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

Örjan Åkerborg, Rapolas Spalinskas, Sailendra Pradhananga, Anandashankar Anil, Pontus Höjer, Flore Anne Poujade, Lasse Folkersen, Per Eriksson, Pelin Sahlén*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

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 (≈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.

Original languageEnglish
Article numbere002353
JournalCirculation: Genomic and precision medicine
Volume12
Issue number3
Pages (from-to)101-112
Number of pages12
ISSN2574-8300
DOIs
Publication statusPublished - 2019

Keywords

  • Coronary artery disease
  • Gene
  • Genomics
  • Haplotype
  • Inflammation

Cite this

Åkerborg, Ö., Spalinskas, R., Pradhananga, S., Anil, A., Höjer, P., Poujade, F. A., ... Sahlén, P. (2019). High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways. Circulation: Genomic and precision medicine, 12(3), 101-112. [e002353]. https://doi.org/10.1161/CIRCGEN.118.002353
Åkerborg, Örjan ; Spalinskas, Rapolas ; Pradhananga, Sailendra ; Anil, Anandashankar ; Höjer, Pontus ; Poujade, Flore Anne ; Folkersen, Lasse ; Eriksson, Per ; Sahlén, Pelin. / High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways. In: Circulation: Genomic and precision medicine. 2019 ; Vol. 12, No. 3. pp. 101-112.
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abstract = "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 (≈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.",
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author = "{\"O}rjan {\AA}kerborg and Rapolas Spalinskas and Sailendra Pradhananga and Anandashankar Anil and Pontus H{\"o}jer and Poujade, {Flore Anne} and Lasse Folkersen and Per Eriksson and Pelin Sahl{\'e}n",
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Åkerborg, Ö, Spalinskas, R, Pradhananga, S, Anil, A, Höjer, P, Poujade, FA, Folkersen, L, Eriksson, P & Sahlén, P 2019, 'High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways', Circulation: Genomic and precision medicine, vol. 12, no. 3, e002353, pp. 101-112. https://doi.org/10.1161/CIRCGEN.118.002353

High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways. / Åkerborg, Örjan; Spalinskas, Rapolas; Pradhananga, Sailendra; Anil, Anandashankar; Höjer, Pontus; Poujade, Flore Anne; Folkersen, Lasse; Eriksson, Per; Sahlén, Pelin.

In: Circulation: Genomic and precision medicine, Vol. 12, No. 3, e002353, 2019, p. 101-112.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways

AU - Åkerborg, Örjan

AU - Spalinskas, Rapolas

AU - Pradhananga, Sailendra

AU - Anil, Anandashankar

AU - Höjer, Pontus

AU - Poujade, Flore Anne

AU - Folkersen, Lasse

AU - Eriksson, Per

AU - Sahlén, Pelin

PY - 2019

Y1 - 2019

N2 - 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 (≈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.

AB - 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 (≈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.

KW - Coronary artery disease

KW - Gene

KW - Genomics

KW - Haplotype

KW - Inflammation

U2 - 10.1161/CIRCGEN.118.002353

DO - 10.1161/CIRCGEN.118.002353

M3 - Journal article

VL - 12

SP - 101

EP - 112

JO - Circulation: Genomic and precision medicine

JF - Circulation: Genomic and precision medicine

SN - 2574-8300

IS - 3

M1 - e002353

ER -