Coronary heart disease risk : family history and gene-environment interaction

J.M.A. Boer

Research output: Thesisinternal PhD, WU


<p>The first part of this thesis describes research into lifestyle, genetic, and biological factors that may underlie the increased risk for coronary heart disease (CHD) in individuals with a family history of this disorder. The second part of this thesis describes whether levels of plasma lipids and lipoproteins - which are among the major CHD risk factors - are influenced by the interaction between common gene polymorphisms and lifestyle-related factors. A large cohort study was used to evaluate the association between family history and CHD mortality. The association of a family history with gene polymorphisms, lifestyle-related and biological CHD risk factors, as well as gene-environment interactions were studied cross-sectionally. For this purpose subsamples from a large population-based project (the Cardiovascular Disease Risk Factor Monitoring Project) and the European Atherosclerosis Research Study (EARS) were used.</p><p>Family history increased the risk for CHD death in men and women. Only a small part was mediated through known CHD risk factors. The most pronounced characteristics of individuals with a family history were the higher levels of total cholesterol and apolipoprotein (apo) B as compared to subjects without a family history. The contribution of lifestyle-related (i.e. modifiable) factors to higher apo B levels in individuals with a family history was small; most of it seemed to be genetically determined. The apo E polymorphism is probably one of the most important genetic factors involved. Besides the apo E4 isoform, the D9N mutation and the N291S mutation in lipoprotein lipase (LPL) were more frequent among subjects with a parental history of premature myocardial infarction. Other gene polymorphisms (LPL S447X, CETP TaqIB and apo CIII SstI) proved to be non-informative.</p><p>Like family history, genotypes can not be modified. However, the effect of some polymorphisms clearly depended on lifestyle-related factors. A significant interaction between the apo E2 isoform and body mass index was found in EARS as well as in the population-based sample of Dutch origin. Surprisingly, in EARS the association between BMI and apo B levels was more pronounced in E2-carriers compared to subjects with other phenotypes, while in the Dutch sample the association was weaker in apo E2-carriers. Further, a strong interaction between the LPL D9N mutation and physical activity became apparent. Physically inactive carriers of the mutation (n=5) had considerably higher total cholesterol and apo B levels compared to non-carriers, whereas their HDL-cholesterol concentrations were lower. This was not the case for physically active carriers of this mutation (n=10). Our studies also showed that only among moderate alcohol consumers, subjects with the CETP B2B2 genotype presented with higher mean HDL-cholesterol levels compared to subjects with other genotypes. Furthermore, smokers with the apo CIII S1S2 genotype had higher levels of triglycerides and apo B and somewhat lower levels of HDL-cholesterol, compared to smokers with the S1S1 genotype. This was not observed among non-smokers.</p><p>It is concluded that the underlying mechanisms for the increased risk in individuals with a family history of CHD remain unclear. The risk of CHD is highest in individuals with a family history and unfavorable levels of other CHD risk factors. Therefore, assessing family history is important for risk prediction and prevention, despite the fact that family history by itself cannot be changed. Since little is known about the most useful definition of a family history more large long-term prospective studies are needed. Furthermore, gene-environment interaction implies that a genetic predisposition to unfavorable lipid levels and consequently CHD risk is not in all cases something of which the consequences cannot be influenced. However, our insights into specific gene-environment interactions is limited. More research is needed before our knowledge about gene-environment interactions can be applied for better focusing preventive measures to subgroups in the population that are susceptible to CHD.</p>
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Kromhout, D., Promotor
  • Kok, Frans, Promotor
  • Feskens, Edith, Promotor
Award date21 Apr 1999
Place of PublicationS.l.
Print ISBNs9789058080349
Publication statusPublished - 1999


  • heart diseases
  • risk factors


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