Ma Lijiang, Tamis-Holland Jacqueline E, Mocci Giuseppe, Wolhuter Kathryn, Bryce Nicole S, Sajja Swathy, Amadori Letizia, Pradhan Payal, Chong Peik Sean, Sukhavasi Katyayani, Cheng Haoxiang, Li Ling, Pang Shichao, Schadt Eric E, Schunkert Heribert, von Scheidt Moritz, Ruusalepp Arno, Moreno Pedro R, Hao Ke, Giannarelli Chiara, Miller Clint L, Kovacic Jason C, Björkegren Johan L M
Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomic Sciences Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1498, New York, NY, 10029-6574, USA.
Basic Res Cardiol. 2025 Jul 1. doi: 10.1007/s00395-025-01105-0.
Coronary artery disease (CAD) is a major cause of global morbidity and mortality. Macrophages play a central role in orchestrating this disease process. In 2016, we initiated the STARNET primary blood macrophage study, followed by the multi-ethnic NGS-PREDICT primary blood macrophage study in 2018. We applied integrative systems genetics analysis to explore and validate the role of macrophage gene regulatory co-expression networks (GRNs) in clinically significant CAD. This study included 318 CAD cases and 134 CAD-free controls in STARNET, and 95 CAD cases and 35 CAD-free controls in NGS-PREDICT. Primary leukocytes were isolated from blood and differentiated into macrophages in vitro, followed by RNA extraction and deep sequencing (RNAseq). In STARNET, we analyzed differentially expressed genes, inferred macrophage GRNs, assessed the phenotypic associations and functions of these GRNs, and determined their key driver genes. Integrative analysis of STARNET expression quantitative traits (eQTLs) with genotype data from genome-wide association studies was performed to determine the content of CAD candidate genes in these GRNs, and their contributions to CAD heritability. Five independent RNAseq datasets were used to retrospectively validate CAD-associated macrophage GRNs, followed by prospective validation in the NGS-PREDICT study. Using the STARNET datasets, we identified 23 macrophage GRNs. Of these, GRN stood out as being causally associated with CAD severity (SYNTAX score) and comprised 729 genes and 90 key drivers, with the top key driver being NEIL1. GRN accounted for 3.73% of CAD heritability and contained 34 candidate genes previously identified by GWAS of CAD. Functional analysis of GRN revealed a large portion of genes involved in the biological process of SRP-dependent co-translational protein targeting to the membrane. GRN replicated retrospectively in five independent human arterial wall RNAseq datasets, and prospectively in the NGS-PREDICT study. To prevent clinically significant CAD, GRN and its top key driver NEIL1 may be suitable therapeutic targets to modify SRP-dependent co-translational targeting of proteins to the endoplasmic reticulum in macrophages.
冠状动脉疾病（CAD）是全球发病和死亡的主要原因。巨噬细胞在这一疾病进程中起着核心作用。2016年，我们启动了STARNET原发性血液巨噬细胞研究，随后在2018年开展了多民族的NGS-PREDICT原发性血液巨噬细胞研究。我们应用综合系统遗传学分析来探索和验证巨噬细胞基因调控共表达网络（GRNs）在具有临床意义的CAD中的作用。本研究在STARNET中纳入了318例CAD病例和134例无CAD对照，在NGS-PREDICT中纳入了95例CAD病例和35例无CAD对照。从血液中分离出原代白细胞并在体外分化为巨噬细胞，随后进行RNA提取和深度测序（RNAseq）。在STARNET中，我们分析了差异表达基因，推断巨噬细胞GRNs，评估了这些GRNs的表型关联和功能，并确定了它们的关键驱动基因。对STARNET表达数量性状（eQTLs）与全基因组关联研究的基因型数据进行综合分析，以确定这些GRNs中CAD候选基因的含量及其对CAD遗传度的贡献。使用五个独立的RNAseq数据集对与CAD相关的巨噬细胞GRNs进行回顾性验证，随后在NGS-PREDICT研究中进行前瞻性验证。利用STARNET数据集，我们鉴定出23个巨噬细胞GRNs。其中，GRN脱颖而出，与CAD严重程度（SYNTAX评分）存在因果关联，包含729个基因和90个关键驱动基因，首要关键驱动基因是NEIL1。GRN占CAD遗传度的3.73%，包含34个先前通过CAD全基因组关联研究鉴定出的候选基因。对GRN的功能分析表明，很大一部分基因参与了依赖信号识别颗粒（SRP）的共翻译蛋白质靶向膜的生物学过程。GRN在五个独立的人类动脉壁RNAseq数据集中得到回顾性验证，并在NGS-PREDICT研究中得到前瞻性验证。为预防具有临床意义的CAD，GRN及其首要关键驱动基因NEIL1可能是合适的治疗靶点，可用于改变巨噬细胞中依赖SRP的蛋白质共翻译靶向内质网的过程。
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