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Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction

Nature volume 518, pages 102–106 (2015)Cite this article

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Abstract

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance1,2. When MI occurs early in life, genetic inheritance is a major component to risk1. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families3,4,5,6,7,8, whereas common variants at more than 45 loci have been associated with MI risk in the population9,10,11,12,13,14,15. 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 cholesterol16. 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 lipase15,17 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.

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Figure 1: Overall design for the early-onset myocardial infarction study within the US National Heart, Lung, and Blood Institute’s exome sequencing project (ESP).
Figure 2: Apolipoprotein A-V (APOA5) mutations discovered after sequencing of 13,432 individuals.
Figure 3: Low-density lipoprotein receptor (LDLR) mutations discovered after sequencing 9,793 individuals.

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Accession codes

Data deposits

DNA sequences have been deposited with the NIH dbGAP repository under accession numbers phs000279 and phs000814.

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Acknowledgements

The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute (NHLBI) and the National Human Genome Research Institute (NHGRI) of the US National Institutes of Health (NIH) and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research. Funding for the exome sequencing project (ESP) was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO) and RC2 HL-102924 (WHISP). Exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). Exome sequencing in the ATVB, PROCARDIS, and Ottawa studies was supported by NHGRI 5U54HG003067-11 to E.S.L. and S.G. Cleveland Clinic GeneBank was supported by NIH grants P01 HL076491 and P01 HL098055. S.K. is supported by a Research Scholar award from the Massachusetts General Hospital (MGH), the Howard Goodman Fellowship from MGH, the Donovan Family Foundation, R01HL107816, and a grant from Fondation Leducq. R.D. is supported by a Banting Fellowship from the Canadian Institutes of Health Research. N.O.S. is supported, in part, by a career development award from the NIH/NHLBI K08HL114642 and by The Foundation for Barnes-Jewish Hospital. N.O.S. was supported by award number T32HL007604 from the NHLBI. G.M.P was supported by award number T32HL007208 from the NHLBI. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHLBI, NHGRI, or NIH. The Italian ATVB Study was supported by a grant from RFPS-2007-3-644382. A full listing of acknowledgements is provided in the Supplementary Information.

Author information

Author notes

  1. Ron Do, Nathan O. Stitziel and Hong-Hee Won: These authors contributed equally to this work.

  2. skathiresan@partners.org

Authors and Affiliations

  1. Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Ron Do, Hong-Hee Won, Gina M. Peloso, David Altshuler & Sekar Kathiresan

  2. Cardiovascular Research Center, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Ron Do, Hong-Hee Won, Gina M. Peloso & Sekar Kathiresan

  3. Department of Medicine, Harvard Medical School, Boston, 02114, Massachusetts, USA

    Ron Do, Hong-Hee Won, Gina M. Peloso & Sekar Kathiresan

  4. Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Ron Do, Hong-Hee Won, Adam Kiezun, Or Zuk, Gina M. Peloso, Deborah N. Farlow, Mark A. DePristo, Eliana Hechter, Eric S. Lander, Shamil R. Sunyaev, David Altshuler, Stacey Gabriel & Sekar Kathiresan

  5. Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.,

    Nathan O. Stitziel & Sharon Cresci

  6. Division of Statistical Genomics, Washington University School of Medicine, St Louis, 63110, Missouri, USA

    Nathan O. Stitziel

  7. Department of Clinical Biochemistry KB3011, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen, 1165, Denmark

    Anders Berg Jørgensen & Anne Tybjaerg-Hansen

  8. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano, 20122, Italy

    Stefano Duga, Illaria Guella & Rosanna Asselta

  9. Division of Cardiology, Ospedale Niguarda, Milano, 20162, Italy

    Pier Angelica Merlini

  10. Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2J, UK.,

    Martin Farrall, Anuj Goel & Hugh Watkins

  11. Department of Genetics, University of North Carolina, Chapel Hill, 27599, North Carolina, USA

    Leslie A. Lange & Ethan M. Lange

  12. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, 98109, Washington, USA

    Paul L. Auer, Alex P. Reiner, Christopher S. Carlson, Charles Kooperberg & Stephen M. Schwartz

  13. Department of Medicine, University of Verona School of Medicine, Verona 37129, Italy.,

    Domenico Girelli, Nicola Martinelli & Oliviero Olivieri

  14. John & Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.,

    Robert Roberts & Alexander F. R. Stewart

  15. Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 1TN, UK.,

    Danish Saleheen & John Danesh

  16. MedStar Health Research Institute, Cardiovascular Research Institute, Hyattsville, 20782, Maryland, USA

    Stephen E. Epstein

  17. Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.,

    Suthesh Sivapalaratnam, G. Kees Hovingh & John J. Kastelein

  18. Department of Cardiovascular Sciences, University of Leicester, and Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE3 9QP, UK.,

