| 4. | Nature. 2015 Feb 5;518(7537):102-6. doi: 10.1038/nature13917. Epub 2014 Dec 10.Do R1, Stitziel NO2, Won HH1, Jørgensen AB3, Duga S4, Angelica Merlini P5, Kiezun A6, Farrall M7, Goel A7, Zuk O6, Guella I4, Asselta R4, Lange LA8, Peloso GM1, Auer PL9; NHLBI Exome Sequencing Project, Girelli D10, Martinelli N10, Farlow DN6, DePristo MA6, Roberts R11, Stewart AF11, Saleheen D12, Danesh J12, Epstein SE13, Sivapalaratnam S14, Hovingh GK14, Kastelein JJ14, Samani NJ15, Schunkert H16, Erdmann J17, Shah SH18, Kraus WE19, Davies R20, Nikpay M20, Johansen CT21, Wang J21, Hegele RA22, Hechter E6, Marz W23, Kleber ME24, Huang J25, Johnson AD26, Li M27, Burke GL28, Gross M29, Liu Y30, Assimes TL31, Heiss G32, Lange EM33, Folsom AR34, Taylor HA35, Olivieri O10, Hamsten A36, Clarke R37, Reilly DF38, Yin W38, Rivas MA39, Donnelly P40, Rossouw JE41, Psaty BM42, Herrington DM43, Wilson JG44, Rich SS45, Bamshad MJ46, Tracy RP47, Cupples LA48, Rader DJ49, Reilly MP50, Spertus JA51, Cresci S52, Hartiala J53, Tang WH54, Hazen SL54, Allayee H53, Reiner AP55, Carlson CS9, Kooperberg C9, Jackson RD56, Boerwinkle E57, Lander ES6, Schwartz SM55, Siscovick DS58, McPherson R20, Tybjaerg-Hansen A59, Abecasis GR60, Watkins H61, Nickerson DA 62, Ardissino D63, Sunyaev SR64, O'Donnell CJ25, Altshuler D65, Gabriel S6, Kathiresan S1 . Collaborators: (396) Gabriel SB, Altshuler DM, Abecasis GR, Allayee H, Cresci S, Daly MJ, de Bakker PI, DePristo MA, Do R, Donnelly P, Farlow DN, Fennell T, Garimella K, Hazen SL, Hu Y, Jordan DM, Jun G, Kathiresan S, Kang HM, Kiezun A, Lettre G, Li B, Li M, Newton-Cheh CH, Padmanabhan S, Peloso G, Pulit S, Rader DJ, Reich D, Reilly MP, Rivas MA, Schwartz S, Scott L, Siscovick DS, Spertus JA, Stitziel NO, Stoletzki N, Sunyaev SR, Voight BF, Willer CJ, Rich SS, Akylbekova E, Atwood LD, Ballantyne CM, Barbalic M, Barr RG, Benjamin EJ, Bis J, Boerwinkle E, Bowden DW, Brody J, Budoff M, Burke G, Buxbaum S, Carr J, Chen DT, Chen IY, Chen WM, Concannon P, Crosby J, Cupples L, D'Agostino R, DeStefano AL, Dreisbach A, Dupuis J, Durda J, Ellis J, Folsom AR, Fornage M, Fox CS, Fox E, Funari V, Ganesh SK, Gardin J, Goff D, Gordon O, Grody W, Gross M, Guo X, Hall IM, Heard-Costa NL, Heckbert SR, Heintz N, Herrington DM, Hickson D, Huang J, Hwang SJ, Jacobs DR, Jenny NS, Johnson AD, Johnson CW, Kawut S, Kronmal R, Kurz R, Lange EM, Lange LA, Larson MG, Lawson M, Lewis CE, Levy D, Li D, Lin H, Liu C, Liu J, Liu K, Liu X, Liu Y, Longstreth WT, Loria C, Lumley T, Lunetta K, Mackey AJ, Mackey R, Manichaikul A, Maxwell T, McKnight B, Meigs JB, Morrison AC, Musani SK, Mychaleckyj JC, Nettleton JA, North K, O'Donnell CJ, O'Leary D, Ong FS, Palmas W, Pankow JS, Pankratz ND, Paul S, Perez M, Person SD, Polak J, Post WS, Psaty BM, Quinlan AR, Raffel LJ, Ramachandran VS, Reiner AP, Rice K, Rotter JI, Sanders JP, Schreiner P, Seshadri S, Shea S, Sidney S, Silverstein K, Siscovick DS, Smith NL, Sotoodehnia N, Srinivasan A, Taylor HA, Taylor K, Thomas F, Tracy RP, Tsai MY, Volcik KA, Wassel CL, Watson K, Wei G, White W, Wiggins KL, Wilk JB, Williams O, Wilson G, Wilson JG, Wolf P, Zakai NA, Hardy J, Meschia JF, Nalls M, Rich SS, Singleton A, Worrall B, Bamshad MJ, Barnes KC, Abdulhamid I, Accurso F, Anbar R, Beaty T, Bigham A, Black P, Bleecker E, Buckingham K, Cairns AM, Chen WM, Caplan D, Chatfield B, Chidekel A, Cho M, Christiani DC, Crapo J, Crouch J, Daley D, Dang A, Dang H, De Paula A, DeCelie-Germana J, Dozor A, Drumm M, Dyson M, Emerson J, Emond MJ, Ferkol T, Fink R, Foster C, Froh D, Gao L, Gershan W, Gibson RL, Godwin E, Gondor M, Gutierrez H, Hansel NN, Hassoun PM, Hiatt P, Hokanson JE, Howenstine M, Hummer LK, Jamal SM, Kanga J, Kim Y, Knowles MR, Konstan M, Lahiri T, Laird N, Lange C, Lin L, Lin X, Louie TL, Lynch D, Make B, Martin TR, Mathai SC, Mathias RA, McNamara J, McNamara S, Meyers D, Millard S, Mogayzel P, Moss R, Murray T, Nielson D, Noyes B, O'Neal W, Orenstein D, O'Sullivan B, Pace R, Pare P, Parker H, Passero MA, Perkett E, Prestridge A, Rafaels NM, Ramsey B, Regan E, Ren C, Retsch-Bogart G, Rock M, Rosen A, Rosenfeld M, Ruczinski I, Sanford A, Schaeffer D, Sell C, Sheehan D, Silverman