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Mouse Model for Common Genetic Risk Factor for Cardiovascular Disease

IB-2789

APPLICATIONS OF TECHNOLOGY:

ADVANTAGES:

ABSTRACT:

Previous large cohort studies of white and Asian populations have indicated that a non-coding region on the 9p21 human chromosome is a risk factor for CAD, independent of other known risk factors such as high cholesterol and diabetes. Unfavorable variations (sequence polymorphisms) in this non-coding region are extremely common, occurring on at least one copy of the 9p21 chromosome in approximately 75% of the studied populations. When these unfavorable variations occur on both copies of the chromosome, as they do in 25% of the studied populations, they are associated with a 30% increase in the risk of CAD.

The mechanism of this genetic risk factor has remained unclear until now. The Berkeley Lab scientists identified the orthologous non-coding DNA region in mice and developed a strain with this region deleted. These knock-out mice had about 90% lower-than-normal expression of Cdkn2a and Cdkn2b in the heart. These genes are known to regulate cell proliferation and to be mutated in certain cancers. In addition, aortic smooth muscle cells from the knock-out mice proliferated at higher rates than did cells from normal mice, and altered smooth muscle cell proliferation is a known contributor to CAD.

In sum, these results suggest that the unfavorable sequence variations in the non-coding DNA region may induce CAD by increasing the growth of vascular cells through the downregulation of Cdkn2a and Cdkn2b. This mechanism may be susceptible to intervention with new or existing drugs that affect these genes or the cellular components that they act upon.

CAD is a leading cause of death worldwide and the cause of one in five deaths in the US. The Berkeley Lab results indicate potential methods for preventing and treating CAD in a large section of the population, while the mouse model opens the door for further research.

DEVELOPMENT STAGE: Knock-out mice and corresponding targeted mouse embryonic stem cells available.

STATUS: Patent pending. Available for licensing/bailment.

FOR MORE INFORMATION:
A. Visel, Zhu Y., May D., Afzal V., Gong E., Attanasio C., Blow M.J., Cohen J.C., Rubin E.M., Pennacchio L.A. “Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice,” Nature 464(7287):409-12 (2010).

SEE THESE OTHER BERKELEY LAB TECHNOLOGIES IN THIS FIELD:

Transgenic Mice: Atherosclerosis Portfolio, IB-1042

Assessing Endothelial Function with a Standard Blood Pressure Cuff, IB-2772

Noninvasive Detection of Preclinical Cardiovascular Disease, IB-1796

REFERENCE NUMBER: IB-2789

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