Genetics of variability of CHD risk.

Many genetic and environmental factors act in combination to determine inter-individual variability in risk factor traits for coronary artery disease (CAD). Geneticists have focused on the study of continuously distributed biological traits such as total plasma cholesterol. In every population, plasma cholesterol has been implicated as a risk factor for CAD. Every biometrical study of the distribution of cholesterol in families has established a significant role of genetic variability in determining inter-individual differences in the population at large. While a few genes have been identified that have rare alleles with large effects on this trait, variability among individuals in most families is influenced by allelic variation in many genes as well as various environmental exposures. Therefore, in most families, one does not expect CAD to cosegregate with allelic variation at a single gene, and one does not expect each family to be segregating for the same subset of genes that influence variability in risk among individuals in the population at large. Strategies have been developed to address questions about the role of genes with common alleles in studies of intra- and interpopulation differences in risk for CAD. These strategies are illustrated here by a review of studies of the association between common allelic variations in the structure of the apolipoprotein (apo) E molecule and levels of total plasma cholesterol. This polymorphic gene may explain as much as 6% of the variation in risk for CAD in a North American population. In international comparisons, populations with a higher relative frequency of the E4 allele at this gene locus have higher cholesterol levels and higher rates of CAD deaths. Other candidate genes, in addition to apo E, need to be studied before individuals, families and populations at high risk for CAD can be identified more accurately.