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