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

Research output: Contribution to journalJournal article – Annual report year: 2017Researchpeer-review

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  • Author: Fairoozy, Roaa Hani

    University College London, United Kingdom

  • Author: Cooper, Jackie

    University College London, United Kingdom

  • Author: White, Jon

    University College London, United Kingdom

  • Author: Giambartolomei, Claudia

    Icahn School of Medicine at Mount Sinai, United States

  • Author: Folkersen, Lasse Westergaard

    Integrative Systems Biology, Department of Bio and Health Informatics, Department of Biotechnology and Biomedicine, Technical University of Denmark, Kemitorvet, 2800, Kgs. Lyngby, Denmark

  • Author: Wannamethee, S. Goya

    University College London, United Kingdom

  • Author: Jefferis, Barbara J.

    University College London, United Kingdom

  • Author: Whincup, Peter H

    St. George's University of London, United Kingdom

  • Author: Ben-Shlomo, Yoav

    University of Bristol, United Kingdom

  • Author: Kumari, Meena

    University of Essex, United Kingdom

  • Author: Kivimaki, Mika

    University College London, United Kingdom

  • Author: Wong, Andrew

    MRC Unit for Lifelong Health and Ageing, United Kingdom

  • Author: Hardy, Rebecca

    MRC Unit for Lifelong Health and Ageing, United Kingdom

  • Author: Kuh, Diana

    MRC Unit for Lifelong Health and Ageing, United Kingdom

  • Author: Gaunt, Tom R.

    Addenbrooke's Hospital, United Kingdom

  • Author: Casas, Juan P.

    University College London, United Kingdom

  • Author: McLachlan, Stela

    University of Edinburgh, United Kingdom

  • Author: Price, Jackie F.

    University of Edinburgh, United Kingdom

  • Author: Hingorani, Aroon D

    University College London, United Kingdom

  • Author: Franco-Cereceda, Anders

    Karolinska Institutet, Sweden

  • Author: Grewal, Thomas

    University of Sydney, Australia

  • Author: Kalea, Anastasia Z.

    University College London, United Kingdom

  • Author: Humphries, Steve E

    University College London, United Kingdom

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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 similar to 2700) and the UCL-LSHTM-EdinburghBristol (UCLEB) consortium (n similar to 14,600). The ANXA2-R1 domain coding-SNP rs17845226 (V98L) associated with LDL-C, homozygotes for the minor allele having approximate to 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 (approximate to 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 x 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. (C) 2017 The Authors. Published by Elsevier Ireland Ltd.
Original languageEnglish
JournalAtherosclerosis
Volume261
Pages (from-to)60-68
Number of pages9
ISSN0021-9150
DOIs
Publication statusPublished - 2017
CitationsWeb of Science® Times Cited: No match on DOI

    Research areas

  • 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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