Obesity is a complex trait with multifactorial etiology, including environmental, behavioral, and genetic factors. The genetic contribution to human body weight has been established through family studies, investigations of parent-offspring relationships, and the study of twins and adopted children (1,2). The estimated heritability for body weight is 40-70% (3). Although obesity was first considered to be a disease that obeys Mendelian inheritance, the application of continuously evolving molecular biology technologies
From: Nutrition and Health: Nutrition and Metabolism Edited by: C.S. Mantzoros, DOI: 10.1007/978-1-60327-453-1_2, © Humana Press, a part of Springer Science + Business Media, LLC 2009
has revealed a far more complex picture for this metabolic disease and has led to fascinating new developments.
The contribution of genetic factors to obesity can be either a single, dysfunctional gene (monogenic obesity) or, as in the case of common (polygenic) obesity, numerous genes that make up minor contributions in determining the phenotype.
In general, the two methods used for the study of genetic factors in complex diseases include the candidate gene approach and the genome-wide scan approach. The candidate gene approach examines the association of a given allele and the presence of the disease, while the genome-wide scan, or linkage analysis, locates genes through their genomic position and is based on the rationale that family members sharing a specific phenotype will also share chromosomal regions surrounding the gene involved. Linkage and linkage disequilibrium analysis in specific rely on the fact that genes with similar chromosome positions will only rarely be separated during genetic recombination, so susceptibility to causative genes can be localized by searching for genetic markers that cosegregate.
In addition to genetic studies in human families, the existence of naturally or genetically modified animal models has provided valuable information on our understanding of the pathophysiology of disease. The mouse represents the most frequently used species for the creation of transgenic or gene knockout animals, allowing the analysis of the effects of gene overexpression, modification, or deletion. Rats are also used for transgenic studies, but this animal model has practical and technical disadvantages over the mouse model and hence is less frequently used. Transgenic animal models provide critical tools for in vivo functional characterization of single genes and for the search of unknown genes implicated in disease manifestation. Nevertheless, there are also limitations that call for great care in interpreting results from transgenic animal models and in translating them to humans. For example, loss or overexpression of individual proteins may produce compensatory mechanisms that could mask the resulting phenotype. Most important however, the phenotypic or pathophysiological consequences of genetic manipulation in animal models may not always match the human disease (4).
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