Mystery of 9p21 link to arterial disease begins to unravel

The strongest genomic link to premature coronary artery disease (CAD) currently known involves a sequence polymorphism in a 58-kilobase (kb) interval on chromosome 9p21.  However, exactly how polymorphisms in this area led to CAD has until now remained a mystery, as the region in question does not contain any protein-coding genes.

Visel et al. created a mouse 9p21 knockout model by finding a region of the mouse genome that corresponded to the 9p21 locus in humans.  Deletion of a 70-kb non-coding interval on mouse chromosome 4 was found not only to affect the proliferation properties of neighbouring genes (Cdkn2a/b), but also to alter the proliferation properties of vascular cells.  Primary cultures of aortic smooth muscle cells from the knockout mice showed increased vascular proliferation and decreased senescence, a phenotype consistent with accelerated CAD.  Overall, knockout mice showed increased mortality both during development and as adults.
Conclusions:
This genetic study reveals potential mechanisms by which 9p21, a locus strongly associated with cardiovascular disease in man, may be connected with early cardiovascular disease.  However, this experimental work was performed in mice, and further work will need to be performed in man to confirm these findings.
Visel A, Zhu Y, May D, et al. Targeted depletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature 2010; DOI:10.1038/nature08801.

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