Association of Genetic Risk Variants With Expression of Proximal Genes Identifies Novel Susceptibility Genes for Cardiovascular Disease
Association of Genetic Risk Variants With Expression of Proximal Genes Identifies Novel Susceptibility Genes for Cardiovascular Disease
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DOI：
10.1161/circgenetics.110.948935
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发表时间：
2010-08-01
影响因子：
--
通讯作者：
Eriksson, Per
中科院分区：
文献类型：
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作者：
Folkersen, Lasse;van't Hooft, Ferdinand;Eriksson, Per
背景-基于人群的全基因组关联研究已经发现了几个与心血管疾病或其危险因素相关的单核苷酸多态性（SNPs）。与这些风险SNP紧密接近的基因通常被认为仅基于其位置就具有重要的致病性。然而，SNPs和疾病mechanisms之间的实际连接仍然在很大程度上unknown.Methods and Results-To识别新的易感基因，我们研究了如何166 SNPs先前发现与心血管风险增加和/或易感代谢性状相关的附近基因的表达。使用表达阵列检测了577例主动脉、肝脏、乳腺动脉和颈动脉粥样硬化斑块的基因表达。对于47个SNP，邻近基因（位于200 kb内）的表达水平受到影响（P = 0.005）。这些基因中有20多个以前没有被确定为心血管或相关代谢性状的候选基因。SNP相关基因的影响是组织特异性和组织特异性是phenotype-dependent. Conclusions，这项研究表明几个实例之间的关联风险SNP和基因紧邻他们。它还证明了相关基因不是疾病的直接近端和明显的候选基因的情况。这表明，作为将全基因组关联研究结果应用于临床的第一步，有必要对遗传标记数据进行仔细研究。(Circ Genet. 2010; 3：365-373）。
Background-Population-based genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with cardiovascular disease or its risk factors. Genes in close proximity to these risk-SNPs are often thought to be pathogenetically important based on their location alone. However, the actual connections between SNPs and disease mechanisms remain largely unknown.Methods and Results-To identify novel susceptibility genes, we investigated how 166 SNPs previously found to be associated with increased cardiovascular risk and/or predisposing metabolic traits relate to the expression of nearby genes. Gene expression in 577 samples of aorta, liver, mammary artery, and carotid atherosclerotic plaque was measured using expression arrays. For 47 SNPs, the expression levels of proximal genes (located within 200 kb) were affected (P = 0.005). More than 20 of these genes had not previously been identified as candidate genes for cardiovascular or related metabolic traits. SNP-associated gene effects were tissue-specific and the tissue specificity was phenotype-dependent.Conclusions-This study demonstrates several instances of association between risk-SNPs and genes immediately adjacent to them. It also demonstrates instances in which the associated gene is not the immediately proximal and obvious candidate gene for disease. This shows the necessity of careful studies of genetic marker data as a first step toward application of genome-wide association studies findings in a clinical setting. (Circ Cardiovasc Genet. 2010; 3: 365-373.)