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The Chromosome 9p21.3 Coronary Heart Disease Risk Allele Is Associated with Altered Gene Expression in Normal Heart and Vascular Tissues
Genome-wide association studies have identified a coronary artery disease (CAD) risk locus in a non-coding region at 9p21.3, the nearest genes being CDKN2A and CDKN2B. To understand the pathways by which this locus might influence CAD susceptibility, we investigated associations between the 9p21.3 r...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387158/ https://www.ncbi.nlm.nih.gov/pubmed/22768093 http://dx.doi.org/10.1371/journal.pone.0039574 |
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author | Pilbrow, Anna P. Folkersen, Lasse Pearson, John F. Brown, Chris M. McNoe, Les Wang, Nancy M. Sweet, Wendy E. Tang, W. H. Wilson Black, Michael A. Troughton, Richard W. Richards, A. Mark Franco-Cereceda, Anders Gabrielsen, Anders Eriksson, Per Moravec, Christine S. Cameron, Vicky A. |
author_facet | Pilbrow, Anna P. Folkersen, Lasse Pearson, John F. Brown, Chris M. McNoe, Les Wang, Nancy M. Sweet, Wendy E. Tang, W. H. Wilson Black, Michael A. Troughton, Richard W. Richards, A. Mark Franco-Cereceda, Anders Gabrielsen, Anders Eriksson, Per Moravec, Christine S. Cameron, Vicky A. |
author_sort | Pilbrow, Anna P. |
collection | PubMed |
description | Genome-wide association studies have identified a coronary artery disease (CAD) risk locus in a non-coding region at 9p21.3, the nearest genes being CDKN2A and CDKN2B. To understand the pathways by which this locus might influence CAD susceptibility, we investigated associations between the 9p21.3 risk genotype and global gene expression in heart tissue from donors with no diagnosed heart disease (n = 108, predominant cause of death, cerebral vascular accident) and in carotid plaque (n = 106), aorta (n = 104) and mammary artery (n = 88) tissues from heart valve and carotid endarterectomy patients. Genotyping was performed with Taqman assays and Illumina arrays, and gene expression profiles generated with Affymetrix microarrays. Associations were analyzed with an additive genetic model. In heart tissue, 46 genes were putatively altered in association with the 9p21.3 risk allele (70% down-regulated, fold-change >1.1 per allele, p<0.05 adjusted for age, gender, ethnicity, cause of death). These genes were enriched for biomarkers of myocardial infarction (p = 1.53×10(−9)), response to wounding (p = 2.65×10(−10)) and inflammatory processes (p<1.97×10(−7)). Among the top 10 most down-regulated genes, 7 genes shared a set of transcription factor binding sites within conserved promoter regions (p<1.14×10(−5)), suggesting they may be co-regulated. Canonical pathway modelling of the most differentially expressed transcripts across all tissues (154 genes, 60% down-regulated, fold-change >1.1 per allele, p<0.01) showed that 75% of the genes could be transcriptionally regulated through the cell cycle G1 phase progression pathway (p<1.08×10(−258)), in which CDKN2A and CDKN2B play a regulatory role. These data suggest that the cell cycle G1 phase progression pathway is activated in individuals with the 9p21.3 risk allele. This may contribute to a proliferative phenotype that promotes adverse cardiac hypertrophy and vascular remodeling, leading to an increased CAD risk. |
format | Online Article Text |
id | pubmed-3387158 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33871582012-07-05 The Chromosome 9p21.3 Coronary Heart Disease Risk Allele Is Associated with Altered Gene Expression in Normal Heart and Vascular Tissues Pilbrow, Anna P. Folkersen, Lasse Pearson, John F. Brown, Chris M. McNoe, Les Wang, Nancy M. Sweet, Wendy E. Tang, W. H. Wilson Black, Michael A. Troughton, Richard W. Richards, A. Mark Franco-Cereceda, Anders Gabrielsen, Anders Eriksson, Per Moravec, Christine S. Cameron, Vicky A. PLoS One Research Article Genome-wide association studies have identified a coronary artery disease (CAD) risk locus in a non-coding region at 9p21.3, the nearest genes being CDKN2A and CDKN2B. To understand the pathways by which this locus might influence CAD susceptibility, we investigated associations between the 9p21.3 risk genotype and global gene expression in heart tissue from donors with no diagnosed heart disease (n = 108, predominant cause of death, cerebral vascular accident) and in carotid plaque (n = 106), aorta (n = 104) and mammary artery (n = 88) tissues from heart valve and carotid endarterectomy patients. Genotyping was performed with Taqman assays and Illumina arrays, and gene expression profiles generated with Affymetrix microarrays. Associations were analyzed with an additive genetic model. In heart tissue, 46 genes were putatively altered in association with the 9p21.3 risk allele (70% down-regulated, fold-change >1.1 per allele, p<0.05 adjusted for age, gender, ethnicity, cause of death). These genes were enriched for biomarkers of myocardial infarction (p = 1.53×10(−9)), response to wounding (p = 2.65×10(−10)) and inflammatory processes (p<1.97×10(−7)). Among the top 10 most down-regulated genes, 7 genes shared a set of transcription factor binding sites within conserved promoter regions (p<1.14×10(−5)), suggesting they may be co-regulated. Canonical pathway modelling of the most differentially expressed transcripts across all tissues (154 genes, 60% down-regulated, fold-change >1.1 per allele, p<0.01) showed that 75% of the genes could be transcriptionally regulated through the cell cycle G1 phase progression pathway (p<1.08×10(−258)), in which CDKN2A and CDKN2B play a regulatory role. These data suggest that the cell cycle G1 phase progression pathway is activated in individuals with the 9p21.3 risk allele. This may contribute to a proliferative phenotype that promotes adverse cardiac hypertrophy and vascular remodeling, leading to an increased CAD risk. Public Library of Science 2012-06-29 /pmc/articles/PMC3387158/ /pubmed/22768093 http://dx.doi.org/10.1371/journal.pone.0039574 Text en Pilbrow et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Pilbrow, Anna P. Folkersen, Lasse Pearson, John F. Brown, Chris M. McNoe, Les Wang, Nancy M. Sweet, Wendy E. Tang, W. H. Wilson Black, Michael A. Troughton, Richard W. Richards, A. Mark Franco-Cereceda, Anders Gabrielsen, Anders Eriksson, Per Moravec, Christine S. Cameron, Vicky A. The Chromosome 9p21.3 Coronary Heart Disease Risk Allele Is Associated with Altered Gene Expression in Normal Heart and Vascular Tissues |
title | The Chromosome 9p21.3 Coronary Heart Disease Risk Allele Is Associated with Altered Gene Expression in Normal Heart and Vascular Tissues |
title_full | The Chromosome 9p21.3 Coronary Heart Disease Risk Allele Is Associated with Altered Gene Expression in Normal Heart and Vascular Tissues |
title_fullStr | The Chromosome 9p21.3 Coronary Heart Disease Risk Allele Is Associated with Altered Gene Expression in Normal Heart and Vascular Tissues |
title_full_unstemmed | The Chromosome 9p21.3 Coronary Heart Disease Risk Allele Is Associated with Altered Gene Expression in Normal Heart and Vascular Tissues |
title_short | The Chromosome 9p21.3 Coronary Heart Disease Risk Allele Is Associated with Altered Gene Expression in Normal Heart and Vascular Tissues |
title_sort | chromosome 9p21.3 coronary heart disease risk allele is associated with altered gene expression in normal heart and vascular tissues |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387158/ https://www.ncbi.nlm.nih.gov/pubmed/22768093 http://dx.doi.org/10.1371/journal.pone.0039574 |
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