Coronary Artery Disease Risk Conferred by a Genetic Variant that Blocks Alternative Polyadenylation of IRF2BP2 in Human Arterial Smooth Muscle Cells

Interferon regulatory factor 2 binding protein 2 (IRF2BP2) suppresses inflammation in macrophages and limits macrophage foam cell formation (Chen et al., Circulation Research, 2015; 117:671-683). We identified a short 9 nucleotide deletion (rs3045215) in the 3’UTR IRF2BP2 mRNA that associates with the risk of coronary artery disease in the Ottawa Heart Genomics Study. Genetic variants that confer risk of coronary artery disease also increase risk of vascular dementia. Here, we show that this deletion disrupts an alternative polyadenylation site enabling IRF2BP2 mRNA to escape translational suppression by miR155. The rs3045215 deletion polymorphism prevents the use of the proximal polyadenylation site, as revealed by ratio of ratio analysis of IRF2BP2 mRNA alternatively polyadenylated transcripts from the Geuvadis database of lymphoblastoid cells genotyped for the rs3045215 polymorphism. miR155 is up-regulated upon exposure of human THP1 macrophage and primary human aortic smooth muscle cells to lipopolysaccharide (LPS). The distal 3’ UTR of IRF2BP2 is targeted by miR155 that suppresses translation of the IRF2BP2 mRNA and down-regulates IRF2BP2 protein expression. In smooth muscle cells, but not THP1 macrophages, the use of the alternative proximal polyadenylation site upsteam of the miR155 target sequence allows IRF2BP2 protein levels to recover even upon prolonged exposure to LPS. This enables smooth muscle cells to suppress their inflammatory response. On the other hand, smooth muscle cells homozygous for the deletion allele cannot use the proximal polyadenylation signal, continue to suppress IRF2BP2 translation and retain an inflammatory phenotype. Our study is the first to identify loss of alternative polyadenylation as a mechanism underlying the risk of coronary artery disease, a mechanism that should be considered at the genome-wide level.