    Nilesh J. Samani

  19. DZHK (German Research Centre for Cardiovascular Research), Munich Heart Alliance, Deutsches Herzzentrum München, Technische Universität München, Berlin 13347, Germany.,

    Heribert Schunkert

  20. Medizinische Klinik II, University of Lübeck, Lübeck 23562, Germany.,

    Jeanette Erdmann

  21. Center for Human Genetics, Duke University, Durham, 27708, North Carolina, USA

    Svati H. Shah

  22. Department of Cardiology and Center for Genomic Medicine, Duke University School of Medicine, Durham, 27708, North Carolina, USA

    Svati H. Shah & William E. Kraus

  23. Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.,

    Robert Davies, Majid Nikpay & Ruth McPherson

  24. Department of Biochemistry, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, Ontario N6A 3K7, Canada.,

    Christopher T. Johansen, Jian Wang & Robert A. Hegele

  25. Department of Medicine, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, Ontario N6A 3K7, Canada.,

    Robert A. Hegele

  26. Medical Faculty Mannheim, Mannheim Institute of Public Health, Social and Preventive Medicine, Heidelberg University, Ludolf Krehl Strasse 7-11, Mannheim D-68167, Germany.,

    Winfried Marz & Marcus E. Kleber

  27. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8036, Austria.,

    Winfried Marz

  28. Synlab Academy, Mannheim 68259, Germany.,

    Winfried Marz

  29. The National Heart, Lung, Blood Institute’s Framingham Heart Study, Framingham, 01702, Massachusetts, USA

    Jie Huang & Christopher J. O'Donnell

  30. National Heart, Lung, and Blood Institute Center for Population Studies, The Framingham Heart Study, Framingham, 01702, Massachusetts, USA

    Andrew D. Johnson

  31. Department of Biostatistics and Epidemiology, School of Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Mingyao Li

  32. Department of Epidemiology, University of Alabama–Birmingham, Birmingham, 35233, Alabama, USA

    Greg L. Burke

  33. Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, 55455, Minnesota, USA

    Myron Gross

  34. School of Medicine, Wake Forest University, Winston–Salem, 27106, North Carolina, USA

    Yongmei Liu

  35. Department of Medicine, Stanford University School of Medicine, Stanford, 94305, California, USA

    Themistocles L. Assimes

  36. Department of Epidemiology, University of North Carolina, Chapel Hill, 27599, North Carolina, USA

    Gerardo Heiss

  37. Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, 27599, North Carolina, USA

    Ethan M. Lange

  38. Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, 55455, Minnesota, USA

    Aaron R. Folsom

  39. University of Mississippi Medical Center, Jackson, 39216, Mississippi, USA

    Herman A. Taylor

  40. Department of Medicine, Atherosclerosis Research Unit, and Center for Molecular Medicine, Karolinska Institutet, Stockholm 171 77, Sweden.,

    Anders Hamsten

  41. Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford OX1 2JD, UK.,

    Robert Clarke

  42. Merck Sharp & Dohme Corporation, Rahway, 08889, New Jersey, USA

    Dermot F. Reilly & Wu Yin

  43. The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2JD, UK.,

    Manuel A. Rivas, Peter Donnelly & Hugh Watkins

  44. Department of Statistics, University of Oxford, Oxford OX1 2JD, UK.,

    Peter Donnelly

  45. National Heart, Lung, and Blood Institute, Bethesda, 20824, Maryland, USA

    Jacques E. Rossouw

  46. Departments of Medicine, Cardiovascular Health Research Unit, Epidemiology, and Health Services, University of Washington, Seattle, 98195, Washington, USA

    Bruce M. Psaty

  47. Group Health Research Institute, Group Health Cooperative, Seattle, 98101, Washington, USA

    Bruce M. Psaty

  48. Section on Cardiology, and Public Health Sciences, Wake Forest School of Medicine, Winston–Salem, North Carolina 27106, USA.,

    David M. Herrington

  49. Jackson Heart Study, University of Mississippi Medical Center, Jackson State University, Jackson, Mississippi 39217, USA.,

