A functional polymorphism of PON1 interferes with microRNA binding to increase the risk of ischemic stroke and carotid atherosclerosis

Mu En Liu, Yi Chu Liao, Ruey Tay Lin, Yung Song Wang, Edward Hsi, Hsiu Fen Lin, Ku Chung Chen, Suh Hang H Juo

Research output: Contribution to journalArticle

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Abstract

Objective: Single nucleotide polymorphisms (SNPs) located at microRNA (miRNA) binding sites (miR-SNPs) can affect the expression of genes. This study aimed to identify the miR-SNPs associated with atherosclerosis and stroke. Methods: Patients with ischemic stroke (n = 657) and stroke- and myocardial infarction-free volunteers (n = 1571) were enrolled. The carotid intima-media thickness (IMT) was measured in the control participants. Seventy-nine stroke susceptibility genes were initially selected and 13 genes were predicted to have miR-SNPs at their 3' untranslated regions (3'UTR). The miRNA arrays were used to further identify potential miR-SNPs. The miR-SNP rs3735590 at the paraoxonase 1 (PON1) gene was finally selected and its associations with stroke and carotid IMT were evaluated. The 3'UTR reporter and SNP functional assays were then performed to validate the results. Results: Compared with CC genotype, patients with CT or TT genotype at rs3735590 had lower risk of ischemic stroke (OR = 0.72, p = 0.036; OR = 0.83, p = 0.077, respectively). Among the healthy participants, the CT or TT genotype was associated with thinner IMT in the internal carotid arteries in comparison with CC genotype (β = -0.76, p = 0.003; β = -0.022, p = 0.452, respectively). Our findings suggested that the minor allele T had a protective effect on atherosclerosis. Results from 3'UTR reporter assays showed that PON1 is a direct target gene of miR-616. In plasmid constructs carrying the risk allele C at rs3735590, miR-616 inhibited the genetic expression of PON1. However, substitution of C by T at rs3735590 reduced the miR-616 binding affinity, leading to overexpression of the PON1 gene. Conclusion: Our study is the first to show that the miR-SNP at PON1 could affect genetic expression and is associated with an elevated risk for ischemic stroke and subclinical atherosclerosis.

Original languageEnglish
Pages (from-to)161-167
Number of pages7
JournalAtherosclerosis
Volume228
Issue number1
DOIs
Publication statusPublished - May 2013

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Aryldialkylphosphatase
Carotid Artery Diseases
MicroRNAs
Single Nucleotide Polymorphism
Stroke
3' Untranslated Regions
Genotype
Atherosclerosis
Carotid Intima-Media Thickness
Genes
Alleles
Internal Carotid Artery
Volunteers
Healthy Volunteers
Plasmids
Myocardial Infarction
Binding Sites
Gene Expression

Keywords

  • Atherosclerosis
  • Intima-media thickness
  • MicroRNAs
  • SNP
  • Stroke

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

A functional polymorphism of PON1 interferes with microRNA binding to increase the risk of ischemic stroke and carotid atherosclerosis. / Liu, Mu En; Liao, Yi Chu; Lin, Ruey Tay; Wang, Yung Song; Hsi, Edward; Lin, Hsiu Fen; Chen, Ku Chung; Juo, Suh Hang H.

In: Atherosclerosis, Vol. 228, No. 1, 05.2013, p. 161-167.

Research output: Contribution to journalArticle

Liu, Mu En ; Liao, Yi Chu ; Lin, Ruey Tay ; Wang, Yung Song ; Hsi, Edward ; Lin, Hsiu Fen ; Chen, Ku Chung ; Juo, Suh Hang H. / A functional polymorphism of PON1 interferes with microRNA binding to increase the risk of ischemic stroke and carotid atherosclerosis. In: Atherosclerosis. 2013 ; Vol. 228, No. 1. pp. 161-167.
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abstract = "Objective: Single nucleotide polymorphisms (SNPs) located at microRNA (miRNA) binding sites (miR-SNPs) can affect the expression of genes. This study aimed to identify the miR-SNPs associated with atherosclerosis and stroke. Methods: Patients with ischemic stroke (n = 657) and stroke- and myocardial infarction-free volunteers (n = 1571) were enrolled. The carotid intima-media thickness (IMT) was measured in the control participants. Seventy-nine stroke susceptibility genes were initially selected and 13 genes were predicted to have miR-SNPs at their 3' untranslated regions (3'UTR). The miRNA arrays were used to further identify potential miR-SNPs. The miR-SNP rs3735590 at the paraoxonase 1 (PON1) gene was finally selected and its associations with stroke and carotid IMT were evaluated. The 3'UTR reporter and SNP functional assays were then performed to validate the results. Results: Compared with CC genotype, patients with CT or TT genotype at rs3735590 had lower risk of ischemic stroke (OR = 0.72, p = 0.036; OR = 0.83, p = 0.077, respectively). Among the healthy participants, the CT or TT genotype was associated with thinner IMT in the internal carotid arteries in comparison with CC genotype (β = -0.76, p = 0.003; β = -0.022, p = 0.452, respectively). Our findings suggested that the minor allele T had a protective effect on atherosclerosis. Results from 3'UTR reporter assays showed that PON1 is a direct target gene of miR-616. In plasmid constructs carrying the risk allele C at rs3735590, miR-616 inhibited the genetic expression of PON1. However, substitution of C by T at rs3735590 reduced the miR-616 binding affinity, leading to overexpression of the PON1 gene. Conclusion: Our study is the first to show that the miR-SNP at PON1 could affect genetic expression and is associated with an elevated risk for ischemic stroke and subclinical atherosclerosis.",
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T1 - A functional polymorphism of PON1 interferes with microRNA binding to increase the risk of ischemic stroke and carotid atherosclerosis

