title: Association of ADAMDEC1 haplotype with high factor VIII levels in venous thromboembolism.
abstract: A suggestive locus on chromosome 8 could be shown to be associated with familial high factor VIII (FVIII) levels in venous thromboembolism. The ADAMDEC 1 gene is a candidate expressing an ectodomain sheddase. However, the ectodomain of the clearance receptor for FVIII, the low-density lipoprotein receptor-related protein (LRP), is subject to proteolysis by metalloproteases like ADAMDEC1. Other LRP-interacting proteins are lipoprotein lipase (LPL) and t-PA. For an association study, 165 thrombotic patients with high FVIII levels (from the MAISTHRO, i.e. Main-Isar-thrombosis register) were included. All patients with known causes for high FVIII levels had been previously excluded. The patients were compared with 214 healthy blood donors. Polymorphisms with usually a minor allele frequency >5%, i.e. 24 SNPs and two insertion/deletion polymorphisms of LPL gene, eight SNPs of the t-PA gene, and five SNPs of the ADAMDEC1 gene, were analyzed. Haplotype differences were calculated using PHASE. A new polymorphism in intron 7 of the t-PA gene with a minor allele frequency of 2.2% was identified. Analysis of each SNP by the Cochrane-Armitage trend test did not show any significant association between genotype and disease status. Interestingly, the ADAMDEC1 haplotype (rs12674766, rs10087305, rs2291577, rs2291578, rs3765124) differed between cases and controls (p = 0.04). In particular, the TGTGG haplotype showed a difference. In conclusion, the ADAMDEC 1 haplotype may indicate an underlying mechanism for high FVIII levels. The only moderate linkage disequilibrium may be due to a possible causal polymorphism in distant introns or the promoter region against a polygenic background.
authors.affiliation: Medical Department, University of Würzburg, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Berger
authors.forename: Henriette
authors.initials: H
authors.lastname: Moscatelli
authors.forename: Bettina
authors.initials: B
authors.lastname: Kulle
authors.forename: Beate
authors.initials: B
authors.lastname: Luxembourg
authors.forename: Katja
authors.initials: K
authors.lastname: Blouin
authors.forename: Michael
authors.initials: M
authors.lastname: Spannagl
authors.forename: Edelgard
authors.initials: E
authors.lastname: Lindhoff-Last
authors.forename: Christian M
authors.initials: CM
authors.lastname: Schambeck
mesh_terms: D051722:ADAM Proteins; D016022:Case-Control Studies; D005169:Factor VIII / Q000378:metabolism*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005858:Germany; D006239:Haplotypes; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008071:Lipoprotein Lipase / Q000235:genetics; D008666:Metalloendopeptidases / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012042:Registries; D012307:Risk Factors; D010959:Tissue Plasminogen Activator / Q000235:genetics; D015854:Up-Regulation; D054556:Venous Thromboembolism / Q000097:blood / Q000201:enzymology / Q000235:genetics*
chemical_list: D005169:Factor VIII; D008071:Lipoprotein Lipase; D010959:Tissue Plasminogen Activator; D051722:ADAM Proteins; D008666:Metalloendopeptidases; C108169:decysin