The buildup of plaque inside coronary arteries can lead to coronary artery disease (CAD), the most common cause of death in the United States for both men and women. Though researchers suspect that both environmental and genetic factors play a role in the development of CAD, they have had trouble pinpointing the genomic loci associated with increased CAD susceptibility. Now, new research on mice provides a potential explanation for why common variants in a stretch of non-coding DNA raise a person's risk of CAD.

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A few years ago, genome-wide association studies found that people who carry certain mutations in a non-coding region of the 9p21 chromosome have an increased risk of developing CAD. But these mutations are not associated with heart disease risk factors such as diabetes or hypertension, hindering our understanding of the link between the mutations and CAD. In an effort to better understand this link, Len Pennacchio of Lawrence Berkeley National Laboratory (Berkeley, California) and colleagues knocked out this non-coding region in a corresponding chromosome in mice.

The research team found that though these 'knock-out' mice were viable, many died earlier than did normal mice. In addition, knock-out mice had reduced expression of two genes that are almost 100,000 base pairs away from the deleted DNA (Nature published online 21 February 2010; doi:10.1038/nature08801). These genes, Cdkn2a and Cdkn2b, control cell cycle proliferation. Reduced expression of these genes might account for why heart muscle cells taken from knock-out mice multiplied faster than did cells from normal mice.

Interestingly, the knock-out mice did not develop plaque buildup in their arteries, a phenomenon that does occur in humans who have mutations in this non-coding region of chromosome 9p21. Additionally, some of the knock-out mice developed tumors, which are not normally associated with heart disease in humans.

Nonetheless, these results provide a possible mechanism for the association of mutations in this non-coding region of DNA with an increased risk of developing CAD. If this mechanistic link is established in humans, researchers might be able to develop therapies that treat or prevent CAD by activating CDKN2A and CDKN2B. Pennacchio thinks that by studying the function of non-coding DNA, scientists will uncover genetic causes of other diseases. “Non-coding DNA is a huge area of the genome, waiting to be explored, which could have huge dividends for understanding and treating disease,” Pennacchio said in a press release from Berkeley Lab.