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

Roaa Hani Fairoozy, Jackie Cooper, Jon White, Claudia Giambartolomei, Lasse Westergaard Folkersen, S. Goya Wannamethee, Barbara J. Jefferis, Peter H. Whincup, Yoav Ben-Shlomo, Meena Kumari, Mika Kivimaki, Andrew Wong, Rebecca Hardy, Diana Kuh, Tom R. Gaunt, Juan P. Casas, Stela McLachlan, Jackie F. Price, Aroon D Hingorani, Anders Franco-Cereceda & 3 others Thomas Grewal, Anastasia Z. Kalea, Steve E Humphries

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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 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

Keywords

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

Cite this

Fairoozy, R. H., Cooper, J., White, J., Giambartolomei, C., Folkersen, L. W., Wannamethee, S. G., ... Humphries, S. E. (2017). Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 (ANXA2) gene. Atherosclerosis, 261, 60-68. https://doi.org/10.1016/j.atherosclerosis.2017.04.010
Fairoozy, Roaa Hani ; Cooper, Jackie ; White, Jon ; Giambartolomei, Claudia ; Folkersen, Lasse Westergaard ; Wannamethee, S. Goya ; Jefferis, Barbara J. ; Whincup, Peter H. ; Ben-Shlomo, Yoav ; Kumari, Meena ; Kivimaki, Mika ; Wong, Andrew ; Hardy, Rebecca ; Kuh, Diana ; Gaunt, Tom R. ; Casas, Juan P. ; McLachlan, Stela ; Price, Jackie F. ; Hingorani, Aroon D ; Franco-Cereceda, Anders ; Grewal, Thomas ; Kalea, Anastasia Z. ; Humphries, Steve E. / Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 (ANXA2) gene. In: Atherosclerosis. 2017 ; Vol. 261. pp. 60-68.
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title = "Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 (ANXA2) gene",
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 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.",
keywords = "Annexin A2, Proprotein convertase subtilisin/kexin type-9, Low-density lipoprotein cholesterol-receptor, Low-density lipoprotein cholesterol, Single nucleotide polymorphism, Coronary heart disease",
author = "Fairoozy, {Roaa Hani} and Jackie Cooper and Jon White and Claudia Giambartolomei and Folkersen, {Lasse Westergaard} and Wannamethee, {S. Goya} and Jefferis, {Barbara J.} and Whincup, {Peter H.} and Yoav Ben-Shlomo and Meena Kumari and Mika Kivimaki and Andrew Wong and Rebecca Hardy and Diana Kuh and Gaunt, {Tom R.} and Casas, {Juan P.} and Stela McLachlan and Price, {Jackie F.} and Hingorani, {Aroon D} and Anders Franco-Cereceda and Thomas Grewal and Kalea, {Anastasia Z.} and Humphries, {Steve E}",
year = "2017",
doi = "10.1016/j.atherosclerosis.2017.04.010",
language = "English",
volume = "261",
pages = "60--68",
journal = "Atherosclerosis",
issn = "0021-9150",
publisher = "Elsevier",

}

Fairoozy, RH, Cooper, J, White, J, Giambartolomei, C, Folkersen, LW, Wannamethee, SG, Jefferis, BJ, Whincup, PH, Ben-Shlomo, Y, Kumari, M, Kivimaki, M, Wong, A, Hardy, R, Kuh, D, Gaunt, TR, Casas, JP, 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. https://doi.org/10.1016/j.atherosclerosis.2017.04.010

Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 (ANXA2) gene. / Fairoozy, Roaa Hani; Cooper, Jackie; White, Jon; Giambartolomei, Claudia; Folkersen, Lasse Westergaard; Wannamethee, S. Goya; Jefferis, Barbara J.; Whincup, Peter H.; Ben-Shlomo, Yoav; Kumari, Meena; Kivimaki, Mika; Wong, Andrew; Hardy, Rebecca; Kuh, Diana; Gaunt, Tom R.; Casas, Juan P.; McLachlan, Stela; Price, Jackie F.; Hingorani, Aroon D; Franco-Cereceda, Anders; Grewal, Thomas; Kalea, Anastasia Z.; Humphries, Steve E.

In: Atherosclerosis, Vol. 261, 2017, p. 60-68.

Research output: Contribution to journalJournal articleResearchpeer-review

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

VL - 261

SP - 60

EP - 68

JO - Atherosclerosis

JF - Atherosclerosis

SN - 0021-9150

ER -