Precision phenotyping, panomics, and system-level bioinformatics to delineate complex biologies of atherosclerosis: Rationale and design of the “Genetic Loci and the Burden of Atherosclerotic Lesions” study

Abstract

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.

Prediction of abdominal aortic aneurysm calcification by means of variation of high-sensitivity C-reactive protein

“…23,24 Beside imaging, currently, no accurate methods exist in order to diagnose calcified AAAs, and clinical examination is still doubtful. For the purpose of this study, we analysed the blood levels for WBC, fibrinogen and hsCRP, but the correlation between different grades of calcification and WBC count or fibrinogen levels does not occur.…”

Genetics paired with CT angiography in the setting of atherosclerosis

“…This clinical trial is by far the single largest international, prospective, multicenter panomic study to identify the novel pathway, biomarker, and drug targets for the development and progression of CAD and risk factors such as atherosclerosis [48]. Up to 10,000 patients from 48 institutions in 9 countries and across North America, Australia, and Europe are to be enrolled.…”

Systems Biology and Noninvasive Imaging of Atherosclerosis

“…A recent study identified the genetic variations influencing the effect of smoking on CIMT, thereby exemplifying how the study of gene-environment interactions may explain the interindividual variation in both cardiovascular events and surrogate measures of cardiovascular risk 121 . The Genetic Loci and the Burden of Atherosclerotic Lesions (GLOBAL) study 122 (NCT01738828) brings this concept to a different level by aiming to comprehensively integrate plaque phenotype by cardiovascular imaging, with a panomic approach including genomic, transcriptomic, proteomic, metabolomics and lipidomic in a systems biology framework. The study plans to examine single-omic and multi-omic associations with each imaging phenotype evaluated (CAC and CT angiography) in training and validation datasets.…”