EFFECTS OF GENDER AND MENOPAUSAL STATUS ON THE ASSOCIATION OF APOLIPOPROTEIN-E PHENOTYPE WITH PLASMA-LIPOPROTEIN LEVELS - RESULTS FROM THE FRAMINGHAM OFFSPRING STUDY

Apolipoprotein (ape)E phenotype is an important genetic determinant of plasma low-density lipoprotein (LDL) cholesterol and apo B levels. We have determined apo E phenotype by isoelectric focusing and plasma lipid, lipoprotein cholesterol, apo A-I, apo B, and lipoprotein(a) levels, as well as LDL particle size, in 2258 men and women participating in the Framingham Offspring Study. Apo E phenotype (E2/2, E2/4, E3/2, E3/3, E3/4, and E4/4) was not associated with plasma lipoprotein(a) levels but was associated with plasma LDL cholesterol levels, apo B levels, and LDL size in men and with plasma total cholesterol, LDL cholesterol, and apo B levels in women. The average effect of the epsilon 2 allele was to lower plasma LDL cholesterol levels by 9.2 mg/dL in men and by 13.7 mg/dL in women, while the average effect of the epsilon 4 allele was to increase LDL cholesterol levels by 2.6 mg/dL in men and by 5.4 mg/dL in women. When men were divided into two groups according to their age (<50 and greater than or equal to 50 years old), the average effect of the epsilon 2 allele was to lower plasma levels of LDL cholesterol by 10.2 mg/dL in younger men and by 7.5 mg/dL in older men. In premenopausal women, the average effect of the epsilon 2 allele was to lower LDL cholesterol by 8.2 mg/dL and, in postmenopausal women, by 20.4 mg/dL. An opposite effect of the epsilon 4 allele was observed: the epsilon 4 allele was associated with increases in plasma LDL cholesterol levels of 4.0 mg/dL in younger men and of 1.0 mg/dL in older men. The epsilon 4 allele was associated with increases in plasma LDL cholesterol levels of 1.6 mg/dL in premenopausal women and of 7.1 mg/dL in postmenopausal women. The apo epsilon locus explained 1.0% of the variance in LDL cholesterol levels in men and 2.1% in women. However, only 0.5% of the LDL cholesterol level variance was due to variation at the epsilon locus in premenopausal women, whereas 5.0% of the LDL cholesterol level variance was explained by apo E polymorphism in postmenopausal women. Our data indicate that the association of apo E phenotype with LDL cholesterol levels is significantly greater in postmenopausal women than in premenopausal women or in men.