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Blood, 1 October 2009, Vol. 114, No. 14, pp. 3084-3091.
Prepublished online as a Blood First Edition Paper on July 30, 2009; DOI 10.1182/blood-2009-05-219485.
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Submitted May 4, 2009
Accepted June 19, 2009
Cell adhesion molecule 1(CADM1): a novel risk factor for venous thrombosis
Sandra J. Hasstedt, Irene D. Bezemer, Peter W. Callas, Carla Y. Vossen, Winifred Trotman, Robert P. Hebbel, Christine Demers, Frits R. Rosendaal, and Edwin G. Bovill*
Department of Human Genetics, University of Utah, Salt Lake City, UT, United States
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands
Department of Pathology, University of Vermont College of Medicine, Burlington, VT, United States
Vascular Biology Center and Division of Hematology-Oncology Transplantation, University of Minnesota Medical School, Minneapolis, MN, United States
Universite Laval, Department of Hematology, Quebec City, Quebec, Canada
Department of Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, Netherlands
* Corresponding author; email: edwin.bovill{at}uvm.edu.
Protein C (PC) deficiency increases the risk of venous thrombosis (VT) among members of Kindred Vermont II, but fails to fully account for the inheritance pattern. A genome scan of the pedigree supported the presence of a prothrombotic gene on chromosome 11q23 (nominal P<0.0001), with weaker support on chromosomes 10p12 (P<0.0003) and 18p11.2-q11 (P<0.0007). Resequencing of 109 genes in the linkage regions identified 5,030 variants in a sample of 20 kindred members. Of 16 SNPs in 6 genes tested in the larger family set, only SNPs in Cell Adhesion Molecule 1 (CADM1) associated with VT. Among the 8 CADM1 SNPs genotyped in the complete sample, rs6589488 was most strongly supported (P<0.000007), but the association was limited to the PC deficient subset of the sample (P<0.000001). Haplotype analysis narrowed the region containing the causative variant to the coding region of the CADM1 gene. CADM1 gene expression analyzed in blood outgrowth endothelial cells cultured from family members was decreased compared to controls, lending phenotypic support to this conclusion. Finally, we have for the first time demonstrated CADM1 in endothelial cells, where it appears to be selectively involved in endothelial cell migration, suggesting a role in endothelial barrier repair. We hypothesize that the interaction of PC deficient blood with endothelium deficient in CADM1 confers increased risk of VT due to impaired endothelial barrier function, which may shed light on the poorly understood third member of Virchow's triad: the vascular wall.
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