NATURE: Frazer et al. Discover Gene Hotspot for Coronary Artery Disease Risk

Dr. Kelly Frazer


Nature, February 10, 2010 – Dr. Kelly Frazer, a pediatrics professor and Division Chief, Genome Information Sciences at UC San Diego and Rady Children’s Hospital, recently published a discovery that a gene desert on chromosome 9 was a hotspot for coronary artery disease (CAD) risk.

Using a new approach to detect long-distance chromosomal interactions, Frazer and colleagues were able to follow up on results of the widely reported genome-wide association studies in 2007 and 2008, noting that the gene desert interval on chromosome 9 contained DNA variants (called single nucleotide polymorphisms or SNPs) that are associated with CAD and type 2 diabetes mellitus.

Genome-wide association studies are used to compare the genomes of many people for genetic variations and have been broadly applied in the past few years to study hundreds of diseases and complex traits. Gene deserts are large genomic segments devoid of genes.

The DNA variants associated with CAD and T2D are located close to one another on chromosome 9, but inherited independently so genetic risk for developing CAD is not associated with risk for the T2D.

In comparing the genomes of people with heart disease and people without, Frazer and colleagues found that those who carried the chromosome 9 DNA risk variants for CAD had a two-fold higher risk of early onset myocardial infarction (a heart attack) than non-carriers.

"The association of this interval with CAD was a surprise and not expected as it is a 'gene desert' and the flanking genes, which are far away, have little to do with lipid metabolism, one of the primary factors in heart disease," Frazer comments.

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 regulatory elements known as ‘enhancers’, that are 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.

"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.

Co-authors of the study include Dimple Notani, Xiaoyuan Song and Bogdan Tanasa of the UCSD Department of Medicine, Howard Hughes Medical Institute; Xiang-Dong Fu of the UCSD Department of Cellular and Molecular Medicine; Nathaniel Heintzman and Bing Ren of the Ludwig Institute for Cancer Research; and Nazli G. Rahim and Eric J. Topol of Scripps Genomic Medicine, Scripps Translational Science Institute and The Scripps Research Institute.

Based on these findings, Francis Collins, director of the National Institutes of Health and a leader in the original Human Genome Project, publicly described the chromosome 9 interval as "like the seat of the soul of the genome."


Olivier Harismendy, Dimple Notani, Xiaoyuan Song, Nazli G. Rahim, Bogdan Tanasa, Nathaniel Heintzman, Bing Ren, Xiang-Dong Fu, Eric J. Topol, Michael G. Rosenfeld, Kelly A. Frazer. 9p21 DNA variants associated with coronary artery disease impair interferon-γ signalling response. Nature, 2011; 470 (7333): 264 DOI: 10.1038/nature09753

Written by: Shivani Singh, Sr. Writer, Pediatrics, UC San Diego, Rady Children's Hospital,

Scientific Contact: Prof. Kelly Frazer, Division Chief, Genome Information Sciences, Pediatrics, UC San Diego, Rady Children's Hospital