EK, Sin D, Spencer T, Stonebraker J, Tabor HK, Varlotta L, Vergara CI, Weiss R, Wigley F, Wise RA, Wright FA, Wurfel MM, Zanni R, Zou F, Nickerson DA, Rieder MJ, Green P, Shendure J, Akey JM, Bamshad MJ, Bustamante CD, Crosslin DR, Eichler EE, Fox P, Fu W, Gordon A, Gravel S, Jarvik GP, Johnsen JM, Kan M, Kenny EE, Kidd JM, Lara-Garduno F, Leal SM, Liu DJ, McGee S, O'Connor TD, Paeper B, Robertson PD, Smith JD, Staples JC, Tennessen JA, Turner EH, Wang G, Yi Q, Jackson R, North K, Peters U, Carlson CS, Anderson G, Anton-Culver H, Assimes TL, Auer PL, Beresford S, Bizon C, Black H, Brunner R, Brzyski R, Burwen D, Caan B, Carty CL, Chlebowski R, Cummings S, Curb JD, Eaton CB, Ford L, Franceschini N, Fullerton SM, Gass M, Geller N, Heiss G, Howard BV, Hsu L, Hutter CM, Ioannidis J, Jiao S, Johnson KC, Kooperberg C, Kuller L, LaCroix A, Lakshminarayan K, Lane D, Lange EM, Lange LA, Lasser N, LeBlanc E, Lewis CE, Li KP, Limacher M, Lin DY, Logsdon BA, Hutchinson F, Ludlam S, Manson JE, Margolis K, Martin L, McGowan J, Monda KL, Kotchen JM, Nathan L, Ockene J, O'Sullivan MJ, Phillips LS, Prentice RL, Reiner AP, Robbins J, Robinson JG, Rossouw JE, Sangi-Haghpeykar H, Sarto GE, Shumaker S, Simon MS, Stefanick ML, Stein E, Tang H, Taylor KC, Thomson CA, Thornton TA, Van Horn L, Vitolins M, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S, Zeng D, Applebaum-Bowden D, Feolo M, Gan W, Paltoo DN, Rossouw JE, Sholinsky P, Sturcke A.Author information: 11] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. [2] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. [3] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA. [4] Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.21] Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA. [2] Division of Statistical Genomics, Washington University School of Medicine, St Louis, Missouri 63110, USA.3Department of Clinical Biochemistry KB3011, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen 1165, Denmark.4Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano 20122, Italy.5Division of Cardiology, Ospedale Niguarda, Milano 20162, Italy.6Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.7Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2J, UK.8 Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.9Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.10University of Verona School of Medicine, Department of Medicine, Verona 37129, Italy.11John &Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.12Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 1TN, UK.13MedStar Health Research Institute, Cardiovascular Research Institute, Hyattsville, Maryland 20782, USA.14Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.15Department of Cardiovascular Sciences, University of Leicester, and Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE3 9QP, UK.16DZHK (German Research Centre for Cardiovascular Research), Munich Heart Alliance, Deutsches Herzzentrum München, Technische Universität München, Berlin 13347, Germany.17Medizinische Klinik II, University of Lübeck, Lübeck 23562, Germany.181] Center for Human Genetics, Duke University, Durham, North Carolina 27708, USA. [2] Department of Cardiology and Center for Genomic Medicine, Duke University School of Medicine, Durham, North Carolina 27708, USA.19Department of Cardiology and Center for Genomic Medicine, Duke University School of Medicine, Durham, North Carolina 27708, USA.20Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.21Department of Biochemistry, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, Ontario N6A 3K7, Canada.221] Department of Biochemistry, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, Ontario N6A 3K7, Canada. [2] Department of Medicine, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, Ontario N6A 3K7, Canada.231] Medical Faculty Mannheim, Mannheim Institute of Public Health, Social and Preventive Medicine, Heidelberg University, Ludolf Krehl Strasse 7-11, Mannheim D-68167, Germany. [2] Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8036, Austria. [3] Synlab Academy, Mannheim 68259, Germany.24Medical Faculty Mannheim, Mannheim Institute of