Journal Article

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

Deng, Alicia, Thorleifsson, Gudmar, Wolford, Brooke N., Tsao, Philip S., Dilmé, Jaume, Tsoi, Lam C., Christensen, Alex H., Shen, Fred, Ferreira, Manuel A., Einarsson, Gudmundur, Tsao, Noah L., Lindholt, Jes S., Tang, Weihong, Damrauer, Scott M., Gellatly, Corry, Locke, Adam E., Hveem, Kristian, Roychowdhury, Tanmoy, Brunak, Søren, Gudjonsson, Johann E., Wanhainen, Anders, Henke, Peter K., Ostrowski, Sisse R., Eliason, Jonathan L., Coleman, Dawn M., Pedersen, Ole B., Stefansson, Kari, Dikilitas, Ozan, Jones, Gregory T., Eldrup, Nikolaj, van Setten, Jessica, Baras, Aris, Judy, Renae L., Wasikowski, Rachael, Ritchie, Marylyn D., Obel, Lasse M., Sillesen, Henrik, Gretarsdottir, Solveig, Peypoch, Olga, Strauss, Ewa, Pattee, Jack W., Chen, Y. Eugene, Guan, Weihua, Mani, Kevin, Verma, Shefali S., Pankow, James S., Saxby, Katie L., Burgess, Stephen, Gill, Dipender, Erikstrup, Christian, Thorsteinsdottir, Unnur, Lee, Regent, van der Laan, Sander W., Willer, Cristen J., Nelson, Christopher P., Nielsen, Jonas B., Brumpton, Ben M., Ullum, Henrik, Levin, Michael G., Camacho, Mercedes, Li, Dadong, Davis, Frank M., Holm,

2023

Overview

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).

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45 / 45/43 / 631/208/205/2138 / 692/699/75 / Abdomen / Agriculture / Animal Genetics and Genomics / Animals / Aorta / Aortic Aneurysm, Abdominal - genetics / Aortic aneurysms / Biobanks / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cardiovascular disease / Cholesterol / Consortia / Coronary vessels / Extracellular matrix / Gene Function / Genes / Genome-Wide Association Study / Genomes / Growth factors / Heritability / Human Genetics / Humans / Kexin / Lipid metabolism / Lipids / Meta-analysis / Metabolism / Mice / Pathogenesis / Population / Proprotein Convertase 9 - genetics / Proprotein Convertase 9 - metabolism / Proprotein Convertases / Risk analysis / Risk factors / Subtilisin / Therapeutic targets