Genetics of atherosclerosis: Some strategies for studies of apolipoprotein E

Many genes are hypothesized to be involved in determining an individual's risk for coronary artery disease (CAD). Recent efforts have focused on the genetic architecture of quantitative traits related to risk for CAD. Studies relating genetic variation in the structural gene for apolipoprotein E to plasma levels of apolipoprotein E illustrate strategies to begin to understand the genetic architecture of plasma levels of apolipoprotein E. Studies using a measured gene approach suggest that variability in the isoforms of apolipoprotein E explain some, but not all, of the variability in plasma levels of apolipoprotein E. Products of other genes may be associated with plasma apolipoprotein E variability. No studies to date have presented findings from an unmeasured gene approach to plasma levels of apolipoprotein E. Models most often used in the unmeasured gene approach are not appropriate for studies of plasma levels of apolipoprotein E and perhaps are inappropriate for the study of other traits. Variations of the models are suggested to ask if a single unmeasured gene is the same gene defined by the apolipoprotein E isoforms. Another model can be used to ask if there is evidence for genes influencing levels of apolipoprotein E after accounting for the effects of the isoforms. Both the measured gene and unmeasured gene strategies have limitations. The failure of most models to allow for the complexity of genotype-phenotype relationships or the heterogeneity of genetic causes will slow the progress to understand the genetic architecture of quantitative traits associated with risk for CAD. © 1993 Wiley-Liss, Inc.