Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA.
Division of Pediatric Cardiology, Baylor College of Medicine, Houston, Texas, USA.
J Am Coll Cardiol. 2022 Aug 30;80(9):857-869. doi: 10.1016/j.jacc.2022.05.054.
Pathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes.
This study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene.
A retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, and location of recruitment.
Significant differences in aortic event risk were identified among the smooth muscle contraction genes (ACTA2, MYLK, and PRKG1; P = 0.002) and among the genes for Loeys-Dietz syndrome, which encode proteins in the transforming growth factor (TGF)-β pathway (SMAD3, TGFB2, TGFBR1, and TGFBR2;P < 0.0001). Cumulative incidence of type A aortic dissection was higher than elective aneurysm surgery in patients with variants in ACTA2, MYLK, PRKG1, and SMAD3; in contrast, patients with TGFBR2 variants had lower cumulative incidence of type A aortic dissection than elective aneurysm surgery. Cumulative incidence of type B aortic dissection was higher for ACTA2, PRKG1, and TGFBR2 than other genes. After adjusting for proband status, sex, and recruitment location, specific variants in ACTA2 and TGFBR2 were associated with substantially higher risk of aortic event with childhood onset.
Gene- and variant-specific data on aortic events in individuals with HTAD support personalized aortic surveillance and clinical management.
11 个基因中的致病变异使个体易患遗传性胸主动脉疾病（HTAD），但可用的用于分层与这些基因相关的主动脉事件风险的数据有限。
本研究旨在比较 7 个 HTAD 基因及其每个基因内的变异类型的首次主动脉事件（具体为胸主动脉瘤手术或主动脉夹层）风险。
对 7 个 HTAD 基因中存在罕见变异的先证者及其亲属的回顾性队列（n=1028）进行了首次主动脉事件风险评估，评估因素包括受影响的基因、致病变异类型、性别、先证者状态以及招募地点。
平滑肌收缩基因（ACTA2、MYLK 和 PRKG1；P=0.002）和编码转化生长因子（TGF）-β 途径蛋白的 Loeys-Dietz 综合征基因（SMAD3、TGFB2、TGFBR1 和 TGFBR2；P<0.0001）之间的主动脉事件风险存在显著差异。在 ACTA2、MYLK、PRKG1 和 SMAD3 变异的患者中，A型主动脉夹层的累积发生率高于择期动脉瘤手术；相反，TGFBR2 变异的患者的 A 型主动脉夹层的累积发生率低于择期动脉瘤手术。在 ACTA2、PRKG1 和 TGFBR2 变异的患者中，B 型主动脉夹层的累积发生率高于其他基因。在调整先证者状态、性别和招募地点后，ACTA2 和 TGFBR2 的特定变异与主动脉事件风险显著增加相关，且发病年龄较小。
HTAD 个体的主动脉事件的基因和变异特异性数据支持个性化主动脉监测和临床管理。
