Additional Candidate Genes for Human Atherosclerotic Disease Identified Through Annotation Based on Chromatin Organization.
BACKGROUND
As genome-wide association efforts, such as CARDIoGRAM and METASTROKE, are ongoing to reveal susceptibility loci for their underlying disease-atherosclerotic disease-identification of candidate genes explaining the associations of these loci has proven the main challenge. Many disease susceptibility loci colocalize with DNA regulatory elements, which influence gene expression through chromatin interactions. Therefore, the target genes of these regulatory elements can be considered candidate genes. Applying these biological principles, we used an alternative approach to annotate susceptibility loci and identify candidate genes for human atherosclerotic disease based on circular chromosome conformation capture followed by sequencing.


RESULTS
In human monocytes and coronary endothelial cells, we generated 63 chromatin interaction data sets for 37 active DNA regulatory elements that colocalize with known susceptibility loci for coronary artery disease (CARDIoGRAMplusC4D) and large artery stroke (METASTROKE). By circular chromosome conformation capture followed by sequencing, we identified a physical 3-dimensional interaction with 326 candidate genes expressed in at least 1 of these cell types, of which 294 have not been reported before. We highlight 16 genes based on expression quantitative trait loci.


CONCLUSIONS
Our findings provide additional candidate-gene annotation for 37 disease susceptibility loci for human atherosclerotic disease that are of potential interest to better understand the complex pathophysiology of cardiovascular diseases.
Saskia
S
Haitjema
Claartje A
CA
Meddens
Sander W
SW
van der Laan
Daniel
D
Kofink
Magdalena
M
Harakalova
Vinicius
V
Tragante
Hassan
H
Foroughi Asl
Jessica
J
van Setten
Maarten M
MM
Brandt
Joshua C
JC
Bis
Christopher
C
O'Donnell
Caroline
C
Cheng
Imo E
IE
Hoefer
Johannes
J
Waltenberger
Erik
E
Biessen
J Wouter
JW
Jukema
Pieter A F M
PA
Doevendans
Edward E S
EE
Nieuwenhuis
Jeanette
J
Erdmann
Johan L M
JL
Björkegren
Gerard
G
Pasterkamp
Folkert W
FW
Asselbergs
Hester M
HM
den Ruijter
Michal
M
Mokry
D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D058977:Molecular Sequence Annotation; D009000:Monocytes / Q000378:metabolism
D002843:Chromatin
atherosclerosis; coronary artery disease; epigenetics; gene regulation; ischemic stroke