Voros Szilard, Maurovich-Horvat Pal, Marvasty Idean B, Bansal Aruna T, Barnes Michael R, Vazquez Gustavo, Murray Sarah S, Voros Viktor, Merkely Bela, Brown Bradley O, Warnick G Russell
Global Genomics Group, LLC, 737 N. 5th Street, Richmond, VA 23219, USA.
Semmelweis University, Budapest, Hungary.
J Cardiovasc Comput Tomogr. 2014 Nov-Dec;8(6):442-51. doi: 10.1016/j.jcct.2014.08.006. Epub 2014 Sep 6.
Complex biological networks of atherosclerosis are largely unknown.
The main objective of the Genetic Loci and the Burden of Atherosclerotic Lesions study is to assemble comprehensive biological networks of atherosclerosis using advanced cardiovascular imaging for phenotyping, a panomic approach to identify underlying genomic, proteomic, metabolomic, and lipidomic underpinnings, analyzed by systems biology-driven bioinformatics.
By design, this is a hypothesis-free unbiased discovery study collecting a large number of biologically related factors to examine biological associations between genomic, proteomic, metabolomic, lipidomic, and phenotypic factors of atherosclerosis. The Genetic Loci and the Burden of Atherosclerotic Lesions study (NCT01738828) is a prospective, multicenter, international observational study of atherosclerotic coronary artery disease. Approximately 7500 patients are enrolled and undergo non-contrast-enhanced coronary calcium scanning by CT for the detection and quantification of coronary artery calcium, as well as coronary artery CT angiography for the detection and quantification of plaque, stenosis, and overall coronary artery disease burden. In addition, patients undergo whole genome sequencing, DNA methylation, whole blood-based transcriptome sequencing, unbiased proteomics based on mass spectrometry, as well as metabolomics and lipidomics on a mass spectrometry platform. The study is analyzed in 3 subsequent phases, and each phase consists of a discovery cohort and an independent validation cohort. For the primary analysis, the primary phenotype will be the presence of any atherosclerotic plaque, as detected by cardiac CT. Additional phenotypic analyses will include per patient maximal luminal stenosis defined as 50% and 70% diameter stenosis. Single-omic and multi-omic associations will be examined for each phenotype; putative biomarkers will be assessed for association, calibration, discrimination, and reclassification.
动脉粥样硬化复杂的生物网络在很大程度上尚不明确。
“遗传位点与动脉粥样硬化病变负担”研究的主要目的是利用先进的心血管成像技术进行表型分析，采用全景方法识别潜在的基因组、蛋白质组、代谢组和脂质组学基础，通过系统生物学驱动的生物信息学分析，构建动脉粥样硬化的综合生物网络。
从设计上看，这是一项无假设的无偏发现研究，收集大量生物学相关因素，以检查动脉粥样硬化的基因组、蛋白质组、代谢组、脂质组和表型因素之间的生物学关联。“遗传位点与动脉粥样硬化病变负担”研究（NCT01738828）是一项针对动脉粥样硬化性冠状动脉疾病的前瞻性、多中心、国际观察性研究。约7500名患者入组，接受CT非增强冠状动脉钙化扫描以检测和量化冠状动脉钙化，以及冠状动脉CT血管造影以检测和量化斑块、狭窄和整体冠状动脉疾病负担。此外，患者还接受全基因组测序、DNA甲基化、基于全血的转录组测序、基于质谱的无偏蛋白质组学，以及质谱平台上的代谢组学和脂质组学分析。该研究分3个后续阶段进行分析，每个阶段包括一个发现队列和一个独立验证队列。对于主要分析，主要表型将是心脏CT检测到的任何动脉粥样硬化斑块的存在。额外的表型分析将包括每位患者定义为直径狭窄50%和70%的最大管腔狭窄。将针对每种表型检查单组学和多组学关联；将评估推定生物标志物的关联、校准、鉴别和重新分类。
