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

Roaa Hani Fairoozy, Jackie A Cooper, Jon White, Claudia Giambartolomei, Lasse Folkersen, SG Wannamethee, Barbara J Jefferis, Peter H Whincup, Yoav Ben-Shlomo, Meena Kumari, Mika Kivimaki, Andrew Wong, Rebecca Hardy, Diana Kuh, Tom Gaunt, JP Casas, Stela McLachlan, Jackie F Price, Aroon D Hingorani, Anders Franco-CerecedaThomas Grewal, Anastasia Z Kalea, Steve E Humphries

Research output: Contribution to journalArticle (Academic Journal)peer-review

3 Citations (Scopus)
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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 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.
Original languageEnglish
Pages (from-to)60-68
Number of pages9
JournalAtherosclerosis
Volume261
Early online date13 Apr 2017
DOIs
Publication statusPublished - Jun 2017

Keywords

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

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