Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice

Axel Visel, Yiwen Zhu, Dalit May, Veena Afzal, Elaine Gong, Catia Attanasio, Matthew J. Blow, Jonathan C. Cohen, Edward M. Rubin and Len A. Pennacchio ()
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Axel Visel: MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
Yiwen Zhu: MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
Dalit May: MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
Veena Afzal: MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
Elaine Gong: MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
Catia Attanasio: MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
Matthew J. Blow: MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
Jonathan C. Cohen: and Center for Human Nutrition, UT Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA
Edward M. Rubin: MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
Len A. Pennacchio: MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA

Nature, 2010, vol. 464, issue 7287, 409-412

Abstract: Heart disease risk identified It has been know for several years that genetic variations in a stretch of DNA on chromosome 9p21 are linked to the incidence of coronary artery disease. The nature of this link has remained unknown, not least because the 58-kilobase culprit genomic interval contains no known protein-encoding genes, and it appears unlinked to known major contributors to the disease. Now an experiment in which the corresponding stretch of DNA was deleted in mice shows that this part of the chromosome regulates cardiac expression of two genes located some 100,000 base pairs away. The genes, Cdkn2a and Cdkn2b, encode cyclin-dependent kinase inhibitors, and their down-regulation in a mouse model results in excessive aortic smooth muscle cell proliferation. This suggests that dysregulation of vascular cell proliferation underlies cardiac disease susceptibility linked to chromosome 9p21 variation.

Date: 2010
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DOI: 10.1038/nature08801

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