背景:在一个蛋白C缺陷家族中,我们最近发现了一个候选基因,CADM1与蛋白C缺乏相互作用,增加静脉血栓形成(VT)的风险。这项研究旨在确定CADM1变体是否也与蛋白C通路异常相互作用,以增加该家族以外的VT风险。
方法:我们在基于人群的MEGA病例对照研究中对300多个CADM1变异进行了基因分型。我们比较了低蛋白C活性病例之间的VT风险(n=194),低蛋白S水平(n=23),高因子VIII活性(n=165)或因子V莱顿携带者(n=580),和所有4004控件。在所有3496例和4004例对照中重复正相关。
结果:我们在一个蛋白C通路风险组中发现了22种与VT相关的变异。相互调整后,仍有6种变异与VT相关.最有力的证据是rs220842和rs11608105。对于rs220842,与对照组相比,具有高VIII因子活性的病例的VT比值比(OR)为3.2(95%CI1.2-9.0)。此外,在整个研究人群中,该变异与VT风险增加相关(OR:1.5,95%CI1.0~2.2).另一种变体,rs11608105,在整个研究人群中与VT无关(OR:1.0,95%CI0.8-1.1),但当与低蛋白C或S水平结合时,对VT风险有强烈影响(OR:21,95%CI5.1-88)。
结论:在一项基于人群的关联研究中,我们通过与蛋白C通路异常的相互作用,证实了CADM1变异体在增加VT风险中的作用.
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.