1
Medical Department, University of Oslo, Oslo, Norway
,
Bettina Kulle
3
Department of Biostatistics and Department of Mathematics, University of Oslo, Oslo, Norway
,
Beate Luxembourg
4
Medical Department, University of Frankfurt, Frankfurt, Germany
,
Katja Blouin
1
Medical Department, University of Oslo, Oslo, Norway
2
Institute of Clinical Biochemistry and Pathobiochemistry – Central Laboratory, University of Würzburg, Würzburg, Germany
,
Michael Spannagl
5
Medical Department, University of Munich, Munich, Germany
,
Edelgard Lindhoff-Last
4
Medical Department, University of Frankfurt, Frankfurt, Germany
,
Christian M. Schambeck
6
Institute of Clinical Chemistry – Campus Kiel, University Hospital Schleswig-Holstein, Kiel, Germany
› Author AffiliationsFinancial support:This work was kindly supported by grants from the Deutsche Forschungsgemeinschaft (SCHA 90/1–2), the Gesellschaft für Thrombose– und Hämostaseforschung, and Octa pharma
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.
Keywords
Factor VIII -
inherited thrombophilia -
metalloprotease -
venous thromboembolism
* These authors contributed equally.
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