Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
The Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
BMC Med Genomics. 2019 Jul 25;12(Suppl 6):108. doi: 10.1186/s12920-019-0542-3.
Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene.
We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight.
In sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.
与疾病特征相关的遗传功能丧失变异（LoF）越来越被认为是选择治疗靶点的关键证据。我们整合了来自 Mount Sinai BioMe 生物库的 10511 个人的遗传和临床数据进行分析，以确定与心血管疾病（CVD）特征显著相关的具有功能丧失变异（LoF）的基因，并使用来自 600 名 CVD 患者的七个代谢和血管组织的 RNA-seq 数据在 Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) 研究中进行验证。我们还对几个候选基因进行了体外功能研究，并对一个基因进行了体内研究。
我们确定了 433 个基因的 LoF，这些基因与 10 种主要 CVD 特征中的至少一种显著相关。接下来，我们使用 STARNET 研究中的 RNA-seq 数据验证了 433 个 LoF 携带基因中的 115 个，这些基因的表达水平与相应的 CVD 特征一致。加上已被证实具有降肝脂作用的 APOC3 基因，另外 6 个肝脏 LoF 基因的表达水平与 STARNET 中的血浆脂质水平呈正相关。候选 LoF 基因在 HepG2 细胞中进行基因沉默，对细胞 LDLR、甘油三酯水平以及分泌的 APOB100 和 PCSK9 水平均有明显的整体影响。此外，我们在 BioMe 中发现了与胆固醇和葡萄糖水平降低相关的新型 DGAT2 LoF，这些结果在 STARNET 中也得到了证实，并在 C57BL/6 小鼠中显示了一种选择性的 DGAT2 抑制剂不仅显著降低了空腹血糖水平，还影响了体重。
总之，通过整合遗传和电子病历数据，并利用世界上最大的人类 RNA-seq 数据集之一（STARNET），我们确定了与 CVD 特征相关的已知和新型基因，这些基因可能成为 CVD 治疗的靶点，值得进一步研究。
