National Institutes of Health/National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA, USA.
Circulation. 2013 Feb 19;127(7):799-810. doi: 10.1161/CIRCULATIONAHA.112.111559. Epub 2013 Jan 11.
9p21.3 is among the most strongly replicated regions for cardiovascular disease. There are few reports of sequencing the associated 9p21.3 interval. We set out to sequence the 9p21.3 region followed by a comprehensive study of genetic associations with clinical and subclinical cardiovascular disease and its risk factors, as well as with copy number variation and gene expression, in the Framingham Heart Study (FHS).
We sequenced 281 individuals (94 with myocardial infarction, 94 with high coronary artery calcium levels, and 93 control subjects free of elevated coronary artery calcium or myocardial infarction), followed by genotyping and association in >7000 additional FHS individuals. We assessed genetic associations with clinical and subclinical cardiovascular disease, risk factor phenotypes, and gene expression levels of the protein-coding genes CDKN2A and CDKN2B and the noncoding gene ANRIL in freshly harvested leukocytes and platelets. Within this large sample, we found strong associations of 9p21.3 variants with increased risk for myocardial infarction, higher coronary artery calcium levels, and larger abdominal aorta diameters and no evidence for association with traditional cardiovascular disease risk factors. No common protein-coding variation, variants in splice donor or acceptor sites, or copy number variation events were observed. By contrast, strong associations were observed between genetic variants and gene expression, particularly for a short isoform of ANRIL and for CDKN2B.
Our thorough genomic characterization of 9p21.3 suggests common variants likely account for observed disease associations and provides further support for the hypothesis that complex regulatory variation affecting ANRIL and CDKN2B gene expression may contribute to increased risk for clinically apparent and subclinical coronary artery disease and aortic disease.
9p21.3 是心血管疾病复制最强烈的区域之一。很少有关于该相关 9p21.3 区间测序的报道。我们着手对 9p21.3 区域进行测序，然后对其与临床和亚临床心血管疾病及其危险因素的遗传相关性进行全面研究，以及与拷贝数变异和基因表达的相关性，在弗雷明汉心脏研究（FHS）中。
我们对 281 个人（94 例心肌梗死，94 例冠状动脉钙水平升高，93 例无升高冠状动脉钙或心肌梗死的对照）进行了测序，随后对 >7000 名 FHS 个体进行了基因分型和关联研究。我们评估了遗传相关性与临床和亚临床心血管疾病、危险因素表型以及白细胞和血小板中蛋白质编码基因 CDKN2A 和 CDKN2B 及非编码基因 ANRIL 的基因表达水平。在这个大样本中，我们发现 9p21.3 变体与心肌梗死风险增加、冠状动脉钙水平升高、腹主动脉直径增大强烈相关，而与传统心血管疾病危险因素无关联。没有观察到常见的蛋白质编码变异、剪接受体或供体位点的变异或拷贝数变异事件。相比之下，遗传变异与基因表达之间存在强烈的相关性，特别是对于 ANRIL 的短亚型和 CDKN2B。
我们对 9p21.3 进行了全面的基因组特征描述，表明常见变异可能导致观察到的疾病相关性，并进一步支持了这样一种假设，即影响 ANRIL 和 CDKN2B 基因表达的复杂调节变异可能导致临床明显和亚临床冠状动脉疾病和主动脉疾病的风险增加。
