The chromosome 9p21.3 coronary heart disease risk allele is associated with altered gene expression in normal heart and vascular tissues

• Published in: PloS one Vol. 7; no. 6; p. e39574
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.06.2012; Public Library of Science (PLoS)
• Subjects: Acids; Alleles; Aorta; Binding sites; Biochemistry; Bioinformatics; Biology; Biomarkers; Cardiovascular disease; Cardiovascular diseases; Cell adhesion & migration; Cell cycle; Chromosome 9; Chromosomes, Human, Pair 9 - genetics; Coronary artery; Coronary artery disease; Coronary Artery Disease - genetics; Diabetes; DNA microarrays; Endarterectomy, Carotid; Female; G1 phase; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Gene Frequency - genetics; Gene Regulatory Networks - genetics; Genes; Genetic aspects; Genetic Predisposition to Disease; Genome-wide association studies; Genomes; Genomics; Genotyping; Health risks; Heart; Heart attack; Heart diseases; Heart failure; Heart Valve Diseases - genetics; Humans; Hypertrophy; Inflammation; Kinases; Loci; Male; Medical research; Medicin och hälsovetenskap; Medicine; Middle Aged; Minority & ethnic groups; Models, Genetic; Myocardial infarction; Myocardium - metabolism; Myocardium - pathology; Oligonucleotide Array Sequence Analysis; Phenols; Polymorphism, Single Nucleotide - genetics; Public health; Real-Time Polymerase Chain Reaction; Risk; Risk Factors; Tissue Donors; Tissues; Transcription (Genetics); Transcription factors; Type 2 diabetes; Wounding; Cleveland Ohio; Sweden; Ohio; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0039574

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.