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A promoter interaction map for cardiovascular disease genetics.

ABSTRACT: Over 500 genetic loci have been associated with risk of cardiovascular diseases (CVDs); however, most loci are located in gene-distal non-coding regions and their target genes are not known. Here, we generated high-resolution promoter capture Hi-C (PCHi-C) maps in human induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (CMs) to provide a resource for identifying and prioritizing the functional targets of CVD associations. We validate these maps by demonstrating that promoters preferentially contact distal sequences enriched for tissue-specific transcription factor motifs and are enriched for chromatin marks that correlate with dynamic changes in gene expression. Using the CM PCHi-C map, we linked 1999 CVD-associated SNPs to 347 target genes. Remarkably, more than 90% of SNP-target gene interactions did not involve the nearest gene, while 40% of SNPs interacted with at least two genes, demonstrating the importance of considering long-range chromatin interactions when interpreting functional targets of disease loci.

SUBMITTER: Montefiori LE

PROVIDER: S-EPMC6053306 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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A promoter interaction map for cardiovascular disease genetics.

Montefiori Lindsey E LE Sobreira Debora R DR Sakabe Noboru J NJ Aneas Ivy I Joslin Amelia C AC Hansen Grace T GT Bozek Grazyna G Moskowitz Ivan P IP McNally Elizabeth M EM Nóbrega Marcelo A MA

eLife 20180710

Over 500 genetic loci have been associated with risk of cardiovascular diseases (CVDs); however, most loci are located in gene-distal non-coding regions and their target genes are not known. Here, we generated high-resolution promoter capture Hi-C (PCHi-C) maps in human induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (CMs) to provide a resource for identifying and prioritizing the functional targets of CVD associations. We validate these maps by demonstrating that promoter ...[more]

PMID: 29988018

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Project description:Coronary artery disease (CAD) is a complex disease with environmental and genetic determinants. Many other cardiovascular (CV) conditions also have a genetic basis. A positive family history of CV disease in first-degree relatives is a strong independent risk factor for CAD as well as several other cardiac disorders. This genetic susceptibility to CV diseases will be understood more clearly when combined with genomics, proteomics and genotyping.The Department of Cardiology at Gold Coast Hospital (Queensland, Australia) with the Faculty of Health, Science and Medicine at Bond University (Queensland, Australia) established the Gold Coast Cardiovascular DNA bank in 2006. The dataset on each individual volunteer includes coronary angiograms, clinical information (including a coronary risk factor profile), biochemical (including cardiac biomarkers) and hematological parameters, and electrocardiograms and echocardiograms. The establishment of the DNA biobank was associated with several key challenges, both technical and logistic.Given the comprehensive nature of the information gathered, the present study has the added potential of identifying genes associated with nonischemic cardiomyopathies, valvular heart disease, congenital heart diseases and other cardiomyopathies. Pooling data from results obtained here with multiple existing DNA biobanks and registries will help in finding answers to the genetic conundrum in CV diseases. The present DNA biobank will serve as a resource well into the future as the technology and science of medical genetics evolve.The most frequent pathology encountered in the biobank is CAD. The significance of the familial occurrence of CAD has been the focus of research for at least 50 years, with a positive family history of CV disease emerging as an independent predictor of risk in the development of CAD. By applying the knowledge learned from studies on CV genetics together with the data from the DNA biobank, scientists may be able to effectively prevent and treat CV diseases in the future.

Dataset Information

A promoter interaction map for cardiovascular disease genetics.

Publications

A promoter interaction map for cardiovascular disease genetics.

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