Cell adhesion molecule 1: a novel risk factor for venous thrombosis.
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 < .0001), with weaker support on chromosomes 10p12 (P < .0003) and 18p11.2-q11 (P < .0007). Resequencing of 109 genes in the linkage regions identified 5030 variants in a sample of 20 kindred members. Of 16 single nucleotide polymorphisms in 6 genes tested in the larger family set, only single nucleotide polymorphisms in cell adhesion molecule 1 (CADM1) associated with VT. Among the 8 CADM1 single nucleotide polymorphisms genotyped in the complete sample, rs6589488 was most strongly supported (P < .000007), but the association was limited to the PC-deficient subset of the sample (P < .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 with control subjects, 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.
Hasstedt
Sandra J
SJ
Department of Human Genetics, University of Utah, Salt Lake City, USA.
Bezemer
Irene D
ID
Callas
Peter W
PW
Vossen
Carla Y
CY
Trotman
Winifred
W
Hebbel
Robert P
RP
Demers
Christine
C
Rosendaal
Frits R
FR
Bovill
Edwin G
EG
D000328:Adult; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D002478:Cells, Cultured; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D007136:Immunoglobulins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020151:Protein C Deficiency; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D020246:Venous Thrombosis / Q000235:genetics* / Q000473:pathology
C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins