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

Published version
Peer-reviewed

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Abstract

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.

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Keywords

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

Journal Title

Nat Genet

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

55

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (204623/Z/16/Z)
Medical Research Council (MC_UU_00002/7)
National Institute for Health and Care Research (IS-BRC-1215-20014)