Whole-exome sequencing in individuals with multiple cardiovascular risk factors and normal coronary arteries
Whole-exome sequencing in individuals with multiple cardiovascular risk factors and normal coronary arteries
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DOI：
10.1097/mca.0000000000000357
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发表时间：
2016-06-01
影响因子：
1.8
通讯作者：
Friedman, Eitan
中科院分区：
文献类型：
--
作者：
Abramowitz, Yigal;Roth, Arie;Friedman, Eitan
目的：大多数关于冠心病相关基因的研究针对的是经血管造影或临床证实的冠心病患者。关注具有正常冠状动脉（NCA）的高危个体可能为冠心病的发病机制提供新的见解。我们的目的是鉴定被认为对CAD的发展有保护作用的基因。方法对17例合并多种心血管危险因素的NCA患者和17例合并多血管CAD的对照组进行全外显子组测序（WES）。随后，使用Fluidigm平台在100个额外的CAD对照和100个一般人群对照中单独验证了罕见的nca独特序列变异。结果在研究组中至少一个WES池中检测到555 100个变异，而在对照组WES池中没有检测到变异。在第二阶段的验证中，我们将重点放在罕见的、非同义的变异上，共得到40个基因中的144个变异，其中96个被选中用于后续的基因分型。验证阶段基因分型结果显示，在NCA组中发现了16个基因中的19个变异，而在CAD对照组中没有发现。SPTBN5、NID2和ADAMTSL4基因在不止一名CAD保护患者中携带序列变异，而在117名CAD对照中没有。结论应用WES技术并关注那些似乎可以保护不发生CAD的个体，成功地鉴定出19种可能通过未知机制保护不发生CAD的变异。研究冠心病高危人群的遗传学可能为冠心病的发病机制提供新的见解。版权所有2016威科集团有限公司版权所有。
Objectives Most studies on the genes involved in coronary artery disease (CAD) targeted individuals with angiographically or clinically proven CAD. Focusing on high-risk individuals with normal coronary arteries (NCA) may offer novel insights into the pathogenesis of CAD. We aimed to identify genes putatively protective for development of CAD.Methods Pooled whole-exome sequencing (WES) was performed on 17 patients with multiple cardiovascular risk factors and NCA and on 17 controls with multivessel CAD. Rare NCA-unique sequence variants were subsequently individually validated using the Fluidigm platform in 100 additional CAD controls and 100 general population controls.Results In total, 555 100 variants were detected in at least one WES pool in the study group and in none of the control WES pools. For second phase validation, we focused on rare, nonsynonymous variants, resulting in a total of 144 variants in 40 genes, of which 96 were selected for subsequent genotyping. Validation phase genotyping resulted in 19 variants in 16 genes that were found in the NCA group and in none of the CAD controls. The SPTBN5, NID2, and ADAMTSL4 genes harbored sequence variants in more than one CAD-protected patient and none of the 117 CAD controls.Conclusion Applying WES technology and focusing on individuals seemingly protected from developing CAD successfully identified 19 variants that may offer protection from CAD by undetermined mechanisms. Studying the genetics of high-risk individuals apparently protected from CAD may provide novel insights into the pathogenesis of CAD. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.