Enhancer promoter interactome and Mendelian randomization identify network of druggable vascular genes in coronary artery disease.
Arnaud ChignonSamuel MathieuAnne RufiangeDéborah ArgaudPierre VoisineYohan BosséBenoit J ArsenaultSébastien ThériaultPatrick MathieuPublished in: Human genomics (2022)
Coronary artery disease (CAD) is a multifactorial disorder, which is partly heritable. Herein, we implemented a mapping of CAD-associated candidate genes by using genome-wide enhancer-promoter conformation (H3K27ac-HiChIP) and expression quantitative trait loci (eQTL). Enhancer-promoter anchor loops from human coronary artery smooth muscle cells (HCASMC) explained 22% of the heritability for CAD. 3D enhancer-promoter genome mapping of CAD-genes in HCASMC was enriched in vascular eQTL genes. By using colocalization and Mendelian randomization analyses, we identified 58 causal candidate vascular genes including some druggable targets (MAP3K11, CAMK1D, PDGFD, IPO9 and CETP). A network analysis of causal candidate genes was enriched in TGF beta and MAPK pathways. The pharmacologic inhibition of causal candidate gene MAP3K11 in vascular SMC reduced the expression of athero-relevant genes and lowered cell migration, a cardinal process in CAD. Genes connected to enhancers are enriched in vascular eQTL and druggable genes causally associated with CAD.
Keyphrases
- genome wide
- coronary artery disease
- dna methylation
- transcription factor
- genome wide identification
- copy number
- binding protein
- coronary artery
- gene expression
- percutaneous coronary intervention
- bioinformatics analysis
- cardiovascular events
- poor prognosis
- coronary artery bypass grafting
- high resolution
- genome wide analysis
- heart failure
- oxidative stress
- cell proliferation
- mass spectrometry
- signaling pathway
- aortic valve
- molecular dynamics simulations
- pi k akt
- genome wide association study