Thrombomodulin gene polymorphisms or haplotypes as potential risk factors for venous thromboembolism:: a population-based case-control study
Thrombomodulin gene polymorphisms or haplotypes as potential risk factors for venous thromboembolism:: a population-based case-control study
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DOI：
10.1111/j.1538-7836.2005.01187.x
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发表时间：
2005-04-01
影响因子：
10.4
通讯作者：
Melton, LJ
中科院分区：
文献类型：
--
作者：
Heit, JA;Petterson, TM;Melton, LJ
蛋白C抗凝系统的功能障碍与静脉血栓栓塞（VTE）有关，而血栓调节素（ITM）是蛋白C系统中的关键辅助因子。本研究的目的是验证TM基因内的多态性或单倍型是VTE常见危险因素的假设。我们在随机样本（n = 266）中筛选了TM假定的启动子、外显子和3'-未翻译区域的序列变异，这些随机样本来自梅奥诊所的连续特发性、客观确诊的非奥姆斯特德县静脉血栓栓塞患者。然后，我们对明尼苏达州奥姆斯特德县（Olmsted County）的样本进行了基因分型，这些样本在1966- 1990年的25年间客观证实了VTE (n = 223)，以及奥姆斯特德县（Olmsted County）没有VTE的居民样本（n = 237）进行了基因分型，以确定在筛查人群中发现的或先前发表的多态性，并分别使用无条件逻辑回归和广义线性模型测试了VTE与TM基因型或单倍型的关联。我们还对这些奥姆斯特德县病例和对照进行了20个“零”基因标记位点的基因分型，并检测了群体混杂。在筛查人群中发现了9个新的突变和3个先前描述的突变。TM启动子、EGF（1-5）、富含丝氨酸/苏氨酸、跨膜和细胞质区域的突变缺失或罕见。TM845G -> A （Ala25Thr；凝集素区）、TM2136T -> C （Ala455Val； EGF(6)区）、TM2470C缺失（3'-未翻译区）、4363A -> G（3'-侧翼区）较常见，但与VTE的基因型和单倍型相关性不高。无效遗传标记等位基因频率在病例和对照组之间无显著差异。我们得出结论，TM基因内的多态性或单倍型不是发生VTE的常见危险因素。
Dysfunction of the protein C anticoagulant system is associated with venous thromboembolism (VTE) and thrombomodulin ITM) is a critical cofactor within the protein C system. The aim of this study was to test the hypotheses that polymorphisms or haplotypes within the TM gene are common risk factors for VTE. We screened the TM putative promoter, exon and 3'-untranslated region for sequence variations in a random sample (n = 266) of consecutive idiopathic, objectively confirmed non-Olmsted County VTE patients referred to the Mayo Clinic. We then genotyped a sample of Olmsted County, MN residents with a first lifetime, objectively confirmed VTE in the 25-year period, 1966-90 (n = 223), and a sample of Olmsted County residents without VTE (n = 237) for polyinorphisms either discovered in the screening population or previously published, and tested for an association of VTE with TM genotype or haplotypes using unconditional logistic regression and generalized linear models, respectively. We also genotyped these Olmsted County cases and controls at 20 'null' genetic maker loci and tested for population admixture. Nine novel and three previously described mutations were identified in the screening population. Mutations within the TM promoter, EGF(1-5), serine/threonine-rich, transmembrane, and cytoplasm regions were absent or uncommon. TM845G -> A (Ala25Thr; lectin region), TM2136T -> C (Ala455Val; EGF(6) region), TM2470C deletion (3'-untranslated region), and 4363A -> G (3'-flanking region) were more common, but were not associated with VTE by genotype or haplotype. Null genetic marker allele frequencies did not differ significantly among cases and controls. We conclude that polymorphisms or haplotypes within the TM gene are not common risk factors for incident VTE.