小柯机器人

人类心脏心肌间质纤维化的遗传学及其与疾病的关系
2023-04-27 10:00

美国麻省理工学院布罗德学院和美国马萨诸塞州剑桥市哈佛大学Steven A. Lubitz和Patrick T. Ellinor共同合作,近期取得重要工作进展。他们研究提出了人类心脏心肌间质纤维化的遗传学及其与疾病的关系。相关研究成果2023年4月20日在线发表于《自然—遗传学》杂志上。

据介绍,心肌间质纤维化与心血管疾病和不良预后有关。

为了研究人类心脏纤维化的生物学途径,研究人员开发了一个机器学习模型,在41505名接受心脏磁共振成像的英国生物库(UK Biobank)参与者中测量心肌纤维化的标志物天然心肌T1时间。较长的T1时间与糖尿病、肾病、主动脉狭窄、心肌病、心力衰竭、心房颤动、传导疾病和类风湿性关节炎有关。全基因组关联分析确定了11个与T1时间相关的独立基因座。所鉴定的基因座涉及葡萄糖转运(SLC2A12)、铁稳态(HFETMPRSS6)、组织修复(ADAMTSL1VEGFC)、氧化应激(SOD2)、心肌肥大(MYH7B)和钙信号传导(CAMK2D)的基因。使用转化生长因子β1介导的心脏成纤维细胞活化试验,研究人员发现11个基因座中有9个基因座由表达或开放染色质构象发生时间变化的基因组成,支持其与肌成纤维细胞状态获取的生物学相关性。

总之,通过利用机器学习使用心脏成像对心肌间质纤维化进行大规模量化,研究人员验证了心脏纤维化与疾病之间的联系,并确定了纤维化背后新的生物学相关途径。

附:英文原文

Title: Genetics of myocardial interstitial fibrosis in the human heart and association with disease

Author: Nauffal, Victor, Di Achille, Paolo, Klarqvist, Marcus D. R., Cunningham, Jonathan W., Hill, Matthew C., Pirruccello, James P., Weng, Lu-Chen, Morrill, Valerie N., Choi, Seung Hoan, Khurshid, Shaan, Friedman, Samuel F., Nekoui, Mahan, Roselli, Carolina, Ng, Kenney, Philippakis, Anthony A., Batra, Puneet, Ellinor, Patrick T., Lubitz, Steven A.

Issue&Volume: 2023-04-20

Abstract: Myocardial interstitial fibrosis is associated with cardiovascular disease and adverse prognosis. Here, to investigate the biological pathways that underlie fibrosis in the human heart, we developed a machine learning model to measure native myocardial T1 time, a marker of myocardial fibrosis, in 41,505 UK Biobank participants who underwent cardiac magnetic resonance imaging. Greater T1 time was associated with diabetes mellitus, renal disease, aortic stenosis, cardiomyopathy, heart failure, atrial fibrillation, conduction disease and rheumatoid arthritis. Genome-wide association analysis identified 11 independent loci associated with T1 time. The identified loci implicated genes involved in glucose transport (SLC2A12), iron homeostasis (HFE, TMPRSS6), tissue repair (ADAMTSL1, VEGFC), oxidative stress (SOD2), cardiac hypertrophy (MYH7B) and calcium signaling (CAMK2D). Using a transforming growth factor β1-mediated cardiac fibroblast activation assay, we found that 9 of the 11 loci consisted of genes that exhibited temporal changes in expression or open chromatin conformation supporting their biological relevance to myofibroblast cell state acquisition. By harnessing machine learning to perform large-scale quantification of myocardial interstitial fibrosis using cardiac imaging, we validate associations between cardiac fibrosis and disease, and identify new biologically relevant pathways underlying fibrosis.

DOI: 10.1038/s41588-023-01371-5

Source: https://www.nature.com/articles/s41588-023-01371-5

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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