ABSTRACT
It is assumed that the combined effects of multiple common genetic variants explain a large part of variation of high-density lipoprotein cholesterol (HDL-C) plasma levels, but little evidence exists to corroborate this assumption. It was our objective to study the contribution of multiple common genetic variants of HDL-C-related genes to variation of HDL-C plasma levels. A well-characterized cohort of 546 Caucasian men with documented coronary artery disease was genotyped for common functional variants in genes that control reverse cholesterol transport: ATP-binding cassette transporter A1, apolipoprotein A-I and apolipoprotein-E, cholesteryl ester transfer protein, hepatic lipase, lecithin : cholesterol-acyl transferase, lipoprotein lipase, and scavenger receptor class B type 1. Multivariate linear regression showed that these variants, in conjunction, explain 12.4% (95% confidence interval: 6.9-17.9%) of variation in HDL-C plasma levels. When the covariates smoking and body mass index were taken into account, the explained variation increased to 15.3% (9.4-21.2%), and when 10 two-way interactions were incorporated, this percentage rose to 25.2% (18.9-31.5%). This study supports the hypothesis that multiple, mildly penetrant, but highly prevalent genetic variants explain part of the variation of HDL-C plasma levels, albeit to a very modest extent. Multiple environmental and genetic influences on HDL-C plasma levels still have to be elucidated.
Subject(s)
Cholesterol, HDL/blood , Cholesterol/metabolism , Genetic Variation , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/genetics , Alleles , Apolipoprotein A-I/genetics , Apolipoproteins E/genetics , Biological Transport, Active/genetics , Carrier Proteins/genetics , Cholesterol Ester Transfer Proteins , Cohort Studies , Coronary Artery Disease/genetics , Coronary Artery Disease/metabolism , Genotype , Glycoproteins/genetics , Humans , Lipase/genetics , Lipoprotein Lipase/genetics , Male , Middle Aged , Models, Biological , Phosphatidylcholine-Sterol O-Acyltransferase/genetics , Scavenger Receptors, Class B/geneticsABSTRACT
Changes in arterial stiffness and structure occur during cardiovascular diseases and can be modified by angiotensin-converting enzyme (ACE) inhibitors. In the present study we investigated the role of membrane-bound ACE (t-ACE) in the regulation of arterial structure and mechanics. Large and small arteries of t-ACE-/- mice were isolated to determine the passive pressure-diameter relationship. We observed that t-ACE-/- mice exhibit a reduced arterial distensibility compared to t-ACE+/+ mice. This reduced arterial distensibility was also observed after 9 weeks of captopril treatment (80 mg/kg/ day). We hypothesized that bradykinin type 2 receptor (BK(2)) stimulation might be involved in the regulation of arterial stiffness. t-ACE-/- and t-ACE+/+ mice were treated with Hoe 140 (1 mg/kg/day) for 14 days. After Hoe 140 treatment, both the structural and mechanical changes observed in the t-ACE-/- carotid artery were abolished. Although Hoe 140 administration increased blood pressure in both groups by approximately 10 mm Hg, the pressure difference between the two groups did not change. Thus, t-ACE is involved in the regulation of arterial distensibility. The changes observed in t-ACE-/- mice are not caused by an altered fetal development. Moreover, it is likely that the regulation of arterial distensibility by ACE involves stimulation of the BK(2) receptor.
