LETTER TO THE EDITOR
Mild hypercholesterolemia and premature heart disease: Reply
B.ørge G. Nordestgaard, MD, DMSca,
Ruth Frikke-Schmidt, MD and
Anne Tybjaerg-Hansen, MD, DMSc
a Department of Clinical Biochemistry, Herlev University Hospital, DK-2730 Herlev, Denmark
brno{at}herlevhosp.kbhamt.dk
Batalla and colleagues found in a sample of 220 Spanish men with coronary heart disease that frequencies of epsilon43 and epsilon44 genotypes did not differ from those among 200 age-matched controls. In contrast, we observed in the Danish population (by comparing genotype frequencies in 693 male patients with those among 4,129 men sampled from the general population) that the epsilon43 and epsilon44 genotypes compared with the wild-type epsilon33 genotype in men predicted 40% and 60% increases in risk of ischemic heart disease, respectively (1).
It is well established that there is a north-to-south decreasing gradient of the epsilon4 allele frequency throughout Europe (2,3). This is exemplified by an epsilon4 relative allele frequency of 17% in the Danish population (1) versus 8% in the Spanish population, as demonstrated by Batalla et al. We agree that the lower frequency of the epsilon4 allele in Southern versus Northern Europe may partly explain the relatively lower incidence of ischemic heart disease in Southern Europe; however, differences in genotpye frequencies most likely cannot explain differences in associations between genotype and risk of ischemic heart disease in different parts of the world. Other possible explanations for such differences exist.
First, the apolipoprotein E polymorphism may act as a susceptibility mutation for ischemic heart disease; such mutations need certain contexts before their impact on risk of disease is expressed. Perhaps a diet rich in saturated fat can explain part of a higher prevalence in cardiovascular disease associated with the epsilon4 allele in Northern Europe compared with Southern Europe.
Second, as the study by Batalla et al. included only 220 patients and 200 controls it is also possible that lack of power in that study explains the negative findings: The power in that study given a two-sided p value <0.05 to exclude the 40% and 60% increases in risk of ischemic heart disease associated with epsilon43 and epsilon44 (as observed in our study), was only 30% and 10%, respectively.
Finally, our observations of increased risk associated with epsilon43 and epsilon44 genotypes could represent chance findings. However, we find this unlikely because 1) epsilon43 and epsilon44 were (in our study and many other studies) also associated with increases in both cholesterol and triglyceride levels, explaining the increased risk of ischemic heart disease, and 2) our observations of increased risk of ischemic heart disease associated with the epsilon4 allele in men agrees with that of a previous meta-analysis including mainly men (4).
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References
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- Frikke-Schmidt R, Tybjaerg-Hansen A, Steffensen R, Jensen G, Nordestgaard BG. Apolipoprotein E genotype: epsilon-32 women are protected while epsilon-43 and epsilon-44 men are susceptible to ischemic heart disease. J Am Coll Cardiol. 2000;35:1192–1199[Abstract/Free Full Text]
- Gerdes LU, Klausen IC, Sihm I, Faergeman O. Apolipoprotein E polymorphism in a Danish population compared to findings in 45 other study populations around the world. Genet Epidemiol. 1992;9:155–167[CrossRef][Medline]
- Tiret L, de Knijff P, Menzel H, Ehnholm C, Nicaud V, Havekes LM. Apo E polymorphism and predisposition to coronary heart disease in youths of different European populations: the EARS study. Arterioscler Thromb. 1994;14:1617–1624[Abstract/Free Full Text]
- Wilson PWF, Schaefer EL, Larson MG, Ordovas JM. Apolipoprotein E alleles and risk of coronary disease. A meta-analysis. Arterioscler Thromb Vasc Biol. 1996;16:1250–1255[Abstract/Free Full Text]
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