    James G. Wilson

  50. Center for Public Health Genomics, University of Virginia, Charlottesville, 22904, Virginia, USA

    Stephen S. Rich

  51. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, 98195, Washington, USA

    Michael J. Bamshad

  52. Seattle Children’s Hospital, Seattle, 98105, Washington, USA

    Michael J. Bamshad

  53. Department of Genome Sciences, University of Washington, Seattle, 98195, Washington, USA

    Michael J. Bamshad & Deborah A. Nickerson

  54. Department of Biochemistry, University of Vermont, Burlington, 05405, Vermont, USA

    Russell P. Tracy

  55. Department of Biostatistics, Boston University School of Public Health, Boston, 02118, Massachusetts, USA

    L. Adrienne Cupples

  56. Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Daniel J. Rader

  57. Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Muredach P. Reilly

  58. St Luke’s Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, 64111, Missouri, USA

    John A. Spertus

  59. Department of Genetics, Washington University in St Louis, 63130, Missouri, USA

    Sharon Cresci

  60. Department of Preventive Medicine and Institute for Genetic Medicine, University of Southern California Keck School of Medicine, Los Angeles, 90033, California, USA

    Jaana Hartiala & Hooman Allayee

  61. Cardiovascular Medicine, Cleveland Clinic, Cleveland, 44195, Ohio, USA

    W. H. Wilson Tang & Stanley L. Hazen

  62. Department of Epidemiology, University of Washington, Seattle, 98195, Washington, USA

    Alex P. Reiner, Stephen M. Schwartz & David S. Siscovick

  63. Ohio State University, Columbus, 43210, Ohio, USA

    Rebecca D. Jackson

  64. Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, 77030, Texas, USA

    Eric Boerwinkle

  65. Department of Medicine, School of Medicine, University of Washington, Seattle, 98195, Washington, USA

    David S. Siscovick

  66. Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 København N, Denmark.,

    Anne Tybjaerg-Hansen

  67. Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Missouri 48109, USA.,

    Goncalo R. Abecasis

  68. Department of Cardiology, Parma Hospital, Parma 43100, Italy.,

    Diego Ardissino

  69. Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Shamil R. Sunyaev

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Consortia

NHLBI Exome Sequencing Project

Contributions

R.Do, N.O.S., H.-H.W., A.B.J., and A.K. carried out the primary data analyses. R.Do, N.O.S., L.A.L., G.M.P., P.L.A., J.E.R., B.M.P., D.M.H., J.G.W., S.S.R., M.J.B., R.P.T., L.A.C., S.L.H., H.A., J.A.S., S.C., C.S.C., C.K., R.D.J., E.B., G.R.A., S.M.S., D.S.S., D.A.N., S.R.S., C.J.O., D. Altshuler, S.G., and S.K. contributed to the design and conduct of the discovery exome sequencing study. S.G., D.N.F., and M.A.D. enabled the exome sequencing, variant calling, and annotation. R.Do, N.O.S., H.-H.W., A.B.J., S.D., P.A.M., M.F., A.G., I.G., R.A., D.G., N.M., O.O., R.R., A.F.R.S., D.S., J.D., S.E.E., S.S., G.K.H., J.J.K., N.J.S., H.S., J.E., S.H.S., W.E.K., C.T.J., R.A.H., O.Z, E.H., W.M., M.N., J.W., A.H., R.C., D.F.R, W.Y., M.E.K., J.H., A.D.J., M.L., G.L.B., M.G., Y.L., T.L.A., G.H., E.M.L., A.R.F., H.A.T., M.A.R., P.D., D.J.R., M.P.R., J.H., W.W.H.T., A.P.R., D. Ardissino, D. Altshuler, R.M., A.T.-H., H.W., and S.K. contributed to the design and conduct of the imputation-based validation, genotyping-based validation, and/or the re-sequencing based validation study. S.S. supervised the analysis of exome sequencing data and power analysis. R.Do, N.O.S., H.-H.W., S.D., P.A.M., M.F., A.G., R.A., E.S.L., R.M., H.W., D. Ardissino, S.G., and S.K. contributed to the design and conduct of the replication exome sequencing study. S.G., E.S.L., S.K., D.A.N., and D. Altshuler obtained funding. D. Altshuler, D.A.N., S.S.R., R.D.J., and M.J.B. comprised the executive committee of the NHLBI Exome Sequencing Project. C.J.O. and S.K. led the Early-Onset Myocardial Infarction study team within the NHLBI Exome Sequencing Project. R.Do, N.O.S., H.-H.W. and S.K. wrote the manuscript.

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Supplementary Information

This file contains a list of acknowledgements, Supplementary Figures 1-32, Supplementary Tables 1-26 and Supplementary References. (PDF 6382 kb)

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Do, R., Stitziel, N., Won, HH. et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 518, 102–106 (2015). https://doi.org/10.1038/nature13917

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