In a study recently published in the Journal of Biological Chemistry, investigators from Cleveland Clinic Lerner Research Institute identified the specific causal gene associated with a chromosomal region (loci) long connected with risk for coronary artery disease (CAD).
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The researchers, co-led by Qing Kenneth Wang, PhD, MBA, and Qiuyun Chen, PhD, both of the Lerner Research Institute’s Department of Cardiovascular and Metabolic Sciences, focused their investigation on genes found within a specific locus of chromosome 9 (9p21.3). Previous genome-wide association studies revealed that this chromosomal region is highly correlated with CAD risk, but the gene connected to that region had not previously been identified.
While the locus contains a handful of different genes, one in particular stood out to the researchers. ANRIL is a long noncoding gene that, notably, is highly expressed in endothelial cells, which play an important role in CAD. Damage to endothelial cells in the coronary arteries spurs an inflammatory response that leads to development of arterial plaques characteristic of CAD.
The researchers observed that using small interfering RNA to silence ANRIL caused an uptick in CAD-driving endothelial cell behavior, while increasing its expression reduced these behaviors, suggesting that inhibited ANRIL expression may increase disease risk.
As a long noncoding RNA, ANRIL does not actually code for proteins but instead affects expression of other genes. To determine which downstream genes were affected by ANRIL manipulation, the team conducted a series of gene expression analyses. While a total of 10 genes were dysregulated in response to ANRIL knockdown, further investigation revealed that three of these are of particular importance. They found that “turning off” ANRIL reduced expression of the downstream genes CLIP1, EZR and LYVE1, which also affect the activity of endothelial and inflammatory cells that play a role in atherosclerotic plaque and CAD development.
While future studies will be important to elucidate the specific molecular mechanisms at play, these findings are important in that they show for the first time that ANRIL is the causal gene for CAD at the locus within chromosome 9, the most common CAD locus implicated in genome-wide association studies, and they identify the other genes with which it interacts to drive disease. Furthermore, the findings suggest that maintaining or increasing ANRIL expression may be a viable target for future CAD therapies.
Hyosuk Cho, Department of Cardiovascular and Metabolic Sciences, is first author on the paper, which was supported in part by grants from the National Heart, Lung, and Blood Institute and the American Heart Association. Qiuyun Chen, PhD, is project staff in Dr. Wang’s laboratory.