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Publication - Dr Tom Gaunt

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

    Citation

    Fairoozy, RH, Cooper, JA, White, J, Giambartolomei, C, Folkersen, L, Wannamethee, S, Jefferis, BJ, Whincup, PH, Ben-Shlomo, Y, Kumari, M, Kivimaki, M, Wong, A, Hardy, R, Kuh, D, Gaunt, T, Casas, J, McLachlan, S, Price, JF, Hingorani, AD, Franco-Cereceda, A, Grewal, T, Kalea, AZ & Humphries, SE, 2017, ‘Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 (ANXA2) gene’. Atherosclerosis, vol 261., pp. 60-68

    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.

    Full details in the University publications repository