Genetic variation in the rate-limiting enzyme in cholesterol catabolism (cholesterol 7α-hydroxylase) influences the progression of atherosclerosis and risk of new clinical events
article
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 7α-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. © 2005 The Biochemical Society. Chemicals / CAS: cholesterol 7alpha monooxygenase, 9037-53-0; cholesterol, 57-88-5; pravastatin, 81131-74-0; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cholesterol, 57-88-5; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Pravastatin, 81093-37-0; Triglycerides
Topics
Biomedical ResearchAtherosclerosisCardiovascular eventCholesterol metabolismCYP7A1Genetic variantREGRESSRisk factorcholesterolcholesterol 7alpha monooxygenasepravastatinadultagedartery diametercardiovascular riskcatabolismcholesterol blood levelcholesterol metabolismcontrolled studycoronary artery atherosclerosisgenetic polymorphismgenetic variabilitygenotypeheterozygotehumanischemic heart diseasemajor clinical studypromoter regionrisk factorAnalysis of VarianceChi-Square DistributionCholesterolCholesterol 7-alpha-HydroxylaseCoronary ArteriosclerosisDouble-Blind MethodGene FrequencyGenetic Predisposition to DiseaseHumansHydroxymethylglutaryl-CoA Reductase InhibitorsLipidsMaleMiddle AgedPolymorphism, GeneticPravastatinPromoter Regions (Genetics)Risk AssessmentTriglycerides
TNO Identifier
238541
ISSN
01435221
Source
Clinical Science, 108(6), pp. 539-545.
Pages
539-545
Files
To receive the publication files, please send an e-mail request to TNO Repository.