Metabolic Syndrome: From the Genetics to the Pathophysiology

Abstract

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.

PNPLA3 and TNF-<i>α</i> G238A Genetic Polymorphisms in Egyptian Patients with Different Grades of Severity of NAFLD

“…The homozygous GG genotype was most frequent among the patients with NASH (26%) when compared to subjects with borderline NASH (20.5%) and those with simple steatosis (20%). This was concordant to the results of the meta-analysis by Sookoian and Pirola which showed that the rs738409 exerts a strong influence on the susceptibility to a more aggressive disease with greater hepatic injury, as the GG homozygous subjects had a 3.24-fold more risk of higher necro-inflammatory scores when compared with those who had the CC genotype [8]. Also a meta-analysis by Xu et al reported that the rs738409 polymorphism was more likely to increase the risk of NASH instead of simple steatosis [35].…”

“…The association of PNPLA3 gene polymorphisms not only with fatty liver and triglyceride content, but also with histological severity of NAFLD was shown in subsequent studies [7] [8].…”

Dyslipidemia: Genetics and Role in the Metabolic Syndrome

“…The use of other forms of 'causal modeling' (edge/node; integrative genetics) has been proposed (Lusis et al, 2008), particularly, to improve our understanding of differential effects by gender as well as to better understand how maternal nutrition and epigenetics affect MetSyn. Furthermore, a complex model for the genetic determinants of MetSyn associated phenotypes was recently proposed and, using gene enrichment analysis and protein-protein interaction network approaches, the retinoid X receptor and farnesoid X receptor (FXR) were identified as key players in MetSyn given their multiple interactions with metabolism, cell proliferation and oxidative stress (Sookoian and Pirola, 2011). However, more elegant kinetic models may be required to understand the true influence of genetic variants on Dsylipidemia and MetSyn given the presence of multiple feedback loops and reversible reactions (Bakker et al, 2010;Gutierrez-Cirlos et al, 2011).…”

Chronobiology and Metabolic Syndrome: From Genes to Systems Biology

“…The genetic component of each individual component of the MetS has been largely investigated and both genome-wide and candidate gene association studies have identi fi ed several loci that in fl uence the susceptibility of all the clustering traits [ 2,3 ] .…”