Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target
Por:
Roychowdhury T., Klarin D., Levin M.G., Spin J.M., Rhee Y.H., Deng A., Headley C.A., Tsao N.L., Gellatly C., Zuber V., Shen F., Hornsby W.E., Laursen I.H., Verma S.S., Locke A.E., Einarsson G., Thorleifsson G., Graham S.E., Dikilitas O., Pattee J.W., Judy R.L., Pauls-Verges F., Nielsen J.B., Wolford B.N., Brumpton B.M., Dilmé J., Peypoch O., Juscafresa L.C., Edwards T.L., Li D., Banasik K., Brunak S., Jacobsen R.L., Garcia-Barrio M.T., Zhang J., Rasmussen L.M., Lee R., Handa A., Wanhainen A., Mani K., Lindholt J.S., Obel L.M., Strauss E., Oszkinis G., Nelson C.P., Saxby K.L., van Herwaarden J.A., van der Laan S.W., van Setten J., Camacho M., Davis F.M., Wasikowski R., Tsoi L.C., Gudjonsson J.E., Eliason J.L., Coleman D.M., Henke P.K., Ganesh S.K., Chen Y.E., Guan W., Pankow J.S., Pankratz N., Pedersen O.B., Erikstrup C., Tang W., Hveem K., Gudbjartsson D., Gretarsdottir S., Thorsteinsdottir U., Holm H., Stefansson K., Ferreira M.A., Baras A., Kullo I.J., Ritchie M.D., Christensen A.H., Iversen K.K., Eldrup N., Sillesen H., Ostrowski S.R., Bundgaard H., Ullum H., Burgess S., Gill D., Gallagher K., Sabater-Lleal M., Dudbridge F., Samani N.J., Surakka I., Jones G.T., Bown M.J., Tsao P.S., Willer C.J., Damrauer S.M.
Publicada:
16 oct 2023
Ahead of Print:
1 ene 2023
Resumen:
Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor beta signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model.
Genome-wide association meta-analysis of AAA identifies 121 independent risk loci and highlights potential therapeutic targets such as proprotein convertase, subtilisin/kexin-type 9 (PCSK9).
Filiaciones:
Roychowdhury T.:
Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, United States
Department of Genetics, Yale School of Medicine, New Haven, CT, United States
Klarin D.:
Department of Surgery, Stanford University School of Medicine, Stanford, CA, United States
VA Palo Alto Healthcare System, Palo Alto, CA, United States
Levin M.G.:
Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States
Spin J.M.:
VA Palo Alto Healthcare System, Palo Alto, CA, United States
Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
Rhee Y.H.:
VA Palo Alto Healthcare System, Palo Alto, CA, United States
Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
Deng A.:
VA Palo Alto Healthcare System, Palo Alto, CA, United States
Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
Headley C.A.:
VA Palo Alto Healthcare System, Palo Alto, CA, United States
Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
Tsao N.L.:
Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States
Gellatly C.:
Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, United Kingdom
Zuber V.:
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom
UK Dementia Research Institute at Imperial College, Imperial College London, London, United Kingdom
Shen F.:
University of Michigan Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, United States
Hornsby W.E.:
Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, United States
Laursen I.H.:
Department of Clinical Immunology, Copenhagen University Hospital—Rigshospitalet, Copenhagen, Denmark
Verma S.S.:
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, Philadelphia, PA, United States
Locke A.E.:
Regeneron Genetics Center, LLC, Tarrytown, NY, United States
Einarsson G.:
deCODE genetics/Amgen Inc., Reykjavik, Iceland
Thorleifsson G.:
deCODE genetics/Amgen Inc., Reykjavik, Iceland
Graham S.E.:
Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, United States
Dikilitas O.:
Department of Internal Medicine, Mayo Clinic Rochester, Rochester, MN, United States
Department of Cardiovascular Medicine and the Gonda Vascular Center, Mayo Clinic Rochester, Rochester, MN, United States
Mayo Clinician Investigator Training Program, Mayo Clinic Rochester, Rochester, MN, United States
Pattee J.W.:
University of Minnesota, Minneapolis, MN, United States
Judy R.L.:
Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States
Pauls-Verges F.:
Unit of Genomics of Complex Diseases, Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain
Nielsen J.B.:
Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, United States
HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway
Wolford B.N.:
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, United States
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
Brumpton B.M.:
HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
Dilmé J.:
Department of Vascular and Endovascular Surgery, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Peypoch O.:
Unit of Genomics of Complex Diseases, Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain
Department of Vascular and Endovascular Surgery, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Juscafresa L.C.:
Vascular Surgery Department, Parc de Salut Mar-Hospital del Mar, Barcelona, Spain
Edwards T.L.:
Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States
Li D.:
Regeneron Genetics Center, LLC, Tarrytown, NY, United States
Banasik K.:
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Brunak S.:
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Jacobsen R.L.:
Department of Clinical Immunology, Copenhagen University Hospital—Rigshospitalet, Copenhagen, Denmark
Garcia-Barrio M.T.:
Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, United States
Zhang J.:
Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, United States
Rasmussen L.M.:
Department of Clinical Biochemistry, Odense University Hospital, Elite Research Centre of Individualized Medicine in Arterial Disease (CIMA), Odense, Denmark
Lee R.:
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
Handa A.:
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
Wanhainen A.:
Department of Surgical Sciences, Vascular Surgery, Uppsala University, Uppsala, Sweden
Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden
Mani K.:
Department of Surgical Sciences, Vascular Surgery, Uppsala University, Uppsala, Sweden
Lindholt J.S.:
