The cis and trans effects of the risk variants of coronary artery disease in the Chr9p21 region

Wei Zhao, Jennifer A. Smith, Guangmei Mao, Myriam Fornage, Patricia A. Peyser, Yan V. Sun, Stephen T Turner, Sharon L R Kardia

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: Recent genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in the Chr9p21 region are associated with coronary artery disease (CAD). Most of the SNPs identified in this region are non-coding SNPs, suggesting that they may influence gene expression by cis or trans mechanisms to affect disease susceptibility. Since all cells from an individual have the same DNA sequence variations, levels of gene expression in immortalized cell lines can reflect the functional effects of DNA sequence variations that influence or regulate gene expression. The objective of this study is to evaluate the functional consequences of the risk variants in the Chr9p21 region on gene expression. Methods: We examined the association between the variants in the Chr9p21 region and the transcript-level mRNA expression of the adjacent genes (cis) as well as all other genes across the whole genome (trans) from transformed beta-lymphocytes in 801 non-Hispanic white participants from The Genetic Epidemiology Network of Arteriopathy (GENOA) study. Results: We found that the CAD risk variants in the Chr9p21 region were significantly associated with the mRNA expression of the ANRIL transcript ENST00000428597 (p = 8.58e-06). Importantly, a few distant transcripts were also found to be associated with the variants in this region, including the well-known CAD risk gene ABCA1 (p = 1.01e-05). Gene enrichment testing suggests that retinol metabolism, N-Glycan biosynthesis, and TGF signaling pathways may be involved. Conclusion: These results suggest that the effect of risk variants in the Chr9p21 region on susceptibility to CAD is likely to be mediated through both cis and trans mechanisms.

Original languageEnglish (US)
Article number21
JournalBMC Medical Genomics
Volume8
Issue number1
DOIs
StatePublished - May 10 2015

Fingerprint

Coronary Artery Disease
Gene Expression
Single Nucleotide Polymorphism
Genes
Messenger RNA
Molecular Epidemiology
Genome-Wide Association Study
Disease Susceptibility
Vitamin A
Polysaccharides
Genome
Lymphocytes
Cell Line

Keywords

  • CAD
  • Chr9p21
  • Gene expression
  • GENOA
  • SNP

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Zhao, W., Smith, J. A., Mao, G., Fornage, M., Peyser, P. A., Sun, Y. V., ... Kardia, S. L. R. (2015). The cis and trans effects of the risk variants of coronary artery disease in the Chr9p21 region. BMC Medical Genomics, 8(1), [21]. https://doi.org/10.1186/s12920-015-0094-0

The cis and trans effects of the risk variants of coronary artery disease in the Chr9p21 region. / Zhao, Wei; Smith, Jennifer A.; Mao, Guangmei; Fornage, Myriam; Peyser, Patricia A.; Sun, Yan V.; Turner, Stephen T; Kardia, Sharon L R.

In: BMC Medical Genomics, Vol. 8, No. 1, 21, 10.05.2015.

Research output: Contribution to journalArticle

Zhao, Wei ; Smith, Jennifer A. ; Mao, Guangmei ; Fornage, Myriam ; Peyser, Patricia A. ; Sun, Yan V. ; Turner, Stephen T ; Kardia, Sharon L R. / The cis and trans effects of the risk variants of coronary artery disease in the Chr9p21 region. In: BMC Medical Genomics. 2015 ; Vol. 8, No. 1.
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abstract = "Background: Recent genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in the Chr9p21 region are associated with coronary artery disease (CAD). Most of the SNPs identified in this region are non-coding SNPs, suggesting that they may influence gene expression by cis or trans mechanisms to affect disease susceptibility. Since all cells from an individual have the same DNA sequence variations, levels of gene expression in immortalized cell lines can reflect the functional effects of DNA sequence variations that influence or regulate gene expression. The objective of this study is to evaluate the functional consequences of the risk variants in the Chr9p21 region on gene expression. Methods: We examined the association between the variants in the Chr9p21 region and the transcript-level mRNA expression of the adjacent genes (cis) as well as all other genes across the whole genome (trans) from transformed beta-lymphocytes in 801 non-Hispanic white participants from The Genetic Epidemiology Network of Arteriopathy (GENOA) study. Results: We found that the CAD risk variants in the Chr9p21 region were significantly associated with the mRNA expression of the ANRIL transcript ENST00000428597 (p = 8.58e-06). Importantly, a few distant transcripts were also found to be associated with the variants in this region, including the well-known CAD risk gene ABCA1 (p = 1.01e-05). Gene enrichment testing suggests that retinol metabolism, N-Glycan biosynthesis, and TGF signaling pathways may be involved. Conclusion: These results suggest that the effect of risk variants in the Chr9p21 region on susceptibility to CAD is likely to be mediated through both cis and trans mechanisms.",
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AU - Turner, Stephen T

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AB - Background: Recent genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in the Chr9p21 region are associated with coronary artery disease (CAD). Most of the SNPs identified in this region are non-coding SNPs, suggesting that they may influence gene expression by cis or trans mechanisms to affect disease susceptibility. Since all cells from an individual have the same DNA sequence variations, levels of gene expression in immortalized cell lines can reflect the functional effects of DNA sequence variations that influence or regulate gene expression. The objective of this study is to evaluate the functional consequences of the risk variants in the Chr9p21 region on gene expression. Methods: We examined the association between the variants in the Chr9p21 region and the transcript-level mRNA expression of the adjacent genes (cis) as well as all other genes across the whole genome (trans) from transformed beta-lymphocytes in 801 non-Hispanic white participants from The Genetic Epidemiology Network of Arteriopathy (GENOA) study. Results: We found that the CAD risk variants in the Chr9p21 region were significantly associated with the mRNA expression of the ANRIL transcript ENST00000428597 (p = 8.58e-06). Importantly, a few distant transcripts were also found to be associated with the variants in this region, including the well-known CAD risk gene ABCA1 (p = 1.01e-05). Gene enrichment testing suggests that retinol metabolism, N-Glycan biosynthesis, and TGF signaling pathways may be involved. Conclusion: These results suggest that the effect of risk variants in the Chr9p21 region on susceptibility to CAD is likely to be mediated through both cis and trans mechanisms.

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