Hugoline G de Haan1, Irene D Bezemer2, Carla Y Vossen3, Astrid van Hylckama Vlieg2, Stefan Böehringer4, Sandra J Hasstedt5, Samuel Levy6, Frits R Rosendaal2, Edwin G Bovill7. 1. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: h.g.de_haan@lumc.nl. 2. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 3. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 4. Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands. 5. Department of Human Genetics, University of Utah, Salt Lake City, UT, USA. 6. Scripps Translational Science Institute, Scripps Research Institute, San Diego, CA, USA. 7. Department of Pathology, University of Vermont, Burlington, VT, USA. Electronic address: edwin.bovill@uvm.edu.
Abstract
INTRODUCTION: 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. MATERIALS AND 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.
INTRODUCTION: 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. MATERIALS AND 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: Thomas Biederer; Yildirim Sara; Marina Mozhayeva; Deniz Atasoy; Xinran Liu; Ege T Kavalali; Thomas C Südhof Journal: Science Date: 2002-08-30 Impact factor: 47.728
Authors: H Gomyo; Y Arai; A Tanigami; Y Murakami; M Hattori; F Hosoda; K Arai; Y Aikawa; H Tsuda; S Hirohashi; S Asakawa; N Shimizu; E Soeda; Y Sakaki; M Ohki Journal: Genomics Date: 1999-12-01 Impact factor: 5.736