title: Polymorphisms at LDLR locus may be associated with coronary artery disease through modulation of coagulation factor VIII activity and independently from lipid profile.
abstract: High levels of coagulation factor VIII (FVIII) have been associated with cardiovascular disease. Low-density lipoprotein receptor (LDLR) has been recently demonstrated to contribute to FVIII clearance from plasma. The aim of this study was to evaluate 3 single nucleotide polymorphisms in SMARCA4-LDLR gene locus (rs1122608, rs2228671, and rs688) and FVIII coagulant activity (FVIII:c) in subjects with (n = 692) or without (n = 291) angiographically confirmed coronary artery disease (CAD). High FVIII:c levels were an independent risk factor for CAD. The rs688 and rs2228671 genotypes were predictors of FVIII:c with T alleles associated with higher FVIII:c levels. The rs2228671T allele was associated also with reduced total and LDL-cholesterol levels. With respect to the risk of CAD, no association was found for rs2228671. Consistently with higher FVIII:c levels, the rs688T allele was associated with CAD, whereas, consistently with a favorable lipid profile, the rs1122608T allele was associated with a decreased CAD prevalence. After adjustment for classic cardiovascular risk factors, including plasma lipids, rs688 remained associated with CAD (OR for T carriers: 1.67 with 95% confidence interval, 1.10-2.54). Haplotype analysis confirmed such results. Our data suggest that polymorphisms at LDLR locus modulate FVIII:c levels and may be associated with CAD risk independently from plasma lipids.
authors.affiliation: Department of Medicine, University of Verona, Verona, Italy. nicola.martinelli@univr.it
authors.forename: Nicola
authors.initials: N
authors.lastname: Martinelli
authors.forename: Domenico
authors.initials: D
authors.lastname: Girelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Lunghi
authors.forename: Mirko
authors.initials: M
authors.lastname: Pinotti
authors.forename: Giovanna
authors.initials: G
authors.lastname: Marchetti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Malerba
authors.forename: Pier Franco
authors.initials: PF
authors.lastname: Pignatti
authors.forename: Roberto
authors.initials: R
authors.lastname: Corrocher
authors.forename: Oliviero
authors.initials: O
authors.lastname: Olivieri
authors.forename: Francesco
authors.initials: F
authors.lastname: Bernardi
mesh_terms: D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004265:DNA Helicases / Q000235:genetics*; D005169:Factor VIII / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008055:Lipids / Q000032:analysis* / Q000097:blood; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011973:Receptors, LDL / Q000235:genetics*; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D008055:Lipids; D009687:Nuclear Proteins; D011973:Receptors, LDL; D014157:Transcription Factors; D005169:Factor VIII; C084108:SMARCA4 protein, human; D004265:DNA Helicases