BACKGROUND:Coronary artery disease (CAD), the leading cause of death worldwide, is influenced by both environmental and genetic factors. Although over 250 genetic risk loci have been identified through genome-wide association studies, the specific causal variants and their regulatory mechanisms are still largely unknown, particularly in disease-relevant cell types like macrophages.METHODS:We utilized single-cell RNA-seq and single-cell multiomics approaches in primary human monocyte–derived macrophages to explore the transcriptional regulatory network involved in a critical pathogenic event of coronary atherosclerosis—the formation of lipid-laden foam cells. The relative genetic contribution to CAD was assessed by partitioning disease heritability across different macrophage subpopulations. Meta-analysis of single-cell RNA-seq data sets from 38 human atherosclerotic samples was conducted to provide high-resolution cross-referencing to macrophage subpopulations in vivo.RESULTS:We identified 18 782 cis-regulatory elements by jointly profiling the gene expression and chromatin accessibility of >5000 macrophages. Integration with CAD genome-wide association study data prioritized 121 CAD-related genetic variants and 56 candidate causal genes. We showed that CAD heritability was not uniformly distributed and was particularly enriched in the gene programs of a novel CD52-hi lipid-handling macrophage subpopulation. These CD52-hi macrophages displayed significantly less lipoprotein accumulation and were also found in human atherosclerotic plaques. We investigated the cis-regulatory effect of a risk variant rs10488763 on FDX1, implicating the recruitment of AP-1 and C/EBP-β in the causal mechanisms at this locus.CONCLUSIONS:Our results provide genetic evidence of the divergent roles of macrophage subsets in atherogenesis and highlight lipid-handling macrophages as a key subpopulation through which genetic variants operate to influence disease. These findings provide an unbiased framework for functional fine-mapping of genome-wide association study results using single-cell multiomics and offer new insights into the genotype-environment interactions underlying atherosclerotic disease.

中文翻译：

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一种新的巨噬细胞亚群增加了冠状​​动脉疾病的遗传风险

背景：冠状动脉疾病（CAD）是全世界死亡的主要原因，受到环境和遗传因素的影响。尽管通过全基因组关联研究已经确定了超过 250 个遗传风险位点，但具体的致病变异及其调控机制仍然很大程度上未知，特别是在巨噬细胞等疾病相关细胞类型中。 方法：我们利用单细胞 RNA 测序和在原代人单核细胞衍生的巨噬细胞中采用单细胞多组学方法，探索参与冠状动脉粥样硬化关键致病事件（富含脂质的泡沫细胞的形成）的转录调控网络。通过划分不同巨噬细胞亚群的疾病遗传力来评估对 CAD 的相对遗传贡献。对 38 个人类动脉粥样硬化样本的单细胞 RNA-seq 数据集进行荟萃分析，为体内巨噬细胞亚群提供高分辨率交叉参考。 结果：我们通过联合分析基因表达和> 5000 个巨噬细胞的染色质可及性。与 CAD 全基因组关联研究数据的整合优先考虑了 121 个 CAD 相关遗传变异和 56 个候选致病基因。我们发现 CAD 遗传力分布并不均匀，并且在新型 CD52-hi 脂质处理巨噬细胞亚群的基因程序中特别丰富。这些 CD52-hi 巨噬细胞的脂蛋白积累明显减少，并且也在人类动脉粥样硬化斑块中发现。我们研究了风险变异 rs10488763 对FDX1的顺式调节作用，暗示在该位点的因果机制中招募 AP-1 和 C/EBP-β。 结论：我们的结果提供了巨噬细胞亚群不同作用的遗传证据动脉粥样硬化形成中的作用，并强调脂质处理巨噬细胞是遗传变异影响疾病的关键亚群。这些发现为使用单细胞多组学对全基因组关联研究结果进行功能精细绘图提供了一个公正的框架，并为动脉粥样硬化疾病背后的基因型-环境相互作用提供了新的见解。