| Effects of apolipoprotein and low density lipoprotein receptor gene polymorphisms on lipid metabolism, and the lipid risk factors of coronary artery disease | ||
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The frequency of the e 4 allele was slightly higher in our hypercholesterolemic group (0.26) than in the average population (Ehnholm et al. 1986). The baseline plasma lipid concentrations did not, however, differ significantly between the apo E phenotypes, a finding that has been reported earlier in a large sample of dyslipidemic men (Mänttäri et al. 1991).The frequency of the e 2 allele of apo E, which is 0.03 in patients with > 50% stenosis, is lower than the e 2 frequencies reported in other coronary artery disease series (Nieminen et al. 1992), and also lower than reported in any population studies (Hallman et al. 1991). The e 3 frequency, 0.75, is in accordance with other Northern European populations, but lower than in most voluntary populations (Tiret et al. 1994). The present e 4 frequency exceeds that of the other populations (Davignon et al. 1988, Hallman et al. 1991). Compared with CAD patients in southern Finland, the e 3 frequency is higher (0.75 vs. 0.63) and the e 4 frequency lower (0.23 vs. 0.32)(Kuusi et al. 1989). There were no statistically significant differences in the lipid concentrations between the apo E phenotype groups in patients with > 50% and < 50% stenosis, suggesting that the elevated plasma lipids of coronary patients in this series were not mediated by the apo E phenotypes. Accordingly, our results suggest that the apo E 4 phenotype is not so strongly associated with CAD in Northern Finland as in other populations.
Individuals with apo E 4 absorb cholesterol most efficiently, and their FCR is low (Miettinen et al. 1992). Our results on the effect of apo E 4 on VLDL and IDL lipids and the apo B concentration are in accordance with the earlier studies. However, we did not detect significant differences in the plasma total cholesterol concentrations or the LDL fractional catabolic rates between our patients with apo E 4 and apo E 3/3. This could be due to some yet unknown genetic or environmental effect, since similar results on normolipemic individuals have been reported (Savolainen et al. 1991). The patients were also on a low-fat, low-cholesterol diet, which may have masked the differences between the apo E 3 and apo E 4 individuals.
We found a tendency towards smaller LDL cholesterol reductions by colestipol and lovastatin in the patients with the apo E 4 allele than in the patients with the apo E phenotype 2/3. The finding is in accordance with the earlier reports, where the apo E 4 allele has been associated with smaller reductions in total and LDL cholesterol during lovastatin treatment in hypercholesterolemia (O`Malley & Illingworth 1990) in non FH (Ojala et al. 1991) and FH patients (Carmena et al. 1993) compared to E 2 and E 3.
During treatment with the prostaglandin E analogue RS-86505-007, the reductions in total and LDL cholesterol and triglyceride concentrations tended to be smaller in the patients with apo E 4 than in those with apo E 3/3. This finding suggests that the absorption of cholesterol is not so easily affected by such medical interventions in patients with apo E 4 than in patients with apo E 3.
The plasma HDL cholesterol concentration decreased during colestipol and lovastatin treatment in the individuals with the apo E 4/4 phenotype in contrast to an elevation in the individuals with the other phenotypes. The colestipol-induced change in HDL cholesterol correlated well with the change in CETP activity regardless of the apo E phenotype, whereas no correlation could be detected during lovastatin treatment. Thus, the variation in HDL cholesterol in patients with different apo E phenotypes cannot be explained by apo E-induced variation in CETP activity.
The apo E phenotype response to a pharmaceutical lowering of cholesterol seems to differ from the diet-induced change, which has been equal (Boerwinkle et al. 1991a, Martin et al. 1993) in many and more profound in some (Mänttäri et al. 1991, Lehtimäki et al. 1995) studies on patients with the E 4 allele. A low-fat, low-cholesterol diet also induces larger (Mänttäri et al. 1991, Savolainen et al. 1991) reductions in total and LDL cholesterol in patients with the E 4 allele than in those without, the HDL responses being similar in the phenotype groups (Mänttäri et al. 1991).