Calderon-Martinez Ernesto, Velasco Walter V, Guo Dongchuan, Hostetler Ellen H, Xun Zhang, Stephens Sara, Shalhub Sherene, De Backer Julie, Ouzounian Maral, LeMaire Scott A, Milleron Olivier, Hanna Nadine, Arnaud Pauline, Tchitchinadze Maria, Prakash Siddharth K, Lindsay Mark, Marcadier Julien, Jeremy Richmond, Morris Shaine A, Yetman Anji T, Boileau Catherine, Braverman Alan C, Jondeau Guillaume, Milewicz Dianna M
Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.
Division of Cardiology, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA.
J Am Coll Cardiol. 2025 Jun 24;85(24):2355-2367. doi: 10.1016/j.jacc.2025.04.023.
Heritable thoracic aortic disease is due to altered genes that confer a highly penetrant risk for thoracic aortic aneurysm and dissection, and a subset of these genes also cause aneurysms and dissections of peripheral arteries beyond the aorta. Arterial aneurysms, dissections, and ruptures are associated with pathogenic variants (PVs) in COL3A1, which is responsible for vascular Ehlers-Danlos syndrome, but arterial events are rare in Marfan syndrome due to PVs in FBN1, and poorly characterized in Loeys-Dietz syndrome due to PVs in the transforming growth factor (TGF)-β pathway genes.
This study sought to define the relative risk of arterial and aortic events in individuals with PVs in FBN1, COL3A1, and TGF-β pathway genes.
The Montalcino Aortic Consortium provided a retrospective cohort of 1,780 individuals with PVs in COL3A1 (n = 125), FBN1 (n = 1028), and the TGF-β pathway genes (TGFBR1, n = 137; TGFBR2, n = 168; SMAD3, n = 196; TGFB2, n = 126). Arterial events were defined as dissections, ruptures, or aneurysms in arteries beyond the aorta requiring open or endovascular repair, and aortic events were defined by aortic dissections or repair of an aortic aneurysm.
Arterial events were identified in 83 individuals, with the highest prevalence in COL3A1 (20.8%), followed by TGFBR2 (7.7%), TGFBR1 (7.3%), TGFB2 (6.4%), SMAD3 (5.6%), and FBN1 (1.5%). Kaplan-Meier curves identified significant gene differences, with COL3A1 having the most and earliest arterial events when compared with TGF-β genes and FBN1. For TGF-β genes and FBN1, aortic events were significantly earlier and more penetrant than arterial events, whereas this difference was not present with COL3A1. Sex impacts arterial events; males with COL3A1 had earlier and more arterial events compared with males with TGF-β genes, and these differences were not observed in females. Arterial events in FBN1 cases occur primarily in men.
There are significant gene- and sex-specific differences in the prevalence and age of onset of arterial events associated with these heritable thoracic aortic disease genes, highlighting the importance of tailored counseling and surveillance based on the causative gene. Furthermore, smoking cessation and hypertension control should be emphasized in these patients to reduce the risk of arterial events.
遗传性胸主动脉疾病是由基因改变引起的，这些基因赋予了胸主动脉瘤和夹层高度的发病风险，其中一部分基因还会导致主动脉以外的外周动脉出现动脉瘤和夹层。动脉动脉瘤、夹层和破裂与COL3A1基因的致病性变异（PVs）相关，COL3A1基因负责血管型埃勒斯-当洛综合征，但在因FBN1基因的PVs导致的马凡综合征中，动脉事件较为罕见，而在因转化生长因子（TGF）-β通路基因的PVs导致的洛伊茨-迪茨综合征中，动脉事件的特征尚不明确。
本研究旨在确定携带FBN1、COL3A1和TGF-β通路基因PVs的个体发生动脉和主动脉事件的相对风险。
蒙塔尔奇诺主动脉联盟提供了一个回顾性队列，包括1780名携带COL3A1基因PVs（n = 125）、FBN1基因PVs（n = 1028）和TGF-β通路基因PVs（TGFBR1，n = 137；TGFBR2，n = 168；SMAD3，n = 196；TGFB2，n = 126）的个体。动脉事件定义为主动脉以外的动脉发生夹层、破裂或动脉瘤，需要进行开放或血管腔内修复，主动脉事件定义为主动脉夹层或主动脉瘤修复。
83名个体发生了动脉事件，其中COL3A1基因携带者的患病率最高（20.8%），其次是TGFBR2（7.7%）、TGFBR1（7.3%）、TGFB2（6.4%）、SMAD3（5.6%）和FBN1（1.5%）。Kaplan-Meier曲线显示基因差异显著，与TGF-β基因和FBN1相比，COL3A1基因携带者发生动脉事件的数量最多且最早。对于TGF-β基因和FBN1，主动脉事件比动脉事件发生得更早且更具普遍性，而COL3A1基因携带者则不存在这种差异。性别对动脉事件有影响；携带COL3A1基因的男性比携带TGF-β基因的男性发生动脉事件更早且更多，而女性中未观察到这些差异。FBN1基因携带者的动脉事件主要发生在男性中。
与这些遗传性胸主动脉疾病基因相关的动脉事件的患病率和发病年龄存在显著的基因和性别差异，突出了基于致病基因进行个性化咨询和监测的重要性。此外，应强调这些患者戒烟和控制高血压，以降低动脉事件的风险。