Public Health, Social and Preventive Medicine, Heidelberg University, Ludolf Krehl Strasse 7-11, Mannheim D-68167, Germany.25The National Heart, Lung, Blood Institute's Framingham Heart Study, Framingham, Massachusetts 01702, USA.26National Heart, Lung, and Blood Institute Center for Population Studies, The Framingham Heart Study, Framingham, Massachusetts 01702, USA.27Department of Biostatistics and Epidemiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.28Department of Epidemiology, University of Alabama-Birmingham, Birmingham, Alabama 35233, USA.29Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA.30School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27106, USA.31Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.32Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.331] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA. [2] Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina 27599, USA.34Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota 55455, USA.35University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.36Atherosclerosis Research Unit, Department of Medicine, and Center for Molecular Medicine, Karolinska Institutet, Stockholm 171 77, Sweden.37Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford OX1 2JD, UK.38Merck Sharp &Dohme Corporation, Rahway, New Jersey 08889, USA.39The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2JD, UK.401] The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2JD, UK. [2] Department of Statistics, University of Oxford, Oxford OX1 2JD, UK.41National Heart, Lung, and Blood Institute, Bethesda, Maryland 20824, USA.421] Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington 98195, USA. [2] Group Health Research Institute, Group Health Cooperative, Seattle, Washington 98101, USA.43Section on Cardiology, and Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27106, USA.44Jackson Heart Study, University of Mississippi Medical Center, Jackson State University, Jackson, Mississippi 39217, USA.45Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22904, USA.461] Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA. [2] Seattle Children's Hospital, Seattle, Washington 98105, USA. [3] Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.47Department of Biochemistry, University of Vermont, Burlington, Vermont 05405, USA.48Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.49Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.50Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.51St Luke's Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, Missouri 64111, USA.521] Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA. [2] Department of Genetics, Washington University in St Louis, Missouri 63130, USA.53Department of Preventive Medicine and Institute for Genetic Medicine, University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA.54Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195, USA.551] Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. [2] Department of Epidemiology, University of Washington, Seattle, Washington 98195, USA.56Ohio State University, Columbus, Ohio 43210, USA.57Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.581] Department of Epidemiology, University of Washington, Seattle, Washington 98195, USA. [2] Department of Medicine, School of Medicine, University of Washington, Seattle, Washington 98195, USA.591] Department of Clinical Biochemistry KB3011, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen 1165, Denmark. [2] Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 København N, Denmark.60Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Missouri 48109, USA.611] Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2J, UK. [2] The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2JD, UK.62Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.63Department of Cardiology, Parma Hospital, Parma 43100, Italy.641] Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.651] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. [2] Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.AbstractMyocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk. |
