Background:Randomized clinical trials indicate that the immune response plays a significant role in coronary artery disease (CAD), a disorder impacting the lifespan potential. However, the identification of targets critical to the immune response in atheroma is still hampered by a lack of solid inference.Methods:Herein, we implemented a system genetics approach to identify causally associated immune targets implicated in atheroma. We leveraged genome-wide association studies to perform mapping and Mendelian randomization to assess causal associations between gene expression in blood cells with CAD and the lifespan. Expressed genes (eGenes) were prioritized in network and in single-cell expression derived from plaque immune cells.Results:Among 840 CAD-associated blood eGenes, 37 were predicted causally associated with CAD and 6 were also associated with the parental lifespan in Mendelian randomization. In multivariable Mendelian randomization, the impact of eGenes on the lifespan potential was mediated by the CAD risk. Predicted causal eGenes were central in network. FLT1 and CCR5 were identified as targets of approved drugs, whereas 22 eGenes were deemed tractable for the development of small molecules and antibodies. Analyses of plaque immune single-cell expression identified predicted causal eGenes enriched in macrophages (GPX1, C4orf3) and involved in ligand-receptor interactions (CCR5).Conclusions:We identified 37 blood eGenes predicted causally associated with CAD. The predicted expression for 6 eGenes impacted the lifespan potential through the risk of CAD. Prioritization based on network, annotations, and single-cell expression identified targets deemed tractable for the development of drugs and for drug repurposing.

中文翻译：

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包括因果推断在内的系统遗传学确定冠状动脉疾病的免疫靶点和寿命

背景：随机临床试验表明，免疫反应在冠状动脉疾病 (CAD) 中起着重要作用，冠状动脉疾病是一种影响寿命潜力的疾病。然而，由于缺乏可靠的推论，仍然阻碍了对动脉粥样硬化中免疫反应至关重要的靶标的鉴定。方法：在此，我们实施了系统遗传学方法来鉴定与动脉粥样硬化有关的因果关联的免疫靶标。我们利用全基因组关联研究进行映射和孟德尔随机化，以评估血细胞中基因表达与 CAD 和寿命之间的因果关联。表达的基因 (eGenes) 在网络和源自斑块免疫细胞的单细胞表达中被优先考虑。结果：在 840 个 CAD 相关血液 eGenes 中，在孟德尔随机化中，预测 37 例与 CAD 有因果关系，6 例也与父母寿命相关。在多变量孟德尔随机化中，eGenes 对寿命潜力的影响是由 CAD 风险介导的。预测的因果 eGenes 是网络的核心。FLT1和CCR5被确定为批准药物的目标，而 22 个 eGenes 被认为易于开发小分子和抗体。斑块免疫单细胞表达分析确定了富含巨噬细胞（GPX1、C4orf3）并参与配体-受体相互作用（CCR5）的预测因果 eGenes。结论：我们确定了 37 个预测与 CAD 因果相关的血液 eGenes。6 个 eGenes 的预测表达通过 CAD 风险影响寿命潜力。基于网络、注释和单细胞表达的优先级确定了被认为易于药物开发和药物再利用的目标。