AU - Liu, Mu En

AU - Liao, Yi Chu

AU - Lin, Ruey Tay

AU - Wang, Yung Song

AU - Hsi, Edward

AU - Lin, Hsiu Fen

AU - Chen, Ku Chung

AU - Juo, Suh Hang H

PY - 2013/5

Y1 - 2013/5

N2 - Objective: Single nucleotide polymorphisms (SNPs) located at microRNA (miRNA) binding sites (miR-SNPs) can affect the expression of genes. This study aimed to identify the miR-SNPs associated with atherosclerosis and stroke. Methods: Patients with ischemic stroke (n = 657) and stroke- and myocardial infarction-free volunteers (n = 1571) were enrolled. The carotid intima-media thickness (IMT) was measured in the control participants. Seventy-nine stroke susceptibility genes were initially selected and 13 genes were predicted to have miR-SNPs at their 3' untranslated regions (3'UTR). The miRNA arrays were used to further identify potential miR-SNPs. The miR-SNP rs3735590 at the paraoxonase 1 (PON1) gene was finally selected and its associations with stroke and carotid IMT were evaluated. The 3'UTR reporter and SNP functional assays were then performed to validate the results. Results: Compared with CC genotype, patients with CT or TT genotype at rs3735590 had lower risk of ischemic stroke (OR = 0.72, p = 0.036; OR = 0.83, p = 0.077, respectively). Among the healthy participants, the CT or TT genotype was associated with thinner IMT in the internal carotid arteries in comparison with CC genotype (β = -0.76, p = 0.003; β = -0.022, p = 0.452, respectively). Our findings suggested that the minor allele T had a protective effect on atherosclerosis. Results from 3'UTR reporter assays showed that PON1 is a direct target gene of miR-616. In plasmid constructs carrying the risk allele C at rs3735590, miR-616 inhibited the genetic expression of PON1. However, substitution of C by T at rs3735590 reduced the miR-616 binding affinity, leading to overexpression of the PON1 gene. Conclusion: Our study is the first to show that the miR-SNP at PON1 could affect genetic expression and is associated with an elevated risk for ischemic stroke and subclinical atherosclerosis.

AB - Objective: Single nucleotide polymorphisms (SNPs) located at microRNA (miRNA) binding sites (miR-SNPs) can affect the expression of genes. This study aimed to identify the miR-SNPs associated with atherosclerosis and stroke. Methods: Patients with ischemic stroke (n = 657) and stroke- and myocardial infarction-free volunteers (n = 1571) were enrolled. The carotid intima-media thickness (IMT) was measured in the control participants. Seventy-nine stroke susceptibility genes were initially selected and 13 genes were predicted to have miR-SNPs at their 3' untranslated regions (3'UTR). The miRNA arrays were used to further identify potential miR-SNPs. The miR-SNP rs3735590 at the paraoxonase 1 (PON1) gene was finally selected and its associations with stroke and carotid IMT were evaluated. The 3'UTR reporter and SNP functional assays were then performed to validate the results. Results: Compared with CC genotype, patients with CT or TT genotype at rs3735590 had lower risk of ischemic stroke (OR = 0.72, p = 0.036; OR = 0.83, p = 0.077, respectively). Among the healthy participants, the CT or TT genotype was associated with thinner IMT in the internal carotid arteries in comparison with CC genotype (β = -0.76, p = 0.003; β = -0.022, p = 0.452, respectively). Our findings suggested that the minor allele T had a protective effect on atherosclerosis. Results from 3'UTR reporter assays showed that PON1 is a direct target gene of miR-616. In plasmid constructs carrying the risk allele C at rs3735590, miR-616 inhibited the genetic expression of PON1. However, substitution of C by T at rs3735590 reduced the miR-616 binding affinity, leading to overexpression of the PON1 gene. Conclusion: Our study is the first to show that the miR-SNP at PON1 could affect genetic expression and is associated with an elevated risk for ischemic stroke and subclinical atherosclerosis.

KW - Atherosclerosis

KW - Intima-media thickness

KW - MicroRNAs

KW - SNP

KW - Stroke

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