Abstract 19809: Interferon Regulatory Factor 2 Binding Protein 2 Inhibits Macrophage Inflammation and Reduces Susceptibility to Atherosclerosis in Mice and Humans
Introduction: Genetic variants near the gene encoding the transcription cofactor Interferon Regulatory Factor 2 Binding Protein 2 (IRF2BP2) have been tied to ischemic heart disease progression and elevated serum cholesterol. Expression of IRF2BP2 is suppressed in inflammatory macrophages, but the significance of this down-regulation was not known.
Hypothesis: This study sought to determine the function of IRF2BP2 in macrophages and its effect on atherosclerosis in mice and humans.
Methods and Results: We generated mice that delete IRF2BP2 in macrophages (LysMCre/IRF2BP2flox). IRF2BP2-deficient macrophages increased atherosclerosis in irradiated LDL-receptor null recipient mice and in ApoE null mice. Atherosclerosis was associated with a skewed inflammatory macrophage polarization and increased foam cell formation. Microarray analysis revealed and promoter studies confirmed that the anti-inflammatory transcription factor KLF2 is a target of IRF2BP2, indicating an important role for IRF2BP2 in macrophage polarization.
A deletion polymorphism (rs3045215) in the 3’ untranslated sequence of human IRF2BP2 mRNA was examined for its effect on protein expression and on the susceptibility to coronary artery disease (CAD) risk in a cohort of 1,066 angiographic cases and 1,011 controls. Homozygous carriers of this deletion had lower IRF2BP2 (and its target KLF2) protein levels in peripheral blood mononuclear cells and a higher risk of CAD (recessive model, odds ratio (95%CI) = 1.560 (1.179-2.065), p=1.73E-03). The effect of this deletion to suppress protein expression was confirmed with luciferase reporter studies. Haplotype phasing identified two surrogate SNPs in modest LD (rs1887917, r2= 0.755 and rs632180, r2=0.614) that also associated with CAD in a recessive model. These SNPs are being tested for association with CAD in a large international consortium.
Conclusion: Ablation of IRF2BP2 in macrophages worsens atherosclerosis in mice and a deletion variant that lowers IRF2BP2 expression predisposes to CAD in humans.
Author Disclosures: R.O. Vilmundarson: None. H. Chen: None. K. Keyhanian: None. X. Zhou: None. M. Nikpay: None. S.A. Cruz: None. N.R. Pandey: None. N.A. Almontashiri: None. N.L. Yap: None. T. Ho: None. C.A. Stewart: None. H. Huang: None. A. Hari: None. M. Geoffrion: None. R. McPherson: None. K.J. Rayner: None. A.F. Stewart: None.
- © 2015 by American Heart Association, Inc.