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.
Highlights
Hypercholesterolemia is a major risk factor for atherosclerosis and coronary heart disease (CHD), most often caused by an individual having a greater than average number of common lipidraising single nucleotide polymorphism (SNP)
The ANXA2-R1 rs17845226 SNP is located in exon 6 of the gene and causes a Valine/Leucine amino acid change; the minor allele frequency (MAF) is 12% in European populations (1000 Genomes Project Phase 3)
The SNP is located in an open chromatin region, where the markers of DNAase I, formaldehyde assisted isolation of regulatory elements (FAIRE), and transcription factor binding are strong (Fig. 1)
Summary
Hypercholesterolemia is a major risk factor for atherosclerosis and coronary heart disease (CHD), most often caused by an individual having a greater than average number of common lipidraising SNPs. The Global Lipids Genetics consortium (2013) has identified 157 novel loci associated with lipid levels, 15 of which are known to influence plasma levels of Low Density Lipoprotein cholesterol (LDL-C) [1]. Gain-of-function mutations in PCSK9 strongly promote LDL-R degradation and lead to FH, whereas loss-of-function mutations of PCSK9 are unable to enhance LDL-R downregulation and result in lower levels of LDL-C [5]. This suggests that lowering PCSK9 will protect against atherosclerosis and CAD. In the expression quantitative trait loci (eQTL) study, minor allele homozygotes have significantly lower levels of ANXA2-mRNA expression (p 1⁄4 1.36 Â 10À05)
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