Publication Date:
2010-02-23
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938076/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938076/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Visel, Axel -- Zhu, Yiwen -- May, Dalit -- Afzal, Veena -- Gong, Elaine -- Attanasio, Catia -- Blow, Matthew J -- Cohen, Jonathan C -- Rubin, Edward M -- Pennacchio, Len A -- DK59630/DK/NIDDK NIH HHS/ -- R01 HG003988/HG/NHGRI NIH HHS/ -- R01 HG003988-04/HG/NHGRI NIH HHS/ -- R01 HL082896/HL/NHLBI NIH HHS/ -- R01 HL082896-03/HL/NHLBI NIH HHS/ -- R21 HL098940/HL/NHLBI NIH HHS/ -- R21 HL098940-01/HL/NHLBI NIH HHS/ -- U01 HL066681/HL/NHLBI NIH HHS/ -- U01 HL066681-08/HL/NHLBI NIH HHS/ -- England -- Nature. 2010 Mar 18;464(7287):409-12. doi: 10.1038/nature08801. Epub 2010 Feb 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20173736" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Aorta/pathology
;
Cell Aging/genetics
;
Cell Proliferation
;
Cells, Cultured
;
*Chromosome Deletion
;
Chromosomes, Human, Pair 9/genetics
;
Chromosomes, Mammalian/*genetics
;
Coronary Artery Disease/*genetics/pathology
;
Cyclin-Dependent Kinase Inhibitor p15/deficiency/genetics
;
Cyclin-Dependent Kinase Inhibitor p16/deficiency/genetics
;
Embryo, Mammalian/embryology
;
Gene Expression Regulation/genetics
;
Genetic Predisposition to Disease/genetics
;
Humans
;
Mice
;
Myocytes, Smooth Muscle/pathology
;
Survival Analysis
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
