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High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0002-1648-6426
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
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2019 (English)In: Circulation. Genomic and precision medicine, ISSN 2574-8300, Vol. 12, no 3, article id e002353Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Genetic variant landscape of coronary artery disease is dominated by noncoding 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 (similar to 750 bases) in aortic endothelial, smooth muscle cells and THP-1 (human leukemia monocytic cell line) macrophages stimulated with lipopolysaccharide using Hi-C coupled with sequence capture targeting 25 429 features, including variants associated with coronary artery disease. 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 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 genome-wide association studies variants using haplotype information, thereby identifying additional relevant genes and functions. Importantly, we discovered that a subset of risk variants interact with multiple promoters and their expression levels were strongly correlated. CONCLUSIONS: In summary, we present a catalog of candidate genes regulated by coronary artery disease-related variants and think that it will be an invaluable resource to further the investigation of cardiovascular pathologies and disease.

Place, publisher, year, edition, pages
NLM (Medline) , 2019. Vol. 12, no 3, article id e002353
Keywords [en]
coronary artery disease, gene, haplotype, inflammation, genomics
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:kth:diva-251721DOI: 10.1161/CIRCGEN.118.002353ISI: 000466741300003PubMedID: 30786239Scopus ID: 2-s2.0-85063933618OAI: oai:DiVA.org:kth-251721DiVA, id: diva2:1316600
Note

QC 20190520

Available from: 2019-05-20 Created: 2019-05-20 Last updated: 2019-05-29Bibliographically approved

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Spalinskas, RapolasPradhananga, SailendraSahlén, Pelin

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Åkerborg, ÖrjanSpalinskas, RapolasPradhananga, SailendraAnil, AnandashankarHöjer, PontusSahlén, Pelin
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