Nature genetics · 2023

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

МетаанализСтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен

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Roychowdhury Tanmoy, Klarin Derek, Levin Michael G, Spin Joshua M, Rhee Yae Hyun, Deng Alicia, Headley Colwyn A, Tsao Noah L, Gellatly Corry, Zuber Verena, Shen Fred, Hornsby Whitney E, Laursen Ina Holst, Verma Shefali S, Locke Adam E, Einarsson Gudmundur, Thorleifsson Gudmar, Graham Sarah E, Dikilitas Ozan, Pattee Jack W, Judy Renae L, Pauls-Verges Ferran, Nielsen Jonas B, Wolford Brooke N, Brumpton Ben M, Dilmé Jaume, Peypoch Olga, Juscafresa Laura Calsina, Edwards Todd L, Li Dadong, Banasik Karina, Brunak Søren, Jacobsen Rikke L, Garcia-Barrio Minerva T, Zhang Jifeng, Rasmussen Lars M, Lee Regent, Handa Ashok, Wanhainen Anders, Mani Kevin, Lindholt Jes S, Obel Lasse M, Strauss Ewa, Oszkinis Grzegorz, Nelson Christopher P, Saxby Katie L, van Herwaarden Joost A, van der Laan Sander W, van Setten Jessica, Camacho Mercedes, Davis Frank M, Wasikowski Rachael, Tsoi Lam C, Gudjonsson Johann E, Eliason Jonathan L, Coleman Dawn M, Henke Peter K, Ganesh Santhi K, Chen Y Eugene, Guan Weihua, Pankow James S, Pankratz Nathan, Pedersen Ole B, Erikstrup Christian, Tang Weihong, Hveem Kristian, Gudbjartsson Daniel, Gretarsdottir Solveig, Thorsteinsdottir Unnur, Holm Hilma, Stefansson Kari, Ferreira Manuel A, Baras Aris, Kullo Iftikhar J, Ritchie Marylyn D, Christensen Alex H, Iversen Kasper K, Eldrup Nikolaj, Sillesen Henrik, Ostrowski Sisse R, Bundgaard Henning, Ullum Henrik, Burgess Stephen, Gill Dipender, Gallagher Katherine, Sabater-Lleal Maria, DiscovEHR, Regeneron Genetics Center, UK Aneurysm Growth Study, DBDS Genomic Consortium, VA Million Veteran Program, Surakka Ida, Jones Gregory T, Bown Matthew J, Tsao Philip S, Willer Cristen J, Damrauer Scott M

Аннотация

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.

Предметные рубрики MeSH

Humans Animals Mice Genome-Wide Association Study Proprotein Convertase 9 Subtilisin Proprotein Convertases Aortic Aneurysm, Abdominal

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

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Аннотация

Предметные рубрики MeSH