Research Repository

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

Fairoozy, Roaa Hani and Cooper, Jackie and White, Jon and Giambartolomei, Claudia and Folkersen, Lasse and Wannamethee, S Goya and Jefferis, Barbara J and Whincup, Peter and Ben-Shlomo, Yoav and Kumari, Meena and Kivimaki, Mika and Wong, Andrew and Hardy, Rebecca and Kuh, Diana and Gaunt, Tom R and Casas, JP and McLachlan, Stela and Price, Jackie F and Hingorani, Aroon and Franco-Cereceda, Anders and Grewal, Thomas and Kalea, Anastasia Z and Humphries, Steve E (2017) 'Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 ( ANXA2 ) gene.' Atherosclerosis, 261. pp. 60-68. ISSN 0021-9150

[img]
Preview
Text
1-s2.0-S0021915017301697-main.pdf - Published Version
Available under License Creative Commons Attribution.

Download (896kB) | Preview

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.

Item Type: Article
Uncontrolled Keywords: Annexin A2; Proprotein convertase subtilisin/kexin type-9; Low-density lipoprotein cholesterol-receptor; Low-density lipoprotein cholesterol; Single nucleotide polymorphism; Coronary heart disease
Subjects: H Social Sciences > H Social Sciences (General)
R Medicine > R Medicine (General)
Divisions: Faculty of Social Sciences
Faculty of Social Sciences > Institute for Social and Economic Research
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 19 May 2017 15:49
Last Modified: 18 Aug 2022 10:46
URI: http://repository.essex.ac.uk/id/eprint/19476

Actions (login required)

View Item View Item