Candidate genes, small effects, and the prediction of atherosclerosis

Atherogenesis is a complex process that involves the contributions of several pathophysiological subsystems. The dissection of the genetic component of atherosclerosis has become possible using current molecular technologies and analytical methods. Genetic factors are considered to determine the limits under which atherosclerosis develops and environmental factors are considered to position an individual's risk within these limits. Atherosclerosis proceeds through a well-characterized series of pathological stages that involve key cell types and the expression of particular gene products. Reductionist experimental models have helped to produce a list of several hundred candidate genes for the study of the genetic component of atherosclerosis. Within certain families and isolated communities, the effect of a single candidate gene on atherosclerosis susceptibility may be profound, as in the case of mutations in the gene encoding the low-density lipoprotein receptor, which produce familial hypercholesterolemia and premature atherosclerosis. However, particular candidate genes have small effects on atherosclerosis, or to one of its intermediate phenotypes, in whole populations. In addition, pleiotropy and epistasis can confound the identification of the genetic component of atherosclerosis. Despite these limitations, it might still be possible to use genetic information clinically in order to classify individuals who are susceptible to atherosclerosis, especially if as-yet undiscovered candidate genes, which are found to be important determinants of disease. However, it will be impossible to predict the onset of a clinical manifestation of atherosclerosis in a particular person. This is due to the confounding influence of other forces, such as variations in interindividual environmental landscape, nonlinear interactions between genes and environment, and even the possible influence of biological chaos.