肥厚性心肌病的基因型-表型分类。

IF 6 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation: Genomic and Precision Medicine Pub Date : 2023-12-01 Epub Date: 2023-11-28 DOI:10.1161/CIRCGEN.123.004200
Lara Curran, Antonio de Marvao, Paolo Inglese, Kathryn A McGurk, Pierre-Raphaël Schiratti, Adam Clement, Sean L Zheng, Surui Li, Chee Jian Pua, Mit Shah, Mina Jafari, Pantazis Theotokis, Rachel J Buchan, Sean J Jurgens, Claire E Raphael, Arun John Baksi, Antonis Pantazis, Brian P Halliday, Dudley J Pennell, Wenjia Bai, Calvin W L Chin, Rafik Tadros, Connie R Bezzina, Hugh Watkins, Stuart A Cook, Sanjay K Prasad, James S Ware, Declan P O'Regan
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引用次数: 0

摘要

背景:肥厚性心肌病(HCM)是与异质性表型相关的心源性猝死的重要原因,但目前尚无系统的形态学分类或相关风险评估框架。在这里,我们定量调查了HCM中的基因型-表型关联,以获得疾病表达的数据驱动分类。方法:我们招募了436例HCM患者(中位年龄60岁;28.8%女性),有临床、遗传和影像学资料。来自新加坡的60例HCM患者的独立队列研究(中位年龄59岁;11%女性)和参考人群来自UK Biobank (n= 16691;平均年龄55岁;52.5%的女性)也被招募。我们利用机器学习分析了心脏磁共振成像左心室的三维结构,并建立了基于树的HCM表型分类。基因型和死亡风险分布被预测到树上。结果:与基因型阴性个体相比,HCM致病性或可能致病性变异携带者左心室体积较小,但基底间隔肥大较大,寿命缩短(平均随访时间9.9年)(风险比2.66 [95% CI, 1.42-4.96];页= 0.0001)。HCM的多基因风险也与不同的疾病表达模式和程度有关。该模型可推广到一个独立的队列(可信度,M1: 0.86-0.88)。结论:我们报告了一种数据驱动的HCM分类方法,用于识别具有相似形态学的患者群体,同时保留疾病严重程度、遗传风险和结果的连续性。这种方法将有助于理解疾病多样性的原因和后果。
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Genotype-Phenotype Taxonomy of Hypertrophic Cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression.

Methods: We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree.

Results: Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42-4.96]; P<0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93-2.28]; P=0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M1: 0.86-0.88).

Conclusions: We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.

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来源期刊
Circulation: Genomic and Precision Medicine
Circulation: Genomic and Precision Medicine Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
9.20
自引率
5.40%
发文量
144
期刊介绍: Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations. Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.
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