The research team took an even closer look at the relevant region of chromosome 9, called 9p21, and discovered that the 9p21 DNA sequence, which is devoid of protein-coding genes, is particularly rich in potential regulatory elements influencing disease risk. They identified 33 "enhancers" or regulatory elements responsible for activating or repressing genes. The researchers determined that the 9p21 interval is the second densest interval for predicted enhancers in the entire human genome, and six times denser than the genome on average.

The DNA variants associated with CAD appear to disrupt enhancer activity involved in cellular signaling and response to inflammation in vascular endothelial cells - the cells that form the inner lining of major blood vessels.

"Our work highlights the new approach we developed for analyzing long-range chromosomal interactions and the utility of such methods for deciphering the functions of non-coding DNA variants associated with disease risk," said Michael G. Rosenfeld, MD, a professor in the UCSD Department of Medicine, Howard Hughes Medical Institute investigator and a corresponding author of the study.

The UCSD researchers plan to scale up the new approach and use other methods to annotate additional non-coding DNA variants identified through GWAS studies as being linked to human disease.

"There are thousands of DNA regulatory variants that incur increased risk for disease that we can functionally characterize for their effect on long-range interactions," said Olivier Harismendy, PhD, first author of the study and an assistant project scientist in the UCSD Department of Pediatrics and Moores Cancer Center.

Source: University of California