| 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 apolipoprotein E allele distribution of the individuals in study IV is given in Table 4-4, and the allele frequencies of the male and the female CAD patients and controls are given in Table 5-3 and Table 5-4 respectively. This series included no patients with the apo E phenotype 2/2, and all the CAD patients with an e 2 allele were smokers.
Table 5-3. Lipid values and apolipoprotein E gene frequencies of male controls and patients with different extensions of coronary artery disease.
| Controls | <50% stenosis | 1-vessel stenosis | 2-vessel stenosis | 3-vessel stenosis | F-ratio | p | |
|---|---|---|---|---|---|---|---|
| N=33 | N=10 | N=19 | N=18 | N=51 | |||
| Total cholesterol | 5.6 (0.9) | 5.8 (1.2) | 6.6 (1.1) | 6.1 (1.1) | 6.4 (1.3) | 1.69 | 0.158 |
| LDL cholesterol | 3.7 (0.9) | 3.7 (1.2) | 4.5 (0.9)* | 4.8 (0.7)* | 4.5 (1.1)* | 3.31 | 0.013 |
| HDL cholesterol | 1.2 (0.2) | 1.1 (0.3) | 1.1 (0.2)* | 1.0 (0.2)* | 1.0 (0.3)* | 8.05 | 0.0001 |
| VLDL cholesterol | 0.3(0.1-2.5) | 0.5 (0.1-2.2) | 0.5* (0.2-1.9) | 0.5(0.2-1.1) | 0.6*(0.1-1.9) | 3.65 | 0.008 |
| Total triglycerides | 1.3(0.4-5.5) | 1.4(0.8-4.8) | 1.8*(0.8-5.7) | 1.7*(0.9-2.8) | 1.8*(0.6-4.5) | 2.80 | 0.029 |
| VLDL triglycerides | 0.7(0.1-4.6) | 0.9(0.4-4.2) | 1.2*(0.4-4.6) | 1.0*(0.4-2.1) | 1.1*(0.3-3.6) | 4.48 | 0.002 |
| Lp(a)>35mg/dl (%) | 15 | 20 | 28 | 33 | 33 | 1.68 | 0.79 |
| e 4 | 0.29 | 0.15 | 0.34 | 0.17 | 0.23 | ||
| e 3 | 0.70 | 0.75 | 0.61 | 0.81 | 0.75 | ||
| e 2 | 0.02 | 0 | 0.05 | 0.03 | 0.03 | ||
| The values for total, LDL and HDL- cholesterol are expressed as mmol/l, mean and (SD), and those for total triglycerides, VLDL cholesterol and VLDL triglycerides as mmol/l, median and range. For the statistical analyses, total cholesterol, LDL cholesterol, HDL cholesterol and total triglycerides were age-adjusted. Logarithmic transformation was done for the analyses of total triglycerides, VLDL cholesterol and VLDL triglycerides. * p<0.05 compared to controls. | |||||||
Table 5-4. Lipid values and apolipoprotein E gene frequencies of female controls and patients with different extensions of coronary artery disease
| Controls | <50% stenosis | 1-vessel stenosis | 2-vessel stenosis | 3-vessel stenosis | F-ratio | p | |
|---|---|---|---|---|---|---|---|
| N=27 | N=8 | N=6 | N=7 | N=7 | |||
| Total cholesterol | 5.6 (1.1) | 6.3 (2.2) | 6.2 (1.2) | 7.4 (1.4) | 6.8 (1.2) | 1.85 | 0.135 |
| LDL cholesterol | 3.6 (1.0) | 4.1 (1.1) | 4.4 (1.1) | 5.0 (1.0) | 4.4 (1.3) | 1.89 | 0.127 |
| HDL cholesterol | 1.6 (0.4) | 1.3 (0.4) | 1.1 (0.2)* | 1.3 (0.7) | 1.1 (0.3)* | 4.47 | 0.003 |
| VLDL cholesterol | 0.2 (0.1-0.5) | 0.3 (0.1-2.2) | 0.3 (0.2-1.1) | 0.7* (0.2-1.2) | 1.0*xd (0.5-2.3) | 8.82 | 0.0001 |
| Total triglycerides | 0.9 (0.4-1.9) | 1.5 (0.5-5.2) | 1.4 (1.0-2.9) | 2.0* (0.9-3.1) | 2.6*xd (1.5-5.6) | 8.72 | 0.0001 |
| VLDLtriglycerides | 0.4 (0.1-1.1) | 0.7 (0.2-2.3) | 0.7* (0.5-1.8) | 1.6* (0.3-2.1) | 1.7*xd (1.2-3.7) | 11.67 | 0.0001 |
| Lp(a) >35mg/dl (%) | 7 | 12 | 13 | 33 | 0 | 3.67 | 0.45 |
