Quantitative Genetics of Body Composition and Homeostasis Model Assessment (HOMA) Measures of Insulin Sensitivity and Beta-Cell Function
Insulin resistance and impaired glucose tolerance often co-occur with overweight. Measures of insulin and glucose metabolism, and of adiposity, also have significant heritable components, and studies suggest that there are pleiotropic effects of genes on measures of adiposity and fasting insulin and glucose levels. Because clinical tests of insulin resistance and glucose tolerance are time consuming and expensive, however, the Homeostasis Model Assessment (HOMA; Matthews et al., 1985) has been used as a surrogate for direct measures of insulin and glucose metabolism in population-based epidemiological studies. The computerized HOMA (Levy et al., 1998) yields indices of insulin sensitivity (%S) and beta-cell function (%B) based on fasting insulin and glucose values, and has been validated against clinical measures. The goal of this study was to evaluate the utility of %S and %B in elucidating the genetic architecture of insulin and glucose metabolism and body composition. Maximum likelihood methods were used to analyze familial data from 645 adults aged 18-70 years from 124 kindreds participating in the Fels Longitudinal Study. Heritability estimates were 0.30 for both %S and fasting insulin, 0.17 for %B, 0.16 for fasting glucose, and 0.50 for BMI. The genetic correlations were -0.61 between %S and BMI, 0.62 between fasting insulin and BMI, 0.35 between %B and BMI, and 0.44 between fasting glucose and BMI. Although different in sign, the genetic correlations between %S and BMI, and fasting insulin and BMI, are essentially identical in magnitude. This is explained by the complete (i.e., 1.0) genetic correlation between %S and fasting insulin. That is, %S and fasting insulin are influenced by the same set of genes. The genetic correlations between %B and fasting insulin, and between %B and fasting glucose, however, are less than 1.0, indicating that %B is not completely regulated by the same set of genes that regulate either fasting insulin or glucose. Thus, %B may be a useful adjunct parameterization of insulin and glucose homeostasis in genetic epidemiological studies of insulin and glucose metabolism and body composition.