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Genetic variation in ABCG1 and risk of myocardial infarction and ischemic heart disease.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2012 Feb; Vol. 32 (2), pp. 506-15. Date of Electronic Publication: 2011 Dec 08. - Publication Year :
- 2012
-
Abstract
- Objective: ATP binding cassette transporter G1 (ABCG1) facilitates cholesterol efflux from macrophages to mature high-density lipoprotein particles. Whether genetic variation in ABCG1 affects risk of atherosclerosis in humans remains to be determined.<br />Methods and Results: We resequenced the core promoter and coding regions of ABCG1 in 380 individuals from the general population. Next, we genotyped 10 237 individuals from the Copenhagen City Heart Study for the identified variants and determined the effect on lipid and lipoprotein levels and on risk of myocardial infarction (MI) and ischemic heart disease (IHD). g.-376C>T, g.-311T>A, and Ser630Leu predicted risk of MI in the Copenhagen City Heart Study, with hazard ratios of 2.2 (95% confidence interval: 1.2-4.3), 1.7 (1.0-2.9), and 7.5 (1.9-30), respectively. These results were confirmed for g.-376C>T in a case-control study comprising 4983 independently ascertained IHD cases and 7489 controls. Expression levels of ABCG1 mRNA were decreased by approximately 40% in g.-376C>T heterozygotes versus noncarriers (probability values: 0.005-0.009). Finally, in vitro specificity protein 1 (Sp1) bound specifically to a putative Sp1 binding site at position -382 to -373 in the ABCG1 promoter, and the presence of the -376 T allele reduced binding and transactivation of the promoter by Sp1.<br />Conclusions: This is the first report of a functional variant in ABCG1 that associates with increased risk of MI and IHD in the general population.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily G, Member 1
Adult
Aged
Case-Control Studies
DNA genetics
Female
Genetic Predisposition to Disease genetics
Genotype
Heterozygote
Humans
Male
Middle Aged
Promoter Regions, Genetic genetics
RNA, Messenger genetics
Risk Factors
ATP-Binding Cassette Transporters genetics
Genetic Variation genetics
Myocardial Infarction epidemiology
Myocardial Infarction genetics
Myocardial Ischemia epidemiology
Myocardial Ischemia genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4636
- Volume :
- 32
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 22155456
- Full Text :
- https://doi.org/10.1161/ATVBAHA.111.234872