Christchurch Cardioendocrine Research Group, Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.
PLoS One. 2012;7(6):e39574. doi: 10.1371/journal.pone.0039574. Epub 2012 Jun 29.
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.
全基因组关联研究在非编码区域 9p21.3 发现了一个冠心病（CAD）风险位点，最近的基因是 CDKN2A 和 CDKN2B。为了了解该位点可能影响 CAD 易感性的途径，我们研究了 9p21.3 风险基因型与无诊断心脏病（n=108，主要死因是脑血管意外）供体心脏组织、颈动脉斑块（n=106）、主动脉（n=104）和乳内动脉（n=88）组织中整体基因表达之间的关联。通过 Taqman 测定法和 Illumina 阵列进行基因分型，通过 Affymetrix 微阵列生成基因表达谱。采用加性遗传模型分析关联。在心脏组织中，有 46 个基因与 9p21.3 风险等位基因相关（70%下调，每个等位基因的倍数变化>1.1，经年龄、性别、种族、死因校正后 p<0.05）。这些基因富含心肌梗死（p=1.53×10(-9)）、创伤反应（p=2.65×10(-10)）和炎症过程（p<1.97×10(-7)）的生物标志物。在下调最明显的 10 个基因中，有 7 个基因在保守启动子区域共享一组转录因子结合位点（p<1.14×10(-5)），提示它们可能受到共同调控。对所有组织中差异表达转录本进行的经典途径建模（154 个基因，60%下调，每个等位基因的倍数变化>1.1，p<0.01）表明，75%的基因可以通过细胞周期 G1 期进展途径进行转录调控（p<1.08×10(-258)），其中 CDKN2A 和 CDKN2B 发挥调节作用。这些数据表明，细胞周期 G1 期进展途径在携带 9p21.3 风险等位基因的个体中被激活。这可能导致促进不良心肌肥厚和血管重塑的增殖表型，从而增加 CAD 风险。
