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9p21 DNA variants associated with coronary artery disease impair interferon-γ signalling response

Authors :
Harismendy, Olivier
Notani, Dimple
Song, Xiaoyuan
Rahim, Nazli G.
Tanasa, Bogdan
Heintzman, Nathaniel
Ren, Bing
Fu, Xiang-Dong
Topol, Eric J.
Rosenfeld, Michael G.
Frazer, Kelly A.
Source :
Nature. February 10, 2011, Vol. 470 Issue 7333, p264, 7 p.
Publication Year :
2011

Abstract

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the 9p21 gene desert associated with coronary artery disease (CAD) (1-4) and type 2 diabetes (5-7). Despite evidence for a role of the associated interval in neighbouring gene regulation (8-10), the biological underpinnings of these genetic associations with CAD or type 2 diabetes have not yet been explained. Here we identify 33 enhancers in 9p21; the interval is the second densest gene desert for predicted enhancers and six times denser than the whole genome (P < 6.55 x [10.sup.-33]). The CAD risk alleles of SNPs rs10811656 and rs10757278 are located in one of these enhancers and disrupt a binding site for STAT1. Lymphoblastoid cell lines homozygous for the CAD risk haplotype show no binding of STAT1, and in lymphoblastoid cell lines homozygous for the CAD non-risk haplotype, binding of STAT1 inhibits CDKN2BAS (also known as CDKN2B-AS1) expression, which is reversed by short interfering RNA knockdown of STAT1. Using a new, open-ended approach to detect long-distance interactions, we find that in human vascular endothelial cells the enhancer interval containing the CAD locus physically interacts with the CDKN2A/B locus, the MTAP gene and an interval downstream of IFNA21. In human vascular endothelial cells, interferon-y activation strongly affects the structure of the chromatin and the transcriptional regulation in the 9p21 locus, including STAT1-binding, long-range enhancer interactions and altered expression of neighbouring genes. Our findings establish a link between CAD genetic susceptibility and the response to inflammatory signalling in a vascular cell type and thus demonstrate the utility of genome-wide association study findings in directing studies to novel genomic loci and biological processes important for disease aetiology.<br />Genome-wide association studies (GWAS) have identified eight SNPs in the 9p21 interval strongly associated with CAD (1-4) and other vascular diseases (11,12), all of which are highly correlated ([r.sup.2] > [...]

Details

Language :
English
ISSN :
00280836
Volume :
470
Issue :
7333
Database :
Gale General OneFile
Journal :
Nature
Publication Type :
Academic Journal
Accession number :
edsgcl.249463620
Full Text :
https://doi.org/10.1038/nature09753