Abstract
<p>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.</p><p>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.</p><p>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. </p>
Highlights
During the last two decades genetics focused on to scarce single-gene diseases encountered in less than 1% of the general population [1]
The novel genomewide case-control association approach which is designated as GWAS (Genome Wide Association Studies) proved effective in the identification of specific markers related to a disease [1]
The study of the atherosclerotic process with the systems biology approach can follow certain steps in four conceptual areas of interest: 1) the two previously mentioned potential directions of study of the atherosclerotic phenomenon, functional composition and functional decomposition; 2) the disciplines or levels of complexity and integration of the atherosclerotic process: the genetic and genomics level, the cellular and molecular level, the modular level and the model level; 3) the concept of network construction extending across the discipline levels of the atherosclerotic process; 4) the atherosclerotic plaque development and progression across the discipline levels of the atherosclerotic process (Table 1)
Summary
During the last two decades genetics focused on to scarce single-gene diseases encountered in less than 1% of the general population [1]. In complex cardiac disorders the role of the causative genes is expressed only through systems genetics and epigenetic mechanisms that are constructing functional molecular networks. A shortcoming of the systems biology approach is that we don’t have yet all the necessary biological networks of the early stages of the atherosclerotic plaque It is obvious, that the recognition of the missing biological networks will increase our understanding of the progression patterns of the clinical phenotypes. Bjorkegren et al [12], using network models based on genetic and genomic datasets, are proposing the systems genetics approach to explain CAD heritability and etiology They argue that GWAS recognized 153 possible CAD loci with 46 of those having genome-wide importance. The construction of similar networks in atherosclerosis and CAD will increase the knowledge of the basic underlying molecular and cellular mechanisms responsible for the progression of the atherosclerotic plaque to clinical phenotypes.
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