Obesity is a complex multifactorial chronic disease developing from interactive influences of numerous factorssocial, behavioral, physiological, metabolic, cellular, and molecular. Genetic influences are difficult to elucidate and identification of the genes is not easily achieved in familial or pedigree studies. Furthermore, whatever the influence the genotype has on the etiology of obesity, it is generally attenuated or exacerbated by nongenetic factors.
A large number of twin, adoption, and family studies have explored the level of heritability of obesity; that is, the fraction of the population variation in a trait (e.g., BMI) that can be explained by genetic transmission. Recent studies of individuals with a wide range of BMIs, together with information obtained on their parents, siblings, and spouses, suggest that about 25 to 40 percent of the individual differences in body mass or body fat may depend on genetic factors (329-331). However, studies with identical twins reared apart suggest that the genetic contribution to BMI may be higher, i.e., about 70 percent (332). There are several other studies of monozygotic twins reared apart that yielded remarkably consistent results (333). Some of the reasons behind the different results obtained from twin versus family studies have been reported (334-336). The relative risk of obesity for first-degree relatives of overweight, moderately obese, or severely obese persons in comparison to the population prevalence of the condition reaches about 2 for overweight, 3 to 4 for moderate obesity, and 5 and more for more severe obesity (337, 338).
Support for a role of specific genes in human obesity of body fat content has been obtained from studies of Mendelian disorders with obesity as one of the clinical features, single-gene rodent models, quantitative trait loci from crossbreeding experiments, association studies, and linkage studies. From the research currently available, several genes seem to have the capacity to cause obesity or to increase the likelihood of becoming obese (339). The rodent obesity gene for leptin, a natural appetite-suppressant hormone, has been cloned (340) as has been its receptor (341). In addition, other single gene mutants have been cloned (341, 342). However, their relationship to human disease has not been established, except for one study describing two subjects with a leptin mutation (342). This suggests that for most cases of human obesity, susceptibility genotypes may result from variations of several genes.
Severely or morbidly obese persons are, on the average, about 10 to 12 BMI units heavier than their parents and siblings. Several studies have reported that a single major gene for high body mass was transmitted from the parents to their children. The trend implies that a major recessive gene, accounting for about 20 to 25 percent of the variance, is influenced by age and has a frequency of about 0.2 to 0.3 (343). However, no gene(s) has (have) yet been identified. Evidence from several studies has shown that some persons are more susceptible to either weight gain or weight loss than others (344, 345). It is important for the practitioner to recognize that the phenomenon of weight gain cannot always be attributed to lack of adherence to prescribed treatment regimens.