Abstract 3706: Functional Mutation in ABCG1 Predicts Risk of Ischemic Heart Disease in the General Population
The ATP-Binding Cassette transporter G1 (ABCG1) has recently been identified as a facilitator of cholesterol and phospholipid efflux from macrophages to HDL. In studies of ABCG1−/− versus ABCG1+/+mice, total body expression of ABCG1 protected against atherosclerosis, without affecting HDL cholesterol (HDL-C) or other lipid or lipoprotein levels. To determine the role of ABCG1 in atherogenesis in humans, we investigated the ability of a functional variant in the ABCG1 promoter to predict risk of ischemic heart disease (IHD) in the general population. We resequenced the ABCG1 promoter in 380 individuals with extreme levels of HDL cholesterol, and determined the ability of a new variant, g.-376C>T located in a putative SP1 binding site, to predict risk of IHD in a large prospective study of the general population, The Copenhagen City Heart Study (N=10,313, 31 years follow-up). In the prospective study, the cumulative incidence of IHD was increased in g.-376C>T heterozygotes (frequency: 0.5%) versus non-carriers (P=0.002). The age and gender adjusted hazard ratio for IHD was 2.4 (95% confidence interval 1.5–3.9). These results for IHD were verified in an independent case-control study (N=10,585; odds ratio: 2.7 (1.4 –5.0)). Genotype did not affect HDL-C or any other lipid or lipoprotein levels. Furthermore, in functional studies in vitro and in vivo, the presence of the -376T mutation completely abolished the binding of Sp1 to the ABCG1 promoter.
Conclusion: We have identified a loss of function mutation in the ABCG1 promoter which reproducibly predicts a 2–3 fold risk of IHD in the general population. This is the first study to demonstrate a role for ABCG1 in atherogenesis in humans.