The metabolic syndrome (MS) constitutes a combination of underlying risk factors for an adverse outcome, cardiovascular disease. Thus, the clinical behavior of the MS can be regarded as a whole. Nevertheless, from a pathogenic point of view, understanding of the underlying mechanisms of each MS intermediate phenotype is far beyond their understanding as an integrative process. Systems biology introduces a new concept for revealing the pathogenesis of human disorders and suggests the presence of common physiologic processes and molecular networks influencing the risk of a disease. This paper shows a model of this concept to explain the genetic determinants of MS-associated phenotypes. Based on the hypothesis that common physiologic processes and molecular networks may influence the risk of MS disease components, we propose two systems-biology approaches: a gene enrichment analysis and the use of a protein-protein interaction network. Our results show that a network driven by many members of the nuclear receptor superfamily of proteins, including retinoid X receptor and farnesoid X receptor (FXR), may be implicated in the pathogenesis of the MS by its interactions at multiple levels of complexity with genes associated with metabolism, cell differentiation, and oxidative stress. In addition, we review two alternative genetic mechanisms that are gaining acceptance in the physiopathology of the MS: the regulation of transcriptional and post-transcriptional gene expression by microRNAs and epigenetic modifications such as DNA methylation.
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Supported in part by Grants UBACYT M055 (Universidad de Buenos Aires) and PICT 2006-124 (Agencia Nacional de Promoción Científica y Tecnológica). SS and CJP are members of Consejo Nacional de Investigaciones Científicas (CONICET).
No potential conflicts of interest relevant to this article were reported.
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Sookoian, S., Pirola, C.J. Metabolic Syndrome: From the Genetics to the Pathophysiology. Curr Hypertens Rep 13, 149–157 (2011). https://doi.org/10.1007/s11906-010-0164-9
- Cardiometabolic syndrome
- Insulin resistance
- Arterial blood pressure
- DNA methylation
- Systems biology
- Small for gestational age