Bad Genes or Genes Behaving Badly

A key factor in the determination of body composition over the lifecourse is fat accumulation during childhood. Periods of life associated with the greatest changes in organ development and growth, i.e. early childhood, have the most significant effect on body composition, energy balance, and metabolism. Early childhood (age 3 to 7 years) represents a critical transition for the basis of adaptability in body composition, due to the rapid growth and development that occurs. Plausibly the phenotype underlying obesity and related health risk may be determined by body composition during this critical period.

Our previous research in children has consistently indicated that HA children accumulate greater amounts of fat, particularly in the intra-abdominal compartment, even at similar a BMI, and lower bone mineral content relative to EA children. The reason for these differences in body composition over the lifecourse is not clear.

Racial/ethnic differences in risk factors for health, including 'thriftiness' in body fat accumulation are often evident before the age of 7, suggesting that the racial/ethnic differences in energy utilization and subsequent fat storage may be accounted for by genetic make-up, the environment (e.g. diet), or an interaction of the two. The physiologic or behavioral process(es) that cause(s) certain children to take a trajectory towards obesity while others accrue less fat is not known. However, the economic decision of fuel utilization is a physiologic trait enabling the body to choose between shuttling 'energy' towards accrual of a particular tissue (e.g. bone vs. fat) and this trait likely has a genetic component. This genetic component may be embedded in fat storage capacity evolved from gene by environment interactions that promote thrift, particularly conserved in some populations. Although genetic background plays a role, it not known whether there is a relationship between genetic background, known candidate genes or candidate pathways and environmental contributors (e.g. diet) that impact body composition trajectory. Of central importance to our understanding of early fat mass accumulation in health disparities are the mechanisms that lead to chronic disease progression.

It is likely that variations within candidate genes may have a differential impact on individuals based on their genetic background. It is also probable that body composition is influenced by many genes, often within the same metabolic pathways, with small individual effects. These genes may not be significantly associated individually, but when examined as a unit (in a candidate pathway or gene-gene interaction framework) the association becomes significant. Further, children's early environmental exposures (e.g. diet) may interact with both genetic background and variations in candidate genes along resulting in alterations in body composition that predispose HA to excess fat accumulation throughout the lifecourse. To that end, the following specific aims will be evaluated:

Aim 1. To examine the associations between genetic admixture and body composition in children aged 3-7 years after controlling for dietary intake.

1. Hypothesis 1.1: There is a direct association between Amerindian admixture and fat mass and in inverse association between Amerindian admixture and bone mass. 2. Hypothesis 1.2: There is a direct association between energy intake and fat accumulation and the relationship will be particularly evident in individuals with a greater proportion of Amerindian admixture.

Aim 2. To examine the associations between genetic admixture and bone marrow fat in children aged 3-7 years after controlling for dietary intake.

1. Hypothesis 2.1: There is a direct association between Amerindian admixture and bone marrow fat. 2. Hypothesis 2.2: There is a direct association between energy intake and fat accumulation in bone marrow and the relationship will be particularly evident in individuals with a greater proportion of Amerindian admixture.

Aim 3. To examine the relationship between variation in candidate genes and pathways and Amerindian admixture controlling for dietary intake.

a. Hypothesis 3.1: Amerindian admixture will be associated with variations in candidate genes and pathways known to be associated with fat accumulation.