Chromatin Capture Identifies SCARB1-LAG3 Proinflammatory Cardiovascular Disease Gene Networks

Increased high density lipoprotein (HDL) cholesterol levels have been associated with mutations in the cholesterol efflux receptor gene SCARB1, contributing to coronary artery disease (CAD). Using chromatin capture techniques (4C-Seq and HiC), ChIP-Seq and RNA-Seq, we identified a potential mechanism between a non-coding SNP (rs10846744) within the first intron of SCARB1 and LAG3, a negative regulator of T cells, both on chromosome 12. We previously demonstrated how loss of LAG3 is associated with inflammation and CAD found in carriers of the rs10846744 risk allele (C) both in our hyperalphalipoproteinemia (HALP) participants and the Multi-Ethnic Study of Atherosclerosis (MESA), increasing the risk of a coronary event by 45% (PMID: 27777974). NR2F2 transcription factor binding, as detected by (yeast 1 hybrid assay, ChIP, and ChIP-Seq) to the rs10846744 risk (C) allele, bridges NR2F2, SCARB1, and LAG3 loci, altering gene networks associated with a CAD proinflammatory signature. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

高密度脂蛋白（High Density Lipoprotein, HDL）胆固醇水平升高与胆固醇流出受体基因SCARB1的突变相关，该突变可增加冠状动脉疾病（Coronary Artery Disease, CAD）的发病风险。本研究采用染色质捕获技术（4C-Seq与HiC）、染色质免疫共沉淀测序（ChIP-Seq）及RNA测序（RNA-Seq），在12号染色体上鉴定出SCARB1基因第一内含子内的非编码单核苷酸多态性（Single Nucleotide Polymorphism, SNP）rs10846744与T细胞负调控因子LAG3之间的潜在调控机制。此前本团队已证实，在高α脂蛋白血症（Hyperalphalipoproteinemia, HALP）受试者及多种族动脉粥样硬化研究（Multi-Ethnic Study of Atherosclerosis, MESA）队列中，携带rs10846744风险等位基因（C）的人群若出现LAG3缺失，会伴随炎症反应与冠状动脉疾病，且该人群的冠状动脉事件风险升高45%（PMID: 27777974）。通过酵母单杂交实验、染色质免疫共沉淀（ChIP）及ChIP-Seq检测发现，转录因子NR2F2可结合rs10846744的风险等位基因（C），进而桥接NR2F2、SCARB1与LAG3基因座，重塑与冠状动脉疾病促炎特征相关的基因调控网络。本超级数据集（SuperSeries）由下述子数据集（SubSeries）组成，详细信息请参阅各单个数据集。