Abstract
Earlier we reported that allelic variation in the gene coding for apolipoprotein (apoE) is a significant predictor of variation in the risk of coronary heart disease (CHD) death in a longitudinal study of elderly Finnish men. Here we address the question: which of the apoE genotypes confers the risk information in these men, and whether such information persists after other CHD risk factors are considered? We followed two cohorts of elderly Finnish men aged 65 to 84 years, one in Eastern (n = 281) and the other in the Southwestern (n = 344) Finland for 5 years during which 26 (9.3%) of the men from the Eastern cohort and 40 (11.6%) of the men in the Southwestern cohort died from CHD. Baseline high density lipoprotein (HDL) cholesterol and (HDL cholesterol)2 in the Eastern cohort and age, and total and HDL cholesterol and smoking status in the Southwestern cohort were significant predictors of CHD death (P < 0.05). The apoE genotypes were significant predictors in the Southwestern cohort atP = 0.02 and in the Eastern cohort atP = 0.18. In multivariable models, information about apoE genotypes improved the prediction atP = 0.10 level of statistical significance in both cohorts. When genotypes were considered separately, the ε2/4 combined with the ε4/4 in the Eastern cohort (odds ratio = 7.69, 95% CI = 1.67-35.52) and the ε3/4 in the Southwestern cohort (odds ratio = 2.44, 95% CI = 1.16–5.10) had sigificanctly greater odds of CHD death compared to the common ε3/3 genotype. We conclude that apoE genotypes confer risk information about CHD death in two cohorts of elderly Finnish men in a longitudinal study, and this information persists after adjustment for other CHD risk factors. Because different genotypes were predictors in these two cohorts, we further conclude that the utility of a particular genotype as a predictor of CHD death in other populations may depend on the distribution of risk factor profiles at baseline, geographically defined environmental exposures, the CHD mortality history, and the evolutionary history of background genotypes in the population considered.
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Andrade M, Thandi I, Brown S, Gotto A Jr, Patsch W, Boerwinkle E (1995) Relationship of the apolipoprotein E polymorphism with carotid artery atherosclerosis. Am J Hum Genet 56: 1379–1390
Assmann G, Schulte H (1989) Diabetes mellitus and hypertension in the elderly: concomitant hyperlipidemia and coronary heart disease risk. Am J Cardiol 63:33H-37H
Badimon JJ, Fuster V, Chesebro JH, Badimon L (1993) Coronary atherosclerosis: a multifactorial disease. Circulation 87[Suppl 2]:3–16
Barrett-Connor E, Suarez L, Khaw K-T, Criqui MH, Wingard DL (1984) Ischemic heart disease risk factors after age 50. J Chronic Dis 37:903–908
Cooper R, Rotimi C (1994) Hypertension in populations of West African origin: is there a genetic predisposition? J Hypertens 12:215–227
Dawber TR (1980) The Framingham study. Harvard University Press, Cambridge
Davignon J (1993) Apolipoprotein E polymorphism and atherosclerosis. In: Born GVR, Schwartz CJ (eds) New horizons in coronary heart disease. Science Press, London, pp 5.1–5.21
Davignon J, Gregg RE, Sing CF (1988) Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis 8:1–21
avignon J, Roederer G, Trudeau P, Dallongeville J, Sing CF (1989) Atherogenic dyslipidemias: disorders of apolipoprotein E isoforms. In: Crepaldi G, Gotto AM, Manzato E, Gaggio G, (eds) Atherosclerosis VIII. Elsevier, Amsterdam, pp 389–393
Ehnholm C, Lukka M, Kuusi T, Nikkilä E, Utermann G (1986) Apolipoprotein E polymorphism in the Finnish population: gene frequencies and relation to lipoprotein concentrations. J Lipid Res 27:227–235
Ferrannini E (1991) Metabolic abnormalities of hypertension: a lesson in complexity of hypertension 18:636–639
Ferrières J, Sing CF, Roy M, Davignon J, Lussier-Cacan S (1994) Apolipoprotein E polymorphism and heterozygous familial hypercholesterolemia: sex-specific effects. Arterioscler Thromb 14:1553–1560
Gerdes LU, Klausen IC, Sihm I, Faergeman O (1992) Apolipoprotein E polymorphism in a Danish population compared to findings in 45 other study populations around the world. Genet Epidemiol 9:155–167
Gordon T, Kannel WB (1982) Multiple risk functions for predicting coronary heart disease: the concept, accuracy, and application. Am Heart J 103:1031–1039
Harris T, Cook EF, Kannel WB, Goldman L (1988) Proportional hazards analysis of risk factors for coronary heart disease in individuals aged 65 or older. J Am Geriatr Soc 36:1023–1028
Havekes LM, et al (1987) A rapid micromethod for apolipoprotein E phenotyping directly in serum. J Lipid Res 28:455–463
Haviland MB, Lussier-Cacan S, Davignon J, Sing CF (1995) Impact of apolipoprotein E genotype variation on means, variances and correlations of plasma lipid, lipoprotein and apolipoprotein traits in octogenarians. Am J Med Genet 58:315–331
