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Atherosclerosis. 2017 Jun;261:60-68. doi: 10.1016/j.atherosclerosis.2017.04.010. Epub 2017 Apr 13.

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

Author information

1
Cardiovascular Genetics, BHF Laboratories, Institute of Cardiovascular Science, University College London, London, United Kingdom. Electronic address: roaa.fairoozy.12@ucl.ac.uk.
2
Cardiovascular Genetics, BHF Laboratories, Institute of Cardiovascular Science, University College London, London, United Kingdom.
3
UCL Genetics Institute, Department of Genetics, Environment and Evolution, University College London, London, United Kingdom.
4
Division of Psychiatric Genomics, Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
5
The Karolinska Institute, Stockholm, Sweden; Department of Bioinformatics, Technical University of Denmark, Lyngby, Denmark.
6
UCL Department of Primary Care & Population Health, UCL Institute of Epidemiology, University College London, London, United Kingdom.
7
Population Health Research Institute, St George's University of London, Cranmer Terrace, London, United Kingdom.
8
School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
9
Institute for Social and Economic Research, University of Essex, Colchester, United Kingdom; Department of Epidemiology & Public Health, UCL Institute of Epidemiology & Health Care, University College London, London, United Kingdom.
10
Department of Epidemiology & Public Health, UCL Institute of Epidemiology & Health Care, University College London, London, United Kingdom.
11
MRC Unit for Lifelong Health and Ageing, London, United Kingdom.
12
MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.
13
Farr Institute of Health Informatics, University College London, London, United Kingdom.
14
Centre for Population Health Sciences, The University of Edinburgh, Edinburgh, United Kingdom.
15
Genetic Epidemiology Group, Institute of Cardiovascular Science, University College London, London, United Kingdom.
16
Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
17
Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia.

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.

KEYWORDS:

Annexin A2; Coronary heart disease; Low-density lipoprotein cholesterol; Low-density lipoprotein cholesterol-receptor; Proprotein convertase subtilisin/kexin type-9; Single nucleotide polymorphism

[Indexed for MEDLINE]
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