title: ABCG8 gene polymorphisms, plasma cholesterol concentrations, and risk of cardiovascular disease in familial hypercholesterolemia.
abstract: Elevated plasma plant sterol concentrations may be a risk factor of cardiovascular disease (CVD). Polymorphisms in the ABCG8 gene have been identified that contribute to the variation in plasma concentrations of plant sterols. However, data on the direct relationship of ABCG8 gene polymorphisms with CVD are lacking. Therefore, we examined associations between the D19H and T400K polymorphisms in the ABCG8 gene and CVD in a large cohort study of 2012 patients with heterozygous familial hypercholesterolemia (FH). A total of 244 individuals carried one or two alleles of the D19H variant and 568 individuals the T400K variant. During 94,809 person years, 648 (32.2%) individuals developed CVD of which coronary heart disease (CHD) was the most frequent cardiovascular event (N=553). In a Cox proportional hazard regression model adjusted for relevant cardiovascular risk factors, the D19H polymorphism was not associated with total CVD risk (p=0.2), but there was evidence of an association with higher risk of CHD (RR 1.42, CI 1.04-1.95; p=0.03). We observed no relationship between the T400K polymorphism and cardiovascular endpoints (p>0.1). However, FH individuals carrying the risk genotype for both ABCG8 variants had an increased risk of CVD (RR 1.57, 95% CI 1.13-2.18; p=0.01) and CHD (RR 1.72, 95% CI 1.23-2.41; p=0.002). In conclusion, our data suggest that genetic variation in the ABCG8 gene may influence the burden of atherosclerosis.
authors.affiliation: Department of Internal Medicine, Rotterdam, The Netherlands.
authors.forename: Kristel C M C
authors.initials: KC
authors.lastname: Koeijvoets
authors.forename: Jeroen B
authors.initials: JB
authors.lastname: van der Net
authors.forename: Geesje M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.forename: Ewout W
authors.initials: EW
authors.lastname: Steyerberg
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Mensink
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Eric J G
authors.initials: EJ
authors.lastname: Sijbrands
authors.forename: Jogchum
authors.initials: J
authors.lastname: Plat
mesh_terms: D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics*; D002784:Cholesterol / Q000097:blood*; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000150:complications / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010641:Phenotype; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: C416946:ABCG8 protein, human; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol