TY - JOUR
T1 - Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 (ANXA2) gene
AU - Fairoozy, Roaa Hani
AU - Cooper, Jackie
AU - White, Jon
AU - Giambartolomei, Claudia
AU - Folkersen, Lasse Westergaard
AU - Wannamethee, S. Goya
AU - Jefferis, Barbara J.
AU - Whincup, Peter H.
AU - Ben-Shlomo, Yoav
AU - Kumari, Meena
AU - Kivimaki, Mika
AU - Wong, Andrew
AU - Hardy, Rebecca
AU - Kuh, Diana
AU - Gaunt, Tom R.
AU - Casas, Juan P.
AU - McLachlan, Stela
AU - Price, Jackie F.
AU - Hingorani, Aroon D
AU - Franco-Cereceda, Anders
AU - Grewal, Thomas
AU - Kalea, Anastasia Z.
AU - Humphries, Steve E
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Annexin A2
KW - Proprotein convertase subtilisin/kexin type-9
KW - Low-density lipoprotein cholesterol-receptor
KW - Low-density lipoprotein cholesterol
KW - Single nucleotide polymorphism
KW - Coronary heart disease
U2 - 10.1016/j.atherosclerosis.2017.04.010
DO - 10.1016/j.atherosclerosis.2017.04.010
M3 - Journal article
C2 - 28456096
SN - 0021-9150
VL - 261
SP - 60
EP - 68
JO - Atherosclerosis
JF - Atherosclerosis
ER -