Genetics of Coronary Heart Disease and its Risk Factors

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Abstract
Lipoprotein parameters related to coronary heart disease (CHD) exhibit impressive heritability, and several traditional genetic marker systems are associated with lipid levels or CHD. Recent studies indicate a population-attributable risk of 28% for myocardial infarction for men below age 60 in the top quartile of Lp(a) lipoprotein levels. Thus, a high level of Lp(a) lipoprotein emerges as a major genetic risk factor for premature CHD. Studies of DNA polymorphisms at apolipoprotein loci have uncovered associations with lipid levels and genetic linkage between DNA polymorphisms at the apolipoprotein B (apoB) locus and the Ag(x) antigenic polymorphism of low density lipoprotein. This finding proves that the Ag(x) antigenic variation resides in apoB and co-assigns its locus to chromosome 2. Lipid associations of the Ag(x) polymorphism and of DNA polymorphisms at the apoB locus are internally consistent and consistent with association between Ag(x) and DNA variants. A new approach to the study of gene-environment interactions, using monozygotic twin pairs makes it possible to uncover genes that contribute to the frame within which lifestyle factors can cause changes in a clinically relevant quantitative parameter such as serum cholesterol concentration. A new concept of interaction between 'level genes' and 'variability genes' in the aetiology of atherosclerosis emerges from these studies.