The identification of causal variants and mechanisms underlying complex disease traits in humans is important for the progress of human disease genetics; this requires finding strategies to detect functional regulatory variants in disease-relevant cell types. To achieve this, we collected genetic and transcriptomic data from the aortic endothelial cells of up to 157 donors and four epigenomic phenotypes in up to 44 human donors representing individuals of both sexes and three major ancestries. We found thousands of expression quantitative trait loci (eQTLs) at all ranges of effect sizes not detected by the Gene-Tissue Expression Project (GTEx) in human tissues, showing that novel biological relationships unique to endothelial cells (ECs) are enriched in this dataset. Epigenetic profiling enabled discovery of over 3,000 regulatory elements whose activity is modulated by genetic variants that most frequently mutated ETS, AP-1, and NF-kB binding motifs, implicating these motifs as governors of EC regulation. Using CRISPR interference (CRISPRi), allele-specific reporter assays, and chromatin conformation capture, we validated candidate enhancer variants located up to 750 kb from their target genes, VEGFC, FGD6, and KIF26B. Regulatory SNPs identified were enriched in coronary artery disease (CAD) loci, and this result has specific implications for PECAM-1, FES, and AXL. We also found significant roles for EC regulatory variants in modifying the traits pulse pressure, blood protein levels, and monocyte count. Lastly, we present two unlinked SNPs in the promoter of MFAP2 that exhibit pleiotropic effects on human disease traits. Together, this supports the possibility that genetic predisposition for complex disease is manifested through the endothelium.

识别人类复杂疾病特征的因果变异和机制对于人类疾病遗传学的发展很重要；这就需要找到策略来检测疾病相关细胞类型中的功能性调控变异。为了实现这一目标，我们从多达157个供体的主动脉内皮细胞和多达44个代表性别和三个主要祖先的人类供体中的四种表观基因组表型中收集了遗传和转录组数据。我们发现在人类组织中基因组织表达计划（GTEx）未能检测到的所有大小的效应大小下，成千上万的表达定量性状基因座（eQTL），表明内皮细胞（EC）独有的新型生物学关系在此数据集中得到了丰富。表观遗传学分析可发现3种以上，000个调节元件，其活性受遗传变异控制，这些变异最常使ETS，AP-1和NF-kB结合基序突变，暗示这些基序是EC调控的调控因子。使用CRISPR干扰（CRISPRi），等位基因特异的报告基因检测和染色质构象捕获，我们验证了距离其靶基因最远750 kb的候选增强子变体，VEGFC，FGD6和KIF26B。鉴定出的调​​节性SNP富含冠状动脉疾病（CAD）基因座，这一结果对PECAM-1，FES和AXL具有特定意义。我们还发现EC调节变体在改变性状脉压，血液蛋白水平和单核细胞计数方面起着重要作用。最后，我们介绍了MFAP2启动子中的两个未连接的SNP ，它们对人类疾病特征表现出多效作用。总之，这支持了通过内皮表现出复杂疾病的遗传易感性的可能性。