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Nature genetics · 2025

Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction.

СтатьяМетаанализПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Small Aeron M, Yang Ta-Yu, Itoh Shinsuke, Thériault Sébastien, Dufresne Line, Kurosawa Ryo, Komuro Issei, Matsuda Koichi, Vy Ha My T, Farber-Eger Eric H, Shaffer Lauren Lee, Boulier Kristin M, Corey Kristin M, Ramaker Megan E, Laporte Fabien, Schott Jean-Jacques, Le Scouarnec Solena, Singh Sasha A, Sonawane Abhijeet R, Smith Harry A, Rafaels Nicholas, Colorado Center for Personalized Medicine, Ghouse Jonas, Raja Anna A, Ostrowski Sisse R, Sørensen Erik, Mikkelsen Christina, Pedersen Ole B, Erikstrup Christian, Ullum Henrik, DBDS Genomic Consortium, Sveinbjornsson Gardar, Gudbjartsson Daniel F, Abner Erik, Estonian Biobank Research Team, Lee Jiwoo, Ganna Andrea, Nowak-Göttl Ulrike, Finer Sarah, Genes & Health Research Team, Schumacher Johannes, Maj Carlo, Al-Kassou Baravan, Nickenig Georg, Trenkwalder Teresa, Dreβen Martina, Krane Markus, Nöthen Markus M, Moksnes Marta R, Brumpton Ben M, Knight Stacey, Knowlton Kirk U, Nadauld Lincoln, Debiec Radek, Musameh Muntaser D, Braund Peter S, Nelson Christopher P, Czuba Tomasz, Melander Olle, Selvaraj Margaret Sunitha, Koyama Satoshi, Bhukar Rohan, Ruan Yunfeng, Ljungberg Johan, Damrauer Scott M, Levin Michael G, Franke Andre, Berger Klaus, Ruff Christian T, Melloni Giorgio E M, Kamanu Frederick K, Ito Kaoru, Do Ron, Loos Ruth J F, Schunkert Heribert, Wells Quinn S, Shah Svati H, Le Tourneau Thierry, Messika-Zeitoun David, Gignoux Christopher, Bundgaard Henning, Larsson Susanna C, Michaëlsson Karl, Holm Hilma, Helgadottir Anna, Esko Tonu, van Heel David A, Mathieu Patrick, Samani Nilesh J, Smith J Gustav, Söderberg Stefan, Rader Daniel J, Marston Nicholas A, Sabatine Marc S, Pasaniuc Bogdan, Cho Kelly, Wilson Peter W F, O'Donnell Christopher J, Stefansson Kari, Bossé Yohan, Aikawa Elena, Engert James C, Peloso Gina M, Natarajan Pradeep, Thanassoulis George

Аннотация

Aortic stenosis (AS) is a common valvular heart disease and has no pharmacological therapies. We performed a multi-ancestry genome-wide association meta-analysis of 86,864 AS cases among 2,853,408 individuals, discovering 241 autosomal independent risk loci and 3 X chromosome risk loci. We additionally performed sex-stratified and ancestry-stratified genome-wide association studies (GWASs), identifying an additional 5 sex-specific risk loci, 11 risk loci in European ancestry individuals and 1 risk locus in African ancestry individuals. We also performed a transcriptome-wide association study using expression quantitative trait loci from human aortic valves, discovering 54 new genes for which genetically predicted expression influences the risk of AS. We then generated a new polygenic risk score for AS. Finally, we performed gene silencing experiments targeting biologically relevant genes identified by our GWAS. Silencing of CMKLR1 and LTBP4 in human valvular interstitial cells substantially decreased mineralization, implicating a role for polyunsaturated fatty acids and transforming growth factor β signaling in AS.

Предметные рубрики MeSH

ИП Урсолов Владлен Сергеевич

ИНН 500118482352 · ОГРНИП 314500117700049

Реквизиты и контакты