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
{"title":"肥厚性心肌病的基因型-表型分类。","authors":"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","doi":"10.1161/CIRCGEN.123.004200","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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]; <i>P</i><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]; <i>P</i>=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, M<sub>1</sub>: 0.86-0.88).</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004200"},"PeriodicalIF":6.0000,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10729901/pdf/","citationCount":"0","resultStr":"{\"title\":\"Genotype-Phenotype Taxonomy of Hypertrophic Cardiomyopathy.\",\"authors\":\"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\",\"doi\":\"10.1161/CIRCGEN.123.004200\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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]; <i>P</i><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]; <i>P</i>=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, M<sub>1</sub>: 0.86-0.88).</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":10326,\"journal\":{\"name\":\"Circulation: Genomic and Precision Medicine\",\"volume\":\" \",\"pages\":\"e004200\"},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2023-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10729901/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation: Genomic and Precision Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCGEN.123.004200\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/11/28 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation: Genomic and Precision Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCGEN.123.004200","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/11/28 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
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.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
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.
期刊最新文献
Cardiovascular Disease Pathogenicity Predictor (CVD-PP): A Tissue-Specific In Silico Tool for Discriminating Pathogenicity of Variants of Unknown Significance in Cardiovascular Disease Genes. Yield of Genetic Testing for Long-QT Syndrome in Elderly Patients With Torsades de Pointes. How Normal Is Low-Normal Left Ventricular Ejection Fraction in Familial Dilated Cardiomyopathy? Polygenic Risk and Coronary Artery Disease Severity. Clinical Utility of Protein Language Models in Resolution of Variants of Uncertain Significance in KCNQ1, KCNH2, and SCN5A Compared With Patch-Clamp Functional Characterization.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1