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The Capital Region of Denmark - a part of Copenhagen University Hospital
E-pub ahead of print

High-resolution Regulatory Maps Connect Vascular Risk Variants to Disease Related Pathways

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  • Örjan Åkerborg
  • Rapolas Spalinskas
  • Sailendra Pradhananga
  • Anandashankar Anil
  • Pontus Höjer
  • Flore-Anne Poujade
  • Lasse Folkersen
  • Per Eriksson
  • Pelin Sahlén
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BACKGROUND: Genetic variant landscape of coronary artery disease (CAD) is dominated by non-coding variants among which many occur within putative enhancers regulating the expression levels of relevant genes. It is crucial to assign the genetic variants to their correct genes both to gain insights into perturbed functions and better assess the risk of disease.

METHODS: In this study, we generated high-resolution genomic interaction maps (~750 bases) in aortic endothelial, smooth muscle cells and THP-1 macrophages stimulated with lipopolysaccharide using Hi-C coupled with sequence capture targeting 25,429 features including variants associated with CAD. We also sequenced their transcriptomes and mapped putative enhancers using chromatin immunoprecipitation with an antibody against H3K27Ac.

RESULTS: The regions interacting with promoters showed strong enrichment for enhancer elements and validated several previously known interactions and enhancers. We detected interactions for 727 risk variants obtained by genome-wide association studies (GWAS) and identified novel as well as established genes and functions associated with cardiovascular diseases. We were able to assign potential target genes for additional 398 GWAS variants using haplotype information, thereby identifying additional relevant genes and functions. Importantly, we discover that a subset of risk variants interact with multiple promoters and their expression levels were strongly correlated.

CONCLUSIONS: In summary, we present a catalogue of candidate genes regulated by coronary artery disease related variants and believe that it will be an invaluable resource to further the investigation of cardiovascular pathologies and disease.

Original languageEnglish
JournalCirculation. Genomic and precision medicine
ISSN2574-8300
DOIs
Publication statusE-pub ahead of print - 20 Feb 2019

ID: 56747005