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

Fairoozy, RH and Cooper, J and White, J and Giambartolomei, C and Folkersen, L and Wannamethee, SG and Jefferis, BJ and Whincup, P and Ben-Shlomo, Y and Kumari, M and Kivimaki, M and Wong, A and Hardy, R and Kuh, D and Gaunt, TR and Casas, JP and McLachlan, S and Price, JF and Hingorani, A and Franco-Cereceda, A and Grewal, T and Kalea, AZ and Humphries, SE (2017) 'Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 (ANXA2) gene.' Atherosclerosis, 261. 60 - 68. ISSN 0021-9150

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© 2017 The Authors 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.

Item Type: Article
Subjects: H Social Sciences > H Social Sciences (General)
R Medicine > R Medicine (General)
Divisions: Faculty of Social Sciences > Institute for Social and Economic Research
Depositing User: Jim Jamieson
Date Deposited: 19 May 2017 15:49
Last Modified: 17 Aug 2017 17:17

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