Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice.
Nature
; 464(7287): 409-12, 2010 Mar 18.
Article
en En
| MEDLINE
| ID: mdl-20173736
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(Delta70kb/Delta70kb) 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(Delta70kb/Delta70kb) 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(Delta70kb/Delta70kb) 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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Enfermedad de la Arteria Coronaria
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Deleción Cromosómica
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Cromosomas de los Mamíferos
Tipo de estudio:
Etiology_studies
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Risk_factors_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Nature
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos