From the Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.H., M.P.M., J.B., K.B.M., T.P.C.); Cardiovascular Research Center (N.R.T., V.A.P., P.T.E.) and Center for Human Genetic Research and Cardiovascular Research Center (C.N.-C.), Massachusetts General Hospital, Boston; Department of Statistics, University of Illinois at Urbana-Champaign (S.D.Z.); Heidelberg University Hospital, Germany (B.M., H.A.K.); Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Germany (F.R., M.S.); INSERM UMRS1166-IACN, Hôpital Pitié-Salpêtrière, Paris, France (E.V., F.C.); Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, MA (H.L.); Department of Epidemiology, University of Washington, Seattle (N.L.S.); Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, the Netherlands (J.F.F.); Boston University School of Medicine, MA (R.S.V.); Department of Cardiology, University of Groningen, University Medical Center Groningen, the Netherlands (P.v.d.H.); Medical and Population Genetics Program, Broad Institute, Cambridge, MA (C.N.-C.); Center for Applied Genomics, Children's Hospital of Philadelphia, PA (J.L., C.E.K., H.H.); Center for Bioinformatics and Computational Biology, University of Maryland, College Park (S.H.); Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, CA (E.A.A.); Department of Cardiovascular Medicine, Cleveland Clinic, OH (C.S.M., W.H.W.T.); and Howard Hughes Medical Institute and Cincinnati Children's Hospital Medical Center, OH (M.M., J.D.M.).
Circ Genom Precis Med. 2018 Mar;11(3):e001901. doi: 10.1161/CIRCGEN.117.001901.
Inhibition of PKC-α (protein kinase C-α) enhances contractility and cardioprotection in animal models, but effects in humans are unknown. Genotypes at rs9912468 strongly associate with expression in the left ventricle, enabling genetic approaches to measure effects of reduced PKC-α in human populations.
We analyzed the expression quantitative trait locus for marked by rs9912468 using 313 left ventricular specimens from European Ancestry patients. The forward strand minor allele (G) at rs9912468 is associated with reduced PKC-α transcript abundance (1.7-fold reduction in minor allele homozygotes, =1×10). This association was cardiac specific in expression quantitative trait locus data sets that span 16 human tissues. Cardiac epigenomic data revealed a predicted enhancer in complete (=1.0) linkage disequilibrium with rs9912468 within intron 2 of We cloned this region and used reporter constructs to verify cardiac-specific enhancer activity in vitro in cardiac and noncardiac cells and in vivo in zebrafish. The enhancer contains 2 common genetic variants and 4 haplotypes; the haplotype correlated with the rs9912468 PKC-α-lowering allele (G) showed lowest activity. In contrast to previous reports in animal models, the PKC-α-lowering allele is associated with adverse left ventricular remodeling (higher mass, larger diastolic dimension), reduced fractional shortening, and higher risk of dilated cardiomyopathy in human populations.
These findings support PKC-α as a regulator of the human heart but suggest that PKC-α inhibition may adversely affect the left ventricle depending on timing and duration. Pharmacological studies in human subjects are required to discern potential benefits and harms of PKC-α inhibitors as an approach to treat heart disease.
抑制蛋白激酶 C-α（PKC-α）可增强动物模型的收缩性和心脏保护作用，但在人类中的作用尚不清楚。rs9912468 处的基因型与左心室中的表达强烈相关，使人们能够通过遗传方法来测量人类群体中 PKC-α 减少的影响。
我们分析了 rs9912468 标记的左心室标本来自欧洲血统患者的 313 个样本。rs9912468 的前向链次要等位基因（G）与 PKC-α 转录物丰度降低相关（次要等位基因纯合子减少 1.7 倍，=1×10）。在跨越 16 个人类组织的表达数量性状基因座数据集中，这种关联具有心脏特异性。心脏表观基因组数据显示，在 2 号内含子中与 rs9912468 完全（=1.0）连锁不平衡的一个预测增强子在心脏和非心脏细胞的体外和斑马鱼的体内均具有心脏特异性增强子活性。该增强子包含 2 个常见的遗传变异和 4 个单倍型；与 rs9912468 降低 PKC-α 等位基因（G）相关的单倍型显示出最低的活性。与动物模型中的先前报道相反，降低 PKC-α 的等位基因与人类人群中左心室重构不良（质量更高，舒张尺寸更大）、射血分数降低和扩张型心肌病风险增加相关。
这些发现支持 PKC-α 作为人类心脏的调节剂，但表明 PKC-α 抑制可能会根据时间和持续时间对左心室产生不利影响。需要对人类受试者进行药理学研究，以辨别 PKC-α 抑制剂作为治疗心脏病的方法的潜在益处和危害。
