Metabolic Syndrome and Genetics

The incidence of Metabolic Syndrome (MetS) has increased dramatically over the past decade, and research has shown that some prevalent forms of MetS have at least one genetic component. Multiple gene targets must be involved in the pathogenesis and progression of this disease, and their identification would enable evaluation for genetic susceptibility to MetS.

Epigenetic alterations in utero are also affected by environmental factors that cause phenotypic changes later in life. Within the human population, there are low responders and high responders to lifestyle changes caused by different degrees of gene expression across subpopulations of related phenotypes. We need to understand these mechanisms in order to develop approaches tailored to the individual’s genotype/phenotype.

Approaches such as genome-wide linkage analysis, genome-wide association analysis, and candidate-gene association analysis have furthered understanding of the polygenic character of MetS. It is important to study candidate genes for each component of the disease’s phenotype. Only through a complete understanding of the gene-gene, gene-gender, and diet-gene (environment-gene) interactions underlying MetS, will it become possible to determine the principal complications, produced by gene interactions between common pathways involved in obesity, type 2 diabetes (T2DM), and cardiovascular disease (Pollex and Hegele, 2006).

MetS may prove to be a good disease model for nutritional genomics research evaluation. For example, dietary fat is an important factor that can affect development of MetS. The resultant response to dietary fatty acids (FAs) may be affected by the individual genetic profile.

Genetic determinants of MetS, with an emphasis on the recent genome-wide association studies, have led to the identity of several important susceptibility genes for T2DM, with emphasis on FAs for various components of the syndrome (Phillips et al., 2008). The expression of several genes associated with the various metabolic components of MetS occurs through signal binding of FAs to a class of nuclear receptors called peroxisome proliferatoractivated receptors (PPARs).

The role of PPARs as endogenous receptors of FAs and lipid metabolites in the metabolic and inflammatory processes are associated with adipocyte hypertrophy, regulation of glucose utilization, macrophage infiltration into adipose tissue, and macrophage function and lipoprotein metabolism (Guri et al., 2008).

Maternal nutritional imbalance and metabolic disturbances during development may affect the health of the offspring and may be transmitted to the next generation (Gallou-Kabani and Junien, 2005). The idea that epigenetic changes associated with chromatin remodeling and regulation of gene expression underlie the developmental programming of MetS is gaining acceptance (Clemens and Pressman, 2006). Less obvious epigenetic alterations have also been shown to be relevant to diseases such as atherosclerosis and T2DM. Imprinted genes, with their key roles in controlling feto-placental nutrient supply and demand and their epigenetic liability in response to nutrients, may play an important role in adaption. Several types of sequences can be targets of environmental factors associated with specific epigenetic signatures and patterns of gene expression. Depending on the nature and intensity of the development of lifelong processes involved, these epigenetic alterations can lead to permanent changes in tissue and organ structures and function, or to reversible changes using appropriate epigenetic tools.

Deciphering the epigenetic patterns at stake should allow us to evaluate their potential reversibility; when specific epigenetic patterns corresponding to labile or locked situations are identified, these patterns should be useful for diagnosis/ prognosis. They also present new targets for diets to prevent or abolish aberrant gene silencing, which may be involved in resistance to treatment.

Numerous dietary changes have been promoted over the past three decades. Individual subtypes of gene pools, including epigenetic regulations or regulatory controls of gene network pathways, have caused mixed population responses. Personalized nutrition holds the promise to target regulation of specific genes by bioactive food components. The role of diet—through our understanding and application of nutritional genomics—to alter, delay, or mitigate gene expression to affect health and longevity may begin with our children.