Characterization of genomic regulation profiles in human mitral valve whole tissue, primary fibroblasts and artery primary cells to annotate genetic risk loci for mitral valve prolapse and fibromuscular dysplasia

Mitral valve prolapse (MVP) is a common valvopathy that leads to mitral insufficiency, heart failure and sudden death. Fibromuscular dysplasi (FMD) is a disease of middle size arteries such as the carotid or coronary arteries, leading to hypertension and stroke. Functional genomic studies in relevant cell types or tissues are needed to better characterize MVP associated variants and target genes. To establish the chromatin accessibility profiles, assess the functionality of variants and narrow down target genes at MVP and FMD loci, we mapped the open chromatin regions in nuclei from 11 human pathogenic, 7 non-pathogenic mitral valves, 3 primary fibroblasts cell lines and 6 arterial primary cell lines by an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq). We determined that MVP associated variants were highly enriched in mitral valve open chromatin regions, compared to heart and fibroblasts open chromatin regions, and identified potential causal variants at several loci. FMD associated variants were enriched in smooth muscle cells and fibroblasts open chromatin regions. We additionally performed circular chromatin conformation capture (4C-Seq) experiments on human dermal fibroblasts to provide evidence for potential target genes at 6 MVP loci.