Additional Candidate Genes for Human Atherosclerotic Disease Identified Through Annotation Based on Chromatin Organization

Haitjema S, Meddens CA, Laan SW, Kofink D, Harakalova M, Tragante V, {Foroughi Asl} H, Setten J, Brandt MM, Bis JC, O'Donnell C, Cheng C, Hoefer IE, Waltenberger J, Biessen E, Jukema JW, Doevendans PA, Nieuwenhuis EE, Erdmann J, Bjorkegren JL, Pasterkamp G, Asselbergs FW, Ruijter HM, Mokry M

Abstract

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. METHODS AND 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.