Genetic variants in Cell Adhesion Molecule 1 (CADM1): A validation study of a novel endothelial cell venous thrombosis risk factor

- We genotyped over 300 variants in CADM1 in a population-based case-control study
- We compared VT risk between cases with a protein C pathway defect and controls
- One variant increased the risk of VT when combined with low protein C or S levels
- One variant showed an increased risk of VT in the overall study population
- We confirmed a joined role for CADM1 and protein C pathway abnormalities in VT risk

IntroductionIn 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.Materials and methodsWe 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.ResultsWe 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.ConclusionsIn 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.