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Despite remarkable advances in diagnosis and therapy, ischemic heart disease (IHD) remains a leading cause of morbidity and mortality in industrialized countries. Recent efforts to estimate the influence of genetic variation on IHD risk have focused on predicting individual plasma high-density lipoprotein cholesterol (HDL-C) concentration. Plasma HDL-C concentration (mg/dl), a quantitative risk factor for IHD, has a complex multifactorial etiology that involves the actions of many genes. Single gene variations may be necessary but are not individually sufficient to predict a statistically significant increase in risk of disease. The complexity of phenotype-genotype-environment relationships involved in determining plasma HDL-C concentration has challenged commonly held assumptions about genetic causation and has led to the question of which combination of variations, in which subset of genes, in which environmental strata of a particular population significantly improves our ability to predict high or low risk phenotypes. We document the limitations of inferences from genetic research based on commonly accepted biological models, consider how evidence for real-world dynamical interactions between HDL-C determinants challenges the simplifying assumptions implicit in traditional linear statistical genetic models, and conclude by considering research options for evaluating the utility of genetic information in predicting traits with complex etiologies.