Genetic Variation in Bile Acid Metabolism: Implications for Lipoprotein Homeostasis

Genetic factors play an important role in the homeostasis of cholesterol in the human body. An important pathway for eliminating cholesterol from the body is to convert it into bile acids in the liver. The rate-limiting enzyme in this catabolism of cholesterol is CYP7A1. In the gene of CYP7A1, a sequence variation was found: the CYP7A1 A-278C polymorphism. We found that this polymorphism affects triglyceride concentrations in healthy individuals and cholesterol concentrations in patients with Hypertriglyceridemia. However, we found that this polymorphism probably plays no role in the response of serum lipid levels to diet. Interestingly, subjects with the genotype CC of the CYP7A1 A-278C polymorphism have an almost twice as high risk of a new clinical event, as compared to subjects with the genotype AA. In addition, subjects with the genotype CC display more progression of atherosclerosis. The results of this thesis contribute to the understanding of the role of variations in genes in cholesterol homeostasis in human.