931

9. 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 : 1461–1465. doi: 10.1038/ng.257 18820647

10. Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjærg-Hansen A, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. Nature Publishing Group; 2014;46 : 352–356. doi: 10.1038/ng.2901 24531328

11. 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 : 1443–1448. doi: 10.1038/ng.3417 26482880

12. Speliotes EK, Butler JL, Palmer CD, Voight BF, GIANT consortium, MIGen Consortium, et al. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology. Wiley-Blackwell; 2010;52 : 904–912. doi: 10.1002/hep.23768 20648472

13. Liu Y-L, 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. Nature Publishing Group; 2014;5 : 4309. doi: 10.1038/ncomms5309 24978903

14. 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. Wiley-Blackwell; 2011;53 : 791–799. doi: 10.1002/hep.24123 21319195

15. 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. Nature Publishing Group; 2017;7 : 9273. doi: 10.1038/s41598-017-09548-9 28839198

16. 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 : 1096–1106. doi: 10.1056/NEJMoa1712191 29562163

17. About F, Abel L, Cobat A. HCV-Associated Liver Fibrosis and HSD17B13. N Engl J Med. Massachusetts Medical Society; 2018;379 : 1875–1876. doi: 10.1056/NEJMc1804638 30403944

18. Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology (Baltimore, Md.). Wiley-Blackwell; 2011. pp. 328–343. doi: 10.1002/hep.24330 21452290

19. Dürr R, Caselmann WH. Carcinogenesis of primary liver malignancies. Langenbecks Arch Surg. 2000;385 : 154–161. doi: 10.1007/s004230050259 10857485

20. 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. Nature Publishing Group; 2017;49 : 1758–1766. doi: 10.1038/ng.3977 29083408

21. Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease. N Engl J Med. Massachusetts Medical Society; 2016;374 : 1134–1144. doi: 10.1056/NEJMoa1507652 26934567

22. Havemeyer A, Bittner F, Wollers S, Mendel R, Kunze T, Clement B. Identification of the missing component in the mitochondrial benzamidoxime prodrug-converting system as a novel molybdenum enzyme. J Biol Chem. American Society for Biochemistry and Molecular Biology; 2006;281 : 34796–34802. doi: 10.1074/jbc.M607697200 16973608

23. Klein JM, Busch JD, Potting C, Baker MJ, Langer T, Schwarz G. The mitochondrial amidoxime-reducing component (mARC1) is a novel signal-anchored protein of the outer mitochondrial membrane. J Biol Chem. American Society for Biochemistry and Molecular Biology; 2012;287 : 42795–42803. doi: 10.1074/jbc.M112.419424 23086957

24. Kubitza C, Bittner F, Ginsel C, Havemeyer A, Clement B, Scheidig AJ. Crystal structure of human mARC1 reveals its exceptional position among eukaryotic molybdenum enzymes. Proc Natl Acad Sci USA. National Academy of Sciences; 2018;34 : 201808576. doi: 10.1073/pnas.1808576115 30397129

25. Gruenewald S, Wahl B, Bittner F, Hungeling H, Kanzow S, Kotthaus J, et al. The fourth molybdenum containing enzyme mARC: cloning and involvement in the activation of N-hydroxylated prodrugs. J Med Chem. American Chemical Society; 2008;51 : 8173–8177. doi: 10.1021/jm8010417 19053771

26. Sparacino-Watkins CE, Tejero J, Sun B, Gauthier MC, Thomas J, Ragireddy V, et al. Nitrite reductase and nitric-oxide synthase activity of the mitochondrial molybdopterin enzymes mARC1 and mARC2. J Biol Chem. American Society for Biochemistry and Molecular Biology; 2014;289 : 10345–10358. doi: 10.1074/jbc.M114.555177 24500710

27. Schneider J, Girreser U, Havemeyer A, Bittner F, Clement B. Detoxification of Trimethylamine N-Oxide by the Mitochondrial Amidoxime Reducing Component mARC. Chem Res Toxicol. American Chemical Society; 2018;31 : 447–453. doi: 10.1021/acs.chemrestox.7b00329 29856598

28. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Elsevier; 2012;380 : 2095–2128. doi: 10.1016/S0140-6736(12)61728-0

