title: Genetic variants in Cell Adhesion Molecule 1 (CADM1): a validation study of a novel endothelial cell venous thrombosis risk factor.
abstract: BACKGROUND
  In a protein C deficient family, we recently identified a candidate gene, CADM1, which interacted with protein C deficiency in increasing the risk of venous thrombosis (VT). This study aimed to determine whether CADM1 variants also interact with protein C pathway abnormalities in increasing VT risk outside this family.
  
  
  METHODS
  We genotyped over 300 CADM1 variants in the population-based MEGA case-control study. We compared VT risks between cases with low protein C activity (n=194), low protein S levels (n=23), high factor VIII activity (n=165) or factor V Leiden carriers (n=580), and all 4004 controls. Positive associations were repeated in all 3496 cases and 4004 controls.
  
  
  RESULTS
  We found 22 variants which were associated with VT in one of the protein C pathway risk groups. After mutual adjustment, six variants remained associated with VT. The strongest evidence was found for rs220842 and rs11608105. For rs220842, the odds ratio (OR) for VT was 3.2 (95% CI 1.2-9.0) for cases with high factor VIII activity compared with controls. In addition, this variant was associated with an increased risk of VT in the overall study population (OR: 1.5, 95% CI 1.0-2.2). The other variant, rs11608105, was not associated with VT in the overall study population (OR: 1.0, 95% CI 0.8-1.1), but showed a strong effect on VT risk (OR: 21, 95% CI 5.1-88) when combined with low protein C or S levels.
  
  
  CONCLUSIONS
  In a population-based association study, we confirm a role for CADM1 variants in increasing the risk of VT by interaction with protein C pathway abnormalities.
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: h.g.de_haan@lumc.nl.
authors.forename: Hugoline G
authors.initials: HG
authors.lastname: de Haan
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Irene D
authors.initials: ID
authors.lastname: Bezemer
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Carla Y
authors.initials: CY
authors.lastname: Vossen
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Astrid
authors.initials: A
authors.lastname: van Hylckama Vlieg
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Böehringer
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Hasstedt
authors.affiliation: Scripps Translational Science Institute, Scripps Research Institute, San Diego, CA, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Levy
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frits R
authors.initials: FR
authors.lastname: Rosendaal
authors.affiliation: Department of Pathology, University of Vermont, Burlington, VT, USA. Electronic address: edwin.bovill@uvm.edu.
authors.forename: Edwin G
authors.initials: EG
authors.lastname: Bovill
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics*; D015897:Comorbidity; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011486:Protein C / Q000032:analysis / Q000235:genetics; D020151:Protein C Deficiency / Q000097:blood / Q000453:epidemiology* / Q000235:genetics*; D015203:Reproducibility of Results; D012307:Risk Factors; D012680:Sensitivity and Specificity; D020246:Venous Thrombosis / Q000453:epidemiology* / Q000235:genetics*; D055815:Young Adult
chemical_list: C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D005819:Genetic Markers; D007136:Immunoglobulins; D011486:Protein C
keywords: CADM1; genetic variation; protein C pathway; venous thrombosis