ANALYSIS OF WHOLE-BLOOD TRANSCRIPTOME DIFFERENCES AND FUNCTIONAL INFERENCES IN SUBJECTS WITH NON-OBSTRUCTIVE OR OBSTRUCTIVE CAD, DETECTED BY CCTA, COMPARED TO SUBJECTS WITHOUT CORONARY ATHEROSCLEROSIS

Background - Despite the presence of the same CAD symptoms and pre-tests suggestive for the presence of CAD, a not irrelevant number of coronary computed tomography angiography do not detect the presence of coronary atherosclerosis. In fact, individuals could share the same symptoms even having different disease profiles from a biological point of view. Thus, there is an urgent unmet need of new tools/gene-expression patterns that allowed to detect the presence and the severity of coronary artery disease. In this context, the aim of this thesis project is to identify, through RNA-sequencing: i) gene-expression patterns in the whole blood that could differentiate patients with obstructive and non-obstructive coronary atherosclerosis, detected by coronary CT angiography (CCTA), from subjects without the presence of coronary stenosis; ii) biological processes and/or pathways associated to obstructive or non-obstructive CAD. Methods - A total of 730 consecutive patients, undergoing coronary computed tomography angiography (CCTA) for suspected CAD, have been enrolled and coronary stenosis was quantified. Total RNA was isolated from whole blood collected at baseline. The whole-blood transcriptome of 315 patients, matched for age, sex and with (obCAD, n=105) or without (non-obCAD, n=105) obstructive coronary stenosis and of subjects with complete absence of coronary atherosclerosis (noCAD=105), was profiled and compared by RNA-sequencing. Statistical and data analysis was performed with R packages, GSEA and GraphPad Prism. Results - Differential gene expression analysis reveals that whole blood gene expression patterns could differentiate obstructive and non-obstructive CAD patients from subjects with the complete absence of coronary atherosclerosis. Gene-Set Enrichment Analysis revealed that both obstructive and non-obstructive CAD were negatively associated to the regulation of innate and adaptive immunity. Non-obstructive coronary artery disease were positively associated to B cell receptor signalling pathway while obstructive CAD to circadian rhythms. Conclusions - Whole-blood transcriptome profiling revealed differences between patients with obstructive or non-obstructive coronary artery disease as detected by CCTA and subjects with complete absence of coronary atherosclerosis. The main findings confirm the hypothesis that the integration of non-invasive imaging and whole-blood transcriptional profiles could be useful for new tools/blood-based test, able to detect the presence and the severity of coronary atherosclerosis as detected by CCTA and find biological processes associated with obstructive and non-obstructive CAD.