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Updated: Jun 26, 2025
Isolation of Macrophage Subsets and Stromal Cells from Human and Mouse Myocardial Specimens
Published on: December 17, 2019
A Novel Macrophage Subpopulation Conveys Increased Genetic Risk of Coronary Artery Disease
Jiahao Jiang1, Thomas K Hiron1, Thomas A Agbaedeng1
1Nuffield Department of Medicine, Wellcome Centre for Human Genetics (J.J., T.K.H., T.A.A., Y.M., E.D., J.B., L.J.D., C.A.O.), University of Oxford, United Kingdom.
Insights
This study reveals that specific macrophage subpopulations, particularly CD52-hi lipid-handling cells, are crucial for coronary artery disease (CAD) heritability. These findings illuminate genetic influences on atherosclerosis and identify novel therapeutic targets.
Area of Science:
- Genomics and Cardiovascular Research
- Single-cell Multiomics
- Atherosclerosis Pathogenesis
Background:
- Coronary artery disease (CAD) is a leading global cause of death, influenced by genetic and environmental factors.
- While numerous genetic risk loci for CAD exist, causal variants and regulatory mechanisms in macrophages remain largely unknown.
- Macrophages play a critical role in the development of coronary atherosclerosis, particularly in foam cell formation.
Purpose of the Study:
- To explore the transcriptional regulatory network in macrophages involved in coronary atherosclerosis.
- To assess the genetic contribution to CAD by partitioning heritability across macrophage subpopulations.
- To identify specific genetic variants and genes influencing CAD pathogenesis in macrophages.
Main Methods:
- Utilized single-cell RNA sequencing (scRNA-seq) and multiomics in human monocyte-derived macrophages.
- Conducted meta-analysis of scRNA-seq data from 38 human atherosclerotic samples.
- Integrated CAD genome-wide association study (GWAS) data with chromatin accessibility and gene expression profiles.
Main Results:
- Identified 18,782 cis-regulatory elements and profiled >5000 macrophages.
- Prioritized 121 CAD-related genetic variants and 56 candidate causal genes.
- Discovered enriched CAD heritability in a novel CD52-hi lipid-handling macrophage subpopulation, which showed reduced lipoprotein accumulation.
Conclusions:
- Macrophage subsets play divergent roles in atherogenesis, with lipid-handling macrophages being key mediators of genetic risk.
- Provides a framework for functional fine-mapping of GWAS results using single-cell multiomics.
- Offers new insights into genotype-environment interactions in atherosclerotic disease.
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 such as 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.
