A Novel Macrophage Subpopulation Conveys Increased Genetic Risk of Coronary Artery Disease

Jiang, Jiahao; Hiron, Thomas K.; Agbaedeng, Thomas; Malhotra, Yashaswat; Drydale, Edward; Bancroft, James; Ng, Esther; Reschen, Michael E.; Davison, Lucy J.; O’Callaghan, Chris A.

Abstract

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.

Citation

Jiang, J., Hiron, T. K., Agbaedeng, T., Malhotra, Y., Drydale, E., Bancroft, J., Ng, E., Reschen, M. E., Davison, L. J., & O’Callaghan, C. A. (2024). A Novel Macrophage Subpopulation Conveys Increased Genetic Risk of Coronary Artery Disease. Circulation Research, 135(1), 6-25. https://doi.org/10.1161/circresaha.123.324172

• Journal Article Type: Article
• Acceptance Date: May 1, 2024
• Online Publication Date: May 15, 2024
• Publication Date: 2024
• Deposit Date: May 16, 2024
• Publicly Available Date: Jul 15, 2024
• Journal: Circulation Research
• Print ISSN: 0009-7330
• Publisher: American Heart Association
• Peer Reviewed: Peer Reviewed
• Volume: 135
• Issue: 1
• Pages: 6-25
• DOI: https://doi.org/10.1161/circresaha.123.324172
• Keywords: atherosclerosis; coronary artery disease; cholesterol, LDL; genome-wide association study; macrophages; multiomics; single cell analysis; SINGLE-CELL; MONOCYTE; ATHEROSCLEROSIS; TRANSCRIPTION; ARCHITECTURE; LOCI; HERITABILITY; ASSOCIATION; ANNOTATION; EXP
• Additional Information: Received: 2023-12-21; Accepted: 2024-05-01; Published: 2024-05-15