TaqIB polymorphism in CETP gene: the influence on incidence of cardiovascular disease in statin-treated patients with familial hypercholesterolemia.

The effects of TaqI restriction fragment length polymorphism of the CETP gene on the occurrence of cardiovascular disease (CVD) events were investigated in patients with familial hypercholesterolemia (FH). A total of 300 FH patients, of which 116 (39%) had CVD at the start of the study, were treated with statins during a mean period of 8.5 years. The distribution of Taq1B genotypes was 31% B1B1, 49% B1B2, and 20% B2B2. No differences were found at baseline between the three genotypes, except for an association of the B1 allele with lower high-density lipoprotein (HDL)-cholesterol levels (P=0.003). All patients were put on statins within 6-8 weeks after the first visit; about 60% received simvastatin (20-40 mg daily) and 40% either pravastatin (40 mg daily) or atorvastatin (20-40 mg daily). The different statin treatments were similar for all groups. The mean change of plasma HDL-cholesterol, low-density lipoprotein-cholesterol, and triglyceride concentration during statin therapy was similar for the three genotypes. During follow-up, new CVD events were recorded in 22 (37%) of the B2B2 patients (n=59) and in 67 (28%) of B1 allele carriers (n=241) (P=0.36). The relative risk for CVD events, after adjustment for age, gender, and CVD at intake, was 1.8 (CI: 1.1-3.0) for B2B2 carriers compared to B1 allele carriers. The Taq1B polymorphism is a significant predictor of future CVD events in statin-treated patients with FH. In spite of similar improvement of the lipoprotein profile during statin therapy, our FH patients with the B2B2 genotype may have a higher CVD risk in comparison with the B1 allele carriers.

Coffee oil consumption increases plasma levels of 7alpha-hydroxy-4-cholesten-3-one in humans.

Unfiltered coffee brews such as French press and espresso contain a lipid from coffee beans named cafestol that raises serum cholesterol in humans. Cafestol decreases the expression and activity of cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in the classical pathway of bile acid synthesis, in cultured rat hepatocytes and livers of APOE3Leiden mice. Inhibition of bile acid synthesis has been suggested to be responsible for the cholesterol-raising effect of cafestol. Therefore, we assessed whether cafestol decreases the activity of cholesterol 7alpha-hydroxylase in humans. Because liver biopsies were not feasible, we measured plasma levels of 7alpha-hydroxy-4-cholesten-3-one, a marker for the activity of cholesterol 7alpha-hydroxylase in the liver. Plasma 7alpha-hydroxy-4-cholesten-3-one was measured in 2 separate periods in which healthy volunteers consumed coffee oil containing cafestol (69 mg/d) for 5 wk. Plasma levels of 7alpha-hydroxy-4-cholesten-3-one increased by 47 +/- 13% (mean +/- SEM, n = 38, P = 0.001) in the first period and by 23 +/- 10% (n = 31, P = 0.03) in the second treatment period. Serum cholesterol was raised by 23 +/- 2% (P < 0.001) in the first period and by 18 +/- 2% (P < 0.001) in the second period. We corrected individual 7alpha-hydroxy-4-cholesten-3-one levels for serum cholesterol levels, because coffee oil increases serum cholesterol and 7alpha-hydroxy-4-cholesten-3-one is probably present in the lipoprotein fraction of serum. After correction, the increase in 7alpha-hydroxy-4-cholesten-3-one was 24 +/- 11% (P = 0.04) in the first period and there was no effect in period 2. Our study showed that coffee oil did not decrease, and actually increased, plasma levels of 7alpha-hydroxy-4-cholesten-3-one in humans in 2 separate treatment periods. Therefore, this study does not support the hypothesis that cafestol decreases bile acid synthesis in humans.

Genetic variation in the rate-limiting enzyme in cholesterol catabolism (cholesterol 7alpha-hydroxylase) influences the progression of atherosclerosis and risk of new clinical events.

CHD (coronary heart disease) is a complex disorder which is, in part, related to serum cholesterol levels. The rate-limiting enzyme in the catabolism of cholesterol into bile acids is CYP7A1 (cholesterol 7alpha-hydroxylase). The effect of the CYP7A1 A-278C promoter polymorphism on the progression of atherosclerosis, risk of a new clinical event and the influence of this variant on cholesterol-lowering therapy was investigated in 715 male patients with coronary atherosclerosis participating in REGRESS (Regression Growth Evaluation Statin Study). Genotype distributions were as follows: 283 with AA; 330 with AC and 102 with CC. There were no significant differences in baseline characteristics and serum lipids between genotypes. After 2 years, CC carriers had more progression of diffuse and focal atherosclerosis compared with AA carriers, as indicated by a larger decrease in MSD (mean segment diameter; 0.09 mm compared with 0.06 mm respectively; P=0.009) and MOD (minimum obstruction diameter; 0.09 mm compared with 0.05 mm respectively; P=0.024). Inclusion of risk factors for CHD in the model showed the same trend, although not significant for MOD (P=0.01 for MSD, and P=0.06 for MOD). In addition, CC carriers had an almost 2-fold higher risk of a new clinical event compared with AA carriers [RR (95% CI) 1.93 (1.11-3.36); P=0.02; where RR is relative risk and CI is confidence interval]. Inclusion of risk factors for CHD in the model showed the same trend, although not significant [RR (95% CI), 1.74 (0.96-3.12); P=0.06]. In conclusion, we present evidence that the CC variant of the A-278C polymorphism in the rate-limiting enzyme in the catabolism of cholesterol, CYP7A1, increases the progression of atherosclerosis and possibly the risk of a new clinical event.

CYP7A1 A-278C polymorphism affects the response of plasma lipids after dietary cholesterol or cafestol interventions in humans.

The response of plasma lipids to dietary cholesterol and fat varies among individuals. Variations in genes involved in cholesterol metabolism can be important in these interindividual differences. The rate-limiting enzyme in the conversion of cholesterol into bile acids is cholesterol 7alpha-hydroxylase (CYP7A1). We investigated the effect of the A278-C promoter polymorphism in the CYP7A1 gene on responses of plasma lipids to an increased intake in dietary cholesterol (742 +/- 114 mg/d), cafestol (57 +/- 6 mg/d), saturated fat [change of 8-9 energy percent/d (en%/d)] and trans fat (change of 10-11 en%/d) in 496 normolipidemic subjects. These responses were measured in 26 previously published dietary trials. After adjustment for the apolipoprotein E genotype effect, AA-subjects consuming a cholesterol-rich diet had a smaller increase in plasma HDL cholesterol than CC-subjects (0.00 +/- 0.02 vs. 0.17 +/- 0.04 mmol/L; P < 0.001). Upon intake of cafestol, AA-subjects had a smaller increase in plasma total cholesterol than CC-subjects (0.69 +/- 0.10 vs. 1.01 +/- 0.10 mmol/L; P = 0.028). No effects of the polymorphism were found in the saturated and trans fat interventions. In conclusion, the CYP7A1 polymorphism has a small but significant effect on the increase in plasma HDL cholesterol and plasma total cholesterol after an increased intake of dietary cholesterol and cafestol, respectively.