Journal article
Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 (ANXA2) gene
University College London1
Addenbrooke's Hospital2
University of Edinburgh3
Karolinska Institutet4
University of Sydney5
Icahn School of Medicine at Mount Sinai6
Department of Biotechnology and Biomedicine, Technical University of Denmark7
Department of Bio and Health Informatics, Technical University of Denmark8
Integrative Systems Biology, Department of Bio and Health Informatics, Technical University of Denmark9
St. George's University of London10
University of Bristol11
University of Essex12
MRC Unit for Lifelong Health and Ageing13
...and 3 moreBackground 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.
| Language: | English |
|---|---|
| Publisher: | Elsevier |
| Year: | 2017 |
| Pages: | 60-68 |
| ISSN: | 18791484 , 00219150 , 18785050 and 15675688 |
| Types: | Journal article |
| DOI: | 10.1016/j.atherosclerosis.2017.04.010 |
| ORCIDs: | Folkersen, Lasse Westergaard |
Annexin A2 Coronary heart disease Low-density lipoprotein cholesterol Low-density lipoprotein cholesterol-receptor Proprotein convertase subtilisin/kexin type-9 Single nucleotide polymorphism
ANXA2 protein, human AnxA2, annexin A2 Biomarkers CHRD, cysteine-histidine-rich domain of PCSK9 CTCF, CTC-binding factor Cholesterol, LDL Computational Biology Coronary Disease Databases, Genetic FAIRE, formaldehyde assisted isolation of regulatory elements Female Gene Frequency Genes, Reporter Genetic Association Studies Genetic Predisposition to Disease Hep G2 Cells Heterozygote Homozygote Humans K562 Cells LDL-C, low-density lipoprotein cholesterol LDLR, low-density lipoprotein cholesterol-receptor Linkage Disequilibrium Male Middle Aged NPHSII, Second-Northwick-Park Heart Study PCSK9 protein, human PCSK9, proprotein convertase subtilisin/kexin type-9 Phenotype Polymorphism, Single Nucleotide Proprotein Convertase 9 Quantitative Trait Loci Transfection UCLEB, UCL-LSHTM-Edinburgh-Bristol consortium United Kingdom
