Systems Genetics in Human Endothelial Cells Identifies Non-coding Variants Modifying Enhancers, Expression, and
Lindsey K Stolze1, Austin C Conklin1, Michael B Whalen1
1Department of Cellular and Molecular Medicine, College of Medicine, University of Arizona, Tucson, AZ 85721, USA.
American Journal of Human Genetics
|May 23, 2020
Summary
This study identifies novel genetic variants in endothelial cells (ECs) that regulate gene expression and influence complex diseases like coronary artery disease (CAD). These findings highlight the endothelium
Area of Science:
- Human Genetics
- Molecular Biology
- Cardiovascular Research
Background:
- Identifying causal variants for complex diseases requires understanding functional regulatory elements in relevant cell types.
- Endothelial cells (ECs) play a critical role in cardiovascular health and disease, yet their regulatory landscape is not fully understood.
Purpose of the Study:
- To discover functional regulatory genetic variants within human aortic endothelial cells.
- To investigate the impact of these variants on gene expression and complex disease traits.
- To elucidate the role of the endothelium in genetic predisposition to disease.
Main Methods:
- Collected genetic and transcriptomic data from up to 157 human donors.
- Performed epigenomic profiling (e.g., eQTL analysis) on up to 44 donors.
- Utilized CRISPR interference, allele-specific reporter assays, and chromatin conformation capture for validation.
Main Results:
- Discovered thousands of novel expression quantitative trait loci (eQTLs) specific to endothelial cells.
- Identified over 3,000 regulatory elements modulated by variants affecting ETS, AP-1, and NF-kB binding motifs.
- Validated long-range enhancer variants influencing VEGFC, FGD6, and KIF26B.
- Found enrichment of identified regulatory SNPs in coronary artery disease (CAD) loci, implicating genes like PECAM-1, FES, and AXL.
- Demonstrated significant roles for EC regulatory variants in traits including pulse pressure, blood protein levels, and monocyte count.
- Identified pleiotropic effects of MFAP2 promoter SNPs on human disease traits.
Conclusions:
- Genetic predisposition to complex diseases may be significantly mediated through endothelial cell regulation.
- Novel endothelial cell-specific regulatory variants contribute to cardiovascular disease risk.
- The endothelium represents a key cellular target for understanding and potentially treating complex human diseases.
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