Heliövaara M, Karvonen MJ, Punsar S, Rautanen Y, Haapakoski J (1981) Serum thiocyanate concentration and cigarette smoking in relation to overall mortality and to deaths from coronary heart disease and lung cancer. J Chronic Dis 34:305–311
Hosmer DW, Lemeshow S (1989) Applied logistic regression. Wiley, Toronto
Jacobsen SJ, et al (1992) Cholesterol and coronary artery disease: age as an effect modifier. J Clin Epidemiol 45: 1053–1059
Kahn HA (1983) An introduction to epidemiologic methods. Oxford University Press, New York
Kaprio J, Ferrell RE, Kottke BA, Kamboh MI, Sing CF (1991) Effects of polymorphisms in apolipoproteins E, A–IV, and H on quantitative traits related to risk for cardiovascular disease. Arterioscler Thromb 11: 1330–1348
Karvonen MJ, et al (1970) VI. Five-year experience in Finland. Circulation 41/42 [Suppl 1]:1–62
Keys A (1970) Coronary heart disease in seven countries. Circulation 41:1–211
Keys A, et al (1967) Epidemiological studies related to coronary heart disease: characteristics of men aged 40–59 in seven countries. Acta Med Scand 460 [Suppl]: 1–392
Kostner GM (1976) Enzymatic determination of cholesterol in HDL fractions prepared by polyanion precipitation. Clin Chem 22:695
Kuusi T, et al (1989) Apoprotein E polymorphism and coronary artery disease: increased prevalence of apolipoprotein E-4 in angiographically verified coronary patients. Arteriosclerosis 9:237–241
Lehtimäki T, et al (1990) Apolipoprotein E phenotypes in Finnish youths: a cross-sectional and 6-year follow-up study. J Lipid Res 31:487–495
Lewontin RC (1974) The genetic basis of evolutionary change. Columbia University Press, New York
Mänttäri M, Koskinen P, Ehnholm C, Huttunen JK, Manninen V (1991) Apolipoprotein E polymorphism influences the serum cholesterol response to dietary intervention. Metabolism 40: 217–221
Nestruck AC, Bouthillier D, Sing CF, Davignon J (1987) Apolipoprotein E polymorphism and plasma cholesterol response to probucol. Metabolism 36:743–747
Nieminen MS, et al (1992) Lipoproteins and their genetic variation in subjects with and without angiographically verified coronary artery disease. Arterioscler Thromb 12:58–69
Nissinen A, et al (1986) Levels of some biological risk indicators among elderly men in Finland. Age Aging 15:203–211
Nissinen A, et al (1993) Prevalence and change of cardiovascular risk factors among men born 1900–1919: the Finnish cohorts of the Seven Countries Study. Age Ageing 22:365–376
Pekkanen J (1987) Coronary heart disease during a 25-year follow-up: risk factors and their secular trends in the Finnish cohorts of the Seven Countries Study. Thesis, University of Helsinki
Reilly SL, Ferrell RE, Kottke BA, Kamboh MI, Sing CF (1991) The gender-specific apolipoprotein E genotype influence on the distribution of lipids and apolipoproteins in the population of Rochester, MN. 1. Pleiotropic effects on means and variances. Am J Hum Genet 49:1155–1166
Reilly SL, Ferrell RE, Sing CF (1994) The gender-specific apolipoprotein E genotype influence on the distribution of plasma lipids and apolipoproteins in the population of Rochester, MN. III. Correlations and covariances. Am J Hum Genet 55: 1001–1018
SAS Institute (1985) SAS user's guide: statistics. SAS Institute, Cary, NC
Sing CF, Moll PP (1989) Genetics of variability of CHD risk. Int J Epidemiol 18 [Suppl 1]:S183-S195
Sing CF, Zerba KE, Reilly SL (1994) Traversing the biological complexity in the hierarchy between genome and CAD endpoints in the population at large. Clin Genet 46:6–14
Stavenow L, et al (1990) Eighty-year-old men without cardiovascular disease in the community of Malmö. I. Social and medical factors, with special reference to the lipoprotein pattern. J Intern Med 228:9–15
Stengård JH, et al (1995) Apolipoprotein E polymorphism predicts death from coronary heart disease in a longitudinal study of elderly Finnish men. Circulation 91:265–269
Wahlsten D (1990) Insensitivity of the analysis of variance to heredity-environment interaction. Behav Brain Sci 13:109–161
Weiss KM (1993) Genetic variation and human disease: principles and evolutionary approaches. Cambridge University Press, Cambridge, UK
Wilson PWF, et al (1994) Apolipoprotein E alleles, dyslipidemia, and coronary heart disease: the Framingham offspring study. JAMA 272: 1666–1671
Xhignesse M, Lussier-Cacan S, Sing CF, Kessling AM, Davignon J (1991) Influences of common variants of apolipoprotein E on measures of lipid metabolism in a sample selected for health. Arterioscler Thromb 11:1100–1110
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Stengård, J.H., Pekkanen, J., Ehnholm, C. et al. Genotypes with the apolipoprotein ε4 allele are predictors of coronary heart disease mortality in a longitudinal study of elderly Finnish men. Hum Genet 97, 677–684 (1996). https://doi.org/10.1007/BF02281882
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DOI: https://doi.org/10.1007/BF02281882