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

Nature. 2011 Feb 10;470(7333):264-8. doi: 10.1038/nature09753.

Abstract

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the 9p21 gene desert associated with coronary artery disease (CAD) and type 2 diabetes. Despite evidence for a role of the associated interval in neighbouring gene regulation, 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 × 10(-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-γ 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alleles
  • Cell Line
  • Chromatin / drug effects
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chromosomes, Human, Pair 9 / genetics*
  • Conserved Sequence / genetics
  • Coronary Artery Disease / genetics*
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics
  • Diabetes Mellitus, Type 2 / genetics
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Enhancer Elements, Genetic / genetics*
  • European Continental Ancestry Group / genetics
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Gene Knockdown Techniques
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation*
  • Genome-Wide Association Study
  • Haplotypes / genetics
  • HeLa Cells
  • Humans
  • Interferon-alpha / genetics
  • Interferon-gamma / pharmacology*
  • Linkage Disequilibrium
  • Male
  • Polymorphism, Single Nucleotide / genetics
  • Protein Binding / drug effects
  • Purine-Nucleoside Phosphorylase / genetics
  • STAT1 Transcription Factor / biosynthesis
  • STAT1 Transcription Factor / deficiency
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / drug effects*

Substances

  • CDKN2B protein, human
  • Chromatin
  • Cyclin-Dependent Kinase Inhibitor p15
  • IFNA21 protein, human
  • Interferon-alpha
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Interferon-gamma
  • Purine-Nucleoside Phosphorylase
  • 5'-methylthioadenosine phosphorylase