Journal of the American College of Cardiology ( IF 24.0 ) Pub Date : 2022-07-25 , DOI: 10.1016/j.jacc.2022.05.024 Mahan Nekoui 1 , James P Pirruccello 2 , Paolo Di Achille 3 , Seung Hoan Choi 4 , Samuel N Friedman 3 , Victor Nauffal 5 , Kenney Ng 6 , Puneet Batra 3 , Jennifer E Ho 7 , Anthony A Philippakis 8 , Steven A Lubitz 9 , Mark E Lindsay 10 , Patrick T Ellinor 9
Background
The left ventricular outflow tract (LVOT) and ascending aorta are spatially complex, with distinct pathologies and embryologic origins. Prior work examined the genetics of thoracic aortic diameter in a single plane.
Objectives
We sought to elucidate the genetic basis for the diameter of the LVOT, aortic root, and ascending aorta.
Methods
Using deep learning, we analyzed 2.3 million cardiac magnetic resonance images from 43,317 UK Biobank participants. We computed the diameters of the LVOT, the aortic root, and at 6 locations of ascending aorta. For each diameter, we conducted a genome-wide association study and generated a polygenic score. Finally, we investigated associations between these scores and disease incidence.
Results
A total of 79 loci were significantly associated with at least 1 diameter. Of these, 35 were novel, and most were associated with 1 or 2 diameters. A polygenic score of aortic diameter approximately 13 mm from the sinotubular junction most strongly predicted thoracic aortic aneurysm (n = 427,016; mean HR: 1.42 per SD; 95% CI: 1.34-1.50; P = 6.67 × 10−21). A polygenic score predicting a smaller aortic root was predictive of aortic stenosis (n = 426,502; mean HR: 1.08 per SD; 95% CI: 1.03-1.12; P = 5 × 10−6).
Conclusions
We detected distinct genetic loci underpinning the diameters of the LVOT, aortic root, and at several segments of ascending aorta. We spatially defined a region of aorta whose genetics may be most relevant to predicting thoracic aortic aneurysm. We further described a genetic signature that may predispose to aortic stenosis. Understanding genetic contributions to proximal aortic diameter may enable identification of individuals at risk for aortic disease and facilitate prioritization of therapeutic targets.
中文翻译:
主动脉尺寸的空间不同遗传决定因素影响动脉瘤和狭窄的风险
背景
左心室流出道 (LVOT) 和升主动脉在空间上很复杂,具有不同的病理学和胚胎学起源。之前的工作在一个平面上检查了胸主动脉直径的遗传学。
目标
我们试图阐明 LVOT、主动脉根部和升主动脉直径的遗传基础。
方法
使用深度学习,我们分析了来自 43,317 名英国生物样本库参与者的 230 万张心脏磁共振图像。我们计算了 LVOT、主动脉根部和升主动脉 6 个位置的直径。对于每个直径,我们进行了全基因组关联研究并生成了多基因评分。最后,我们调查了这些分数与疾病发病率之间的关联。
结果
共有 79 个位点与至少 1 个直径显着相关。其中,35 个是新颖的,并且大多数与 1 或 2 个直径相关。距窦管交界处约 13 毫米的主动脉直径多基因评分最能预测胸主动脉瘤(n = 427,016;平均 HR:1.42/SD;95% CI:1.34-1.50;P = 6.67 × 10 -21 )。预测较小主动脉根部的多基因评分可预测主动脉瓣狭窄(n = 426,502;平均 HR:1.08/SD;95% CI:1.03-1.12;P = 5 × 10 -6)。
结论
我们检测到支持 LVOT、主动脉根部和升主动脉几个节段直径的不同基因位点。我们在空间上定义了一个主动脉区域,其遗传学可能与预测胸主动脉瘤最相关。我们进一步描述了可能导致主动脉瓣狭窄的遗传特征。了解基因对近端主动脉直径的贡献可能有助于识别有主动脉疾病风险的个体,并有助于确定治疗目标的优先次序。