Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target
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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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Genetics |
| Vol/bind | 55 |
| Sider (fra-til) | 1831–1842 |
| Antal sider | 13 |
| ISSN | 1061-4036 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
This work was supported by funding from Health Research Council of New Zealand (awards 14/155, 17/402, 20/144 to G.T.J.), British Heart Foundation (grants CS/14/2/30841 and RG/18/10/33842 to M.B.), Veterans Administration Office of Research and Development (I01-BX003362) and Tobacco-Related Disease Research Program (T29IR0636 to P.S.T.), the National Institutes of Health (NIH; R35-HL135824-03 and R01-HL142023-02 to C.J.W., R01-HL166991 to S.M.D.). A.H.C. is supported by the Independent Research Fund Denmark (0134-00363B) and the Novo Nordisk Foundation (NNF20OC0065799). C.A.H. is supported by the NIH/National Heart, Lung and Blood Institute (NHLBI) Institutional Training Grant (T32HL098049) and the Propel Postdoctoral Scholars Program of the Stanford University School of Medicine. C.G. is funded by the British Heart Foundation under grants CS/14/2/30841 and RG/18/10/33842. D.G. is supported by the British Heart Foundation Center of Research Excellence (RE/18/4/34215) at Imperial College. D.K. is supported by the Department of Veterans Affairs (IK2BX005759-01), the American Heart Association (23SCEFIA1153369), and the Baszucki Research Initiative provided to Stanford Vascular Surgery. J.M.S. is supported by the Tobacco-Related Disease Research Program (T31IR1845). I.J.K. is funded by grants HG06379 and HG11710 from the National Human Genome Research Institute and K24HL137010 from the NHLBI. K.B. and S.B. acknowledge the Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001). K.L.S. is supported by Wellcome Trust Doctoral Training Program reference 222959/Z/21/Z. M.S.-L. is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and cofinanced by the European Social Fund. M.G.L. is supported by the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania and the NIH/NHLBI National Research Service Award postdoctoral fellowship (T32HL007843). O.D. is supported by the Mayo Clinic Clinician Investigator training program. S.W.v.d.L. is funded through EU H2020 TO_AITION (grant 848146), has received Roche funding for unrelated work and would like to thank the support of the Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation (CVON 2011/B019 and CVON 2017-20: generating the best evidence-based pharmaceutical targets for atherosclerosis (GENIUS I&II)), the ERA-CVD program ‘druggable-MI-targets’ (grant 01KL1802) and the Leducq Foundation ‘PlaqOmics’. S.B. is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z). This research was funded by the United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7) and supported by the National Institute for Health Research Cambridge Biomedical Research Center (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. S.K.G. is supported by NIH (grant R35HL161016), the Department of Defense and the University of Michigan A. Alfred Taubman Institute. S.M.D. is supported by a Career Development Award (IK2-CX001780) from the US Department of Veterans Affairs Clinical Science Research and Development Service. Y.H.R. is supported by the Dean’s Postdoctoral Fellowship from the Stanford University School of Medicine. Y.E.C. is supported by NIH (grant R01-HL109946). This publication does not represent the views of the Department of Veteran Affairs or the US Government.
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© 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
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