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Genetics of coronary heart disease and its risk factors
1Institute of Medical Genetics, University of Oslo, Norway.
Insights
High levels of lipoprotein(a) [Lp(a)] are a significant genetic risk factor for premature coronary heart disease (CHD). Studies link apolipoprotein B (apoB) gene variations to lipid levels and CHD risk.
Area of Science:
- Genetics
- Cardiovascular Disease Research
- Biochemistry
Background:
- Lipoprotein parameters significantly influence coronary heart disease (CHD) risk and show high heritability.
- Elevated lipoprotein(a) [Lp(a)] levels represent a major genetic risk factor for premature CHD, accounting for substantial population-attributable risk in younger men.
- Traditional genetic markers are associated with lipid levels and CHD, necessitating further investigation into specific genetic factors.
Purpose of the Study:
- To investigate the genetic basis of lipid levels and their association with coronary heart disease (CHD).
- To identify specific genetic polymorphisms, such as those at the apolipoprotein B (apoB) locus, linked to lipid variations and CHD risk.
- To explore gene-environment interactions in the context of atherosclerosis using novel methodologies like monozygotic twin studies.
Main Methods:
- Analysis of DNA polymorphisms at apolipoprotein loci to identify associations with lipid levels.
- Genetic linkage studies to map the locus of the Ag(x) antigenic polymorphism of low-density lipoprotein to the apolipoprotein B (apoB) gene on chromosome 2.
- Utilizing monozygotic twin pairs to study gene-environment interactions influencing quantitative traits like serum cholesterol concentration.
Main Results:
- Established that the Ag(x) antigenic variation is located within the apolipoprotein B (apoB) protein.
- Demonstrated consistent associations between Ag(x) polymorphism, apoB locus DNA polymorphisms, and lipid levels.
- Introduced a framework for studying gene-environment interactions, differentiating between 'level genes' and 'variability genes' in atherosclerosis etiology.
Conclusions:
- Apolipoprotein B (apoB) gene variations are significantly associated with lipid profiles and coronary heart disease (CHD) risk.
- The Ag(x) polymorphism serves as a genetic marker linked to apoB and lipid levels, contributing to CHD risk.
- Gene-environment interactions play a crucial role in the development of atherosclerosis, with distinct genetic factors influencing both baseline levels and variability of lipid parameters.
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.