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, Len A. Pennacchio

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Abstract

Sequence polymorphisms in a 58-kilobase (kb) interval on chromosome 9p21 confer a markedly increased risk of coronary artery disease (CAD), the leading cause of death worldwide. The variants have a substantial effect on the epidemiology of CAD and other life-threatening vascular conditions because nearly one-quarter of Caucasians are homozygous for risk alleles. However, the risk interval is devoid of protein-coding genes and the mechanism linking the region to CAD risk has remained enigmatic. Here we show that deletion of the orthologous 70-kb non-coding interval on mouse chromosome 4 affects cardiac expression of neighbouring genes, as well as proliferation properties of vascular cells. Chr4 Δ70kb70kb mice are viable, but show increased mortality both during development and as adults. Cardiac expression of two genes near the non-coding interval, Cdkn2a and Cdkn2b, is severely reduced in chr4 Δ70kb70kb mice, indicating that distant-acting gene regulatory functions are located in the non-coding CAD risk interval. Allele-specific expression of Cdkn2b transcripts in heterozygous mice showed that the deletion affects expression through a cis-acting mechanism. Primary cultures of chr4 Δ70kb/ Δ70kb aortic smooth muscle cells exhibited excessive proliferation and diminished senescence, a cellular phenotype consistent with accelerated CAD pathogenesis. Taken together, our results provide direct evidence that the CAD risk interval has a pivotal role in regulation of cardiac Cdkn2a/b expression, and suggest that this region affects CAD progression by altering the dynamics of vascular cell proliferation.

Original languageEnglish (US)
Pages (from-to)409-412
Number of pages4
JournalNature
Volume464
Issue number7287
DOIs
Publication statusPublished - Mar 18 2010

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Visel, A., Zhu, Y., May, D., Afzal, V., Gong, E., Attanasio, C., ... Pennacchio, L. A. (2010). Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature, 464(7287), 409-412. https://doi.org/10.1038/nature08801