IRF2BP2 3′UTR Polymorphism Increases Coronary Artery Calcification in Men

Abstract

Interferon regulatory factor 2 binding protein 2 (IRF2BP2) suppresses the innate inflammatory response of macrophages. A 9-nucleotide deletion (rs3045215) in the 3′ untranslated region (3′-UTR) of human IRF2BP2 mRNA confers risk of coronary artery disease (CAD) in the Ottawa Heart Genomics Study (OHGS). Here, we sought to identify regulatory mechanisms that may contribute to this risk. We tested how lipopolysaccharides (LPS) affects IRF2BP2 expression in human THP-1 macrophages and primary aortic smooth muscle cells (HAoSMC) genotyped for the deletion allele. Both cell types are implicated in coronary atherosclerosis. We also examined how the deletion affects interaction with RNA binding proteins (RBPs) to regulate IRF2BP2 expression. LPS altered allele-specific binding of RBPs in RNA gel shift assays with the THP-1 macrophage protein extracts. The RBP ELAVL1 suppressed the expression of a luciferase reporter carrying the 3′UTR of IRF2BP2 with the deletion allele. Other RBPs AUF1 or KHSRP did not confer such allele specific regulation. Since it is co-inherited with a risk variant for osteoporosis, a condition tied to arterial calcification, we examined the association of the deletion allele with coronary artery calcification in individuals who had undergone computed tomography angiography in the OHGS. In 323 individuals with a minimal burden of atherosclerosis (<30% coronary stenosis) and 138 CAD cases (>50% stenosis), Mendelian randomization revealed that the rs3045215 deletion allele significantly increased coronary artery calcification in men with minimal coronary stenosis. Thus, not only does the rs3045215 deletion allele predict atherosclerosis, but it also predisposes to early-onset calcification in men.

Functional characterization of the disease-associatedCCL2rs1024611G-rs13900T haplotype: The role of the RNA-binding protein HuR

“…Genome-wide association studies (GWASs) have led to the discovery of numerous disease susceptibility genetic variants/genes and biological pathways involved in specific diseases, including many with immunological etiologies (Buniello et al, 2019;Manolio, 2010;Visscher et al, 2017). Most of the disease-associated genetic variants identified are present in the noncoding regions of the genome (Maurano et al, 2012;Zhang and Lupski, 2015;Zou et al, 2019).…”

“…While there are several examples of genetic variants that influence mRNA stability (Akdeli et al, 2014;Duan et al, 2013;Vilmundarson et al, 2021;Wang, Pitarque and Ingelman-Sundberg, 2006), very few studies have examined the role of RBPs such as HuR in differentially influencing gene expression levels in humans (Steri et al, 2018). A notable exception is the report showing that RBP AUF1 regulates the allele-specific stability of thymidylate synthase (Pullmann et al, 2006).…”

“…Another study showed that a type 2 diabetes associated polymorphism in the 3′ UTR of PPP1R3 alters distance between two ARE motifs and results in differential binding of protein complexes and may be associated with altered mRNA stability (Xia, Bogardus and Prochazka, 1999). Vilmundarson et al demonstrated that HuR differentially modulates IRF2BP2 translation through a 3′ UTR polymorphism that is associated with increased coronary artery calcification (Vilmundarson et al, 2021). Our exploratory studies did not resolve whether the rs13900 allelic variation leads to differences in polysomal loading and additional studies are required to address this issue.…”

“…Identification of functional and/or causal genetic variants continues to pose a significant challenge in the post-genome-wide association studies (post-GWAS) era (MacArthur et al, 2017;Tam et al, 2019;Visscher et al, 2017). While emphasis has been placed on polymorphisms that map to cis-elements in enhancers and promoters, genetic variants that disrupt cis-elements in RNA binding protein (RBP) motifs in 3' UTR have received much less attention.…”

Savior Siblings Might Rescue Fetal Lethality But Not Adult Lymphoma in Irf2bp2-Null Mice

“…More recently, IRF2BP2 was also reported to co-activate transcription regulated by the glucocorticoid and androgen steroid hormone receptors ( 6 ). Human IRF2BP2 genetic polymorphisms that reduce IRF2BP2 expression are tied to coronary atherosclerosis ( 7 ) and coronary artery calcification ( 8 ). Selective ablation of Irf2bp2 in macrophages triggers an inflammatory response and worsens atherosclerosis in mice ( 7 ).…”