Single-base changes in DNA can affect biochemical measures, such as blood cholesterol or lipid levels. Such changes or “variants” can be associated with a trait either because they cause the trait or because they are linked to other causal variants. In either case, the associated variant(s) may be useful in predicting the trait. The chromosomes in which DNA is packaged cross over and recombine with each other in each generation, so that in historically separate populations, such as Africans and Europeans, the patterns of genetic linkage between variants differ. In the current study, we analyzed a large group of African Americans, testing genetic variants that had been associated with cholesterol and lipid levels in European-derived populations to assess their predictive value on two different genetic backgrounds within the same cohort. The ability of some variants to predict cholesterol or lipid traits was strongly dependent on genetic background, indicating that they may be tightly linked to other causal variant(s) in European populations and may not, themselves, be directly responsible for trait variability. We conclude that the predictive value of specific variants for risk assessment can differ critically across populations.