Cell adhesion molecule 1: a novel risk factor for venous thrombosis
Cell adhesion molecule 1: a novel risk factor for venous thrombosis
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DOI：
10.1182/blood-2009-05-219485
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发表时间：
2009-10-01
期刊：
影响因子：
20.3
通讯作者：
Bovill, Edwin G.
中科院分区：
文献类型：
--
作者：
Hasstedt, Sandra J.;Bezemer, Irene D.;Bovill, Edwin G.
蛋白C（PC）缺乏症增加了佛蒙特州II家族成员静脉血栓形成（VT）的风险，但未能完全解释遗传模式。该家系的基因组扫描支持在染色体11 q23上存在促血栓形成基因（名义P <0.0001），在染色体10 p12（P <0.0003）和18p11.2-q11（P <0.0007）上的支持较弱。对连锁区的109个基因进行重测序，在20个亲缘成员的样本中鉴定出5030个变异。在较大的家族组中检测的6个基因的16个单核苷酸多态性中，只有细胞粘附分子1（CADM 1）的单核苷酸多态性与VT相关。在完整样本中的8个CADM 1单核苷酸多态性基因分型中，rs6589488得到最有力的支持（P < .000007），但这种关联仅限于样本的PC缺陷子集（P < .000001）。单倍型分析将包含致病变异的区域缩小到CADM 1基因的编码区。与对照组相比，从家族成员培养的血液生长内皮细胞中分析的CADM 1基因表达降低，为这一结论提供了表型支持。最后，我们第一次证明了CADM 1在内皮细胞中，它似乎选择性地参与内皮细胞迁移，这表明在内皮屏障修复中的作用。（血。2009; 114：3084-3091）
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. (Blood. 2009; 114: 3084-3091)