Department of Cardiothoracic and Vascular Surgery, Odense University Hospital, Elite Research Centre of Individualized Medicine in Arterial Disease (CIMA), Odense, Denmark
Obel L.M.:
Department of Cardiothoracic and Vascular Surgery, Odense University Hospital, Elite Research Centre of Individualized Medicine in Arterial Disease (CIMA), Odense, Denmark
Strauss E.:
Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
Department of General and Vascular Surgery, Poznan University of Medical Sciences, Poznan, Poland
Oszkinis G.:
Department of General and Vascular Surgery, Poznan University of Medical Sciences, Poznan, Poland
Department of Vascular and General Surgery, Institute of Medical Sciences, University of Opole, Opole, Poland
Nelson C.P.:
Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, United Kingdom
Saxby K.L.:
Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, United Kingdom
van Herwaarden J.A.:
Department of Vascular Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
van der Laan S.W.:
Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
van Setten J.:
Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
Camacho M.:
Unit of Genomics of Complex Diseases, Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain
Davis F.M.:
Department of Surgery, University of Michigan, Ann Arbor, MI, United States
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, United States
Wasikowski R.:
Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, United States
Tsoi L.C.:
Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, United States
Gudjonsson J.E.:
Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, United States
Eliason J.L.:
Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, United States
Coleman D.M.:
Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, United States
Henke P.K.:
Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI, United States
Ganesh S.K.:
Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, United States
Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States
Chen Y.E.:
Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, United States
Guan W.:
University of Minnesota, Minneapolis, MN, United States
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, United States
Pankow J.S.:
University of Minnesota, Minneapolis, MN, United States
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, United States
Pankratz N.:
University of Minnesota, Minneapolis, MN, United States
Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, MN, United States
Pedersen O.B.:
Department of Clinical Immunology, Zealand University Hospital—Køge, Køge, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Erikstrup C.:
Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
Tang W.:
University of Minnesota, Minneapolis, MN, United States
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, United States
Hveem K.:
HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
Gudbjartsson D.:
deCODE genetics/Amgen Inc., Reykjavik, Iceland
School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland
Gretarsdottir S.:
deCODE genetics/Amgen Inc., Reykjavik, Iceland
Thorsteinsdottir U.:
deCODE genetics/Amgen Inc., Reykjavik, Iceland
Faculty of Medicine, University of Iceland, Reykjavik, Iceland
Holm H.:
deCODE genetics/Amgen Inc., Reykjavik, Iceland
Stefansson K.:
deCODE genetics/Amgen Inc., Reykjavik, Iceland
Faculty of Medicine, University of Iceland, Reykjavik, Iceland
Ferreira M.A.:
Regeneron Genetics Center, LLC, Tarrytown, NY, United States
Baras A.:
Regeneron Genetics Center, LLC, Tarrytown, NY, United States
Kullo I.J.:
Department of Cardiovascular Medicine and the Gonda Vascular Center, Mayo Clinic Rochester, Rochester, MN, United States
Ritchie M.D.:
Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States
Christensen A.H.:
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Cardiology, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark
Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
Iversen K.K.:
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
Eldrup N.:
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Vascular Surgery, Copenhagen University Hospital—Rigshospitalet, Copenhagen, Denmark
Sillesen H.:
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Ostrowski S.R.:
Department of Clinical Immunology, Copenhagen University Hospital—Rigshospitalet, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Bundgaard H.:
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Cardiology, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark
Ullum H.:
Statens Serum Institut, Copenhagen, Denmark
Burgess S.:
MRC Biostatistics Unit, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Gill D.:
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
Chief Scientific Advisor Office, Research and Early Development, Novo Nordisk, Copenhagen, Denmark
Gallagher K.:
Department of Surgery, University of Michigan, Ann Arbor, MI, United States
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, United States
Sabater-Lleal M.:
Unit of Genomics of Complex Diseases, Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain
Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden
Dudbridge F.:
Department of Population Health Sciences, University of Leicester, Leicester, United Kingdom
Samani N.J.:
Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, United Kingdom
Surakka I.:
Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, United States
Jones G.T.:
Department of Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
Bown M.J.:
Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, United Kingdom
Tsao P.S.:
VA Palo Alto Healthcare System, Palo Alto, CA, United States
Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
Willer C.J.:
Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, United States
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, United States
Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States
Damrauer S.M.:
Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, United States
Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
All Open Access; Hybrid Gold
|