IRF2BP2 3'UTR Polymorphism Increases Coronary Artery Calcification in Men

Area of Science:

• Genetics
• Cardiovascular Biology
• Molecular Biology

Background:

• Interferon regulatory factor 2 binding protein 2 (IRF2BP2) plays a role in suppressing macrophage inflammatory responses.
• A specific 9-nucleotide deletion (rs3045215) in the 3'-UTR of IRF2BP2 mRNA is associated with increased risk of coronary artery disease (CAD).

Purpose of the Study:

• To investigate the regulatory mechanisms underlying the CAD risk conferred by the IRF2BP2 3'-UTR deletion.
• To examine how this deletion influences IRF2BP2 expression and RNA binding protein (RBP) interactions.
• To assess the association of the deletion allele with coronary artery calcification.

Main Methods:

• Lipopolysaccharides (LPS) were used to stimulate IRF2BP2 expression in human THP-1 macrophages and primary aortic smooth muscle cells (HAoSMC).
• RNA gel shift assays were performed to analyze RBP binding to the IRF2BP2 3'-UTR.
• Luciferase reporter assays were conducted to assess the regulatory effects of RBPs on IRF2BP2 expression.
• Mendelian randomization analysis was applied to evaluate the association of the deletion allele with coronary artery calcification in individuals from the Ottawa Heart Genomics Study (OHGS).

Main Results:

• LPS treatment altered allele-specific RBP binding to the IRF2BP2 3'-UTR in THP-1 macrophages.
• The RBP ELAVL1 suppressed reporter gene expression driven by the IRF2BP2 3'-UTR containing the deletion allele.
• The rs3045215 deletion allele was significantly associated with increased coronary artery calcification in men with minimal coronary stenosis.

Conclusions:

• The 9-nucleotide deletion in the IRF2BP2 3'-UTR contributes to CAD risk through altered RBP interactions, specifically with ELAVL1.
• This deletion allele not only predicts atherosclerosis but also predisposes to early-onset arterial calcification in men.