29. Roerecke M, Rehm J. Ischemic heart disease mortality and morbidity rates in former drinkers: a meta-analysis. American journal of epidemiology. 2011;173 : 245–258. doi: 10.1093/aje/kwq364 21156750

30. Qiu F, Tang R, Zuo X, Shi X, Wei Y, Zheng X, et al. A genome-wide association study identifies six novel risk loci for primary biliary cholangitis. Nat Commun. Nature Publishing Group; 2017;8 : 14828. doi: 10.1038/ncomms14828 28425483

31. Ji S-G, Juran BD, Mucha S, Folseraas T, Jostins L, Melum E, et al. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat Genet. Nature Publishing Group; 2017;49 : 269–273. doi: 10.1038/ng.3745 27992413

32. McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood AR, Teumer A, et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. Nature Publishing Group; 2016;48 : 1279–1283. doi: 10.1038/ng.3643 27548312

33. Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4 : 7. doi: 10.1186/s13742-015-0047-8 25722852

34. Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26 : 2190–2191. doi: 10.1093/bioinformatics/btq340 20616382

35. Denny JC, Ritchie MD, Basford MA, Pulley JM, Bastarache L, Brown-Gentry K, et al. PheWAS: demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations. Bioinformatics. 2010;26 : 1205–1210. doi: 10.1093/bioinformatics/btq126 20335276

36. Zhou W, Nielsen JB, Fritsche LG, Dey R, Gabrielsen ME, Wolford BN, et al. Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nat Genet. Nature Publishing Group; 2018;50 : 1335–1341. doi: 10.1038/s41588-018-0184-y 30104761

37. Speliotes EK, Massaro JM, Hoffmann U, Foster MC, Sahani DV, Hirschhorn JN, et al. Liver fat is reproducibly measured using computed tomography in the Framingham Heart Study. J Gastroenterol Hepatol. Wiley/Blackwell (10.1111); 2008;23 : 894–899. doi: 10.1111/j.1440-1746.2008.05420.x 18565021

38. Chambers JC, Zhang W, Sehmi J, Li X, Wass MN, van der Harst P, et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet. Nature Publishing Group; 2011;43 : 1131–1138. doi: 10.1038/ng.970 22001757

39. Kanai M, Akiyama M, Takahashi A, Matoba N, Momozawa Y, Ikeda M, et al. Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases. Nat Genet. Nature Publishing Group; 2018;50 : 390–400. doi: 10.1038/s41588-018-0047-6 29403010

40. Global Lipids Genetics Consortium, Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45 : 1274–1283. doi: 10.1038/ng.2797 24097068

41. Shungin D, Winkler TW, Croteau-Chonka DC, Ferreira T, Locke AE, Mägi R, et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature. Nature Publishing Group; 2015;518 : 187–196. doi: 10.1038/nature14132 25673412

42. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. Nature Publishing Group; 2015;518 : 197–206. doi: 10.1038/nature14177 25673413

43. Emdin C, Khera AV, Klarin D, Natarajan P, Zekavat SM, Nomura A, et al. Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling. Circulation. American Heart Association, Inc; 2018;137 : 222–232. doi: 10.1161/CIRCULATIONAHA.117.028021 28982690

44. Emdin C, Khera AV, Chaffin M, Klarin D, Natarajan P, Aragam K, et al. Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease. Nat Commun. Nature Publishing Group; 2018;9 : 1613. doi: 10.1038/s41467-018-03911-8 29691411

45. Do R, Stitziel NO, Won H-H, Jørgensen AB, Duga S, Angelica Merlini P, et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. Nature Publishing Group; 2015;518 : 102–106. doi: 10.1038/nature13917 25487149

46. Khera AV, Won H-H, Peloso GM, Lawson KS, Bartz TM, Deng X, et al. Diagnostic Yield of Sequencing Familial Hypercholesterolemia Genes in Patients with Severe Hypercholesterolemia. J Am Coll Cardiol. 2016. doi: 10.1016/j.jacc.2016.03.520 27050191

47. Need AC, Kasperaviciute D, Cirulli ET, Goldstein DB. A genome-wide genetic signature of Jewish ancestry perfectly separates individuals with and without full Jewish ancestry in a large random sample of European Americans. Genome Biol. BioMed Central; 2009;10: R7–7. doi: 10.1186/gb-2009-10-1-r7 19161619

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