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The present technological status of genetics and genomics or the genome-wide association studies (GWAS) are insufficient to explain complex diseases like atherosclerosis and coronary artery disease (CAD). It appears that the genetic risk variants of atherosclerosis are activated concurrently with functionally active specific environmental risk factors. With the systems biology methodological approach the atherosclerotic process and CAD are better explained and studied as a unified entity with significant clinical consequences. Systems biology is an alternative approach for the study of atherosclerosis and CAD. With the systems biology approach the follow-up of the atherosclerotic process requires four conceptual areas of study: 1) the two potential directions, the bottom-up direction (functional composition from genes to phenotypes) and the top-down direction (functional decomposition from phenotypes to genes); 2) the four disciplines or levels of complexity: the genomic, the cellular, the modular and the model (clinical phenotype) level; 3) the concept of network construction; 4) the atherosclerotic plaque development and progression across all levels of complexity. The systems biology methodology is holistic in conception. The proposed systems patterns are able to follow up the progressive nature of atherosclerosis and to explain the appearance of the clinical cardiovascular phenotypes. The phenotypes of CAD are integrated clinical wholes that determine through constrains and therapeutic procedures the behavior of the biological parts in the lower levels of complexity. This way of thinking is leading from genomics, through networks, to the mainstay of clinical cardiology.

The Complex Cardiac Atherosclerotic Disorder: The Elusive Role of Genetics and the New Consensus of Systems Biology Approach