The Phenotypes

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Interest in the genetics of human obesities has increased considerably over the past decade partly because of the realization that some forms of obesity were associated with higher risks than others for various morbid conditions and mortality rate. Obesity can no longer be seen as a homogeneous phenotype.

Obesity is characterized by excess body mass or body fat without any particular reference to the concentration of fat in a given area of the body. Many obese individuals are characterized by an excess amount of subcutaneous fat on the trunk, particularly in the abdominal area, the so-called android obesity, or male type of fat deposition. Another type is characterized by an excessive amount of fat in the abdominal visceral area and has been labeled abdominal visceral obesity. The last is known as gluteofemoral obesity and is observed primarily in women (gynoid obesity). Thus, excess fat can be stored primarily in the truncal-abdominal area or in the gluteal and femoral area. This implies that a given body fat content, say, 30% or 30 kg, may exhibit different anatomical distribution characteristics.

Strictly speaking, one should therefore talk about the obesities rather than obesity. But the situation is even more complex as the phenotypes are not of the simple Mendelian kind. Segregation of the genes is not readily perceived, and whatever the role of the genotype in the etiology, it is generally attenuated or exacerbated by nongenetic factors. In other words, variation in human body fat is caused by a complex network of genetic, nutritional, metabolic, energy expenditure, psychological, and social variables, all playing a role in the modulation of energy balance and nutrient partitioning. Figure 1 depicts the key determinants and suggests how genetic differences can lead to obesity over time.

It is important to recognize that these phenotypes are not fully independent of one another, as shown by the data of Figure 2. The level of covariation among the various body fat phenotypes ranges from ~30% to ~ 50% and perhaps more in some circumstances. One implication of the above is that studies designed to investigate the causes of the individual differences in the various body fat phenotypes, including genetic causes, should control for these levels of covariation.

In clinical settings, the body mass index (BMI), measured in kg/m2, is commonly used to assess the normality of body weight in patients. This is perfectly reasonable as most of the evidence from large-scale prospective studies that have associated obesity with morbidities and premature death is based on the BMI. The correlation between the BMI and total body fat or percent body fat is high in large and heterogeneous samples. The predictive value of the BMI is, however, much less impressive in a given individual, especially when the BMI is < 30 kg/m2 or so. Thus, the BMI is an indicator of heaviness and only indirectly of body fat (2,3). Any estimate of the genetic effect on BMI should not necessarily be considered valid for adiposity, as it is influenced in unknown proportions by the contribution of the genotype to fat mass, muscle mass, skeletal mass, and other components as well. Nevertheless, the BMI is worth considering because of its clinical validity, simplicity to measure, and widespread use.

The data summarized in Table 1 indicate why the BMI is only a partially acceptable surrogate measure of body fat content. The variance explained by BMI in percent body fat derived from underwater weighing in large samples of adult men and women, 35-54 years of age, attains only ~40%. At the extremes of the body fat content distribution, BMI is more closely associated with percent body fat; that is, the variance explained may reach 60% and more. This is not

Figure 1 Diagram of the determinants of positive energy balance and fat deposition with indication about the sites of action of a genetic predisposition.

Figure 1 Diagram of the determinants of positive energy balance and fat deposition with indication about the sites of action of a genetic predisposition.

Figure 2 Common variance between three body fat phenotypes. Percent fat estimated from underwater weighing: truncal-abdominal fat assessed from skinfolds or CT scans; abdominal visceral fat estimated by CT scan at the L4/L5 vertebrae. (From Ref. 219.)

entirely satisfactory as genetic studies deal with individual differences in the phenotype of interest and, for them to be successful, the phenotype of a complex multifactorial trait must be measured with a reasonable degree of precision.

That percent body fat remains quite heterogeneous at any level of BMI is further illustrated in Table 2, based on data from middle-aged adult males. For instance, in 27 men with a BMI of 28-30, the mean percent body fat was 28, but the range varied from 15% to 41%. We have observed the same phenomenon and with as much heterogeneity in women at all levels of BMI.

The same point can be made for regional fat distribution phenotypes. Thus the correlation between the waist-to-hip circumferences ratio (WHR) and abdominal visceral fat is positive and generally significant in various populations, but the association is charac-

terized by a wide scatter of scores. For instance, in a study of 51 adult obese women, the correlation between WHR and CT-assessed abdominal visceral fat reached 0.55 (4). However, for a WHR of ~ 0.80, the visceral fat area at the L4-L5 level ranged from a low of ~ 50 cm2 to a high of ~200 cm2. Even though the covariation between total body fat and abdominal visceral fat is statistically significant, the relationship is also characterized by a high degree of heterogeneity. As shown in Table 3, when BMI and percent body fat (%BF) are constrained to narrow ranges, one finds generally a threefold range for the amount of CT-assessed abdominal visceral fat in adult males. Thus in 16 men with BMI values of 30 or 31 and a percentage of body fat ranging from 30 to 33, mean abdominal visceral fat was 153 cm2 with a range from 77-261 cm2. Again, the same lack of coupling among BMI, %BF, and abdominal visceral fat was observed in adult women.

Table 1 Percent Variance (r x 100) Explained by BMI in Body Composition in Adults, 35-54 Years of Age

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