Hasstedt Sandra J, Bezemer Irene D, Callas Peter W, Vossen Carla Y, Trotman Winifred, Hebbel Robert P, Demers Christine, Rosendaal Frits R, Bovill Edwin G
Department of Human Genetics, University of Utah, Salt Lake City, USA.
Blood. 2009 Oct 1;114(14):3084-91. doi: 10.1182/blood-2009-05-219485. Epub 2009 Jul 30.
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.
蛋白C（PC）缺乏会增加佛蒙特家族II成员发生静脉血栓形成（VT）的风险，但不能完全解释其遗传模式。对该家系的基因组扫描支持在11q23染色体上存在一个促血栓形成基因（名义P <.0001），在10p12染色体（P <.0003）和18p11.2 - q11染色体（P <.0007）上的支持较弱。对连锁区域中的109个基因进行重测序，在20名家系成员的样本中鉴定出5030个变异。在更大的家系组中测试的6个基因中的16个单核苷酸多态性中，只有细胞粘附分子1（CADM1）中的单核苷酸多态性与VT相关。在完整样本中进行基因分型的8个CADM1单核苷酸多态性中，rs6589488得到的支持最强（P <.000007），但这种关联仅限于样本中PC缺乏的亚组（P <.000001）。单倍型分析将包含致病变异的区域缩小到CADM1基因的编码区域。与对照受试者相比，对家系成员培养的血源内皮细胞中CADM1基因表达的分析显示其降低，为这一结论提供了表型支持。最后，我们首次在内皮细胞中证实了CADM1，它似乎选择性地参与内皮细胞迁移，提示其在内皮屏障修复中的作用。
