基因组和分子证据表明,lncRNADSP-AS1调节了Desmoplakin的表达
Luisa Foco1, Marzia De Bortoli1, M Fabiola Del Greco1
1Institute for Biomedicine, Eurac Research, Bolzano, Italy.
medRxiv : the preprint server for health sciences
|April 16, 2025
概括
像DSP这样的desmosomal基因中的常见遗传变异与心脏导电特征有关. 一种特定的DSP变体 (rs2744389) 影响QRS持续时间,可能通过DSP-AS1 lncRNA,为心脏病提供新的治疗点.
科学领域:
- 心血管遗传学 心血管遗传学
- 分子心脏病学分子心脏病学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 德斯莫索姆对心肌细胞机械合至关重要;突变导致心律失常性心肌病.
- 门德尔的疾病和复杂的特征可能有共同的遗传基础.
- 调查与心脏导电相关联的desmosomal基因的常见变异是有必要的.
研究的目的:
- 评估在一般人群中脱体基因和心电图间隔的常见变异之间的关联.
- 探索遗传变异,脱体基因表达和心脏导电之间的功能和因果关系.
- 为了确定与desmoplakin相关的心脏病的潜在治疗点.
主要方法:
- 在CHRIS研究 (N=4342) 中的基因类型归算和线性混合模型,用于解体基因 (DSP,JUP,PKP2,DSG2,DSC2) 和心电图间隔 (P波,PR,QRS,QT).
- 功能注释,GWAS查询,双样本门德尔随机化 (MR) 和使用人类诱导的多能干细胞衍生心肌细胞 (hiPSC-CMs) 的体外研究.
- 在MICROS研究中的复制分析 (n=636).
主要成果:
- 一种DSP变体 (rs2744389) 与QRS持续时间 (P=3.5×10−6) 有显著的关联,在MICROS中复制 (P=0.010).
- 在GTEx-v8数据中,这种变异与DSP-AS1 lncRNA相关,而不是DSP表达.
- 核磁共振分析显示DSP-AS1对DSP表达 (P=6.33×10−5) 和QRS持续时间 (P=0.015) 的因果作用.
- 在hiPSC-CMs中DSP-AS1的下调导致DSP在mRNA和蛋白质水平上的上调.
结论:
- 一种常见的DSP变异影响QRS持续时间,可能是通过DSP-AS1 lncRNA对DSP表达的调节作用.
- DSP-AS1成为潜在的治疗点,用于与减少德斯莫普拉金产生的疾病.
- 这项研究突出了非编码RNA,脱体基因和心脏电生理学之间的相互作用.
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