Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target

作者：Tanmoy Roychowdhury, Derek Klarin, Michael G. Levin, Joshua M. Spin, Yae Hyun Rhee, Alicia Deng, Colwyn A. Headley, Noah L. Tsao, Corry Gellatly, Verena Zuber, Fred Shen, Whitney Hornsby, Ina Holst Laursen, Shefali S. Verma, Adam E. Locke, Guðmundur Einarsson, Guðmar Þorleifsson, Sarah E. Graham, Ozan Dikilitas, Jack Pattee, Renae Judy, Ferran Paüls-Vergés, Jonas B. Nielsen, Brooke N. Wolford, Ben Brumpton, Jaume Dilmé, Olga Peypoch, Laura Calsina Juscafresa, Todd L. Edwards, Dadong Li, Karina Banasik, Søren Brunak, Rikke Louise Jacobsen, Minerva T. Garcia-Barrio, Jifeng Zhang, Lars Melholt Rasmussen, Regent Lee, Ashok Handa, Anders Wanhainen, Kevin Mani, Jes S. Lindholt, Lasse M. Obel, Ewa Strauss, Grzegorz Oszkinis, Christopher P. Nelson, Katie Saxby, Joost A. van Herwaarden, Sander W. van der Laan, Jessica van Setten, Mercedes Camacho, Frank M. Davis, Rachael Wasikowski, Lam C. Tsoi, Jóhann E. Guðjónsson, Jonathan L. Eliason, Dawn M. Coleman, Peter K. Henke, Santhi K. Ganesh, Y. Eugene Chen, Weihua Guan, James S. Pankow, Nathan Pankratz, Ole Birger Pedersen, Christian Erikstrup, Weihong Tang, Kristian Hveem, Daníel F. Guðbjartsson, Sólveig Grétarsdóttir, Unnur Þorsteinsdóttir, Hilma Hólm, Kāri Stefánsson, Manuel A. R. Ferreira, Aris Baras, Iftikhar J. Kullo, Marylyn D. Ritchie, Alex Hørby Christensen, Kasper Iversen, Nikolaj Eldrup, Henrik Sillesen, Sisse Rye Ostrowski, Henning Bundgaard, Henrik Ullum, Stephen Burgess, Dipender Gill, Katherine Gallagher, Maria Sabater‐Lleal, DiscovEHR, UK Aneurysm Growth Study, Frank Dudbridge, Nilesh J. Samani, VA Million Veteran Program, Ida Surakka, Gregory T. Jones, Matthew J. Bown, Philip S. Tsao, Cristen J. Willer, Scott M. Damrauer · 发表于：Nature Genetics · 年份：2023 · DOI：10.1038/s41588-023-01510-y · 被引用次数：101 · 研究领域：Aortic aneurysm repair treatments、Aortic Disease and Treatment Approaches、Connective tissue disorders research

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.