Georges Adrien, Yang Min-Lee, Berrandou Takiy-Eddine, Bakker Mark K, Dikilitas Ozan, Kiando Soto Romuald, Ma Lijiang, Satterfield Benjamin A, Sengupta Sebanti, Yu Mengyao, Deleuze Jean-François, Dupré Delia, Hunker Kristina L, Kyryachenko Sergiy, Liu Lu, Sayoud-Sadeg Ines, Amar Laurence, Brummett Chad M, Coleman Dawn M, d'Escamard Valentina, de Leeuw Peter, Fendrikova-Mahlay Natalia, Kadian-Dodov Daniella, Li Jun Z, Lorthioir Aurélien, Pappaccogli Marco, Prejbisz Aleksander, Smigielski Witold, Stanley James C, Zawistowski Matthew, Zhou Xiang, Zöllner Sebastian, Amouyel Philippe, De Buyzere Marc L, Debette Stéphanie, Dobrowolski Piotr, Drygas Wojciech, Gornik Heather L, Olin Jeffrey W, Piwonski Jerzy, Rietzschel Ernst R, Ruigrok Ynte M, Vikkula Miikka, Warchol Celinska Ewa, Januszewicz Andrzej, Kullo Iftikhar J, Azizi Michel, Jeunemaitre Xavier, Persu Alexandre, Kovacic Jason C, Ganesh Santhi K, Bouatia-Naji Nabila
PARCC, INSERM, Université de Paris, F-750015, Paris, France.
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Nat Commun. 2021 Oct 15;12(1):6031. doi: 10.1038/s41467-021-26174-2.
Fibromuscular dysplasia (FMD) is an arteriopathy associated with hypertension, stroke and myocardial infarction, affecting mostly women. We report results from the first genome-wide association meta-analysis of six studies including 1556 FMD cases and 7100 controls. We find an estimate of SNP-based heritability compatible with FMD having a polygenic basis, and report four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Transcriptome-wide association analysis in arteries identifies one additional locus (SLC24A3). We characterize open chromatin in arterial primary cells and find that FMD associated variants are located in arterial-specific regulatory elements. Target genes are broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. We find significant genetic overlap between FMD and more common cardiovascular diseases and traits including blood pressure, migraine, intracranial aneurysm, and coronary artery disease.
纤维肌发育不良（FMD）是一种与高血压、中风和心肌梗死相关的动脉疾病，主要影响女性。我们报告了六项研究的首次全基因组关联荟萃分析结果，其中包括1556例FMD病例和7100例对照。我们发现基于单核苷酸多态性（SNP）的遗传力估计值与FMD具有多基因基础相符，并报告了四个高度相关的基因座（PHACTR1、LRP1、ATP2B1和LIMA1）。动脉全转录组关联分析确定了另一个基因座（SLC24A3）。我们对动脉原代细胞中的开放染色质进行了表征，发现FMD相关变异位于动脉特异性调控元件中。靶基因广泛参与与肌动蛋白细胞骨架和细胞内钙稳态相关的机制，这些机制是血管收缩的核心。我们发现FMD与更常见的心血管疾病及特征（包括血压、偏头痛、颅内动脉瘤和冠状动脉疾病）之间存在显著的遗传重叠。
