Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target
Roychowdhury, Tanmoy (Yale School of Medicine)
Klarin, Derek (VA Palo Alto Healthcare System)
Levin, Michael G. (University of Pennsylvania)
Spin, Joshua M. (Stanford University School of Medicine)
Rhee, Yae Hyun (Stanford University School of Medicine)
Deng, Alicia (Stanford University School of Medicine)
Headley, Colwyn A. (Stanford University School of Medicine)
Tsao, Noah L. (University of Pennsylvania)
Gellatly, Corry (University of Leicester)
Zuber, Verena (Imperial College London)
Shen, Fred (University of Michigan)
Hornsby, Whitney E. (University of Michigan)
Laursen, Ina Holst (Copenhagen University Hospital-Rigshospitalet)
Verma, Shefali S. (Perelman School of Medicine)
Locke, Adam E. (Regeneron Genetics Center, LLC)
Einarsson, Gudmundur (deCODE genetics/Amgen Inc)
Thorleifsson, Gudmar (deCODE genetics/Amgen Inc)
Graham, Sarah E. (University of Michigan)
Dikilitas, Ozan (Mayo Clinic Rochester)
Pattee, Jack W. (University of Minnesota)
Judy, Renae L. (University of Pennsylvania)
Pauls-Verges, Ferran (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Nielsen, Jonas B. (Norwegian University of Science and Technology)
Wolford, Brooke N. (Norwegian University of Science and Technology)
Brumpton, Ben M. (Trondheim University Hospital)
Dilme, Jaime (Institut d'Investigació Biomèdica Sant Pau)
Peypoch, Olga (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Juscafresa, Laura Calsina (Parc de Salut MAR de Barcelona)
Edwards, Todd L. (Vanderbilt University Medical Center)
Li, Dadong (Regeneron Genetics Center, LLC)
Banasik, Karina (University of Copenhagen)
Brunak, Søren (University of Copenhagen)
Jacobsen, Rikke L. (Copenhagen University Hospital-Rigshospitalet)
Garcia-Barrio, Minerva T. (University of Michigan)
Zhang, Jifeng (University of Michigan)
Rasmussen, Lars M. (Odense University Hospital)
Lee, Regent (University of Oxford)
Handa, Ashok (University of Oxford)
Wanhainen, Anders (Umeå University)
Mani, Kevin (Uppsala University)
Lindholt, Jes S (Odense University Hospital)
Obel, Lasse M. (Odense University Hospital)
Strauss, Ewa (Poznan University of Medical Sciences)
Oszkinis, Grzegorz (University of Opole)
Nelson, Christopher P. (University of Leicester)
Saxby, Katie L. (University of Leicester)
van Herwaarden, Joost A. (Utrecht University)
van der Laan, Sander W (Utrecht University)
van Setten, Jessica (Utrecht University)
Camacho, Mercedes (Institut d'Investigació Biomèdica Sant Pau)
Davis, Frank M. (University of Michigan)
Wasikowski, Rachael (University of Michigan Medical School)
Tsoi, Lam C. (University of Michigan Medical School)
Gudjonsson, Johann E. (University of Michigan Medical School)
Eliason, Jonathan L. (University of Michigan)
Coleman, Dawn M. (University of Michigan)
Henke, Peter K. (University of Michigan)
Ganesh, Santhi K. (University of Michigan)
Chen, Y. Eugene (University of Michigan)
Guan, Weihua (University of Minnesota)
Pankow, James S (University of Minnesota)
Pankratz, Nathan (University of Minnesota)
Pedersen, Ole B. (University of Copenhagen)
Erikstrup, Christian (Aarhus University Hospital (Aarhus, Dinamarca))
Tang, Weihong (University of Minnesota)
Hveem, Kristian (Nord-Trøndelag Hospital Trust)
Gudbjartsson, Daniel F (University of Iceland)
Gretarsdottir, Solveig (deCODE genetics/Amgen Inc)
Thorsteinsdottir, Unnur (University of Iceland)
Holm, Hilma (deCODE genetics/Amgen Inc)
Stefánsson, Kári (University of Iceland)
Ferreira, Manuel A. (Regeneron Genetics Center, LLC)
Baras, Aris (Regeneron Genetics Center, LLC)
Kullo, Iftikhar J. (Mayo Clinic Rochester)
Ritchie, Marylyn D. (University of Pennsylvania)
Christensen, Alex H. (Copenhagen University Hospital)
Iversen, Kasper K. (Copenhagen University Hospital)
Eldrup, Nikolaj (Copenhagen University Hospital-Rigshospitalet)
Sillesen, Henrik (University of Copenhagen)
Ostrowski, Sisse R. (University of Copenhagen)
Bundgaard, Henning (Copenhagen University Hospital-Rigshospitalet)
Ullum, Henrik (Statens Serum Institut)
Burgess, Stephen (University of Cambridge)
Gill, Dipender (Research and Early Development, Novo Nordisk)
Gallagher, Katherine (University of Michigan)
Sabater-Lleal, Maria (Karolinska Institutet (Estocolm, Suècia))
Surakka, Ida (University of Michigan)
Jones, Gregory T. (University of Otago)
Bown, Matthew J. (University of Leicester)
Tsao, Philip S. (Stanford University School of Medicine)
Willer, Cristen J. (University of Michigan)
Damrauer, Scott M. (University of Pennsylvania)
Universitat Autònoma de Barcelona

Data:	2023
Resum:	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 β 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).
Ajuts:	European Commission. Horizon 2020 848146
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cardiovascular diseases ; Genome-wide association studies
Publicat a:	Nature genetics, Vol. 55 (october 2023) , p. 1831-1842, ISSN 1546-1718

DOI: 10.1038/s41588-023-01510-y
PMID: 37845353

20 p, 4.0 MB

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