| e4 | 0.19 | 0.13 | 0 | 0.29 | 0.14 | ||
| e3 | 0.80 | 0.88 | 1.0 | 0.71 | 0.86 | ||
| e2 | 0.02 | 0 | 0 | 0 | 0 | ||
| The values for total, LDL and HDL cholesterol are expressed as mmol/l, mean and (SD), and those for total triglycerides, VLDL cholesterol and VLDL triglycerides as mmol/l, median and range. For the statistical analyses, total cholesterol, LDL cholesterol, HDL cholesterol and total triglycerides were age-adjusted. Logarithmic transformation was done for the analyses of total triglycerides, VLDL cholesterol and VLDL triglycerides. d: p<0.05 compared to1vessel stenosis, x p<0.05 compared to moderate disease, * p<0.05 compared to controls. | |||||||
No statistically significant differences in the plasma total cholesterol, HDL cholesterol or triglyceride values of the CAD patients or the controls were observed in the different apo E groups (phenotypes 2/3 and 2/4, 3/3, and 4/3 and 4/4).
The apo E allele 4 was associated with higher cholesterol concentrations in VLDL and IDL, higher total plasma triglycerides and higher triglyceride concentration in VLDL, IDL and LDL. The protein-cholesterol ratio of LDL was higher and the cholesterol-triglyceride ratio lower in the individuals with an apo E 4 allele. Also, the apo B concentrations of the subjects with at least one apo E 4 allele were higher than those in the subjects with the apo E 3/3 phenotype.
We were unable to detect a difference in the FCR of LDL between patients having the apo E 4 allele and those homozygous for apo E 3. However, in three of the four patients with apo E 4/4, the autologous particle was cleared at a slower rate than the homologous apo E 3/3.
The influence of the apo E polymorphism on the lipid-lowering capacity of RS-86505-007 was studied in patients receiving the drug 6 mg tid. The patients with the apo E phenotype 3/3 had larger reductions in total and LDL cholesterol compared to those with at least one e 4 allele, but these differences were not statistically significant (Table 5-5).
Table 5-5. Plasma total cholesterol, triglyceride, HDL cholesterol and LDL cholesterol concentrations before treatment and their mean reductions during treatment in patients receiving RS-86505-007 6 mg tid according to apolipoprotein E polymorphisms.
| Apo E | ||
|---|---|---|
| E 3/3 (N=14) | E 4/*1 (N=8) | |
| Tot.chol. | 8.09(0.61) | 7.78(1.08) |
| Dchol2 | 1.49(0.95) | 0.61(1.50) |
| Triglyceride | 1.44(0.70) | 1.37(0.46) |
| Dtrigly2 | 0.26(0.46) | 0.13(0.31) |
| HDL chol. | 1.59(0.44) | 1.63(0.21) |
| DHDL2 | 0.02(0.22) | 0.14(0.29) |
| LDL chol. | 5.85(0.63) | 5.53(1.07) |
| DLDL2 | 1.35(1.00) | 0.42(1.32) |
| The values are expressed as mmol/l (SD). The differences are not statistically significant. 1 E 4/* = subjects with E4/3 or E 4/4, 2D= change due to treatment. | ||
The lipid concentrations of the patients did not differ statistically significantly in the apo E groups before or after colestipol and lovastatin treatment. Hypertriglyceridemia was only associated with a reduced HDL cholesterol level in the patients lacking the apo E 4.