title: Low-density lipoprotein receptor-related protein polymorphisms in patients with elevated factor VIII coagulant activity and venous thrombosis.
abstract: Elevated factor VIII coagulant activity (FVIII:C) levels (>150 IU/dl) represent a prevalent independent risk factor for venous thromboembolism (VTE). Low-density lipoprotein receptor-related protein (LRP) is involved in factor VIII clearance in vivo, and elevated FVIII:C was a feature of the LRP knockout mouse model. Three coding polymorphisms of LRP1 (exon 3, C766T; exon 14, A217V; and exon 39, D2080N), together with an insertion/deletion polymorphism within the first intron of lipoprotein receptor-associated protein (LRPAP1), have been identified. In addition, LRP1 2080D was recently reported to be associated with increased plasma FVIII:C levels in normal individuals. In this study, we investigated the role of these four polymorphisms in patients with objectively confirmed VTE and elevated FVIII:C levels. In our control group, genotype distributions were consistent with previous reports. Neither the allele frequencies nor genotype distributions at LRP1 A217V, LRP1 D2080N and LRPAP1 intron 1 were significantly different between the elevated FVIII:C and control groups. In contrast to previous reports, we found no effect of LRP1 D2080N genotype on plasma FVIII:C levels in normal individuals. More importantly, prevalence of the LRP1 2080D allele was not increased in the group of patients with high FVIII:C and VTE. We conclude that LRP1 and LRPAP1 polymorphisms are not responsible for high FVIII:C levels in patients with VTE.
authors.affiliation: Haematology Department, Imperial College London, London, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Cunningham
authors.forename: Michael A
authors.initials: MA
authors.lastname: Laffan
authors.forename: Richard A
authors.initials: RA
authors.lastname: Manning
authors.forename: James S
authors.initials: JS
authors.lastname: O'Donnell
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005169:Factor VIII / Q000378:metabolism*; D005260:Female; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D020246:Venous Thrombosis / Q000097:blood*
chemical_list: D026503:Low Density Lipoprotein Receptor-Related Protein-1; D005169:Factor VIII