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.
Hofman
Maaike K
MK
TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands.
Princen
Hans M G
HM
Zwinderman
Aeilko H
AH
Jukema
J Wouter
JW
D000704:Analysis of Variance; D016009:Chi-Square Distribution; D002784:Cholesterol / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D004311:Double-Blind Method; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017035:Pravastatin / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D018570:Risk Assessment; D014280:Triglycerides / Q000097:blood
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D014280:Triglycerides; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D017035:Pravastatin