孤舟蓑笠翁
(2025-12-31 15:11):
paper 【doi】10.1038/s41588-025-02417-6；【发表年份】2025；【期刊】Nature Genetics；【标题】Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction。【内容总结】这项研究旨在通过大规模基因组分析揭示主动脉瓣狭窄（AS）的遗传基础并发现新的治疗靶点，主要采用了多族裔全基因组关联分析（GWAS）、性别和种族分层GWAS、X染色体分析、转录组关联分析（TWAS）以及基因沉默实验等方法；研究团队对2,853,408人（包括86,864例AS患者）进行了迄今最大规模的AS遗传分析，发现了261个独立风险位点（其中223个是新发现的），并首次识别出X染色体上的3个风险位点、5个男性特异性位点和1个非洲裔特异性位点；通过整合人类主动脉瓣表达数量性状位点（eQTL）数据，确定了54个与AS风险相关的新基因，其中细胞骨架相关基因（如PALLD、SVIL）以及多不饱和脂肪酸代谢通路基因CMKLR1和转化生长因子β信号通路基因LTBP4被实验验证可抑制人类瓣膜间质细胞钙化；此外，新开发的多基因风险评分（PRS）在UK Biobank和TIMI临床试验等独立数据集中显示出比既往评分高一倍的疾病预测能力（风险比HR=1.92），且其预测效能超过多数临床风险因素（如糖尿病、高血脂等），仅低于年龄因素。这些发现不仅深化了对AS分子机制的理解（如细胞骨架调控、脂质代谢异常的核心作用），还为早期干预和靶向治疗提供了新方向。
Nature Genetics,
2025-12-19.
DOI: 10.1038/s41588-025-02417-6
Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction
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Abstract:
Abstract Aortic stenosis (AS) is a common valvular heart disease and has no pharmacological therapies. We performed a multi-ancestry genome-wide association meta-analysis of 86,864 AS cases among 2,853,408 individuals, discovering 241 autosomal independent risk loci and 3 X chromosome risk loci. We additionally performed sex-stratified and ancestry-stratified genome-wide association studies (GWASs), identifying an additional 5 sex-specific risk loci, 11 risk loci in European ancestry individuals and 1 risk locus in African ancestry individuals. We also performed a transcriptome-wide association study using expression quantitative trait loci from human aortic valves, discovering 54 new genes for which genetically predicted expression influences the risk of AS. We then generated a new polygenic risk score for AS. Finally, we performed gene silencing experiments targeting biologically relevant genes identified by our GWAS. Silencing of CMKLR1 and LTBP4 in human valvular interstitial cells substantially decreased mineralization, implicating a role for polyunsaturated fatty acids and transforming growth factor β signaling in AS.
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