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Genome-wide association studies (GWAS) have identified hundreds of cardiometabolic disease (CMD) risk loci. However, they contribute little to genetic variance, and most downstream gene-regulatory mechanisms are unknown. We genotyped and RNA-sequenced vascular and metabolic tissues from 600 coronary artery disease patients in the STARNET study. Gene expression traits associated with CMD risk SNPs identified by GWAS were more extensively found in STARNET than in tissue- and disease-unspecific gene-tissue expression studies, indicating sharing of downstream cis-/trans-gene regulation across tissues and CMDs. In contrast, the regulatory effects of other GWAS risk SNPs were tissue-specific; abdominal fat emerged as an important gene-regulatory site for blood lipids, such as for the LDL-cholesterol and coronary artery disease risk-gene PCSK9. STARNET provides insights into gene-regulatory mechanisms for CMD risk loci, facilitating their translation into opportunities for diagnosis, therapy and prevention.

Cigarette smoking is a powerful cardiovascular risk factor and smoking cessation is the single most effective lifestyle measure for the prevention of a large number of cardiovascular diseases. Impairment of endothelial function, arterial stiffness, inflammation, lipid modification as well as an alteration of antithrombotic and prothrombotic factors are smoking-related major determinants of initiation, and acceleration of the atherothrombotic process, leading to cardiovascular events. Cigarette smoking acutely exerts an hypertensive effect, mainly through the stimulation of the sympathetic nervous system. As concern the impact of chronic smoking on blood pressure, available data do not put clearly in evidence a direct causal relationship between these two cardiovascular risk factors, a concept supported by the evidence that no lower blood pressure values have been observed after chronic smoking cessation. Nevertheless, smoking, affecting arterial stiffness and wave reflection might have greater detrimental effect on central blood pressure, which is more closely related to target organ damage than brachial blood pressure. Hypertensive smokers are more likely to develop severe forms of hypertension, including malignant and renovascular hypertension, an effect likely due to an accelerated atherosclerosis.

Combined treatment with vitamins C and E has beneficial effects on endothelium-dependent vasodilation and arterial stiffness in untreated, essential hypertensive patients. This effect is associated with changes in plasma markers of oxidative stress.

SUMMARY Inferring molecular networks can reveal how genetic perturbations interact with environmental factors to cause common complex diseases. We analyzed genetic and gene expression data from seven tissues relevant to coronary artery disease (CAD) and identified regulatory gene networks (RGNs) and their key drivers. By integrating data from genome-wide association studies, we identified 30 CAD-causal RGNs interconnected in vascular and metabolic tissues, and we validated them with corresponding data from the Hybrid Mouse Diversity Panel. As proof of concept, by targeting the key drivers AIP, DRAP1, POLR2I, and PQBP1 in a cross-species-validated, arterial-wall RGN involving RNA-processing genes, we re-identified this RGN in THP-1 foam cells and independent data from CAD macrophages and carotid lesions. This characterization of the molecular landscape in CAD will help better define the regulation of CAD candidate genes identified by genome-wide association studies and is a first step toward achieving the goals of precision medicine.