Abstract
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.
Highlights
Coronary artery disease (CAD) is a leading cause of mortality and morbidity worldwide [1]
Using genome-wide expression profiling, we have identified genes whose expression patterns may be associated with the 9p21.3 CAD risk allele in donor myocardial tissue and in vascular tissues from CAD patients
Canonical pathway modeling of the most differentially expressed genes across all tissues identified the cell cycle G1 phase progression pathway as the most likely mechanism regulating their expression. This pathway facilitates the activation of genes required for cell cycle progression and cell proliferation [44] and is controlled by proteins encoded by CDKN2A and CDKN2B, two genes located adjacent to the 9p21.3 risk locus
Summary
Coronary artery disease (CAD) is a leading cause of mortality and morbidity worldwide [1]. In 2007, several genome-wide association studies consistently identified a region on chromosome 9p21.3 as being the most strongly associated with CAD [3,4,5,6]. This finding has been replicated in multiple case-control studies in several population groups in numerous ethnicities [7,8,9,10,11,12,13,14,15], making 9p21.3 the most replicated molecular genetic association with coronary heart disease to date. It has been suggested that the 9p21.3 locus may have clinical utility as an early marker for CAD susceptibility [32]
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