Fairoozy, RH;
Cooper, J;
White, J;
Giambartolomei, C;
Folkersen, L;
Wannamethee, SG;
Jefferis, BJ;
Whincup, P;
Ben-Shlomo, Y;
Kumari, M;
et al.
Fairoozy, RH; Cooper, J; White, J; Giambartolomei, C; Folkersen, L; Wannamethee, SG; Jefferis, BJ; Whincup, P; Ben-Shlomo, Y; Kumari, M; Kivimaki, M; Wong, A; Hardy, R; Kuh, D; Gaunt, TR; Casas, JP; McLachlan, S; Price, JF; Hingorani, A; Franco-Cereceda, A; Grewal, T; Kalea, AZ; Humphries, SE; UCLEB consortium
(2017)
Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 (ANXA2) gene.
Atherosclerosis, 261.
pp. 60-68.
ISSN 1879-1484
https://doi.org/10.1016/j.atherosclerosis.2017.04.010
SGUL Authors: Whincup, Peter Hynes
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 (r(2) > 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.
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