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Thromb Haemost 2008; 99(05): 905-908
DOI: 10.1160/TH08-01-0059
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Association of ADAMDEC1 haplotype with high factor VIII levels in venous thromboembolism

Mario Berger   *
1   Medical Department, University of Oslo, Oslo, Norway
2   Institute of Clinical Biochemistry and Pathobiochemistry – Central Laboratory, University of Würzburg, Würzburg, Germany
,
Henriette Moscatelli   *
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
Further Information

Publication History

Received 31 January 2008

Accepted after minor revision 12 March 2008

Publication Date:
30 November 2017 (online)

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Summary

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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