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

Atherosclerosis. 2017 Jun;261:60-68. doi: 10.1016/j.atherosclerosis.2017.04.010. Epub 2017 Apr 13.

Abstract

Background and aims: Annexin-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.

Results: The 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).

Conclusions: Both 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.

Keywords: Annexin A2; Coronary heart disease; Low-density lipoprotein cholesterol; Low-density lipoprotein cholesterol-receptor; Proprotein convertase subtilisin/kexin type-9; Single nucleotide polymorphism.

Publication types

  • Multicenter Study
  • Research Support, U.S. Gov't, P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Annexin A2 / genetics*
  • Annexin A2 / metabolism
  • Biomarkers / blood
  • Cholesterol, LDL / blood*
  • Computational Biology
  • Coronary Disease / blood*
  • Coronary Disease / diagnosis
  • Coronary Disease / genetics*
  • Databases, Genetic
  • Female
  • Gene Frequency
  • Genes, Reporter
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Hep G2 Cells
  • Heterozygote
  • Homozygote
  • Humans
  • K562 Cells
  • Linkage Disequilibrium
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Proprotein Convertase 9 / metabolism
  • Quantitative Trait Loci
  • Transfection
  • United Kingdom

Substances

  • ANXA2 protein, human
  • Annexin A2
  • Biomarkers
  • Cholesterol, LDL
  • PCSK9 protein, human
  • Proprotein Convertase 9