Division of Cardiovascular Medicine, Stanford University, Stanford, CA, 94305, USA.
Biomedical Informatics Program, Stanford University, Stanford, CA, 94305, USA.
Nat Commun. 2019 Jun 24;10(1):2760. doi: 10.1038/s41467-019-10591-5.
Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.
心力衰竭是导致死亡的主要原因，但我们对这种疾病的遗传相互作用的理解仍不完整。在这里，我们直接从移植中心手术室采集了 1352 个健康和衰竭的人类心脏，并对其中的 313 个亚组进行了全基因组基因分型和基因表达测量。我们构建了衰竭和非衰竭的心脏调控基因网络，揭示了重要的调控因子和心脏表达数量性状基因座(eQTLs)。PPP1R3A 是一种调节剂，其网络连接性在健康和疾病之间发生了显著变化。PPP1R3A 敲低后的 RNA 测序验证了基于网络的预测，并突出了与心肌细胞大小增加和呼吸代谢紊乱相关的代谢途径调节。缺乏 PPP1R3A 的小鼠能防止压力超负荷性心力衰竭。我们提出了人类心力衰竭转化的全局基因相互作用图谱，鉴定了以前未报道的心脏 eQTLs，并通过将 PPP1R3A 描述为心力衰竭的中央调节剂，展示了疾病特异性网络的发现潜力。
