Epistatic Effects of Genes on Obesity

There are many complex human diseases and traits that are determined by multiple genetic, environmental, and behavioral influences. The global epidemic of obesity results from a combination of genetic susceptibility, increased availability of high-energy foods, and decreased requirement for physical activity in modern society. The increasing prevalence of obesity is associated with conditions such as Type 2 diabetes mellitus, hypertension, cardiovascular disease, dyslipidemia, osteoarthritis, lower quality of life, some cancers, and premature death.

A multigenic trait, obesity has a substantial genetic component involving multiple genes and gene–gene and gene–environment interactions that contribute to its pathogenesis.

Epistasis, or the interactions among genes, contributes to explain obesity onset and severity. The genetic basis of variation in obesity is thought to be due to many genes of relatively small effect and their interactions. In addition, growing evidence suggests that epistasis plays an important role in the genetic control and evolution of complex traits

Genomics is the study of the entire human genome and involves the actions of single genes and the interactions of multiple genes with each other and with the environment. In humans, there are complex interactions among multiple genes and environmental factors that play an important role in controlling obesity traits. For example, variations at multiple genetic loci contribute to the etiology of typical obesity, and it is probable that allelic effects at some loci may be amplified in the presence of variants at other loci.

The different strategies to study the genetic background is based on linkage analysis and candidate gene approach. However, the genetic background remains stable over many generations and genes have not changed substantially over this time period.

Consequently, the rising prevalence of obesity in developed and developing societies reflects lifestyle changes even though multiple studies show that the genetic contribution to obesity is significant. For example, only 1 to 5 percent of obesity cases can be explained by a single gene mutation, even though a family history of obesity is a strong predictor of the condition.

It seems that numerous genes with modest effect contribute to an individual's predisposition toward the more common forms of obesity. Heritabilities for obesity-related phenotypes vary from 6 to 85 percent among various populations. Although obesity is partly determined by genetic factors, an “obesity-promoting environment” is typically necessary for the phenotypic expression of obesity.

Obesity may be derived from a failure on the homeostasis systems, as a consequence of a dysfunction [Page 230]at the genetic level, which may be affected by changing environmental exposure (dietary habits, sedentarism, etc.). Variants in several candidate genes have been identified and association analyses and functional studies have shown that they contribute to modest obesity and related phenotypes.

In addition, nutrition and physical activity are environmental factors which both influence gene expression. For example, different individuals may respond differently to the same nutritional stimulus and cycles of physical activity and inactivity interact with genes resulting in a functional outcome appropriate for the environment.

The genetically mediated susceptibility to environmental exposure is referred to as gene–environment interaction. Most cases of human obesity probably result from subtle interactions of susceptibility genes with environmental factors favoring deposition of excess calories as fat.

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