Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 ( ANXA2 ) gene

Abstract

Background and aimsAnnexin-A2 (AnxA2) is an endogenous inhibitor of proprotein convertase subtilisin/kexin type-9 (PCSK9). The repeat-one (R1) domain of AnxA2 binds to PCSK9, blocking its ability to promote degradation of low-density lipoprotein cholesterol-receptors (LDL-R) and thereby regulate low-density lipoprotein cholesterol (LDL-C) levels. Here we identify variants in ANXA2 influencing LDL-C levels and we determine the molecular mechanisms of their effects.ResultsThe ANXA2 single nucleotide polymorphism (SNP) genotype-phenotype association was examined using the Second-Northwick-Park Heart Study (NPHSII) (n∼2700) and the UCL-LSHTM-Edinburgh-Bristol (UCLEB) consortium (n∼14,600). The ANXA2-R1 domain coding-SNP rs17845226 (V98L) associated with LDL-C, homozygotes for the minor allele having ≈18.8% higher levels of LDL-C (p = 0.004), and higher risk of coronary heart disease (CHD) (p = 0.04). The SNP is in modest linkage disequilibrium (r2 > 0.5) with two intergenic SNPs, rs17191344 and rs11633032. Both SNPs showed allele-specific protein binding, and the minor alleles caused significant reduction in reporter gene expression (≈18%, p < 0.001). In the expression quantitative trait loci (eQTL) study, minor allele homozygotes have significantly lower levels of ANXA2-mRNA expression (p = 1.36 × 10−05).ConclusionsBoth rs11633032 and rs17191344 SNPs are functional variants, where the minor alleles create repressor-binding protein sites for transcription factors that contribute to reduced ANXA2 gene expression. Lower AnxA2 levels could increase plasma levels of PCSK9 and thus increase LDL-C levels and risk of CHD. This supports, for the first time in humans, previous observations in mouse models that changes in the levels of AnxA2 directly influence plasma LDL-C levels, and thus implicate this protein as a potential therapeutic target for LDL-C lowering.

The lipid-lowering treatment after acute coronary syndrome in the real clinical practice: possible role of the pharmacogenetic interactions

“…The data obtained have revealed an association of the minor allele of the ANXA2 gene with a higher level of LDL-C, which corresponds to the previous data [21]. Carriage of a rare allele has been associated with a decrease in the effectiveness of the statin.…”

Annexin Animal Models—From Fundamental Principles to Translational Research

“…Over recent years, a substantial number of additional studies identified correlations between disease progression and expression patterns of individual annexins; as is the case in many cancer and other acute and chronic diseases [ 1 , 2 , 3 , 21 , 22 , 23 , 90 , 116 , 226 , 242 , 342 , 343 , 368 , 369 ]. However, aided by deep sequencing data, various SNPs were identified, suggesting a potential involvement of AnxA1 in Alzheimer’s disease [ 436 ], and revealed roles for AnxA2 in sickle cell disease [ 119 , 120 ], but also cardiovascular risk due to elevated LDL cholesterol [ 114 , 149 ]. Similarly, the identification of SNPs in the Anxa3 gene locus may imply roles in gastric cancer [ 437 ].…”

“…Vice versa, adenoviral AnxA2 overexpression elevated hepatic LDLR levels in vivo [ 114 ]. The association of LDL-cholesterol levels with Anxa2 gene variants [ 149 ] support modulation of AnxA2 levels as a potential cholesterol-lowering strategy. Applicable for obesity and the metabolic syndrome, AnxA2 depletion attenuated obesity-induced insulin resistance through suppression of NFκB signaling [ 150 ].…”

Altered hepatic glucose homeostasis in AnxA6-KO mice fed a high-fat diet

“…AnxA2 interacts with insulin and insulin-like growth factor receptors [ 17 ], and is phosphorylated and sumoylated upon insulin stimulation [ 18 , 19 ], possibly relevant for cell adhesion [ 17 ], but also translocation of the glucose transporter type 4 (GLUT4) in adipocytes [ 20 ]. Moreover, AnxA2 regulates mouse extrahepatic low density lipoprotein receptor (LDLR) levels in vivo [ 21 , 22 ], which correlates with elevated LDL cholesterol levels in humans carrying AnxA2 gene variants [ 23 ]. Loss of AnxA7 was linked to abnormal insulin secretion [ 24 ]; however, these findings were challenged by others [ 25 ].…”